Note: Descriptions are shown in the official language in which they were submitted.
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MODAFINIL COMPOSITIONS
FIELD OF THE INVENTION
The present invention relates to API-containing compositions, pharmaceutical
compositions comprising such APIs, and methods for preparing the same.
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BACKGROUND OF THE INVENTION
Active pharmaceutical ingredients (API or APIs (plural)) in pharmaceutical
compositions can be prepared in a variety of different forms. Such APIs can be
prepared so as to have a variety of different chemical forms including
chemical
derivatives, solvates, hydrates, co-crystals, or salts. Such APIs can also be
prepared
to have different physical forms. For example, the APIs may be amorphous, may
have different crystalline polymorphs, or may exist in different solvation or
hydration
states. By varying the form of an API, it is possible to vary the physical
properties
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thereof. For example, crystalline polymorphs typically have different
solubilities
from one another, such that a more thermodynamically stable polymorph is less
soluble than a less thermodynamically stable polymorph. Pharmaceutical
polymorphs
can also differ in properties such as shelf-life, bioavailability, morphology,
vapour
pressure, density, colour, and compressibility. Accordingly, variation of the
crystalline state of an API is one of many ways in which to modulate the
physical
properties thereof.
It would be advantageous to have new forms of these APIs that have improved
properties, in particular, as oral formulations. Specifically, it is desirable
to identify
improved forms of APIs that exhibit significantly improved properties
including
increased aqueous solubility and stability. Further, it is desirable to
improve the
processability, or preparation of pharmaceutical formulations. For example,
needle-
like crystal forms or habits of APIs can cause aggregation, even in
compositions
where the API is mixed with other substances, such that a non-uniform mixture
is
obtained. Needle-like morphologies can also give rise to filtration problems
(See e.g.,
Mirmehrabi et al. J. Pharm. Sci. Vol. 93, No. 7, pp. 1692-1700, 2004). It is
also
desirable to increase the dissolution rate of API-containing pharmaceutical
compositions in water, increase the bioavailability of orally-administered
compositions, and provide a more rapid onset to therapeutic effect. It is also
desirable
to have a form of the API which, when administered to a subject, reaches a
peak
plasma level faster, has a longer lasting therapeutic plasma concentration,
and higher
overall exposure when compared to equivalent amounts of the API in its
presently-
known form.
Modafinil, an API used to treat subjects with narcolepsy, is practically
insoluble in water. Modafinil(CAS Registry Number: 68693-11-8) is represented
by
the structure (I):
NH2
S
I ~I
0 0
(I).
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Modafinil is a chiral molecule due to the chiral S=O group. Therefore,
modafinil
exists as two isomers, R-(-)-modafinil and S-(+)-modafinil. It would be
advantageous
to have new forms of modafinil that have improved properties, in particular,
as oral
formulations. Specifically, it is desirable to identify improved forms of
modafinil that
exhibit significantly increased aqueous solubilities and both chemical and
form
stability. It is also desirable to increase the dissolution rate of API-
containing
pharmaceutical compositions in water, increase the bioavailability of orally-
administered compositions, and provide a more rapid onset to therapeutic
effect. It is
also desirable to have a form of the API which, when administered to a
subject,
reaches a peak plasma level faster and/or has a longer lasting plasma
concentration
and higher overall exposure at high doses when compared to equivalent amounts
of
the API in its presently-known form.
SUMMARY OF THE INVENTION
It has now been found that co-crystals and solvates of modafinil can be
obtained, many of which have different properties as compared to the free form
of the
API.
Accordingly, in a first aspect, the present invention provides a co-crystal of
modafinil, wherein the co-crystal former is an ether, thioether, alcohol,
thiol,
aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate
ester, ester,
thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid,
sulfonic
acid, amide, primary amine, secondary amine, ammonia, tertiary amine, sp2
amine,
thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-
heterocyclic ring,
thiophene, N-heterocyclic ring, pyrrole, 0-heterocyclic ring, furan, epoxide,
hydroxamic acid, imidazole, or pyridine.
The invention further provides a pharmaceutical composition comprising a co-
crystal of modafinil. Typically, the pharmaceutical composition further
comprises
one or more pharmaceutically-acceptable carriers, diluents or excipients.
Pharmaceutical compositions according to the invention are described in
further detail
below.
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In a further aspect, the present invention provides a process for the
preparation
of a co-crystal of modafinil, which comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
(d) isolating co-crystals comprising modafinil and the co-crystal former.
In an embodiment, the co-crystal former has at least one functional group
selected from the group consisting of ether, thioether, alcohol, thiol,
aldehyde, ketone,
thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester,
thioester, sulfate
ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid,
amide, primary
amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate,
cyanamide, oxime, nitrile, diazo, organohalide, nitro, S-heterocyclic ring,
thiophene,
N-heterocyclic ring, pyrrole, ()-heterocyclic ring, furan, epoxide, hydroxamic
acid,
imidazole, or pyridine.
Embodiments of the present invention including, but not limited to, co-
crystals, polymorphs, and solvates can comprise racemic modafinil,
enantiomerically
pure modafinil (i.e., R-(-)-modafinil or S-(+)-modafinil), or enriched
modafinil (e.g.,
between about 55 and about 90 percent ee). Similarly, co-crystal formers and
solvent
molecules (e.g., in a solvate) can also exist as racemic, enantiomerically
pure, or an
enriched form in embodiments of the present invention.
In a further aspect, the present invention provides a process for increasing
the
solubility of modafinil in water, simulated gastric fluid (SGF), or simulated
intestinal
fluid (SIF) for use in a pharmaceutical composition or medicament, which
process
comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
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(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
(d) isolating co-crystals comprising the modafinil and the co-crystal
former.
In a further aspect, the present invention provides a process for modulating
the
dissolution of modafinil, whereby the aqueous dissolution rate or the
dissolution rate
in simulated gastric fluid or in simulated intestinal fluid, or in a solvent
or plurality of
solvents is increased, which process comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
(d) isolating co-crystals comprising the modafinil and the co-crystal
former.
In a further aspect, the present invention provides a process for modulating
the
bioavailability of modafinil, whereby the AUC is increased, the time to T,,,a,
is
reduced, the length of time the concentration of modafinil is above %2 Tmax is
increased, or Cma, is increased, which process comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the
modafinil with the co-crystal former under crystallization conditions,
so as to form a solid phase; and
(d) isolating co-crystals comprising the modafinil and the co-crystal
former.
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In a further aspect, the present invention provides a process for modulating
the
dose response of modafinil for use in a pharmaceutical composition or
medicament,
which process comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
(d) isolating co-crystals comprising the modafinil and the co-crystal
former.
In a still further aspect the present invention provides a process for
improving
the stability of modafinil (as compared to a reference form such as its free
form),
which process comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
(d) isolating co-crystals comprising the modafinil and the co-crystal
former.
In a still further aspect the present invention provides a process for
modifying
the morphology of modafinil, which process comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
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(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
(d) isolating co-crystals comprising the modafinil and the co-crystal
former.
In a still further aspect, the present invention therefore provides a process
of
screening for co-crystal compounds, which comprises:
(a) providing (i) modafinil and (ii) a co-crystal former compatible with a
functional group of modafinil such that the co-crystal former and the
modafinil can form a co-crystal; and
(b) screening for co-crystals of modafinil with a co-crystal former by
subjecting each combination of modafinil and co-crystal former to a
procedure comprising:
(i) grinding, heating, co-subliming, co-melting, or contacting in
solution the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
(ii) isolating co-crystals comprising the modafinil and the co-
crystal former.
An alternative embodiment is drawn to a process of screening for co-crystal
compounds, which comprises:
(a) providing (i) modafinil and (ii) a plurality of different co-crystal
formers
compatible with a functional group of modafinil such that each co-
crystal former and the modafinil can form a co-crystal; and
(b) screening for co-crystals of modafinil with co-crystal formers by
subjecting each combination of modafinil and co-crystal former to a procedure
comprising:
(i) grinding, heating, co-subliming, co-melting, or contacting in
solution the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
(ii) isolating co-crystals comprising the modafinil and the co-
crystal former.
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In a further aspect, the present invention provides a co-crystal composition
comprising a co-crystal, wherein said co-crystal comprises modafinil and a co-
crystal
former. In further embodiments the co-crystal has an improved property as
compared
to the free form (which includes hydrates and solvates). In further
embodiments, the
improved property is selected from the group consisting of. increased
solubility,
increased dissolution, increased bioavailability, increased dose response, or
other
property described herein.
In another embodiment, the present invention provides a co-crystal comprising
modafinil and a co-crystal former selected from the group consisting of
malonic acid,
glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid,
gentisic acid, oxalic
acid, 1-hydroxy-2-naphthoic acid, orotic acid, glutaric acid, L-tartaric acid,
palmitic
acid, L-proline, salicylic acid, lauric acid, L-malic acid, and maleic acid.
In further embodiments, the present invention provides the following co-
crystals: modafinil:malonic acid, modafinil: glycolic acid, modafinil:maleic
acid,
modafinil:L-tartaric acid, modafinil:citric acid, modafinil:succinic acid,
modafinil:DL-tartaric acid, modafinil:fumaric acid (Form I), modafinil:fumaric
acid
(Form II), modafinil:gentisic acid, modafinil:oxalic acid, modafinil: 1 -
hydroxy-2-
naphthoic acid, R-(-)-modafinil:malonic acid, R-(-)-modafinil:succinic acid, R-
(-)-
modafinil:citric acid, R-(-)-modafinil:DL-tartaric acid, R-(-)-modafinil:1-
hydroxy-2-
naphthoic acid, R-(-)-modafinil:orotic acid, R-(-)-modafinil:glutaric acid, R-
(-)-
modafinil:L-tartaric acid, R-(-)-modafinil:palmitic acid, R-(-)-modafinil:L-
proline, R-
(-)-modafinil:salicylic acid, R-(-)-modafinil:lauric acid, R-(-)-modafinil:L-
malic acid,
and R-(-)-modafinil:gentisic acid.
In another embodiment, the present invention provides a novel polymorph or
co-crystal of racemic modafinil (form VII).
In another embodiment, the present invention provides the following
modafinil solvates: acetic acid, tetrahydrofuran, 1,4-dioxane, methanol,
nitromethane,
acetone, o-xylene, benzene, ethanol, benzyl alcohol, isopropanol,
acetonitrile, and
toluene.
The processes according to the present invention may each comprise a further
step or steps in which the modafinil co-crystal produced thereby is
incorporated into a
pharmaceutical composition.
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In another embodiment, a pharmaceutical composition comprises a modified
release profile of one or more of racemic modafinil, R-(-)-modafinil, and S-
(+)-
modafinil. The modified release profile can comprise, for example, two or more
maxima of plasma concentration, such as a dual-release profile.
The invention further provides a medicament comprising a co-crystal of
modafinil and methods of making the same. Typically, the medicament further
comprises one or more pharmaceutically-acceptable carriers, diluents or
excipients.
Medicaments according to the invention are described in further detail below.
The processes according to the present invention may each comprise a further
step or steps in which the modafinil co-crystal produced thereby is
incorporated into a
medicament.
In a still further aspect of the invention, a method is provided for treating
a
subject, preferably a human subject, suffering from excessive daytime
sleepiness
associated with narcolepsy, multiple sclerosis related fatigue, infertility,
eating
disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's
disease,
incontinence, sleep apnea, or myopathies where modafinil is an effective
active
pharmaceutical for said disorder. The method comprises administering to the
subject
a therapeutically-effective amount of a co-crystal or a solvate comprising
modafinil,
or a polymorph of modafinil.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1- PXRD diffractogram of a co-crystal comprising modafinil and malonic
acid.
Figure 2- DSC thermogram of a co-crystal comprising modafinil and malonic
acid.
Figure 3- TGA thermogram of a co-crystal comprising modafinil and malonic
acid.
Figure 4A and 4B- Raman spectrum of a co-crystal comprising modafinil and
malonic
acid (Figure 4A), and three Raman spectra of modafinil (bottom spectrum),
malonic
acid (middle spectrum), and a co-crystal comprising modafinil and malonic acid
(top
spectrum) (Figure 4B).
Figure 5A and 5B- Infrared spectrum of a co-crystal comprising modafinil and
malonic acid (Figure 5A), and three Infrared spectra of modafinil (top
spectrum),
malonic acid (middle spectrum), and a co-crystal comprising modafinil and
malonic
acid (bottom spectrum) (Figure 5B).
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Figure 6A- PXRD diffractogram of a co-crystal comprising modafinil and malonic
acid.
Figure 613- DSC thermogram of a co-crystal comprising modafinil and malonic
acid
(from grinding).
Figure 7- Packing diagram for modafinil:malonic acid co-crystal.
Figures 8A and 8B- PXRD diffractograms of a co-crystal comprising modafinil
and
glycolic acid, background removed and as collected, respectively.
Figures 9A and 9B- PXRD diffractograms of a co-crystal comprising modafinil
and
maleic acid, background removed and as collected, respectively.
Figure 10- PXRD diffractogram of a co-crystal comprising modafinil and L-
tartaric
acid.
Figure 11 A- PXRD diffractogram of a co-crystal comprising modafinil and
citric acid.
Figure 11B- DSC thermogram of a co-crystal comprising modafinil and citric
acid.
Figures 12A and 12B- PXRD diffractogram of a co-crystal comprising modafinil
and
succinic acid, background removed and as collected, respectively.
Figure 13- DSC thermogram of a co-crystal comprising modafinil and succinic
acid.
Figure 14- Packing diagram of a co-crystal comprising modafinil and succinic
acid.
Figure 15- PXRD diffractogram of a co-crystal comprising modafinil and DL-
tartaric
acid.
Figure 16- PXRD diffractogram of a co-crystal comprising modafinil and fumaric
acid (Form I).
Figure 17- Packing diagram of a co-crystal comprising modafinil and fumaric
acid
(Form I).
Figure 18- PXRD diffractogram of a co-crystal comprising modafinil and fumaric
acid (Form II).
Figure 19- PXRD diffractogram of a co-crystal comprising modafinil and
gentisic
acid.
Figure 20- PXRD diffractogram of a co-crystal comprising modafinil and oxalic
acid.
Figure 21- PXRD diffractogram of a co-crystal comprising modafinil and 1-
hydroxy-
2-naphthoic acid.
Figure 22- PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and
malonic acid.
Figure 23- DSC thermogram of a co-crystal comprising R-(-)-modafinil and
malonic
acid.
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Figure 24- PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and
succinic acid.
Figure 25- DSC thermogram of a co-crystal comprising R-(-)-modafinil and
succinic
acid.
Figure 26- PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and
citric
acid.
Figure 27- DSC thermogram of a co-crystal comprising R-(-)-modafinil and
citric
acid.
Figure 28- PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and
DL-
tartaric acid.
Figure 29- DSC thermogram of a co-crystal comprising R-(-)-modafinil and DL-
tartaric acid.
Figure 30- PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and 1-
hydroxy-2-naphthoic acid.
Figure 31- DSC thermogram of a co-crystal comprising R-(-)-modafinil and 1-
hydroxy-2-naphthoic acid.
Figure 32- PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and 1-
hydroxy-2-naphthoic acid obtained from a high throughput experiment.
Figure 33- PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and
orotic
acid.
Figure 34- DSC thermogram of a co-crystal comprising R-(-)-modafinil and
orotic
acid.
Figure 35- PXRD diffractogram of a solvate comprising modafinil and acetic
acid.
Figure 36- TGA thermogram of a solvate comprising modafinil and acetic acid.
Figure 37- DSC thermogram of a solvate comprising modafinil and acetic acid.
Figure 38- Raman spectrum of a solvate comprising modafinil and acetic acid.
Figure 39- PXRD diffractogram of a solvate comprising modafinil and
tetrahydrofuran.
Figure 40- PXRD diffractogram of a solvate comprising modafinil and 1,4-
dioxane.
Figure 41- PXRD diffractogram of a solvate comprising modafinil and methanol.
Figure 42- TGA thermogram of a solvate comprising modafinil and methanol.
Figure 43- DSC thermogram of a solvate comprising modafinil and methanol.
Figure 44- PXRD diffractogram of a solvate comprising modafinil and
nitromethane.
Figure 45- PXRD diffractogram of a solvate comprising modafinil and acetone.
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Figure 46- PXRD diffractogram of a possible solvate comprising modafinil and
acetone.
Figure 47- PXRD diffractogram of a possible solvate comprising modafinil and
1,2-
dichloroethane.
Figure 48- PXRD diffractogram of a polymorph of modafinil (Form VII).
Figure 49- Stability plot of modafinil:malonic acid co-crystal over a 26 week
period.
Figure 50- Closer view of stability plot of modafinil:malonic acid co-crystal
over a 26
week period.
Figure 51- PXRD diffractogram comparison of modafinil:malonic acid co-crystal
after several environmental conditions are endured.
Figure 52- Dissolution profile of several formulations of modafinil free form
and
modafinil:malonic acid.
Figure 53- In Vitro dissolution profile of modafinil:malonic acid co-crystal
in SGF
and SIF.
Figure 54- In Vitro dissolution profile of modafinil:malonic acid co-crystal
in HCI.
Figure 55- DVS plot of modafinil:malonic acid co-crystal.
Figure 56- Pharmacokinetics of modafinil:malonic acid co-crystal in dogs.
Figure 57- PXRD diffractogram of a co-crystal comprising R-(-)-modafinil and
gentisic acid.
Figure 58- Packing diagram of acetone channel solvate of modafinil.
Figure 59- Additional packing diagram of acetone channel solvate of modafinil.
Figure 60- PXRD diffractogram of o-xylene solvate.
Figure 61- Raman spectrum of o-xylene solvate (middle spectrum).
Figure 62- TGA thermogram of o-xylene solvate.
Figure 63- DSC thermogram of o-xylene solvate.
Figure 64- PXRD diffractogram of benzene solvate.
Figure 65- Raman spectrum of benzene solvate (middle spectrum).
Figure 66- TGA thermogram of benzene solvate.
Figure 67- DSC thermogram of benzene solvate.
Figure 68- PXRD diffractogram of toluene solvate.
Figure 69- Raman spectrum of toluene solvate (middle spectrum).
Figure 70- TGA thermogram of toluene solvate.
Figure 71- DSC thermogram of toluene solvate.
Figure 72- PXRD diffractogram of R-(-)-modafinil ethanol solvate.
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Figure 73- TGA thermogram of R-(-)-modafinil ethanol solvate.
Figure 74- PXRD diffractogram of R-(-)-modafinil benzyl alcohol solvate.
Figure 75- DSC thermogram of R-(-)-modafinil benzyl alcohol solvate.
Figure 76- TGA thermogram of R-(-)-modafinil benzyl alcohol solvate.
Figure 77- PXRD diffractogram of R-(-)-modafinil isopropanol solvate.
Figure 78- PXRD diffractogram of R-(-)-modafinil acetonitrile solvate.
Figure 79- PXRD diffractogram of R-(-)-modafinil:glutaric acid co-crystal.
Figure 80- PXRD diffractogram of R-(-)-modafinil:citric acid co-crystal.
Figure 81- PXRD diffractogram of R-(-)-modafinil:L-tartaric acid co-crystal.
Figures 82A and 82B- PXRD diffractograms of R-(-)-modafinil:oxalic acid co-
crystal.
Figure 83- PXRD diffractogram of R-(-)-modafinil:palmitic acid co-crystal.
Figure 84- PXRD diffractogram of R-(-)-modafinil:L-proline co-crystal.
Figure 85- PXRD diffractogram of R-(-)-modafinil:salicylic acid co-crystal.
Figure 86- PXRD diffractogram of R-(-)-modafinil:lauric acid co-crystal.
Figure 87- PXRD diffractogram of R-(-)-modafinil:L-malic acid co-crystal.
DETAILED DESCRIPTION OF THE INVENTION
The structure of modafinil includes a stereocenter and, therefore, can exist
as a
racemate, one of two pure isomers, or any ratio of the two isomeric pairs. The
chemical name of racemic modafinil is ( )-2-[(Diphenylmethyl)
sulfinyl]acetamide.
The isomeric pairs of racemic modafinil are R-(-)-2-[(Diphenylmethyl)
sulfinyl]acetamide or R-(-)-modafinil and S-(+)-2-[(Diphenylmethyl)
sulfinyl]acetamide or S-(+)-modafinil.
As used herein and unless otherwise specified, the term "enantiomerically
pure" includes a composition which is substantially enantiomerically pure and
includes, for example, a composition with greater than or equal to about 90,
91, 92,
93, 94, 95, 96, 97, 98, or 99 percent enantiomeric excess. Enantiomeric excess
is
defined by percent enantiomer A - percent enantiomer B, or by the formula:
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ee percent = 100 * ([R] - [S] / ([R] + [S]), where R is moles of R-(-)-
modafinil and S
is moles of S-(+)-modafinil.
As used herein, the term "modafmil" includes the racemate, other mixtures of
R- and S-isomers, and single enantiomers, but may be specifically set forth as
the
racemate, R-isomer, S-isomer, or any mixture of both R- and S-isomers.
As used herein and unless otherwise specified, the term "racemic co-crystal"
refers to a co-crystal which is comprised of an equimolar mixture of the
enantiomers
of modafinil, the co-crystal former, or both. For example, a co-crystal
comprising
modafinil and a non-stereoisomeric co-crystal former is a "racemic co-crystal"
only
when there is present an equimolar mixture of the modafinil enantiomers.
Similarly, a
co-crystal comprising modafinil and a stereoisomeric co-crystal former is a
"racemic
co-crystal" only when there is present an equimolar mixture of the modafinil
enantiomers and of the co-crystal former enantiomers.
As used herein and unless otherwise specified, the term "enantiomerically pure
co-crystal" refers to a co-crystal which is comprised of modafinil and a
stereoisomeric
or non-stereoisomeric co-crystal former where the enantiomeric excess of the
stereoisomeric species is greater than or equal to about 90 percent ee
(enantiomeric
excess).
The term "co-crystal" as used herein means a crystalline material comprised of
two or more unique solids at room temperature (22 degrees C), each containing
distinctive physical characteristics, such as structure, melting point, and
heats of
fusion, with the exception that, if specifically stated, the API may be a
liquid at room
temperature. The co-crystals of the present invention comprise a co-crystal
former H-
bonded to modafinil or a derivative thereof. The co-crystal former may be H-
bonded
directly to modafinil or may be H-bonded to an additional molecule which is
bound to
modafinil. The additional molecule may be H-bonded to modafinil or bound
ionically
to modafinil. The additional molecule could also be a different API. Solvates
of
modafinil compounds that do not further comprise a co-crystal former are not
co-
crystals according to the present invention. The co-crystals may however,
include one
or more solvate molecules in the crystalline lattice. That is, a solvate of co-
crystal, or
a co-crystal further comprising a solvent or compound that is a liquid at room
temperature, is a co-crystal according to the present invention, but
crystalline material
comprised of only modafinil and one or more liquids (at room temperature) are
not
co-crystals for purposes of the present invention. Other modes of molecular
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recognition may also be present including, pi-stacking, guest-host
complexation and
van der Waals interactions. Of the interactions listed above, hydrogen-bonding
is the
dominant interaction in the formation of the co-crystal, (and a required
interaction
according to the present invention) whereby a non-covalent bond is formed
between a
hydrogen bond donor of one of the moieties and a hydrogen bond acceptor of the
other. Hydrogen bonding can result in several different intermolecular
configurations.
For example, hydrogen bonds can result in the formation of dimers, linear
chains, or
cyclic structures. These configurations can further include extended (two-
dimensional) hydrogen bond networks and isolated triads. An alternative
embodiment provides for a co-crystal wherein the co-crystal former is a second
API.
In another embodiment, the co-crystal former is not an API.
For purposes of the present invention, the chemical and physical properties of
modafinil in the form of a co-crystal may be compared to a reference compound
that
is modafinil in a different form. The reference compound may be specified as a
free
form, or more specifically, an anhydrate or hydrate of a free form, or more
specifically, for example, a hemihydrate, monohydrate, dihydrate, trihydrate,
quadrahydrate, pentahydrate; or a solvate of a free form. For example, the
reference
compound for modafinil in free form co-crystallized with a co-crystal former
can be
modafinil in free form. The reference compound may also be specified as
crystalline
or amorphous. The reference compound may also be specified as the most stable
polymorph known of the specified form of the reference compound.
The ratio of modafinil to co-crystal former may be stoichiometric or non-
stoichiometric according to the present invention. Non-limiting examples such
as,
1:1, 1:1.5, 1.5:1, 1:2, and 2:1 ratios of modafinil:co-crystal former are
acceptable. In
addition, co-crystals with vacancies within the crystalline lattice are
included in the
present invention. For example, a co-crystal with less than or about 0.01,
0.1, 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 percent
vacancies within
the crystalline lattice are included in the present invention. The vacancies
can be due
to missing modafinil molecules or missing co-crystal former molecules from the
crystalline lattice, or both.
It has surprisingly been found that when modafinil and a selected co-crystal
former are allowed to form co-crystals, the resulting co-crystals often give
rise to
improved properties of modafinil, as compared to modafinil in the free form,
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particularly with respect to: solubility, dissolution, bioavailability,
stability, Cmax,
Tmax, processability (including compressibility), longer lasting therapeutic
plasma
concentration, etc. For example, a co-crystal form of modafinil is
particularly
advantageous due to the low solubility of modafinil in water. Additionally,
the co-
crystal properties conferred upon modafinil are also useful because the
bioavailability
of modafinil can be improved and the plasma concentration and/or serum
concentration of modafinil can be improved. This is particularly advantageous
for
orally-administrable formulations. Moreover, the dose response of modafinil
can be
improved, for example by increasing the maximum attainable response and/or
increasing the potency of modafinil by increasing the biological activity per
dosing
equivalent.
Accordingly, in a first aspect, the present invention provides a
pharmaceutical
composition (or medicament) comprising a co-crystal of modafinil and a co-
crystal
former, such that the modafinil and the co-crystal former are capable of co-
crystallizing from a solution phase under crystallization conditions or from
the solid-
state, for example, through grinding or heating. In another aspect, the co-
crystal
former which has at least one functional group selected from the group
consisting of
ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester,
phosphate
ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid,
phosphonic
acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine,
ammonia, tertiary amine, sp2 amine, thiocyanate, cyanamide, oxime, nitrile,
diazo,
organohalide, nitro, S-heterocyclic ring, thiophene, N-heterocyclic ring,
pyrrole, 0-
heterocyclic ring, furan, epoxide, hydroxamic acid, imidazole, and pyridine,
or a
functional group in a Table herein, such that the modafinil and co-crystal
former are
capable of co-crystallizing from a solution phase under crystallization
conditions.
In another embodiment, the use of an excess (more than 1 molar equivalent for
a 1:1 co-crystal) of a co-crystal former can be used to drive the formation of
stoichiometric co-crystals. For example, co-crystals with stoichiometries of
1:1, 2:1,
or 1:2 can be produced by adding co-crystal former in an amount that is 2, 3,
4, 5, 6,
7, 8, 9, 10, 15, 20, 25, 50, 75, 100 times or more than the stoichiometric
amount for a
given co-crystal. Such an excessive use of a co-crystal former to form a co-
crystal
can be employed in solution or when grinding modafinil and a co-crystal former
to
cause co-crystal formation.
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In another embodiment of the present invention, a modafinil co-crystal further
comprises a co-crystal former which is hydrogen bonded via a preferred
interaction
between two or more functional groups. For example, modafinil and malonic acid
co-
crystallize through the interaction of a carboxylic acid functional group of
the co-
crystal former with sulfoxide and amide functional groups of modafinil.
In another embodiment of the present invention, the co-crystal comprises
modafinil wherein the modafinil forms a dimeric primary amide structure via
hydrogen bonds with an Reg (8) motif. See e.g., J. Bernstein, Polymorphism in
Molecular Crystals, Oxford University Press, 2002, pp. 55-59, or M. C. Etter,
Acct.
Chem. Res., 1990, 23, 120, or M. C. Etter, J. Phys. Chem., 1991, 95, 4601. In
such a
structure, the NH2 moiety can also participate in a hydrogen bond with a donor
or an
acceptor moiety from, for example, a co-crystal former or an additional
(third)
molecule, and the C=O moiety can participate in a hydrogen bond with a donor
moiety from the co-crystal former or the additional molecule. In a further
embodiment, the dimeric primary amide structure (formed by two modafinil
molecules) further comprises one, two, three, or four hydrogen bond donors
(from
one, two, three, or four co-crystal formers). In a further embodiment, the
dimeric
primary amide structure further comprises one or two hydrogen bond acceptors
(from
one or two co-crystal formers). In a further embodiment, the dimeric primary
amide
structure further comprises a combination of hydrogen bond donors and
acceptors.
For example, the dimeric primary amide structure can further comprise one
hydrogen
bond donor and one hydrogen bond acceptor, one hydrogen bond donor and two
hydrogen bond acceptors, two hydrogen bond donors and one hydrogen bond
acceptor, two hydrogen bond donors and two hydrogen bond acceptors, or three
hydrogen bond donors and one hydrogen bond acceptor.
The co-crystals of the present invention are formed where modafinil and the
co-crystal former are bonded together through hydrogen bonds. Other non-
covalent
interactions, including pi-stacking and van der Waals interactions, may also
be
present.
In one embodiment, the co-crystal former is selected from the co-crystal
formers of Table I and Table II. In other embodiments, the co-crystal former
of Table
I is specified as a Class 1, Class 2, or Class 3 co-crystal former (see column
labeled
"class" Table I). Table I lists multiple pKa values for co-crystal formers
having
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multiple functionalities. It is readily apparent to one skilled in the art the
particular
functional group corresponding to a particular pKa value.
In another embodiment the particular functional group of a co-crystal former
interacting with modafinil is specified (see for example Table I, columns
labeled
"Functionality" and "Molecular Structure" and the column of Table II labeled
"Co-
Crystal Former Functional Group").
In another embodiment, the co-crystal comprises more than one co-crystal
former. For example, two, three, four, five, or more co-crystal formers can be
incorporated in a co-crystal with modafinil. Co-crystals which comprise two or
more
co-crystal formers and an API are bound together via hydrogen bonds. In one
embodiment, incorporated co-crystal formers are hydrogen bonded to modafinil
molecules. In another embodiment, co-crystal formers are hydrogen bonded to
either
the modafinil molecules or the incorporated co-crystal formers.
In each process according to the invention, there is a need to contact
modafinil
with the co-crystal former. This may involve grinding the two solids together
or
melting one or both components and allowing them to recrystallize. This may
also
involve either solubilizing modafinil and adding the co-crystal former, or
solubilizing
the co-crystal former and adding modafinil. Crystallization conditions are
applied to
modafinil and the co-crystal former. This may entail altering a property of
the
solution, such as pH or temperature and may require concentration of the
solute,
usually by removal of the solvent, typically by drying the solution. Solvent
removal
results in the concentration of both modafinil and the co-crystal former
increasing
over time so as to facilitate crystallization. For example, evaporation,
cooling, or the
addition of an antisolvent may be used to crystallize co-crystals. In another
embodiment, a slurry comprising modafinil and a co-crystal former is used to
form
co-crystals. Once the solid phase comprising any crystals is formed, this may
be
tested as described herein.
The co-crystals obtained as a result of such process steps may be readily
incorporated into a pharmaceutical composition (or medicament) by conventional
means. Pharmaceutical compositions and medicaments in general are discussed in
further detail below and may further comprise a pharmaceutically-acceptable
diluent,
excipient or carrier.
In a further aspect, the present invention provides a process for the
preparation
of a co-crystal of modafinil, which comprises:
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(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a co-
crystal;
(c) grinding, heating, co-subliming, co-melting, or contacting in solution the
modafinil with the co-crystal former under crystallization conditions, so as
to form a solid phase; and
(d) isolating co-crystals comprising modafinil and the co-crystal former.
In an embodiment, the co-crystal former has at least one functional group
selected from the group consisting of ether, thioether, alcohol, thiol,
aldehyde, ketone,
thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester,
thioester, sulfate
ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid,
amide, primary
amine, secondary amine, ammonia, tertiary amine, sp2 amine, thiocyanate,
cyanamide, oxime, riitrile, diazo, organohalide, nitro, S-heterocyclic ring,
thiophene,
N-heterocyclic ring, pyrrole, 0-heterocyclic ring, furan, epoxide, hydroxamic
acid,
imidazole, or pyridine.
In a further aspect, the present invention provides a process for the
production
of a pharmaceutical composition or medicament, which process comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a co-
crystal;
(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the modafinil with the co-crystal former under crystallization conditions;
(d) isolating co-crystals formed thereby; and
(e) incorporating the co-crystals into a pharmaceutical composition or
medicament.
In another embodiment, a process for the formation of co-crystals includes a
meta-stable form of modafinil, the co-crystal former, or both. A meta-stable
form can
be for example, but not limited to, a polymorph, solvate, or hydrate of
modafinil or
the co-crystal former. While not bound by theory, the incorporation of a meta-
stable
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form may facilitate co-crystal formation via increasing the thermodynamic
driving
force.
Assaying the solid phase for the presence of co-crystals of modafinil and the
co-crystal former may be carried out by conventional methods known in the art.
For
example, it is convenient and routine to use powder X-ray diffraction
techniques to
assess the presence of co-crystals. This may be affected by comparing the
diffractograms of modafinil, the crystal former and putative co-crystals in
order to
establish whether or not true co-crystals had been formed. Other techniques,
used in
an analogous fashion, include differential scanning calorimetry (DSC),
thermogravimetric analysis (TGA), infrared spectroscopy (IR), and Raman
spectroscopy. Single crystal X-ray diffraction is especially useful in
identifying co-
crystal structures.
In a further aspect, the present invention therefore provides a process of
screening for co-crystal compounds, which comprises:
(a) providing (i) modafinil and (ii) a co-crystal former compatible with a
functional group of modafinil such that the co-crystal former and the
modafinil can
form a co-crystal; and
(b) screening for co-crystals of the modafinil with the co-crystal former by
subjecting each combination of modafinil and co-crystal former to a procedure
comprising:
(i) grinding, heating, co-subliming, co-melting, or contacting in
solution the modafinil with the co-crystal former under crystallization
conditions so as to form a solid phase; and
(ii) isolating co-crystals comprising the modafinil and the co-
crystal former.
An alternative embodiment is drawn to a process of screening for co-crystal
compounds, which comprises:
(a) providing (i) modafinil and (ii) a plurality of different co-crystal
formers compatible with a functional group of modafinil such that the co-
crystal
former and the modafinil can form a co-crystal; and
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(b) screening for co-crystals of the modafinil with the co-crystal formers
by subjecting each combination of the modafinil and the co-crystal formers to
a
procedure comprising:
(i) grinding, heating, co-subliming, co-melting, or contacting in
solution the modafinil with each co-crystal former under crystallization
conditions so as to form a solid phase; and
(ii) isolating co-crystals comprising the modafinil and the co-
crystal former.
The present invention includes several co-crystals comprising modafinil and a
carboxylic acid co-crystal former. Some examples include modafinil co-crystals
comprising malonic acid, tartaric acid (L- and DL-), succinic acid, citric
acid, fumaric
acid, gentisic acid, oxalic acid, and 1-hydroxy-2-naphthoic acid. These
examples
represent mono-, di- and tri-carboxylic acid co-crystal formers. Other acids,
including
carboxylic acids, may be used as co-crystal formers with modafinil including,
but not
limited to, palmitic acid, orotic acid, and adipic acid etc. These co-crystal
formers
may comprise one, two, three, or more carboxylic acid functional groups. Co-
crystal
formers can also include non-carboxylic acid molecules such as, but not
limited to,
urea, saccharin, and caffeine.
In another embodiment, a co-crystal comprises modafinil and a carboxylic
acid as a co-crystal former. In another embodiment, the carboxylic acid co-
crystal
former has one, two, three, or more carboxylic acid functional groups.
Several co-crystals may exhibit one or more particular interactions between
modafinil and a carboxylic acid co-crystal former. For example, a carboxylic
acid
functional group can interact with the primary amide and/or the S=Q functional
group
of modafinil via a hydrogen bond. In another embodiment, a carboxylic acid
functional group from the co-crystal former interacts with the primary amide
functional group or the S=O functional group of modafinil via a hydrogen bond.
In
another embodiment, a carboxylic acid functional group from the co-crystal
former
interacts with the periphery of the amide dimer of modafinil via a hydrogen
bond. In
another embodiment, a carboxylic acid functional group from the co-crystal
former
interacts with the amide dimer and the S=0 functional group of modafinil via a
hydrogen bond. In another embodiment, a carboxylic acid functional group from
the
co-crystal former interacts with two amide dimers of modafinil via a hydrogen
bond.
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Modafinil and some co-crystal formers of the present invention have one or
more chiral centers and may exist in a variety of stereoisomeric
configurations. As a
consequence of these chiral centers, modafinil and several co-crystal formers
of the
present invention occur as racemates, mixtures of enantiomers and as
individual
enantiomers, as well as diastereomers and mixtures of diastereomers. All such
racemates, enantiomers, and diastereomers are within the scope of the present
invention including, for example, cis- and trans-isomers, R- and S-
enantiomers, and
(D)- and (L)-isomers. Co-crystals of the present invention can include
isomeric forms
of either modafinil or the co-crystal former or both. Isomeric forms of
modafinil and
co-crystal formers include, but are not limited to, stereoisomers such as
enantiomers
and diastereomers. In one embodiment, a co-crystal can comprise racemic
modafinil
and/or a co-crystal former. In another embodiment, a co-crystal can comprise
enantiomerically pure R- or S-modafinil and/or a co-crystal former. In another
embodiment, a co-crystal of the present invention can comprise modafinil or a
co-
crystal former with an enantiomeric excess of about 1 percent, 2 percent, 3
percent, 4
percent, 5 percent, 10 percent, 15 percent, 20 percent, 25 percent, 30
percent, 35
percent, 40 percent, 45 percent, 50 percent, 55 percent, 60 percent, 65
percent, 70
percent, 75 percent, 80 percent, 85 percent, 90 percent, 95 percent, 96
percent, 97
percent, 98 percent, 99 percent, greater than 99 percent, or any intermediate
value.
Several non-limiting examples of stereoisomeric co-crystal formers include
tartaric
acid and malic acid. In another embodiment, a polymorph or a solvate of the
present
invention can comprise modafinil with an enantiomeric excess of about 1
percent, 2
percent, 3 percent, 4 percent, 5 percent, 10 percent, 15 percent, 20 percent,
25 percent,
30 percent, 35 percent, 40 percent, 45 percent, 50 percent, 55 percent, 60
percent, 65
percent, 70 percent, 75 percent, 80 percent, 85 percent, 90 percent, 95
percent, 96
percent, 97 percent, 98 percent, 99 percent, greater than 99 percent, or any
intermediate value.
"Enriched" modafinil, according to the present invention, comprises both the
R-(-)- and S-(+)-isomers of modafinil in amounts greater than or equal to
about 5, 6,
7, 8, 9, or 10 percent by weight and less than or equal to about 90, 91, 92,
93, 94, or
95 percent by weight. For example, a composition comprising 67 percent by
weight
R-(-)-modafinil and 33 percent by weight S-(+)-modafinil is an enriched
modafinil
composition. In such an example, the composition is neither racemic nor
enantiomerically pure. The term "enriched R-(-)-modafinil" may be used to
describe
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a composition of modafinil with greater than 50 percent R-(-)-modafinil and
less than
50 percent S-(+)-modafinil. Likewise, the term "enriched S-(+)-modafinil" may
be
used to describe a composition of modafinil with greater than 50 percent S-(+)-
modafinil and less than 50 percent R-(-)-modafinil.
The terms "R-(-)-modafinil" and "S-(+)-modafinil" can be used to describe
enriched modafinil, enantiomerically pure modafinil, or substantially
enantiomerically
pure modafinil, but may also specifically exclude enriched modafinil,
enantiomerically pure modafinil, and/or substantially enantiomerically pure
modafinil.
Co-crystals, solvates, and polymorphs comprising enantiomerically pure
and/or enantiomerically enriched components (e.g., modafinil or co-crystal
former)
can give rise to chemical and/or physical properties which are modulated with
respect
to those of the corresponding co-crystal comprising a racemic component. For
example, the modafinil:malonic acid co-crystal from Example 1 comprises
racemic
modafinil. Enantiomerically pure R-(-)-modafinil:malonic acid is included in
the
scope of the invention. Likewise, enantiomerically pure S-(+)-
modafinil:malonic acid
is included in the scope of the invention. A co-crystal comprising an
enantiomerically
pure component can give rise to a modulation of, for example, activity,
bioavailability, or solubility, with respect to the corresponding co-crystal
comprising a
racemic component. As an example, the co-crystal R-(-)-modafinil:malonic acid
can
have modulated properties as compared to the racemic modafinil:malonic acid co-
crystal.
Polymorphs and solvates of modafinil can also be prepared with racemic
modafinil, enantiomerically pure modafinil, or with any mixture of R-(-)- and
S-(+)-
modafinil according to the present invention.
In another embodiment, the present invention includes a pharmaceutical
composition or medicament comprising a co-crystal with enantiomerically pure
modafinil and/or co-crystal former wherein the bioavailability is modulated
with
respect to the racemic co-crystal. In another embodiment, the present
invention
includes a pharmaceutical composition or medicament comprising a co-crystal
with
enantiomerically pure modafinil and/or co-crystal former wherein the activity
is
modulated with respect to the racemic co-crystal. In another embodiment, the
present
invention includes a pharmaceutical composition or medicament comprising a co-
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crystal with enantiomerically pure modafinil and/or co-crystal former wherein
the
solubility is modulated with respect to the racemic co-crystal.
In another embodiment, a pharmaceutical composition or medicament can be
formulated to contain modafinil in co-crystal form as micronized or nano-sized
particles. More specifically, another embodiment couples the processing of
pure
modafinil to a co-crystal form with the process of making a controlled
particle size for
manipulation into a pharmaceutical dosage form. This embodiment combines two
processing steps into a single step via techniques such as, but not limited
to, grinding,
alloying, or sintering (i.e., heating a powder mix). The coupling of these
processes
overcomes a serious limitation of having to isolate and store the bulk drug
that is
required for a formulation, which in some cases can be difficult to isolate
(e.g.,
amorphous, chemically or physically unstable).
Solubility Modulation
In a further aspect, the present invention provides a process for increasing
the
solubility of modafinil in water, simulated gastric fluid (SGF), or simulated
intestinal
fluid (SIF) for use in a pharmaceutical composition or medicament, which
process
comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
(d) isolating co-crystals comprising the modafinil and the co-crystal
former.
In one embodiment, the solubility of modafinil is modulated such that the
aqueous solubility (mg/mL) is increased by at least 1.1, 1.2, 1.3, 1.5, 2.0,
5.0, 10.0,
20.0, 25.0, 50.0, 75.0, or 100.0 times or more than the free form. Solubility
of
modafinil may be measured by any conventional means such as chromatography
(e.g.,
HPLC) or spectroscopic determination of the amount of modafinil in a saturated
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solution, such as UV-spectroscopy, IR-spectroscopy, Raman spectroscopy,
quantitative mass spectroscopy, or gas chromatography.
In another embodiment, the compositions or medicaments including co-
crystals, solvates, and polymorphs of the present invention can be compared
with free
form modafinil as found in PROVIGIL (Cephalon, Inc.). (See US Reissued Patent
No. RE37,516) For example, the bioavailability of a composition or medicament
of
the present invention can be compared with that of PROVIGIL. As embodiments of
the present invention, solubility can be increased 2, 3, 4, 5, 7, 10, 15, 20,
25, 50, 75, or
100 times by making a co-crystal of the reference form (e.g., crystalline or
amorphous
free form, hydrate or solvate). Further aqueous solubility can be measured in
simulated gastric fluid (SGF) or simulated intestinal fluid (SIF) rather than
water.
SGF (non-diluted) of the present invention is made by combining 1 g/L Triton X-
100
and 2 g/L NaCl in water and adjusting the pH with 20 mM HCI to obtain a
solution
with a final pH=1.7 SIF is 0.68% monobasic potassium phosphate, 1% pancreatin,
and sodium hydroxide where the pH of the final solution is 7.5. The pH of the
solvent
used may also be specified as 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9,
2, 2.1, 2.2,
2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8,
8.5, 9, 9.5, 10,
10.5, 11, 11.5, or 12, or any pH in between successive values.
Examples of embodiments includes: co-crystal compositions with an aqueous
solubility, at 37 degrees C and a pH of 7.0, that is increased at least 5 fold
over the
reference form, co-crystal compositions with a solubility in SGF that is
increased at
least 5 fold over the reference form, co-crystal compositions with a
solubility in SIF
that is increased at least 5 fold over the reference form.
Dissolution Modulation
In another aspect of the present invention, the dissolution profile of
modafinil
is modulated whereby the aqueous dissolution rate or the dissolution rate in
simulated
gastric fluid or in simulated intestinal fluid, or in a solvent or plurality
of solvents is
increased. Dissolution rate is the rate at which API solids dissolve in a
dissolution
medium. For APIs whose absorption rates are faster than the dissolution rates
(e.g.,
steroids), the rate-limiting step in the absorption process is often the
dissolution rate.
Because of a limited residence time at the absorption site, APIs that are not
dissolved
before they are removed from intestinal absorption site are considered
useless.
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Therefore, the rate of dissolution has a major impact on the performance of
APIs that
are poorly soluble. Because of this factor, the dissolution rate of APIs in
solid dosage
forms is an important, routine, quality control parameter used in the API
manufacturing process. The following equation is an approximation,
Dissolution rate = KS(CS-C)
where K is dissolution rate constant, S is the surface area, Cs is the
apparent solubility,
and C is the concentration of API in the dissolution medium.
For rapid API absorption, CS-C is approximately equal to CS
The dissolution rate of modafinil may be measured by conventional means
known in the art.
The increase in the dissolution rate of a co-crystal, as compared to the
reference form (e.g., free form), may be specified, such as by 10, 20, 30, 40,
50,'60,
70, 80, 90, or 100%, or by 2, 3, 4, 5 ,6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50,
75, 100, 125,
150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or 100,000 fold greater
than the
reference form (e.g., free form) in the same solution. Conditions under which
the
dissolution rate is measured are the same as discussed above. The increase in
dissolution may be further specified by the time the composition remains
supersaturated before reaching equilibrium solubility.
In a further aspect, the present invention provides a process for modulating
the
dissolution of modafinil, whereby the aqueous dissolution rate or the
dissolution rate
in simulated gastric fluid or in simulated intestinal fluid, or in a solvent
or plurality of
solvents is increased, which process comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
(d) isolating co-crystals comprising the modafinil and the co-crystal
former.
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Examples of above embodiments include: co-crystal compositions with a
dissolution rate in aqueous solution, at 37 degrees C and a pH of 7.0, that is
increased
at least 5 fold over the reference form, co-crystal compositions with a
dissolution rate
in SGF that is increased at least 5 fold over the reference form, co-crystal
compositions with a dissolution rate in SIF that is increased at least 5 fold
over the
reference form.
Bioavailability Modulation
The methods of the present invention are used to make a pharmaceutical
modafinil formulation with greater solubility, dissolution, and
bioavailability.
Bioavailability can be improved via an increase in AUC, reduced time to Tmax,
(the
time to reach peak blood serum levels), or increased Cm. The present invention
can
result in higher plasma concentrations of modafinil when compared to the free
form
(reference form).
AUC is the area under the plot of plasma concentration of API (not logarithm
of the concentration) against time after API administration. The area is
conveniently
determined by the "trapezoidal rule": The data points are connected by
straight line
segments, perpendiculars are erected from the abscissa to each data point, and
the sum
of the areas of the triangles and trapezoids so constructed is computed. When
the last
measured concentration (Cn, at time tõ) is not zero, the AUC from tõ to
infinite time is
estimated by Cn/ke1.
The AUC is of particular use in estimating bioavailability of APIs, and in
estimating total clearance of APIs (C1T). Following single intravenous doses,
AUC =
D/CIT, for single compartment systems obeying first-order elimination
kinetics, where
D is the dose; alternatively, AUC = Co/kei, where kel is the API elimination
rate
constant. With routes other than the intravenous, AUC = F - D/C1T, where F is
the
absolute bioavailability of the API.
In a further aspect, the present invention provides a process for modulating
the
bioavailability of modafinil, whereby the AUC is increased, the time to Tmax
is
reduced, the length of time the concentration of modafinil is above %2 Tmax is
increased, or Cmax is increased, which process comprises:
(a) providing modafinil;
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(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the
modafinil with the co-crystal former under crystallization conditions,
so as to form a solid phase; and
(d) isolating co-crystals comprising the modafinil and the co-crystal
former.
Examples of the above embodiments include: co-crystal compositions with a
time to Tmax that is increased by at least 5% as compared to the reference
form, co-
crystal compositions with a time to Tmax that is increased by at least 10%
over the
reference form, co-crystal compositions with a time to Tmax that is increased
by at
least 15% over the reference form, co-crystal compositions with a time to Tmax
that is
increased by at least 20% over the reference form, co-crystal compositions
with a Tmax
that is increased by at least 25% over the reference form, co-crystal
compositions with
a Tmax that is increased by at least 30% over the reference form, co-crystal
compositions with a Tmax that is increased by at least 35% over the reference
form, co-
crystal compositions with a Tmax that is increased by at least 40% over the
reference
form, co-crystal compositions with an AUC that is increased by at least 5%
over the
reference form, co-crystal compositions with an AUC that is increased by at
least 10%
over the reference form, co-crystal compositions with an AUC that is increased
by at
least 15% over the reference form, co-crystal compositions with an AUC that is
increased by at least 20% over the reference form, co-crystal compositions
with an
AUC that is increased by at least 25% over the reference form, co-crystal
compositions with an AUC that is increased by at least 30% over the reference
form,
co-crystal compositions with an AUC that is increased by at least 35% over the
reference form, co-crystal compositions with an AUC that is increased by at
least 40%
over the reference form. Other examples include wherein the reference form is
crystalline, wherein the reference form is amorphous, or wherein the reference
form is
an anhydrous crystal form of modafinil.
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Dose Response Modulation
In a further aspect, the present invention provides a process for modulating
the
dose response of modafinil for use in a pharmaceutical composition or
medicament,
which process comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
(d) isolating co-crystals comprising the modafinil and the co-crystal
former.
Dose response is the quantitative relationship between the magnitude of
response and the dose inducing the response and may be measured by
conventional
means known in the art. The curve relating effect (as the dependent variable)
to dose
(as the independent variable) for an API-cell system is the "dose-response
curve".
Typically, the dose-response curve is the measured response to an API plotted
against
the dose of the API (mg/kg) given. The dose response curve can also be a curve
of
AUC against the dose of the API given.
In an embodiment of the present invention, a co-crystal of the present
invention has an increased dose response curve or a more linear dose response
curve
than the corresponding reference compound.
Increased Stability
In a still further aspect the present invention provides a process for
improving
the stability of modafinil (as compared to a reference form such as its free
form),
which process comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
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(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
(d) isolating co-crystals comprising the modafinil and the co-crystal
former.
In a preferred embodiment, the compositions of the present invention,
including modafinil co-crystals, solvates, and formulations comprising
modafinil, are
suitably stable for pharmaceutical use. Preferably, modafinil or formulations
thereof,
of the present invention, are stable such that when stored at 30 degrees C for
2 years,
less than 0.2 % of any one degradant is formed. The term degradant refers
herein to
product(s) of a single type of chemical reaction. For example, if a hydrolysis
event
occurs that cleaves a molecule into two products, for the purpose of the
present
invention, it would be considered a single degradant. More preferably, when
stored at
40 degrees C for 2 years, less than 0.2 % of any one degradant is formed.
Alternatively, when stored at 30 degrees C for 3 months, less than 0.2 % or
0.15 %, or
0.1 % of any one degradant is formed, or when stored at 40 degrees C for 3
months,
less than 0.2 % or 0.15 %, or 0.1 % of any one degradant is formed. Further
alternatively, when stored at 60 degrees C for 4 weeks, less than 0.2 % or
0.15 %, or
0.1 % of any one degradant is formed. The relative humidity (RH) may be
specified
as ambient RH, 75 % RH, or as any single integer between 1 to 99 % RH. In
another
embodiment, a single dose of the present invention comprises less than 0.5 %,
0.2 %,
or 0.1 % degradants upon administration to a subject.
Morphology Modulation
In a still further aspect the present invention provides a process for
modifying
the morphology of modafinil, which process comprises:
(a) providing modafinil;
(b) providing a co-crystal former compatible with a functional group of
modafinil such that the co-crystal former and the modafinil can form a
co-crystal;
(c) grinding, heating, co-subliming, co-melting, or contacting in solution
the modafinil with the co-crystal former under crystallization
conditions, so as to form a solid phase; and
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(d) isolating co-crystals comprising the modafinil and the co-crystal
former.
In an embodiment the co-crystal comprises or consists of modafinil and a co-
crystal former wherein the interaction between the two, e.g., H-bonding,
occurs
between the amino group of modafinil and a co-crystal former with a
corresponding
interacting group of Table III. In a further embodiment, the co-crystal
comprises
modafinil and a co-crystal former of Table I or II. In an aspect of the
invention, only
co-crystals having an H-bond acceptor on the first molecule and an H-bond
donor on
the second molecule, where the first and second molecules are either co-
crystal
former and modafinil respectively, or modafinil and co-crystal former
respectively,
are included in the present invention.
A co-crystal can comprise more than two chemical entities within its co-
crystalline structure. For example, a co-crystal can further comprise a
solvent
molecule, a water molecule, a salt, etc. In addition, a co-crystal can
comprise an API
and two or more co-crystal formers, a co-crystal former and two or more APIs,
two or
more APIs, or two or more co-crystal formers.
As defined herein, a ternary co-crystal is a co-crystal which comprises three
distinct chemical entities in a stoichiometric ratio, where each is a solid at
room
temperature (with the exception that the API may be a liquid at room
temperature).
Specifically, a ternary co-crystal comprises three distinct chemical entities
such as
API:co-crystal former(1):co-crystal former(2), where the ratio of components
can be,
for example, but not limited to, 1:1:1, 2:1:1, 2:1:2, 2:1:0.5, 2:2:1, etc.
Ternary co-
crystals can also comprise other combinations of components such as, but not
limited
to, API(1):API(2):co-crystal former, API(1):API(2):API(3), and co-crystal
former(1):co-crystal former(2):co-crystal former(3).
In another embodiment, the present invention provides a co-crystal comprising
modafinil and a co-crystal former selected from the group consisting of.
malonic acid,
glycolic acid, fumaric acid, tartaric acid, citric acid, succinic acid,
gentisic acid, oxalic
acid, 1-hydroxy-2-naphthoic acid, orotic acid, glutaric acid, L-tartaric acid,
palmitic
acid, L-proline, salicylic acid, lauric acid, L-malic acid, and maleic acid.
In further embodiments, the present invention provides the following co-
crystals: modafinil:malonic acid, modafinil:glycolic acid, modafinil:maleic
acid,
modafinil:L-tartaric acid, modafinil:citric acid, modafinil:succinic acid,
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modafinil:DL-tartaric acid, modafinil:fumaric acid (Form I), modafinil:fumaric
acid
(Form II), modafinil:gentisic acid, modafmil:oxalic acid, modafinil:1-hydroxy-
2-
naphthoic acid, R-(-)-modafinil:malonic acid, R-(-)-modafinil:succinic acid, R-
(-)-
modafinil: citric acid, R-(-)-modafinil:DL-tartaric acid, R-(-)-modafinil:1-
hydroxy-2-
naphthoic acid, R-(-)-modafinil:orotic acid, R-(-)-modafinil:glutaric acid, R-
(-)-
modafinil:L-tartaric acid, R-(-)-modafinil:palmitic acid, R-(-)-modafinil:L-
proline, R-
(-)-modafinil:salicylic acid, R-(-)-modafinil:lauric acid, R-(-)-modafinil:L-
malic acid,
and R-(-)-modafinil:gentisic acid.
In another embodiment, the present invention provides a novel polymorph or
co-crystal of racemic modafinil (form VII).
In another embodiment, the present invention provides the following
modafinil solvates: acetic acid, tetrahydrofuran, 1,4-dioxane, methanol,
nitromethane,
acetone, o-xylene, benzene, and toluene.
Pharmaceutically acceptable co-crystals can be administered by controlled- or
delayed-release means. Controlled-release pharmaceutical products have a
common
goal of improving drug therapy over that achieved by their non-controlled
release
counterparts. Ideally, the use of an optimally designed controlled-release
preparation
in medical treatment is characterized by a minimum of drug substance being
employed to cure or control the condition in a minimum amount of time.
Advantages
of controlled-release formulations include: 1) extended activity of the drug;
2)
reduced dosage frequency; 3) increased patient compliance; 4) usage of less
total
drug; 5) reduction in local or systemic side effects; 6) minimization of drug
accumulation; 7) reduction in blood level fluctuations; 8) improvement in
efficacy of
treatment; 9) reduction of potentiation or loss of drug activity; and 10)
improvement
in speed of control of diseases or conditions. (Kim, Cherng ju, Controlled
Release
Dosage Form Design, 2 Technomic Publishing, Lancaster, Pa.: 2000).
Conventional dosage forms generally provide rapid or immediate drug release
from the formulation. Depending on the pharmacology and pharmacokinetics of
the
drug, use of conventional dosage forms can lead to wide fluctuations in the
concentrations of the drug in a patient's blood and other tissues. These
fluctuations
can impact a number of parameters, such as dose frequency, onset of action,
duration
of efficacy, maintenance of therapeutic blood levels, toxicity, side effects,
and the
like. Advantageously, controlled-release formulations can be used to control a
drug's
onset of action, duration of action, plasma levels within the therapeutic
window, and
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peak blood levels. In particular, controlled- or extended-release dosage forms
or
formulations can be used to ensure that the maximum effectiveness of a drug is
achieved while minimizing potential adverse effects and safety concerns, which
can
occur both from under dosing a drug (i.e., going below the minimum therapeutic
levels) as well as exceeding the toxicity level for the drug.
Most controlled-release formulations are designed to initially release an
amount of drug (active ingredient) that promptly produces the desired
therapeutic
effect, and gradually and continually release other amounts of drug to
maintain this
level of therapeutic or prophylactic effect over an extended period of time.
In order to
maintain this constant level of drug in the body, the drug must be released
from the
dosage form at a rate that will replace the amount of drug being metabolized
and
excreted from the body. Controlled-release of an active ingredient can be
stimulated
by various conditions including, but not limited to, pH, ionic strength,
osmotic
pressure, temperature, enzymes, water, and other physiological conditions or
compounds.
A variety of known controlled- or extended-release dosage forms,
formulations, and devices can be adapted for use with the co-crystals and
compositions of the invention. Examples include, but are not limited to, those
described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123;
4,008,719;
5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556;
5,733,566; and 6,365,185 B1.
These dosage forms can be used to provide slow or controlled-release of one or
more
active ingredients using, for example, hydroxypropylmethyl cellulose, other
polymer
matrices, gels, permeable membranes, osmotic systems (such as OROS (Alza
Corporation, Mountain View, Calif. USA)), multilayer coatings, microparticles,
liposomes, or microspheres or a combination thereof to provide the desired
release
profile in varying proportions. Additionally, ion exchange materials can be
used to
prepare immobilized, adsorbed co-crystals and thus effect controlled delivery
of the
drug. Examples of specific anion exchangers include, but are not limited to,
Duolite
A568 and Duolite AP143 (Rohm & Haas, Spring House, PA. USA).
One embodiment of the invention encompasses a unit dosage form which
comprises a pharmaceutically acceptable co-crystal, or a solvate, hydrate,
dehydrate,
anhydrous, or amorphous form thereof, and one or more pharmaceutically
acceptable
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excipients or diluents, wherein the pharmaceutical composition, medicament or
dosage form is formulated for controlled-release. Specific dosage forms
utilize an
osmotic drug delivery system.
A particular and well-known osmotic drug delivery system is referred to as
OROS (Alza Corporation, Mountain View, Calif. USA). This technology can
readily be adapted for the delivery of compounds and compositions of the
invention.
Various aspects of the technology are disclosed in U.S. Pat. Nos. 6,375,978
BI;
6,368,626 B1; 6,342,249 B1; 6,333,050 B2; 6,287,295 B1; 6,283,953 B1;
6,270,787
BI; 6,245,357 B1; and 6,132,420.
Specific adaptations of OROS that can be used to administer compounds and
compositions of the invention include, but are not limited to, the OROS Push-
PullTM, Delayed Push-PullTM, Multi-Layer Push-PullTM, and Push-Stick TM
Systems,
all of which are well known. See, e.g., http://www.alza.com. Additional OROS
systems that can be used for the controlled oral delivery of compounds and
compositions of the invention include OROS -CT and L-OROS . Id.; see also,
Delivery Times, vol. II, issue II (Alza Corporation).
Conventional OROS oral dosage forms are made by compressing a drug
powder (e.g. co-crystal) into a hard tablet, coating the tablet with cellulose
derivatives
to form a semi-permeable membrane, and then drilling an orifice in the coating
(e.g.,
with a laser). Kim, Cherng-ju, Controlled Release Dosage Form Design, 231-238
(Technomic Publishing, Lancaster, Pa.: 2000). The advantage of such dosage
forms is
that the delivery rate of the drug is not influenced by physiological or
experimental
t> 1~
conditions. Even a drug with a pH-dependent solubility can be delivered at a
constant
rate regardless of the pH of the delivery medium. But because these advantages
are
provided by a build-up of osmotic pressure within the dosage form after
administration, conventional OROSO drug delivery systems cannot be used to
effectively deliver drugs with low water solubility. Id. at 234. Because co-
crystals of
this invention can be far more soluble in water than modafinil itself, they
are well
suited for osmotic-based delivery to patients. This invention does, however,
encompass the incorporation of conventional crystalline modafinil (e.g. pure
modafinil without co-crystal former), and isomers and isomeric mixtures
thereof, into
OROS dosage forms.
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A specific dosage form of the invention comprises: a wall defining a cavity,
the wall having an exit orifice formed or formable therein and at least a
portion of the
wall being semipermeable; an expandable layer located within the cavity remote
from
the exit orifice and in fluid communication with the semipermeable portion of
the
wall; a dry or substantially dry state drug layer located within the cavity
adjacent to
the exit orifice and in direct or indirect contacting relationship with the
expandable
layer; and a flow-promoting layer interposed between the inner surface of the
wall
and at least the external surface of the drug layer located within the cavity,
wherein
the drug layer comprises a co-crystal, or a solvate, hydrate, dehydrate,
anhydrous, or
amorphous form thereof. See U.S. Pat. No. 6,368,626.
Another specific dosage form of the invention comprises: a wall defining a
cavity, the wall having an exit orifice formed or formable therein and at
least a portion
of the wail being semipermeable; an expandable layer located within the cavity
remote from the exit orifice and in fluid communication with the semipermeable
portion of the wall; a drug layer located within the cavity adjacent the exit
orifice and
in direct or indirect contacting relationship with the expandable layer; the
drug layer
comprising a liquid, active agent formulation absorbed in porous particles,
the porous
particles being adapted to resist compaction forces sufficient to form a
compacted
drug layer without significant exudation of the liquid, active agent
formulation, the
dosage form optionally having a placebo layer between the exit orifice and the
drug
layer, wherein the active agent formulation comprises a co-crystal, or a
solvate,
hydrate, dehydrate, anhydrous, or amorphous form thereof See U.S. Pat. No.
6,342,249,
In another embodiment, a pharmaceutical composition or medicament
comprises a mixture of a novel form of modafinil of the present invention
(e.g., a co-
crystal) and the free form of modafinil. This embodiment can be used, for
example,
as a controlled-, sustained-, or extended-release dosage form. In another
embodiment,
an extended-release dosage form comprises free form modafinil and a co-crystal
or a
solvate of the present invention. Such an extended-release dosage form
contains
modafinil in a form (e.g. modafinil:malonic acid co-crystal) which has a
greater
bioavailability than that of free form modafinil. In addition, the Cmax of
such a form
can be greater than that of free form modafinil, facilitating a therapeutic
effect with
longer duration than free form modafinil alone.
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In another embodiment, a pharmaceutical composition or medicament
comprises a modified release profile of one or more of racemic modafinil, R-(-
)-
modafinil, and S-(+)-modafinil. The modified release profile can comprise, for
example, two or more maxima of plasma concentration, such as a dual-release
profile.
Such a modified release profile may aid a patient treated with a composition
or
medicament of the present invention who experiences loss of wakefulness in the
afternoon, for example. A second "burst" or release of API at least 2, 3, 4,
5, or 6
hours after administration may help to overcome such an effect. In another
embodiment, a pharmaceutical composition or medicament comprising a small
loading dose released immediately following administration can be employed,
followed by an approximate zero-order release profile over the following 2, 3,
4, 5, or
6 hours. In such a composition, peak plasma levels can be reached at about
midday.
In another embodiment, a pharmaceutical composition or medicament
comprising a modified release profile of modafinil can comprise R-(-)-
modafinil and
S-(+)-modafinil wherein the R-(-)-modafinil provides an initial increase
(initial Cmax
due to R-(-)-modafinil) in plasma concentration and the S-(+)-modafinil
provides a
delayed increase (subsequent Cmax due to S-(+)-modafinil) in plasma
concentration.
The delayed increase in Cmax due to S-(+)-modafinil can be 2, 3, 4, 5, 6 hours
or more
after the initial Cmax due to R-(-)-modafinil. In another embodiment, the
delayed Cmax
is approximately equal to the initial Cm.. In another embodiment, the delayed
Cmax is
greater than the initial Cmax. In another embodiment, the delayed Cmax is less
than the
initial Cmax. In another embodiment, the delayed Cmax is due to racemic
modafinil,
instead of S-(+)-modafinil. In another embodiment, the delayed Cmax is due to
R-(-)-
modafinil, instead of S-(+)-modafinil. In another embodiment, the initial Cmax
is due
to racemic modafinil, instead of R-(-)-modafinil. In another embodiment, the
initial
Cmax is due to S-(+)-modafinil, instead of R-(-)-modafinil. In another
embodiment,
the modified release profile has 3, 4, 5, or more "bursts" in plasma
concentration.
In another embodiment, a pharmaceutical composition or medicament
comprising a modified release profile of modafinil wherein one or more of
racemic
modafinil, R-(-)-modafinil, or S-(+)-modafinil are present in the form of a co-
crystal,
solvate, free form, or a polymorph thereof.
In another embodiment, a pharmaceutical composition or medicament
comprising a modified release profile wherein R-(-)-modafinil is used in an
oral
formulation. Such a composition can minimize first-pass metabolism of
modafinil to
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the sulfone. In another embodiment, a pharmaceutical composition or medicament
comprising a modified release profile wherein racemic modafinil is used in an
oral
formulation. In another embodiment, a pharmaceutical composition or medicament
comprising a modified release profile wherein S-(+)-modafinil is used in an
oral
formulation. In another embodiment, a pharmaceutical composition or medicament
comprising a modified release profile wherein racemic modafinil and R-(-)-
modafinil
are used in an oral formulation. In another embodiment, a pharmaceutical
composition or medicament comprising a modified release profile wherein
racemic
modafinil and S-(+)-modafinil are used in an oral formulation. In another
embodiment, a pharmaceutical composition or medicament comprising a modified
release profile wherein S-(+)-modafinil and R-(-)-modafinil are used in an
oral
formulation. In another embodiment, a pharmaceutical composition or medicament
comprising a modified release profile wherein racemic modafinil, S-(+)-
modafinil and
R-(-)-modafinil are used in an oral formulation.
In another embodiment, a pharmaceutical composition or medicament
comprising a modified release profile of modafinil is administered
transdermally.
Such a transdermal (TD) delivery can avoid first-pass metabolism.
Additionally, a
"pill-and-patch" strategy can be taken, where only a fraction of the daily
dose is
delivered through the skin to generate basal systemic levels, onto which oral
therapy
is added to ensure the wakefulness effect.
Excipients employed in pharmaceutical compositions and medicaments of the
present invention can be solids, semi-solids, liquids or combinations thereof.
Preferably, excipients are solids. Compositions and medicaments of the
invention
containing excipients can be prepared by known technique of pharmacy that
comprises admixing an excipient with an API or therapeutic agent. A
pharmaceutical
composition or medicament of the invention contains a desired amount of API
per
dose unit and, if intended for oral administration, can be in the form, for
example, of a
tablet, a caplet, a pill, a hard or soft capsule, a lozenge, a cachet, a
dispensable
powder, granules, a suspension, an elixir, a dispersion, a liquid, or any
other form
reasonably adapted for such administration. If intended for parenteral
administration,
it can be in the form, for example, of a suspension or transdermal patch. If
intended
for rectal administration, it can be in the form, for example, of a
suppository.
Presently preferred are oral dosage forms that are discrete dose units each
containing
a predetermined amount of the API, such as tablets or capsules.
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Non-limiting examples follow of excipients that can be used to prepare
pharmaceutical compositions or medicaments of the invention.
Pharmaceutical compositions and medicaments of the invention optionally
comprise one or more pharmaceutically acceptable carriers or diluents as
excipients.
Suitable carriers or diluents illustratively include, but are not limited to,
either
individually or in combination, lactose, including anhydrous lactose and
lactose
monohydrate; starches, including directly compressible starch and hydrolyzed
starches (e.g., CelutabTM and EmdexTM); mannitol; sorbitol; xylitol; dextrose
(e.g.,
CereloseTM 2000) and dextrose monohydrate; dibasic calcium phosphate
dihydrate;
sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate
monohydrate;
calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates;
inositol;
hydrolyzed cereal solids; amylose; celluloses including microcrystalline
cellulose,
food grade sources of alpha- and amorphous cellulose (e.g., RexcelJ), powdered
cellulose, hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose
(HPMC); calcium carbonate; glycine; bentonite; block co-polymers;
polyvinylpyrrolidone; and the like. Such carriers or diluents, if present,
constitute in
total about 5% to about 99%, preferably about 10% to about 85%, and more
preferably about 20% to about 80%, of the total weight of the composition. The
carrier, carriers, diluent, or diluents selected preferably exhibit suitable
flow
properties and, where tablets are desired, compressibility.
Lactose, mannitol, dibasic sodium phosphate, and microcrystalline cellulose
(particularly Avicel PH microcrystalline cellulose such as Avicel PH 101),
either
individually or in combination, are preferred diluents. These diluents are
chemically
compatible with APIs. The use of extragranular microcrystalline cellulose
(that is,
microcrystalline cellulose added to a granulated composition) can be used to
improve
hardness (for tablets) and/or disintegration time. Lactose, especially lactose
monohydrate, is particularly preferred. Lactose typically provides
compositions
having suitable release rates of APIs, stability, pre-compression flowability,
and/or
drying properties at a relatively low diluent cost. It provides a high density
substrate
that aids densification during granulation (where wet granulation is employed)
and
therefore improves blend flow properties and tablet properties.
Pharmaceutical compositions and medicaments of the invention optionally
comprise one or more pharmaceutically acceptable disintegrants as excipients,
particularly for tablet formulations. Suitable disintegrants include, but are
not limited
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to, either individually or in combination, starches, including sodium starch
glycolate
(e.g., ExplotabTM of PenWest) and pregelatinized corn starches (e.g., National
1551
of National Starch and Chemical Company, NationalTM 1550, and ColocornTM
1500),
clays (e.g., VeegumTM HV of R.T. Vanderbilt), celluloses such as purified
cellulose,
microcrystalline cellulose, methylcellulose, carboxymethylcellulose and sodium
carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-SolTM of FMC),
alginates, crospovidone, and gums such as agar, guar, locust bean, karaya,
pectin and
tragacanth gums.
Disintegrants may be added at any suitable step during the preparation of the
composition, particularly prior to granulation or during a lubrication step
prior to
compression. Such disintegrants, if present, constitute in total about 0.2% to
about
30%, preferably about 0.2% to about 10%, and more preferably about 0.2% to
about
5%, of the total weight of the composition.
Croscarmellose sodium is a preferred disintegrant for tablet or capsule
disintegration, and, if present, preferably constitutes about 0.2% to about
10%, more
preferably about 0.2% to about 7%, and still more preferably about 0.2% to
about 5%,
of the total weight of the composition. Croscarmellose sodium confers superior
intragranular disintegration capabilities to granulated pharmaceutical
compositions
and medicaments of the present invention.
Pharmaceutical compositions and medicaments of the invention optionally
comprise one or more pharmaceutically acceptable binding agents or adhesives
as
excipients, particularly for tablet formulations. Such binding agents and
adhesives
preferably impart sufficient cohesion to the powder being tableted to allow
for normal
processing operations such as sizing, lubrication, compression and packaging,
but still
allow the tablet to disintegrate and the composition to be absorbed upon
ingestion.
Such binding agents may also prevent or inhibit crystallization or
recrystallization of
an API of the present invention once the salt has been dissolved in a
solution.
Suitable binding agents and adhesives include, but are not limited to, either
individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose;
starches
such as, but not limited to, pregelatinized starches (e.g., NationalTM 1511
and
NationalTM 1500); celluloses such as, but not limited to, methylcellulose and
carmellose sodium (e.g., TyloseTM); alginic acid and salts of alginic acid;
magnesium
aluminum silicate; PEG; guar gum; polysaccharide acids; bentonites; povidone,
for
example povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC;
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hydroxypropylcellulose (e.g., KlucelTM of Aqualon); and ethylcellulose (e.g.,
EthocelTM of the Dow Chemical Company). Such binding agents and/or adhesives,
if
present, constitute in total about 0.5% to about 25%, preferably about 0.75%
to about
15%, and more preferably about 1% to about 10%, of the total weight of the
pharmaceutical composition or medicament.
Many of the binding agents are polymers comprising amide, ester, ether,
alcohol or ketone groups and, as such, are preferably included in
pharmaceutical
compositions and medicaments of the present invention. Polyvinylpyrrolidones
such
as povidone K-30 are especially preferred. Polymeric binding agents can have
varying molecular weight, degrees of crosslinking, and grades of polymer.
Polymeric
binding agents can also be copolymers, such as block co-polymers that contain
mixtures of ethylene oxide and propylene oxide units. Variation in these
units' ratios
in a given polymer affects properties and performance. Examples of block co-
polymers with varying compositions of block units are Poloxamer 188 and
Poloxamer
237 (BASF Corporation).
Pharmaceutical compositions and medicaments of the invention optionally
comprise one or more pharmaceutically acceptable wetting agents as excipients.
Such
wetting agents are preferably selected to maintain the API in close
association with
water, a condition that is believed to improve bioavailability of the
composition.
Non-limiting examples of surfactants that can be used as wetting agents in
pharmaceutical compositions and medicaments of the invention include
quaternary
ammonium compounds, for example benzalkonium chloride, benzethonium chloride
and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene
alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9,
poloxamers (polyoxyethylene and polyoxypropylene block copolymers),
polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene
(8)
caprylic/capric mono- and diglycerides (e.g., LabrasolTM of Gattefosse),
polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor
oil;
polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl
ether,
polyoxyethylene fatty acid esters, for example polyoxyethylene (40) stearate,
polyoxyethylene sorbitan esters, for example polysorbate 20 and polysorbate 80
(e.g.,
TweenTM 80 of ICI), propylene glycol fatty acid esters, for example propylene
glycol
laurate (e.g., LauroglycolTM of Gattefosse), sodium lauryl sulfate, fatty
acids and salts
thereof, for example oleic acid, sodium oleate and triethanolamine oleate,
glyceryl
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fatty acid esters, for example glyceryl monostearate, sorbitan esters, for
example
sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate and sorbitan
monostearate, tyloxapol, and mixtures thereof. Such wetting agents, if
present,
constitute in total about 0.25% to about 15%, preferably about 0.4% to about
10%,
and more preferably about 0.5% to about 5%, of the total weight of the
pharmaceutical composition or medicament.
Wetting agents that are anionic surfactants are preferred. Sodium lauryl
sulfate is a particularly preferred wetting agent. Sodium lauryl sulfate, if
present,
constitutes about 0.25% to about 7%, more preferably about 0.4% to about 4%,
and
still more preferably about 0.5% to about 2%, of the total weight of the
pharmaceutical composition or medicament.
Pharmaceutical compositions and medicaments of the invention optionally
comprise one or more pharmaceutically acceptable lubricants (including anti-
adherents and/or glidants) as excipients. Suitable lubricants include, but are
not
limited to, either individually or in combination, glyceryl behapate (e.g.,
CompritolTM
888 of Gattefosse); stearic acid and salts thereof, including magnesium,
calcium and
sodium stearates; hydrogenated vegetable oils (e.g., SterotexTM of Abitec);
colloidal
silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium
fumarate;
sodium chloride; DL-leucine; PEG (e.g., CarbowaxTM 4000 and CarbowaxTM 6000 of
the Dow Chemical Company); sodium oleate; sodium lauryl sulfate; and magnesium
lauryl sulfate. Such lubricants, if present, constitute in total about 0. 1%
to about
10%, preferably about 0.2% to about 8%, and more preferably about 0.25% to
about
5%, of the total weight of the pharmaceutical composition or medicament.
Magnesium stearate is a preferred lubricant used, for example, to reduce
friction between the equipment and granulated mixture during compression of
tablet
formulations.
Suitable anti-adherents include, but are not limited to, talc, cornstarch, DL-
leucine, sodium lauryl sulfate and metallic stearates. Talc is a preferred
anti-adherent
or glidant used, for example, to reduce formulation sticking to equipment
surfaces and
also to reduce static in the blend. Talc, if present, constitutes about 0.1%
to about
10%, more preferably about 0.25% to about 5%, and still more preferably about
0.5%
to about 2%, of the total weight of the pharmaceutical composition or
medicament.
Glidants can be used to promote powder flow of a solid formulation. Suitable
glidants include, but are not limited to, colloidal silicon dioxide, starch,
talc, tribasic
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calcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal
silicon
dioxide is particularly preferred.
Other excipients such as colorants, flavors and sweeteners are known in the
pharmaceutical art and can be used in pharmaceutical compositions and
medicaments
of the present invention. Tablets can be coated, for example with an enteric
coating,
or uncoated. Compositions of the invention can further comprise, for example,
buffering agents.
Optionally, one or more effervescent agents can be used as disintegrants
and/or to enhance organoleptic properties of pharmaceutical compositions and
medicaments of the invention. When present in pharmaceutical compositions and
medicaments of the invention to promote dosage form disintegration, one or
more
effervescent agents are preferably present in a total amount of about 30% to
about
75%, and preferably about 45% to about 70%, for example about 60%, by weight
of
the pharmaceutical composition or medicament.
According to a particularly preferred embodiment of the invention, an
effervescent agent, present in a solid dosage form in an amount less than that
effective
to promote disintegration of the dosage form, provides improved dispersion of
the
API in an aqueous medium. Without being bound by theory, it is believed that
the
effervescent agent is effective to accelerate dispersion of the API, from the
dosage
form in the gastrointestinal tract, thereby further enhancing absorption and
rapid onset
of therapeutic effect. When present in a pharmaceutical composition or
medicament
of the invention to promote intragastrointestinal dispersion but not to
enhance
disintegration, an effervescent agent is preferably present in an amount of
about 1% to
about 20%, more preferably about 2.5% to about 15%, and still more preferably
about
5% to about 10%, by weight of the pharmaceutical composition or medicament.
An "effervescent agent" herein is an agent comprising one or more compounds
which, acting together or individually, evolve a gas on contact with water.
The gas
evolved is generally oxygen or, most commonly, carbon dioxide. Preferred
effervescent agents comprise an acid and a base that react in the presence of
water to
generate carbon dioxide gas. Preferably, the base comprises an alkali metal or
alkaline earth metal carbonate or bicarbonate and the acid comprises an
aliphatic
carboxylic acid.
Non-limiting examples of suitable bases as components of effervescent agents
useful in the invention include carbonate salts (e.g., calcium carbonate),
bicarbonate
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salts (e.g., sodium bicarbonate), sesquicarbonate salts, and mixtures thereof.
Calcium
carbonate is a preferred base.
Non-limiting examples of suitable acids as components of effervescent agents
and/or solid acids useful in the invention include citric acid, tartaric acid
(as D-, L-, or
D/L-tartaric acid), malic acid, maleic acid, fumaric acid, adipic acid,
succinic acid,
acid anhydrides of such acids, acid salts of such acids, and mixtures thereof.
Citric
acid is a preferred acid.
In a preferred embodiment of the invention, where the effervescent agent
comprises an acid and a base, the weight ratio of the acid to the base is
about 1:100 to
about 100:1, more preferably about 1:50 to about 50:1, and still more
preferably about
1:10 to about 10:1. In a further preferred embodiment of the invention, where
the
effervescent agent comprises an acid and a base, the ratio of the acid to the
base is
approximately stoichiometric.
Excipients which solubilize metal salts of APIs typically have both
hydrophilic and hydrophobic regions, or are preferably amphiphilic or have
amphiphilic regions. One type of amphiphilic or partially-amphiphilic
excipient
comprises an amphiphilic polymer or is an amphiphilic polymer. A specific
amphiphilic polymer is a polyalkylene glycol, which is commonly comprised of
ethylene glycol and/or propylene glycol subunits. Such polyalkylene glycols
can be
esterified at their termini by a carboxylic acid, ester, acid anhyride or
other suitable
moiety. Examples of such excipients include poloxamers (symmetric block
copolymers of ethylene glycol and propylene glycol; e.g., poloxamer 237),
polyalkyene glycolated esters of tocopherol (including esters formed from a di-
or
multi-functional carboxylic acid; e.g., d-alpha-tocopherol polyethylene glycol-
1000
succinate), and macrogolglycerides (formed by alcoholysis of an oil and
esterification
of a polyalkylene glycol to produce a mixture of mono-, di- and tri-glycerides
and
mono- and di-esters; e.g., stearoyl macrogol-32 glycerides). Such
pharmaceutical
compositions and medicaments are advantageously administered orally.
Pharmaceutical compositions and medicaments of the present invention can
comprise about 10% to about 50%, about 25% to about 50%, about 30% to about
45%, or about 30% to about 35% by weight of API; about 10% to about 50%, about
25% to about 50%, about 30% to about 45%, or about 30% to about 35% by weight
of
a an excipient which inhibits crystallization; and about 5% to about 50%,
about 10%
to about 40%, about 15% to about 35%, or about 30% to about 35% by weight of a
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binding agent. In one example, the weight ratio of the API to the excipient
which
inhibits crystallization to binding agent is about 1 to 1 to 1.
Solid dosage forms of the invention can be prepared by any suitable process,
not limited to processes described herein.
An illustrative process comprises (a) a step of blending a salt of the
invention
with one or more excipients to form a blend, and (b) a step of tableting or
encapsulating the blend to form tablets or capsules, respectively.
In a preferred process, solid dosage forms are prepared by a process
comprising (a) a step of blending an API salt of the invention with one or
more
excipients to form a blend, (b) a step of granulating the blend to form a
granulate, and
(c) a step of tableting or encapsulating the blend to form tablets or capsules
respectively. Step (b) can be accomplished by any dry or wet granulation
technique
known in the art, but is preferably a dry granulation step. A salt of the
present
invention is advantageously granulated to form particles of about 1 micrometer
to
about 100 micrometer, about 5 micrometer to about 50 micrometer, or about 10
micrometer to about 25, micrometer. One or more diluents, one or more
disintegrants
and one or more binding agents are preferably added, for example in the
blending
step, a wetting agent can optionally be added, for example in the granulating
step, and
one or more disintegrants are preferably added after granulating but before
tableting
or encapsulating. A lubricant is preferably added before tableting. Blending
and
granulating can be performed independently under low or high shear. A process
is
preferably selected that forms a granulate that is uniform in API content,
that readily
disintegrates, that flows with sufficient ease so that weight variation can be
reliably
controlled during capsule filling or tableting, and that is dense enough in
bulk so that
a batch can be processed in the selected equipment and individual doses fit
into the
specified capsules or tablet dies.
In an alternative embodiment, solid dosage forms are prepared by a process
that includes a spray drying step, wherein the API is suspended with one or
more
excipients in one or more sprayable liquids, preferably a non-protic (e.g.,
non-aqueous
or non-alcoholic) sprayable liquid, and then is rapidly spray dried over a
current of
warm air.
A granulate or spray dried powder resulting from any of the above illustrative
processes can be compressed or molded to prepare tablets or encapsulated to
prepare
capsules. Conventional tableting and encapsulation techniques known in the art
can
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be employed. Where coated tablets are desired, conventional coating techniques
are
suitable.
Excipients for tablet compositions of the invention are preferably selected to
provide a disintegration time of less than about 30 minutes, preferably about
25
minutes or less, more preferably about 20 minutes or less, and still more
preferably
about 15 minutes or less, in a standard disintegration assay.
In another embodiment of the present invention, a pharmaceutical composition
or medicament comprising modafinil and an additional API can be prepared. The
modafinil and the additional API can be in the form of a co-crystal, or may be
included as a mixture or a combination of active pharmaceutical ingredients.
For
example, a composition can comprise modafinil and caffeine as a combination. A
composition comprising modafinil and caffeine can be used as a therapeutic
agent to
treat the same conditions as modafinil. In such a composition comprising
modafinil
and caffeine, the caffeine can yield a quick release characteristic (small
Tmax relative
to modafinil) to the dissolution profile while the modafinil causes the
therapeutic
effect to be present for hours after administration. For example, the Tmax of
caffeine
may be 0.001, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, or 0.8 times that
of
modafinil. Combination therapies comprise the administration of two or more
APIs
in the same formulation, or in two or more co-administered formulations. The
APIs
can be administered together at the same time, or individually at specified
intervals.
Uses for modafinil are well known in the art and include the treatment of
narcolepsy, multiple sclerosis related fatigue, infertility, eating disorders,
attention
deficit hyperactivity disorder (ADHD), Parkinson's disease, incontinence,
sleep
apnea, or myopathies. In another embodiment, any one or more of the modafinil
compositions of the present invention may be used in the treatment of one or
more of
the above conditions. The dosage and administration for modafinil compositions
of
the present invention can be determined using routine methods in the art but
will
generally fall between about 50 and about 700 mg/day.
In another embodiment, a composition of the present invention can be
administered to a mammal via an injection. Injections include, but are not
limited to,
intravenous, subcutaneous, and intramuscular injections. In another
embodiment, a
composition of the present invention is formulated for injection into a mammal
in
need of therapeutic effect.
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EXAMPLES
General Methods for the Preparation of Co-Crystals
a) High Throughput crystallization using the CrystalMax(V platform
CrystalMax comprises a sequence of automated, integrated high throughput
robotic
stations capable of rapid generation, identification and characterization of
polymorphs, salts, and co-crystals of APIs and API candidates. Worksheet
generation
and combinatorial mixture design is carried out using proprietary design
software
ArchitectTM. Typically, an API or an API candidate is,dispensed from an
organic
solvent into tubes and dried under a stream of nitrogen. Salts and/or co-
crystal
formers may also be dispensed and dried in the same fashion. Water and organic
solvents may be combinatorially dispensed into the tubes using amulti-channel
dispenser. Each tube in a 96-tube array is then sealed within 15 seconds of
combinatorial dispensing to avoid solvent evaporation. The mixtures are then
rendered supersaturated by heating to 70 degrees C for 2 hours followed by a 1
degree
C/minute cooling ramp to 5 degrees C. Optical checks are then conducted to
detect
crystals and/or solid material. Once a solid has been identified in a tube, it
is isolated
through aspiration and drying. Raman spectra are then obtained on the solids
and
cluster classification of the spectral patterns is performed using proprietary
software
(InquireTM).
b) Crystallization from solution
Co-crystals may be obtained by dissolving the separate components in a solvent
and
adding one to the other. The co-crystal may then precipitate or crystallize as
the
solvent mixture is evaporated slowly. The co-crystal may also be obtained by
dissolving the two components in the same solvent or a mixture of solvents.
The co-
crystal may also be obtained by seeding a saturated solution of the two
components
and seeding with a ground mixture of the co-crystal.
c) Crystallization from the melt (Co-melting)
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A co-crystal may be obtained by melting the two components together (i.e., co-
melting) and allowing recrystallization to occur. In some cases, an anti-
solvent may
be added to facilitate crystallization.
d) Thermal microscopy
A co-crystal may be obtained by melting the higher melting component on a
glass
slide and allowing it to recrystallize. The second component is then melted
and is
also allowed to recrystallize. The co-crystal may form as a separated
phase/band in
between the eutectic bands of the two original components.
e) Mixing and/or grinding
A co-crystal may be obtained by mixing or grinding two components together in
the
solid state. For example, Example 12 describes the synthesis of a modafinil:1-
hydroxy-2-naphthoic acid co-crystal obtained by milling with the addition of a
small
amount of an appropriate solvent (wet grinding). Similarly, Example 5
describes the
synthesis of a modafinil:citric acid monohydrate co-crystal obtained by
milling both
with and without the addition of a small amount of an appropriate solvent. In
one
embodiment, a co-crystal is prepared via milling or grinding modafinil with a
co-
crystal former (dry grinding). In another embodiment, a co-crystal is prepared
via
milling or grinding modafinil, a co-crystal former, and a small amount of
solvent (wet
grinding).
In another embodiment, a co-crystal is prepared with the addition of solvent,
without the addition of solvent, or both. Solvents used in such a co-
crystallization
process can be, for example, but not limited to, acetone, methanol, ethanol,
isopropyl
alcohol, ethyl acetate, isopropyl acetate, nitromethane, dichloromethane,
chloroform,
toluene, propylene glycol, dimethyl sulfoxide (DMSO), dimethyl formamide
(DMF),
diethyl ether (ether), ethyl formate, hexane, acetonitrile, benzyl alcohol,
water, or
another organic solvent including alcohols.
f) Co-sublimation
A co-crystal may be obtained by co-subliming a mixture of an API and a co-
crystal
former in the same sample cell as an intimate mixture either by heating,
mixing or
placing the mixture under vacuum. A co-crystal may also be obtained by co-
sublimation using a Kneudsen apparatus where the API and the co-crystal former
are
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contained in separate sample cells, connected to a single cold finger, each of
the
sample cells is maintained at the same or different temperatures under a
vaccum
atmosphere in order to co-sublime the two components onto the cold-finger
forming
the desired co-crystal.
Analytical Methods
Differential scanning calorimetric (DSC) analysis of the samples was
performed using a Q1000 Differential Scanning Calorimeter (TA Instruments, New
Castle, DE, U.S.A.), which uses Advantage for QW-Series, version 1Ø0.78,
Thermal
Advantage Release 2.0 (2001 TA Instruments-Water LLC). In addition, the
analysis
software used was Universal Analysis 2000 for Windows 95/98/2000/NT, version
3.1E;Build 3.1Ø40 (2001 TA Instruments-Water LLC).
For the DSC analysis, the purge gas used was dry nitrogen, the reference
material was an empty aluminum pan that was crimped, and the sample purge was
50
mL/minute.
DSC analysis of the sample was performed by placing the modafinil sample in
an aluminum pan with a crimped pan closure. The starting temperature was
typically
20 degrees C with a heating rate of 10 degrees C/minute, and the ending
temperature
was 200 degrees C. All reported DSC transitions represent the temperature of
endothermic or exothermic transition at their respective peaks with an error
of +/- 2
degrees C, unless otherwise indicated.
Thermogravimetric analysis (TGA) of samples was performed using a Q500
Thermogravimetric Analyzer (TA Instruments, New Castle, DE, U.S.A.), which
uses
Advantage for QW-Series, version 1Ø0.78, Thermal Advantage Release 2.0 (2001
TA Instruments-Water LLC). In addition, the analysis software used was
Universal
Analysis'2000 for Windows 95/98/2000/NT, version 3.1E;Build 3.1Ø40 (2001 TA
Instruments-Water LLC).
For the TGA experiments, the purge gas used was dry nitrogen, the balance
purge was 40 mL/minute N2, and the sample purge was 60 mL/minute N2.
TGA was performed on the sample by placing the modafinil sample in a
platinum pan. The starting temperature was typically 20 degrees C with a
heating rate
of 10 degrees C/minute, and the ending temperature was 300 degrees C.
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A powder X-ray diffraction (PXRD) pattern for the samples was obtained
using a D/Max Rapid, Contact (Rigaku/MSC, The Woodlands, TX, U.S.A.), which
uses as its control software RINT Rapid Control Software, Rigaku Rapid/XRD,
version 1Ø0 (1999 Rigaku Co.). In addition, the analysis software used were
RINT
Rapid display software, version 1.18 (Rigaku/MSC), and JADE XRD Pattern
Processing, versions 5.0 and 6.0 ((1995-2002, Materials Data, Inc.).
For the PXRD analysis, the acquisition parameters were as follows: source
was Cu with a K line at 1.5406 A; x-y stage was manual; collimator size was
0.3 mm;
capillary tube (Charles Supper Company, Natick, MA, U.S.A.) was 0.3 mm ID;
reflection mode was used; the power to the X-ray tube was 46 kV; the current
to the
X-ray tube was 40 mA; the omega-axis was oscillating in a range of 0-5 degrees
at a
speed of 1 degree/minute; the phi-axis was spinning at an angle of 360 degrees
at a
speed of 2 degrees/second; 0.3 mm collimator; the collection time was 60
minutes; the
temperature was room temperature; and the heater was not used. The sample was
presented to'the X-ray source in a boron rich glass capillary.
In addition, the analysis parameters were as follows: the integration 2-theta
range was 2-60 degrees; the integration chi range was 0-360 degrees; the
number of
chi segments was 1; the step size used was 0.02; the integration utility was
cylint;
normalization was used; dark counts were 8; omega offset was 180; and chi and
phi
offsets were 0.
PXRD diffractograms were also acquired via the Bruker AXS D8 Discover X-
ray Diffractometer. This instrument was equipped with GADDSTm (General Area
Diffraction Detection System), a Bruker AXS HI-STAR Area Detector at a
distance
of 15.05 cm as per system calibration, a copper source (Cu/Ks 1.54056
angstroms),
automated x-y-z stage, and 0.5mm collimator. The sample was compacted into
pellet
form and mounted on the x-y-z stage. A diffractogram was acquired under
ambient
conditions (25 degrees C) at a powder setting of 40kV and 40mA in reflection
mode
while the sample remained stationary. The exposure time was varied and
specified
for each sample. The diffractogram obtained underwent a spatial remapping
procedure to account for the geometrical pincushion distortion of the area
detector
then integrated along chi from -118.8 to -61.8 degrees and 2-theta 2.1-37
degrees at a
step size of 0.02 degrees with normalization set to bin normalize.
The relative intensity of peaks in a diffractogram is not necessarily a
limitation
of the PXRD pattern because peak intensity can vary from sample to sample,
e.g., due
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to crystalline impurities. Further, the angles of each peak can vary by about
+/- 0.1
degrees, preferably +/- 0.05. The entire pattern or most of the pattern peaks
may also
shift by about +/- 0.1 degrees to about +/- 0.2 degrees due to differences in
calibration, settings, and other variations from instrument to instrument and
from
operator to operator. All reported PXRD peaks in the Figures, Examples, and
elsewhere herein are reported with an error of about 0.1 degrees 2-theta.
For PXRD data herein, including Tables and Figures, each composition of the
present invention may be characterized by any one, any two, any three, any
four, any
five, any six, any seven, or any eight or more of the 2 theta angle peaks. Any
one,
two, three, four, five, or six DSC transitions,can also be used to
characterize the
compositions of the present invention. The different combinations of the PXRD
peaks and the DSC transitions can also be used to characterize the
compositions.
Thermal (hotstage) microscopy was completed on a Zeiss Axioplan 2
microscope equipped with a Mettler Toledo FP90 controller. The hotstage used
was a
Mettler Toledo FP82HT. All melting point determinations were completed by
placing
the sample on a microscope slide and covered with a coverslip. The initial
temperature was set at 30 degrees C and the temperature was increased at a
rate of 10
degrees C/minute. Melting was observed through a 5x microscope objective.
HPLC Method: (adapted from Donovan et al. Therapeutic Drug Monitorin
25:197-202.
Column: Astec Cyclobond 12000 RSP 250x4.6mm (Part No. 411121)
Mobile Phase A: 20 mM sodium phosphate, pH 3.0
B: 70:30 mobile phase A:acetonitrile
Flow Rate: 1.0 mL/min (1500 PSI)
Flow Program: gradient
Run Time: 35 minutes
Detection: UV @ 225 nm
Injection Volume: 10 microliters
Column Temperature: 30 +/- 1 degrees C
Standard diluent: 90:10 (v/v) Mobile Phase A:acetonitrile
Needle wash: acetonitrile
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Purge solvent & seal wash: 90:10 (v/v) water:acetonitrile
Mobile Phase Preparation:
1. Prep 1 M sodium phosphate monobasic: dissolve 120 g of sodium phosphate
monobasic in water and make up to 1000 mL; filter.
2. Prep Mobile Phase A (20 mM sodium phosphate, pH 3.0): for each liter,
dilute 20
mL 1 M sodium phosphate to 1000 mL with water; adjust pH to 3.0 with
phosphoric acid.
3. Prep Mobile Phase B (70:30 (v/v) 20 mM sodium phosphate, pH
3.0:acetonitrile):
for each liter, mix 700 mL Mobile Phase A and 300 mL of acetonitrile.
Sample Prep:
1. Dissolve samples in 90:10 (v/v) 20 mM sodium phosphate, pH 3.0:acetonitrile
to
an approximate concentration of 20 micrograms/mL
Raman Acquisitions
The sample was either left in the glass vial in which it was processed or an
aliquot of the sample was transferred to a glass slide. The glass vial or
slide was
positioned in the sample chamber. The measurement was made using an AlmegaTM
Dispersive Raman (AlmegaTM Dispersive Raman, Thermo-Nicolet, 5225 Verona
Road, Madison, WI 53711-4495) system fitted with a 785 nm laser source. The
sample was manually brought into focus using the microscope portion of the
apparatus with a 1Ox power objective (unless otherwise noted), thus directing
the laser
onto the surface of the sample. The spectrum was acquired using the
parameters,
outlined in Table A. (Exposure times and number of exposures may vary; changes
to
parameters will be indicated for each acquisition.)
Table A. Raman Spectral acquisition parameters
Parameter Setting Used
Exposure time (s) 2.0
Number of exposures 10
Laser source wavelength (nm) 785
Laser power (%) 100
Aperture shape pin hole
Aperture size (um) 100
Spectral range 104-3428
Grating position Single
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Temperature at acquisition (degrees C) 24.0
IR acquisitions
IR spectra were obtained using NexusTM 470 FT-IR, Thermo-Nicolet, 5225
Verona Road, Madison, WI 53711-4495 and were analyzed with Control and
Analysis software: OMNIC, Version 6.0a, (C) Thermo-Nicolet, 1995-2004.
Data for the co-crystals are shown in Table IV and in the Figures.
Example 1
Racemic Modafinil:Malonic acid Co-crystal
To a solution containing racemic modafinil (150 mg, 0.549 mmol) in acetic
acid (600 microliters) was added malonic acid (114.9 mg, 1.104 mmol). The
mixture
was then heated on a hotplate at 67 degrees C until all material dissolved.
The
solution was then dried under a flow of nitrogen to give a 1:1
modafinil:malonic acid
co-crystal as a, colorless solid. The solid material was characterized using
PXRD.
The material was then dried further under a flow of nitrogen overnight to give
the
same material with a slight excess of malonic acid. The colorless solid was
characterized using PXRD (Bruker), DSC, TGA, IR and Raman spectroscopy. PXRD
data for the modafinil:malonic acid (1:1) co-crystal are listed in Table IV,
and the
diffractogram is shown in Figure 1 (Data as collected/received). DSC showed an
endothermic transition at about 106 degrees C, and the thermogram is shown in
Figure 2. TGA thermogram is shown in Figure 3. Figures 4A and 4B show a Raman
spectrum of the modafinil:malonic acid co-crystal and three Raman spectra of
modafinil, malonic acid, and the co-crystal, respectively. Figures 5A and 5B
show an
IR spectrum of the modafinil:malonic acid co-crystal and three IR spectra of
modafinil, malonic acid, and the co-crystal, respectively. The
modafinil:malonic acid
co-crystal can be characterized by any one, any two, any three, any four, any
five, or
any six or more of the peaks in Figure 1 including, but not limited to, 5.00,
9.17,
10.08, 16.81, 18.26, 19.43, 21.36, 21.94, 22.77, 24.49, 25.63, 26.37, and
28.45
degrees 2-theta.
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The modafinil:malonic acid co-crystal was also prepared by grinding the API
and co-crystal former together. Racemic modafinil (2.50 g, 0.009 mol) and
malonic
acid (1.01 g, 0.0097 mmol) were mixed in a large mortar and pestle over a
period of
seven days (malonic acid added in increments over 7 days with about a 1:1.05
ratio
made on the first day and increments added over the next seven days which
resulted
in a 1:2 modafinil:malonic acid ratio). The mixture was ground for 45 minutes
initially and 20 minutes each time more malonic acid was added. On the seventh
day
the mixture of co-crystal and starting components was heated in a sealed 20 mL
vial
at 80 degrees C for about 35 minutes to facilitate completion of the co-
crystal
formation. PXRD analysis (Bruker) of the resultant material was completed, and
is
shown in Figure 6A (data as received). The modafinil:malonic acid co-crystal
can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 6A including, but not limited to, 5.08, 9.28, 16.81,
18.27, 19.45,
21.39, 21.99, 22.83, 23.50, 24.58, 25.12, and 28.49 degrees 2-theta. DSC
thermogram
for the co-crystal shows, in Figure 6B, an endothermic transition at about 116
degrees
C. Single crystal data of the modafinil:malonic acid co-crystal were acquired
and are
reported below. Figure 7 shows a packing diagram of the modafinil:malonic
acid.
Crystal data: C18H19NO6S, M = 377.40, monoclinic C2/c; a = 18.728(8)
angstroms, b = 5.480(2) angstroms, c = 33.894(13) angstroms, alpha = 90
degrees,
beta = 91.864(9) degrees, gamma = 90 degrees, T = 100(2) K, Z = 8, Dc = 1.442
Mg/m3, V = 3477(2) cubic angstroms, k = 0.71073 angstroms, 6475 reflections
measured, 3307 unique (Rini = 0.1567). Final residuals were R1= 0.1598, wR2 =
0.3301 for I>2sigma(I), and R1= 0.2544, wR2 = 0.3740 for all 3307 data.
Other methods were also used to prepare the modafinil:malonic acid co-
crystal. A third preparation was performed by placing modafinil (30 mg, 0.0001
mol)
and excess malonic acid in a stainless steel vial. 20 microliters of acetone
was added
to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt
Technologies,
115V/60Hz) and the solid mixture was milled for 5 minutes. The resultant
powder
was then collected and characterized using PXRD and DSC. In yet another
preparation of the modafinil:malonic acid co-crystal, the third preparation
above was
completed without the addition of solvent. All of the above methods with
malonic
acid were shown to yield the same co-crystal via PXRD and DSC analysis.
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Example 2
Racemic Modafinil:Glycolic acid Co-crystal
Racemic modafinil (1 mg, 0.0037mmol) and glycolic acid (0.30 mg, 0.0037
mmol) were dissolved in acetone (400 microliters). The solution was allowed to
evaporate to dryness and the resulting solid was characterized using PXRD
(Rigaku).
PXRD data for the modafinil:glycolic acid co-crystal are listed in Table IV.
See
Figures 8A and 8B. Figure 8A shows the PXRD diffractogram after subtraction of
background noise. Figure 8B shows the raw PXRD data as collected.
An alternative method for the preparation of modafinil:glycolic acid co-
crystals was also completed. To a solution of modafinil (1 mg, 0.0037 mmol)
dissolved in a mixture of acetone and methanol (3:1, 100 microliters) was
added
glycolic acid (0.28 mg, 0.0037 mmol) dissolved in methanol (50 microliters).
The
solvent was then evaporated to dryness under a flow of nitrogen to give a
mixture of
the two starting components. Acetone (200 microliters) was then added to the
mixture and it was heated to 70 degrees C and maintained at 70 degrees C for 2
hours.
The sample was then cooled to 5 degrees C and maintained at that temperature
for 1
day. After 1 day, the cap was removed from the vial and the solvent was
evaporated
to dryness to give a modafinil:glycolic acid co-crystal as a colorless solid.
The
modafinil:glycolic acid co-crystal was characterized by PXRD. The
modafinil:glycolic acid co-crystal can be characterized by any one, any two,
any
three, any four, any five, or any six or more of the peaks in Figure 8A
including, 'but
not limited to, 9.51, 14.91, 15.97, 19.01, 20.03, 21.59, 22.75, 25.03, and
25.71
degrees 2-theta. The modafinil:glycolic acid co-crystal can, likewise, be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 8B including, but not limited to, 9.53, 14.93, 15.99,
19.05, 20.05,
21.61, 22.77, and 25.05 degrees 2-theta.
Example 3
Racemic Modafinil:Maleic acid Co-crystal
To a solution containing modafinil (150 mg, 0.549mmol) in acetic acid (600
microliters) was added maleic acid (30.7 mg, 0.264mmol). The mixture was then
heated on a hotplate at 67 degrees C until all material dissolved. The
solution was
then dried under a flow of nitrogen to give a clear amorphous material. The
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amorphous material was stored in a sealed vial at room temperature. After 2
days, a
solid material began to form and and was collected and characterized to be a
modafinil:maleic acid co-crystal using PXRD (Rigaku), as shown in Figures 9A
and
9B. Figure 9A shows the PXRD diffractogram after subtraction of background
noise.
Figure 9B shows the raw PXRD data. PXRD data for the modafmil:maleic acid co-
crystal are listed in Table IV. The modafinil:maleic acid co-crystal can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 9A including, but not limited to, 4.69, 6.15, 9.61, 10.23,
15.65,
16.53, 17.19, 18.01, 19.97, 21.83, and 22.45 degrees 2-theta. The
modafinil:maleic
acid co-crystal can, likewise, be characterized by any one, any two, any
three, any
four, any five, or any six or more of the peaks in Figure 9B including, but
not limited
to, 4.69, 6.17, 9.63, 10.25, 15.67, 16.53, 17.21, 18.05, 19.99, 21.85, and
22.47 degrees
2-theta.
Example 4
Racemic Modafinil:L-tartaric acid Co-crystal
To a solution of racemic modafinil (10.12 mg, 0.037 mmol) in methanol (2
mL) was added L-tartaric acid (5.83 mg, 0.039 mmol). The solution was then
left to
evaporate at room temperature to give a clear, viscous material. The material
was
dried further under flowing nitrogen for 2 days, and then placed in a vial and
capped.
After 6 days, a small amount of colorless solid formed. One day after the
first solids
are seen approximately 60 % of the remaining clear amorphous volume converted
to
the solid form. A sample of this material was analyzed by PXRD (Bruker), as
shown
in Figure 10. The modafinil:L-tartaric acid co-crystal can be characterized by
any
one, any two, any three, any four, any five, or any six or more of the peaks
in Figure
including, but not limited to, 6.10, 7.36, 9.38, 14.33, 16.93, 17.98, 18.81,
20.15,
20.71, 22.49, and 25.04 degrees 2-theta.
Example 5
Racemic Modafinil:Citric acid Co-crystal
Racemic modafinil (25.3 mg, 93 mmol) and citric acid monohydrate (26.8 mg,
128 mmol) were ground together for 3 minutes. 1 mg of the resulting mixture
was
then dissolved in acetone (100 microliters) and heated to 70 degrees C and
maintained
at that temperature for 2 hours. The solution was then cooled to 5 degrees C
and was
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left at that temperature for 2 days. After 2 days the cap was removed from the
vial
and one drop of water was added. The solvent was then evaporated to give a
modafinil:citric acid monohydrate co-crystal as a colorless solid. The
modafinil:citric
acid monohydrate co-crystal was characterized by PXRD (Rigaku), as shown in
Figure 11A (background subtracted). The modafinil:citric acid co-crystal can
be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 11A including, but not limited to, 5.29, 7.29, 9.31,
12.41, 13.29,
17.29, 17.97, 18.79, 21.37, and 23.01 degrees 2-theta.
Other methods were also used to prepare the modafinil:citric acid
monohydrate co-crystal. A second preparation was performed by placing
modafinil
(30 mg, 0.0001 mol) and excess citric acid monohydrate in a stainless steel
vial. 20
microliters of acetone was added to the vial. The vial was then placed in a
grinder
(wig-l-bug, Bratt Technologies, 115V/6OHz) and the solid mixture was milled
for 5
minutes. The resultant powder was then collected and characterized using PXRD
and
DSC. The DSC thermogram is shown in Figure 11B. In yet another preparation of
the modafinil:citric acid monohydrate co-crystal, the second preparation above
was
completed without the addition of solvent. All of the above methods with
citric acid
monohydrate were shown to yield the same co-crystal via PXRD and DSC analysis.
Example 6
Racemic Modafinil:Succinic acid Co-crystal
Racemic modafinil (25mg, 90 mmol) and succinic acid (10.6 mg, 90 mmol)
were placed in a glass vial and dissolved in methanol (20 microliters). The
resulting
solution was heated at 70 degrees C for 2 hours and then cooled to 5 degrees C
and
maintained at that temperature for 2 days. After 2 days, the cap was removed
from
the vial and the solvent was evaporated at 65 degrees C to give a 2:1
modafinil:succinic acid co-crystal as a colorless solid. The co-crystal is a
2:1 co-
crystal comprising two moles of modafinil for every mole of succinic acid. The
modafinil:succinic acid co-crystal was characterized by PXRD (Rigaku) and DSC,
as
shown in Figures 12A, 12B, and 13. Figure 12A shows the PXRD diffractogram
after
subtraction of background noise. Figure 12B shows the raw PXRD data. Figure 13
shows the DSC thermogram.
An alternative method for the preparation of modafinil:succinic acid co-
crystals was also completed. To racemic modafinil (49.7 mg, 0.182 mmol) and
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succinic acid (21.6 mg, 0.182 mmol) in a round bottom flask was added methanol
(1.5
mL). The mixture was then dissolved on a hotplate at 65 degress C. Seed
crystals of
modafinil:succinic acid co-crystal from the above preparation were then added
to the
flask. The methanol was then evaporated using a rotary evaporator and a 65
degrees C
hot water bath to give the modafinil:succinic acid co-crystal as a colorless
solid.
PXRD (Rigaku) of the collected solid confirms the synthesis of the
modafinil:succinic
acid co-crystal. The modafinil:succinic acid co-crystal can be characterized
by any
one, any two, any three, any four, any five, or any six or more of the peaks
in Figure
12A including, but not limited to, 5.45, 9.93, 15.85, 17.97, 18.73, 19.95,
21.33, 21.93,
23.01, and 25.11 degrees 2-theta. The modafinil:succinic acid co-crystal can,
likewise, be characterized by any one, any two, any three, any four, any five,
or any
six or more of the peaks in Figure 12B including, but not limited to, 5.45,
9.93, 15.87,
17.99, 18.75, 19.95, 21.95, 23.03, and 25.07 degrees 2-theta. Single crystal
data of
the modafinil:succinic acid co-crystal were acquired and are reported below.
Figure
14 shows a packing diagram of the modafinil:succinic acid co-crystal.
Crystal data: C17H18NO4S, triclinic P-1; a = 5.672(4) angstroms, b = 8.719(6)
angstroms, c = 16.191(11) angstroms, alpha = 93.807(14) degrees, beta =
96.471(17)
degrees, gamma = 92.513(13) degrees, T = 100(2) K, Z = 2, Dc = 1.392 Mg/m3, V
=
792.8(9) cubic angstroms, 2 = 0.71073 angstroms, 2448 reflections measured,
1961
unique (R11 t = 0.0740). Final residuals were R1 = 0.1008, wR2 = 0.2283 for
I>2sigma(I), and R1= 0.1593, wR2 = 0.2614 for all 1961 data.
A third method was also used to prepare the modafinil:succinic acid co-
crystal. This method was performed by placing modafinil (30 mg, 0.0001 mol)
and
excess succinic acid in a stainless steel vial. 20 microliters of acetone was
added to
the vial. The vial was then placed in a grinder (wig-l-bug, Bratt
Technologies,
11 5V/6OHz) and the solid mixture was milled for 5 minutes. The resultant
powder
was then collected and characterized using PXRD and DSC. All of the above
methods with succinic acid were shown to yield the same co-crystal via PXRD
and
DSC analysis.
Example 7
Racemic Modafinil:DL-tartaric acid Co-crystal
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A suspsension of racemic modafinil (162 mg; 0.591 mmol) and ILL-tartaric
acid (462 mg; 3.08 mmol) in acetone (10 mL) was heated to reflux for 1 minute.
The
undissolved DL-tartaric acid was filtered off while the suspension was still
hot
through a 0.2 micrometer PTFE filter. The remaining solution was allowed to
cool to
room temperature then to 0 degrees C for 1 hour. After 1 hour, large colorless
crystals were observed. The mother liquor was decanted and the solid was
allowed to
air dry and was characterized by PXRD (Rigaku), as shown in Figure 15. The
modafinil:DL-tartaric acid co-crystal can be characterized by any one, any
two, any
three, any four, any five, or any six or more of the peaks in Figure 15
including, but
not limited to, 4.75, 9.53, 10.07, 15.83, 17.61, 19.37, 20.25, 21.53, 22.55,
and 23.75
degrees 2-theta (as collected).
Example 8
Racemic Modafinil:Fumaric acid Co-crystal (Form I)
Racemic modafinil (30 mg, 0.0001 mol) and fumaric acid (2.3 mg, 0.0002
mol) were placed in a stainless steel vial. 20 microliters of acetone was
added to the
vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies,
115V/60Hz) and the solid mixture was milled for 5 minutes. The resultant
powder
was then collected and characterized as modafinil:fumaric acid co-crystal
(Form I)
using PXRD (Rigaku), as shown in Figure 16. The co-crystal is a 2:1 co-crystal
comprising two moles of modafinil for every mole of fumaric acid. The
modafinil:fumaric acid co-crystal (Form I) can be characterized by any one,
any two,
any three, any four, any five, or any six or more of the peaks in Figure 16
including,
but not limited to, 5.45, 9.95, 10.91, 15.93, 18.03, 18.81, 19.93, 20.25,
21.37, 21.95,
23.09, and 25.01 degrees 2-theta (as collected). Single crystal data of the
modafinil:fumaric acid co-crystal (Form I) were acquired and are reported
below.
Figure 17 shows a packing diagram of the modafinil:fumaric acid co-crystal
(Form I).
Crystal data: C17H17N04S, M = 331.38, triclinic P-1; a = 5.7000(15)
angstroms, b = 8.735(2) angstroms, c = 16.204(4) angstroms, alpha = 93.972(6)
degrees, beta = 97.024(6) degrees, gamma = 93.119(7) degrees, T = 100(2) K, Z
= 2,
Dc = 1.381 Mg/m3, V = 797.2(4) cubic angstroms, X = 0.71073 angstroms, 4047
reflections measured, 2615 unique (Rini = 0.0475). Final residuals were R1=
0.0784,
wR2 = 0.1584 for I>2sigma(I), and R1= 0.1154, wR2 = 0.1821 for all 2615 data.
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Example 9
Racemic Modafinil:Fumaric acid Co-crystal (Form II)
Racemic modafinil (30 mg, 0.0001 mol) and fumaric acid (1.2 mg, 0.0001
mol) were placed in a stainless steel vial. 20 microliters of acetone was
added to the
vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies,
115V/6OHz) and the solid mixture was milled for 5 minutes. The resultant
powder
was then collected and characterized as modafinil:fumaric acid co-crystal
(Form II)
using PXRD (Rigaku), as shown in Figure 18. The modafinil:fumaric acid co-
crystal
(Form II) can be characterized by any one, any two, any three, any four, any
five, or
any six or more of the peaks in Figure 18 including, but not limited to, 6.47,
8.57,
9.99, 13.89, 14.53, 16.45, 17.13, 17.51, 18.39, 20.05, 20.79, 25.93, and 27.95
degrees
2-theta (as collected).
Example 10
Racemic Modafinil:Gentisic acid Co-crystal
Racemic modafinil (30 mg, 0.0001 mol) and gentisic acid (1.5 mg, 0.0001
mol) were placed in a stainless steel vial. 20 microliters of acetone was
added to the
vial. The vial was then placed in a grinder (wig-l-bug, Bratt Technologies,
115V/60Hz) and the solid mixture was milled for 5 minutes. The resultant
powder
was then collected and characterized using PXRD (Bruker), as shown in Figure
19.
The modafinil:gentisic acid co-crystal can be characterized by any one, any
two, any
three, any four, any five, or any six or more of the peaks in Figure 19
including, but
not limited to, 6.96, 12.92, 14.76, 17.40, 18.26, 20.10, 20.94, 23.46, and
24.36
degrees 2-theta (as collected).
Example 11
Racemic Modafinil:Oxalic acid Co-crystal
A preparation of modafinil:oxalic acid co-crystal was performed by placing
racemic modafinil (30 mg, 0.0001 mol) and oxalic acid (1-2 mg, 0.0001-0.0002
mol)
in a stainless steel vial. 20 microliters of acetone was added to the vial.
The vial was
then placed in a grinder (wig-l-bug, Bratt Technologies, 115V/60Hz) and the
solid
mixture was milled for 5 minutes. The resultant powder was then collected and
characterized using PXRD (Bruker), as shown in Figure 20. In another
preparation of
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the modafinil:oxalic acid co-crystal, the preparation above was completed
without the
addition of solvent. Both methods were shown to yield the same co-crystal via
PXRD
analysis. The modafinil:oxalic acid co-crystal can be characterized by any
one, any
two, any three, any four, any five, or any six or more of the peaks in Figure
20
including, but not limited to, 5.98, 13.68, 14.80, 17.54, 19.68, 21.12, 21.86,
and 28.90
degrees 2-theta (as collected).
Example 12
Racemic Modafinil:1-hydroxy2-naphthoic acid Co-crystal
Racemic modafinil (30 mg, 0.0001 mol) and 1-hydroxy-2-naphthoic acid (21
mg, 0.0001 mol) were placed in a stainless steel vial. 20 microliters of
acetone was
added to the vial. The vial was then placed in a grinder (wig-l-bug, Bratt
Technologies, 115V/60Hz) and the solid mixture was milled for 5 minutes. The
resultant powder was then collected and characterized using PXRD (Bruker), as
shown in Figure 21. The modafinil:l-hydroxy-2-naphthoic acid co-crystal can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 21 including, but not limited to, 5.72, 7.10, 11.48,
14.16, 15.66,
17.92, 19.18, 20.26, 21.28, 21.94, 24.38, and 26.86 degrees 2-theta (as
collected).
PXRD peaks at 10.05 and 26.36 degrees 2-theta may be from excess co-crystal
former.
Example 13
R-(-)-Modafinil:Malonic acid Co-crystal
R-(-)-modafinil:malonic acid co-crystal was prepared by grinding R-(-)-
modafinil (29.7 mg, 0.109 mmol, 82.2 percent R-isomer) with malonic acid (11.9
mg,
0.114 mmol). The ground mixture was then heated to 80 degrees C for 10
minutes.
The powder was analyzed by PXRD (Bruker) and DSC, as shown in Figures 22 and
23, respectively. The PXRD pattern confirms that the co-crystal was made and
shows
many similarities to the PXRD pattern for the racemic modafinil:malonic acid
co-
crystal. The R-(-)-modafinil:malonic acid co-crystal can be characterized by
any one,
any two, any three, any four, any five, or any six or more of the peaks in
Figure 22
including, but not limited to, 5.04, 9.26, 16.73, 18.23, 19.37, 21.90, 22.74,
24.44, and
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25.67 degrees 2-theta (data as collected). The DSC showed a melting range of
111.5 -
114.7 degrees C with a heat of fusion of 112.9 J/g.
Example 14
R-(;)-Modafinil:Succinic acid Co-crystal
R-(-)-modafinil:succinic acid co-crystal was prepared by grinding R-(-)-
modafinil (30.9 mg, 0.113 mmol, 82.2 percent R-isomer) with succinic acid
(14.8 mg,
0.125 mmol). The ground mixture was then heated to 145 degrees C for 5
minutes.
The powder was analyzed by PXRD (Bruker) and DSC, as shown in Figures 24 and
25, respectively. The PXRD pattern confirms that the co-crystal was made and
shows
many similarities to the PXRD pattern for the racemic modafinil:succinic acid
co-
crystal made from solution. The R-(-)-modafinil:succinic acid co-crystal can
be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 24 including, but not limited to, 5.36, 9.83, 15.80,
17.88, 18.70,
19.87, 21.21, 21.85, and 25.96 degrees 2-theta (data as collected). The DSC
showed a
melting range of 143.3 - 145.2 degrees C with a heat of fusion of 140.7 J/g.
Example 15
R-(-)-Modafinil:Citric acid Co-crystal
R-(-)-modafmil:citric acid co-crystal was prepared by grinding R-(-)-modafinil
(30.0 mg, 0.110 mmol, 82.2 percent R-isomer) with citric acid monohydrate
(27.1 mg,
0.129 mmol). The powder was analyzed by PXRD (Broker) and DSC, as shown in
Figures 26 and 27, respectively. The PXRD pattern confirms that the co-crystal
was
made and shows many similarities to the PXRD pattern for the racemic
modafinil:citric acid co-crystal. The R-(-)-modafinil:citric acid co-crystal
can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 26 including, but not limited to, 5.18, 7.23, 9.23, 12.32,
13.23,
17.25, 17.92, 18.76, 20.25, 21.30, and 23.71 degrees 2-theta (data as
collected). The
DSC showed a melting range of 83.5 - 89.0 degrees C with a heat of fusion of
39.8
J/9-
Example 16
R-(-)-Modafinil:DL-tartaric acid Co-crystal
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The R-(-)-modafinil:DL-tartaric acid co-crystal was found from a high
throughput crystallization experiment from dichloromethane. The vial contained
a
1:2 mixture of R-(-)-modafinil (greater than 98 percent R-isomer) and DL-
tartaric
acid. The co-crystal was also found from a 1:1 mixture of R-(-)-modafinil
(greater
than 98 percent R-isomer) and DL-tartaric acid in nitromethane. The solid
materials
were collected and characterized using PXRD (Bruker) and DSC, as shown in
Figures
28 and 29, respectively. The R-(-)-modafinil:DL-tartaric acid co-crystal can
be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 28 including, but not limited to, 4.67, 15.41, 17.97,
19.46, 20.50,
22.91, and 24.63 degrees 2-theta (as collected). Endothermic transitions were
present
at about 107, 152, and 187 degrees C.
Example 17
R-(-)-Modafinil:l-hydroxy-2-naphthoic acid Co-crystal
To a solid mixture of R-(-)-modafinil (98.6 mg; 0.361 mmol, greater than 98
percent R-isomer) and 1-hydroxy-2-naphthoic acid (71.2 mg; 0.378 mmol) was
added
o-xylene (4.5 mL). The mixture was heated to reflux for less than one minute
at
which point both solids dissolved. The solution was then slowly cooled to room
temperature at which point a solid crystallized. The solid was collected via
filtration
and air-dried. The powder was characterized using PXRD (Bruker), as shown in
Figure 30. The same material has been prepared from benzene, toluene, and
acetone
using the above procedure. The R-(-)-modafinil:1-hydroxy-2-naphthoic acid co-
crystal can be characterized by any one, any two, any three, any four, any
five, or any
six or more of the peaks in Figure 30 including, but not limited to, 5.27,
8.85, 10.60,
12.11, 14.47, 17.80, 18.80, 21.20, 23.03, and 25.61 degrees 2-theta (as
collected).
The R-(-)-modafinil:1-hydroxy-2-naphthoic co-crystal was also obtained from
a high throughput crystallization experiment from a vial containing a 1:1
mixture of
R-(-)-modafinil (greater than 98 percent R-isomer) and 1-hydroxy-2-naphthoic
acid in
nitromethane. The solid material was collected and characterized using DSC and
PXRD (Bruker), as shown in Figures 31 and 32, respectively. The R-(-)-
modafinil:l-
hydroxy-2-naphthoic acid co-crystal can be characterized by any one, any two,
any
three, any four, any five, or any six or more of the peaks in Figure 32
including, but
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not limited to 5.34, 8.99, 10.68, 12.15, 14.51, 21.28, 23.14, and 24.50
degrees 2-theta
(as collected). DSC shows endothermic transitions at about 118 and 179 degrees
C.
Example 18
R-(- -Modafinil:Orotic acid Co-crystal
The R-(-)-modafinil:orotic acid co-crystal was obtained from a high
throughput crystallization experiment from a vial containing R-(-)-modafinil
(1 mg,
0.0036 mmol, greater than 98 percent R-isomer) and orotic acid (1.14 mg,
0.0073
mmol) in acetone (100 microliters). The solid material obtained was
characterized
using PXRD (Broker) and DSC, as shown in Figures 33 and 34, respectively. The
R-
(-)-modafinil:orotic acid co-crystal can be characterized by any one, any two,
any
three, any four, any five, or any six or more of the peaks in Figure 33
including, but
not limited to, 9.77, 17.85, 20.52, 20.95, 24.03, and 26.80 degrees 2-theta
(as
collected). PXRD peaks at 14.61 and 28.60 may correspond to excess co-crystal
former. Endothermic transitions were present at about 116, 130, and 169
degrees C.
Table IV: Co-crystals of Modafinil
6-Crystal former Representative PXRD Peaks (degrees 2-theta)
Malonic acid 5.00, 9.17, 10.08, 16.81, 18.26, 19.43, 21.36, 21.94, 22.77,
24.49, 25.63,
26.37, 28.45
Glycolic acid 9.53, 14.93, 15.99, 19.05, 20.05, 21.61, 22.77, 25.05
Maleic acid 4.69, 617, 9.63, 10.25, 15.67, 16.53, 17.21, 18.05, 19.99, 21.85,
22.47
L-tartaric acid 6.10, 7.36, 9.38, 14.33, 16.93, 17.98, i9:81,20.15, 20.71
22.49, 25.04
Citric acid 5.29, 7.29, 9.31, 12.41, 1329,1729 , 17.97, 18.79, 21.37, 23.01
Succinic acid 5.45, 9.93, 15.87, 17.99, 18.75, 19.95, 21.95, 23.03, 25.07
DL-tartaric acid 4.75, 9.53, 10.07, 15.83, 17.61, 19.37, 20.25, 2133,
22.55,2j.75
Fumaric acid (Form I) 5.45, 9.95, 10.91, 15.93, 18.03, 18.81, 19.93, 20.25,
21.37, 21.95, 23.09,
25.01
Fumaric acid (Form II) 6.47, 8.57, 9.99, 13.89, 14.53, 16.45, 17.13, 17.51,
18.39, 20.05, 20.79,
25.93, 27.95
Gentisic acid 6.96, 12.92, 14.76, 17.40, 18.26, 20.10, 20.94, 23.46, 24.36
Oxalic acid 5.98, 13.68, 14.80, 17.54, 19.68, 21.12, 21.86, 28.90
1-hydroxy-2-naphthoic 5.72, 7.10, 11.48, 14.16, 15.66, 17.92, 19.18, 20.26,
21.28, 21.94, 24.38,
acid 26.86
*Malonic acid 5.04, 9.26, 16.73, 18.23, 19.37, 21.90, 22.74, 24.44, 25.67
*Succinic acid 5.36, 9.83, 15.80, 17.88, 18.70, 19.87, 21.21, 21.85, 25.96
*Citric acid 5.18, 7.23, 9.23, 12.32, 13.23, 17.25, 17.92, 18.76, 20.25,
21.30, 23.71
**DL-tartaric acid 4.67, 15.41, 17.97, 19.46, 20.50, 22.91, 24.63
** 1-hydroxy-2- 5.27, 8.88, 10.60, 12.11, 14.47, 17.80, 18.80, 21.20, 23.03,
25.61
naphthoic acid
**Orotic acid 9.77, 17.85, 20.52, 20.95, 24.03, 26.80
**Gentisic acid 7.07, 7.51, 9.07, 12.31, 16.03, 17.63, 18.39, 19.83, 21.27,
23.57, 26.93, 28.85
* = API is R-(-)-modafinil with 82.2 percent (purity) R-(-)-modafinil (17.8
percent S-(+)-modafinil)
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** = API is R-(-)-modafinil with greater than 98 percent (purity) R-(-)-
modafinil (less than 2 percent S-
(+)-modafinil
All other co-crystals comprise racemic modafinil
Example 19
Acetic acid Solvate of Racemic Modafinil
To racemic modafinil (12.9 mg, 0.047 mmol) was added acetic acid (40
microliters). The mixture was heated at 50 degrees C to completely dissolve
the solid.
The solution was allowed to cool to room temperature, and left overnight,
which
yielded no precipitation. The solution was then evaporated under flowing
nitrogen
until precipitation was observed. The resulting solid was further dried under
flowing
nitrogen. Characterization of the product has been achieved via PXRD (Rigaku),
TGA, DSC, and Raman spectroscopy, as shown in Figures 35-38, respectively. An
alternative method for the preparation of the acetic acid solvate of modafinil
was also
completed. A sample of modafinil acetic acid solvate was prepared by
dissolving
racemic modafinil (12.9 mg, 0.047 mmol) in acetic acid (40 microliters) and
incubating at 65 degrees C for 30 minutes to dissolve, then cooling to 25
degrees C to
incubate overnight. The sample was then evaporated to approximately 1/3
volume.
After centrifugation of the sample, rapid nucleation and growth of crystals
was
observed. An additional 20 microliters of acetic acid was then added. The
sample
was heated at 50 degrees C until partial dissolution of the crystals was
observed. The
sample was then cooled to room temperature over a 1 hour period, then to 5
degrees C
for 3 hours in an attempt to induce crystal growth. The sample was then dried
under
nitrogen gas. Rapid appearance of crystals was observed. The modafinil acetic
acid
solvate can be characterized by any one, any two, any three, any four, any
five, or any
six or more of the peaks in Figure 35 including, but not limited to, 6.17,
9.63, 15.69,
17.97, 19.99, and 21.83 degrees 2-theta (data as collected).
Example 20
Tetrahydrofuran Solvate of Racemic Modafinil
The tetrahydrofuran (THF) solvate of modafinil was prepared by placing
racemic modafinil (10.4 mg, 0.038 mmol) in tetrahydrofuran (1 mL). The powder
did
not completely dissolve in THE and converted overnight into long, fine, needle
shaped crystals which were collected and analyzed by PXRD (Rigaku), as shown
in
Figure 39. The modafinil tetrahydrofuran solvate can be characterized by any
one,
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any two, any three, any four, any five, or any six or more of the peaks in
Figure 39
including, but not limited to, 6.97, 9.79, 10.97, 16.19, 19.03, 19.71, 20.59,
22.25, and
25.13 degrees 2-theta (data as collected).
Example 21
1,4-Dioxane Solvate of Racemic Modafinil
To racemic modafinil (11.6 mg, 0.042 mmol) was added 1,4-dioxane (1 mL).
The mixture was then left overnight and converted to long, fine, needle shaped
crystals which were collected and analyzed by PXRD (Rigaku), as shown in
Figure
40. The modafinil 1,4-dioxane solvate can be characterized by any one, any
two, any
three, any four, any five, or any six or more of the peaks in Figure 40
including, but
not limited to, 6.93, 9.85, 10.97, 16.19, 18.97, 19.61, 20.33, 20.65, and
22.07 degrees
2-theta (data as collected). PXRD pattern also contains several spikes which
were a
result of instrument error and could not be removed.
Example 22
Methanol Solvate of Racemic Modafinil
The methanol solvate of modafinil is obtained by evaporating 2 mL of a 30
mg/mL racemic modafinil solution in methanol under flowing nitrogen overnight.
The methanol solvate was characterized by PXRD (Rigaku), TGA, and DSC, as
shown in Figures 41, 42, and 43, respectively. The modafinil methanol solvate
can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 41 including, but not limited to, 6.15, 9.89, 12.25,
15.69, 17.97,
20.07, 21.85, and 22.73 degrees 2-theta (data as collected).
Example 23
Nitromethane Solvate of Racemic Modafinil
To racemic modafinil (12.9 mg, 0.047 mmol) was added nitromethane (1 mL).
The mixture which did not fully dissolve was left overnight and converted to
large
rectangular crystals. The solid was collected and analyzed by PXRD (Rigaku),
as
shown in Figure 44. The modafinil nitromethane solvate can be characterized by
any
one, any two, any three, any four, any five, or any six or more of the peaks
in Figure
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44 including, but not limited to, 6.17, 9.77, 15.89, 18.11, 20.07, 22.17,
22.91, 25.31,
and 25.83 degrees 2-theta (data as collected).
Example 24
Acetone Solvate of Racemic Modafinil
A solution containing racemic modafinil (300 mg, 0.001 mol) and glutaric
acid (150 mg, 0.001 mol) in acetone (3 mL) was heated until it was boiling in
order to
dissolve all solid material. Once the solids dissolved, the solution was
placed on an
aluminum block at 5 degrees C. After 15 minutes of sitting at 5 degrees C,
crystals
began to form at the bottom of the vial. The solution was then decanted and
the single
crystals were collected and analyzed using PXRD (Rigaku), as shown in Figure
45.
The crystals were determined to be an acetone solvate of modafinil. The
acetone
solvate of modafinil can be characterized by any one, any two, any three, any
four,
any five, or any six or more of the peaks in Figure 45 including, but not
limited to,
6.11, 9.53, 15.81, 18.11, 20.03, 21.63, 22.45, 25.23, 25.65, 28.85, 30.23, and
32.93
degrees 2-theta (as collected). The acetone solvate may also be obtained
following
the procedure above with several other co-crystal formers including adipic
acid,
lactobionic acid, maleic acid, and glycolic acid.
Example 25
Racemic modafinil (1 mg, 0.0037mmol) and mandelic acid (0.55 mg, 0.0037
mmol) were dissolved in acetone (400 microliters). The solution was allowed to
evaporate to dryness and the resulting solid was characterized using PXRD
(Rigaku),
as shown in Figure 46. The obtained solid is a mixture of the acetone solvate
and
another product of modafinil. The form can be characterized by any one, any
two,
any three, any four, any five, or any six or more of the peaks in Figure 46
including,
but not limited to, 6.11, 9.53, 15.77, 18.03, 20.01, and 21.61 degrees 2-theta
(background removed). Other peaks including 6.75, 10.31, 14.77, and 23.27 may
correspond to a modafinil polymorph.
Example 26
Racemic modafinil (1 mg, 0.0037mmol) and fumaric acid (0.42 mg, 0.0037
mmol) were dissolved in 1,2-dichloroethane (400 microliters). The solution was
allowed to evaporate to dryness and the resulting solid was characterized
using PXRD
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(Rigaku), as shown in Figure 47. The obtained solid may be a solvate of
modafinil.
The form can be characterized by any one, any two, any three, any four, any
five, or
any six or more of the peaks in Figure 47 including, but not limited to, 5.87,
8.95,
12.49, 13.99, 18.19, 19.99, 21.57, and 25.01 degrees 2-theta (background
removed).
Example 27
Novel form of Racemic Modafinil
Racemic modafinil was dispensed from a stock solution containing 50 mg of
modafinil in 20 mL of a 15:5 acetone/methanol mixture. The solution was then
evaporated to dryness under a flow of nitrogen. Benzoic acid was dispensed
from an
acetone solution and the mixture was again evaporated to dryness. 200
microliters of
isopropyl alcohol or methanol was then added and the vials were capped. After
standing at room temperature for one day, the caps were removed and the
solvent was
allowed to evaporate. PXRD (Rigaku) was carried out on the sample, as shown in
Figure 48. The novel form of racemic modafinil, which may be a polymorph or a
co-
crystal, is denoted as form VII. Form VII can be characterized by any one, any
two,
any three, any four, any five, or any six or more of the peaks in Figure 48
including,
but not limited to, 5.47, 9.99, 15.73, 17.85, 18.77, 20.05, 21.23, 22.05,
23.15, and
25.13 degrees 2-theta (data as collected).
Example 28
Racemic Modafinil:Malonic acid Co-Crystal Pharmacokinetic Study in Dogs
The racemic modafinil:malonic acid co-crystal (from Example 1) was
administered to dogs in a pharmacokinetic study. Particles of
modafinil:malonic acid
co-crystal with a median particle size of about 16 micrometers were
administered in
the study. As a reference, micronized modafinil with a median particle size of
about 2
micrometers was also administered in the study. The AUC of the
modafinil:malonic
acid co-crystal was determined to be 40 to 60 percent higher than that of the
pure
modafinil. Such a higher bioavailability illustrates the modulation of an
important
pharmacokinetic parameter due to an embodiment of the present invention. A
compilation of important pharmacokinetic parameters measured during the animal
study are included in Table V.
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Table V- Pharmacokinetic parameters of modafinil:malonic acid co-crystal and
pure modafinil in dogs
Parameter Pure Modafinil Modafmil:malonic acid co-crystal
Median particle size 2 micrometers 16 micrometers
Cm. (ng/mL) 11.0 5.9 10.3 3.4
Tmax (hours) 1.3 0.6 1.7 0.6
AUC (relative) 1.0 1.4-1.6
Half-life (hours) 2.1 '0.7 5.1 2.4
Example 29
Racemic Modafinil:Malonic acid Co-crystal Solid-State Stability
The stability of the racemic modafinil:malonic acid co-crystal was measured
at various temperatures and relative humidities over a four week period. No
degradation was found to occur at 20 or 40 degrees C. At 60 degrees C, about
0.14
percent degradation per day was determined based on a simple exponential
model. At
80 degrees C, about 8 percent degradation per day was determined.
The stability of the modafinil:malonic acid co-crystal was also measured at
various temperatures and relative humidities over a 26 week period. Figures 49
and
50 show the % area impurities as measured via HPLC versus time (weeks) for
samples stored at various conditions including: 25 degrees C, 60 % RH; 40
degrees C,
75 percent RH; 40 degrees C, ambient RH; 60 degrees C, ambient RH; 80 degrees
C,
ambient RH; and -20 degrees C. These data show that the compound is stable
when
stored at or below 40 degrees C for at least 26 weeks. Figure 51 compares PXRD
patterns of initial and 26 week old samples of the modafinil:malonic acid co-
crystal
for several temperatures and RH levels.
Example 30
Formulation of Racemic Modafinil:Malonic Acid Co-crystal
The formulation of a racemic modafinil:malonic acid co-crystal was completed
using lactose. Two mixtures, one of modafinil and lactose, and the second of
modafinil:malonic acid co-crystal and lactose, were ground together in a
mortar an
pestle. The mixtures targeted a 1:1 weight ratio of modafinil to lactose. In
the
modafinil and lactose mixture, 901.2 mg of modafinil and 901.6 mg of lactose
were
ground together. In the modafinil:malonic acid co-crystal and lactose mixture,
1221.6
mg of co-crystal and 871.4 mg of lactose were ground together. The resulting
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powders were analyzed by PXRD and DSC. The PXRD patterns and DSC
thermograms of the mixtures showed virtually no change upon comparison with
both
individual components. The DSC of the co-crystal mixture showed only the co-
crystal melting peak at 113.6 degrees C with a heat of fusion of 75.9 J/g.
This heat of
fusion is 59.5 % of that found for the co-crystal alone (127.5 J/g). This
result is
consistent with a 58.4 % weight ratio of co-crystal in the mixture. The DSC of
the
modafinil and lactose mixture had a melting point of 165.7 degrees C. This is
slightly
lower then the measured melting point of modafinil (168.7 degrees Q. The heat
of
fusion of the mixture (59.3 J/g) is 46.9 % that of the modafinil alone (126.6
J/g),
which is consistent with the estimated value of 50 %.
The in vitro dissolution of both the modafinil:malonic acid co-crystal and
pure
modafinil were tested in capsules. Both gelatin and hydroxypropylmethyl
cellulose
(HPMC) capsules were used in the dissolution study. The capsules were
formulated
with and without lactose. All formulations were ground in a mortar and pestle
prior to
transfer into a capsule. The dissolution of the capsules was tested in 0.01 M
HCl (See
Figure 52).
In 0.OINHCI, using sieved and ground materials in gelatin capsules:
Modafinil and the modafinil:malonic acid co-crystal were passed through a 38
micrometer sieve. Gelatin capsules (Size 0, B&B Pharmaceuticals, Lot # 15-
01202)
were filled with 200.0 mg sieved modafinil, 280.4 mg sieved modafinil:malonic
acid
co-crystal, 200.2 mg ground modafinil, or 280.3 mg ground modafinil:malonic
acid
co-crystal. Dissolution studies were performed in a Vankel VK 7000 Benchsaver
Dissolution Testing Apparatus with the VK750D heater/circulator set at 37
degrees C.
At 0 minutes, the capsules were dropped into vessels containing 900 mL 0.01 M
HCl
and stirred by paddles.
Absorbance readings were taken using a Cary 50 Spectrophotometer
(wavelength set at 260nm) at the following time points: 0, 5, 10, 15, 20, 25,
30, 40,
50, and 60 minutes. The absorbance values were compared to those of standards
and
the modafinil concentrations of the solutions were calculated.
In 0.OI N HCI, using ground materials in gelatin or HPMC capsules, with and
without
lactose:
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Modafinil and the modafinil:malonic acid co-crystal were mixed with equivalent
amounts of lactose (Spectrum, Lot QV0460) for approximately 5 minutes. Gelatin
capsules (Size 0, B&B Pharmaceuticals, Lot # 15-01202) were filled with 400.2
mg
modafinil and lactose (approximately 200 mg modafinil), or 561.0 mg
modafinil:malonic acid co-crystal and lactose (approximately 200 mg
modafinil).
HPMC capsules (Size 0, Shionogi, Lot # A312A6) were filled with 399.9 mg
modafinil and lactose, 560.9 mg modafinil:malonic acid co-crystal and lactose,
199.9
mg modafinil, or 280.5 mg modafinil:malonic acid co-crystal. The dissolution
study
was carried out as described above.
Example 31
In Vitro Dissolution
Figure 53 shows in vitro dissolution data of micronized racemic
modafinil:malonic acid co-crystal and of micronized modafinil in simulated
gastric
fluid (SGF) and in simulated intestinal fluid (SIF). Both samples were blended
with
lactose and filled into HPMC capsules. The co-crystal releases modafinil into
solution more quickly in both SGF and SIF than does the free form of
modafinil.
Figure 54 compares the dissolution of an HPMC capsule filled with the
modafinil:malonic acid co-crystal blended with lactose and that of a PROVIGIL
tablet. Figure 55 shows a dynamic vapor sorption (DVS) isotherm plot of the
modafinil:malonic acid co-crystal. This plot shows no appreciable water
adsorption
up to at least 40 percent RH at 26 degrees C.
Example 32
In Vivo Studies
A pharmacokinetic study was completed with dogs using both racemic
modafinil:malonic acid formulated with lactose and PROVIGIL tablets (200 mg).
Seven capsules were filled with the modafinil:malonic acid co-crystal and
lactose to
476.24 +/- 2 mg, each containing 200 mg modafinil. Figure 56 shows the co-
crystal
formulation has an increased Cmax and an increased bioavailability. Severel
important
pharmacokinetic parameters are described in Table VI. In Table VI, "Cm" is the
maximum blood plasma concentration, "AUC (inf)" is the extrapolated area under
the
curve, "t1i2" is the amount of time for the blood plasma level to decrease to
half of the
Cmax level beginning at administration, "Tmax" is the time to maximum blood
plasma
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concentration from administration, "CL" is the clearance rate of modafinil,
and "F %"
is the percent bioavailability.
Table VI- PK parameters of modafinil:malonic acid co-crystal and PROVIGIL from
In Vivo study
PROVIGIL (200 m
Cmax AUC in t1/Z Tmax CL F %
Mean 7838.33 41193.33 1.76 no 524.17 66.48
SD 2734.35 8104.32 0.88 0.63 146.98 13.08
%CV 34.9 19.7 49.7 31.6 28.0 19.7
Modafinil:malonic acid (200 mg modafinil
Cmax AUC in t112 Tmax CL F %
Mean 11246.67 50545.00 1.63 2.00 368.33 81.57
SD 1662.13 10635.46 0.64 0.89 165.60 17.16
OR. CV 14.8 21.0 39.5 44.7 45.0 21.0
Example 33
R-(- -modafinil:Gentisic acid Co-crystal
R-(-)-modafinil (50 mg, 0.183 mmol, greater than 98 percent R-isomer) and
gentisic acid (28.2 mg, 0.183 mmol) were placed in a stainless steel vial. 10
microliters of acetone was added to the vial. The vial was then placed in a
grinder
(wig-l-bug, Bratt Technologies, 11 5V/6OHz) and the solid mixture was milled
for 5
minutes. The resultant powder was then collected and characterized using PXRD
(Rigaku), as shown in Figure 57. The R-(-)-modafinil:gentisic acid co-crystal
can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 57 including, but not limited to, 7.07, 9.07, 12.31,
13.03, 14.09,
18.93, 19.83, and 21.27 degrees 2-theta (as collected). Other PXRD peaks at
7.51,
16.03, 17.63, 18.39, 23.57, 26,93, and 28.85 degrees 2-theta correspond to
excess co-
crystal former.
Example 34
Channel Solvates of Racemic Modafinil
Channel solvates of modafinil have been unexpectedly discovered. The
channel solvate was made from a solution of racemic modafinil (97.9 mg, 0.358
mmol) and 1-hydroxy-2-napthoic acid (68.8 mg, 0.366 mmol) in acetone (3.15
mL),
dissolved over a 60 degrees C hotplate. The solution was then evaporated under
flowing nitrogen while hot to 1.6 mL total volume. Once cooled, the solution
was
seeded with ground racemic modafinil:1-hydroxy-2-naphtoic acid co-crystal.
Single
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crystals were obtained and characterized using single x-ray analysis. Single-
crystal x-
ray parameters: P2(1)/n, a = 12.737(3) angstroms, b = 5.5945(11) angstroms, c
=
22.392(5) angstroms, alpha= 90 degrees, beta= 104.140(4) degrees, gamma = 90
degrees, V = 1547.3(5) cubic angstroms, Z = 2. Figures 58 and 59 show packing
diagrams of the acetone channel solvate of modafinil. The packing diagrams
show
acetone with a variable position within the channel structure. An ethyl
acetate
channel solvate has also been prepared according to the method above using
ethyl
acetate in place of acetone.
Example 35
o-Xylene Hemisolvate of Racemic Modafinil
An o-xylene hemisolvate was formed by preparing a 1:2 solution of racemic
modafinil (49.6 mg, 0.181 mmol) and 1-hydroxy-2-napthoic acid (68.3 mg, 0.363
mmol) in o-xylene (4.5 mL). The mixture was heated on a hotplate with swirling
until all solids were dissolved. The solution was then left to crystallize in
a sealed
vial. The resulting powder was collected in a centrifuge filter and analyzed
by PXRD
(Bruker), as shown in Figure 60. Raman spectroscopy (Figure 61), TGA(Figure
62),
and DSC (Figure 63) were also used to analyze and characterize the
hemisolvate. The
o-xylene solvate can be characterized by any one, any two, any three, any
four, any
five, or any six or more of the peaks in Figure 60 including, but not limited
to, 5.31,
6.53, 6.96, 10.68, 14.20, 17.64, 19.93, 25.69, and 26.79 degrees 2-theta. The
o-xylene
solvate can be characterized by any one, any two, any three, any four, any
five, or any
six or more of the peaks in Figure 61 (middle spectrum) including, but not
limited to,
1641, 1407, 1379, 1211, 1024, and 721 cm- 1.
Example 36
Benzene Hemisolvate of Racemic Modafinil
A benzene hemisolvate was formed by preparing a 1:2 solution of racemic
modafinil (50.6 mg, 0.181 mmol) and 1-hydroxy-2-napthoic acid (70.1 mg, 0.373
mmol) in benzene (1.8 mL). The mixture was heated on a hotplate with swirling
until
all solids were dissolved. The solution was then left to crystallize in a
sealed vial.
The resulting powder was collected in a centrifuge filter and analyzed by PXRD
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(Bruker), as shown in Figure 64. Raman spectroscopy (Figure 65), TGA (Figure
66),
and DSC (Figure 67) were also used to analyze and characterize the
hemisolvate. The
benzene solvate can be characterized by any one, any two, any three, any four,
any
five, or any six or more of the peaks in Figure 64 including, but not limited
to, 5.82,
6.09, 8.11, 10.28, 12.06, 13.28, 14.73, 17.03, 19.11, 19.93, 21.23, 25.38, and
26.43
degrees 2-theta. The benzene solvate can be characterized by any one, any two,
any
three, any four, any five, or any six or more of the peaks in Figure 65
(middle
spectrum) including, but not limited to, 1637, 1600, 1409, 1380, 1214, 1025,
998, and
721 cm 1.
Example 37
Toluene Hemisolvate of Racemic Modafinil
A toluene hemisolvate was formed by making a 1:2 solution of racemic
modafinil (37.3 mg, 0.136 mmol) and 1-hydroxy-2-napthoic acid (51.3 mg, 0.273
mmol) in toluene (1 mL). The mixture was heated on a hotplate with swirling
until all
solids were dissolved. The solution was then left to crystallize in a sealed
vial. The
resulting powder was collected in a centrifuge filter and analyzed by PXRD
(Bruker),
as shown in Figure 68. Raman spectroscopy (Figure 69), TGA (Figure 70), and
DSC
(Figure 71) were also used to analyze and characterize the hemisolvate. The
toluene
solvate can be characterized by any one, any two, any three, any four, any
five, or any
six or more of the peaks in Figure 68 including, but not limited to, 5.30,
5.96, 10.65,
12.90, 14.51, 17.60, and 18.15 degrees 2-theta. The toluene solvate can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 69 (middle spectrum) including, but not limited to, 1640,
1581,
1408, 1380, 1209, 1024, 1001, and 722 cm 1.
Example 38
Pharmacokinetics of Isomers of Modafinil
A dog pharmacokinetic study (N = 6) of a single intravenous dose of R-(-)-
modafinil was completed. The purity of the R-(-)-modafinil in the administered
formulation was ca 80 percent. This formulation was compared to a formulation
of
racemic modafinil, also administered by the intravenous route to the same dogs
in a
crossover design. Results are reported in Table VII. In Table VII, "Cm" is the
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maximum blood plasma concentration, "AUC (inf)" is the extrapolated area under
the
curve, "ti/ 2" is the amount of time for the blood plasma level to decrease to
half of the
Cn,ax level beginning at administration, "Vd" is the volume of distribution,
and "CL" is
the clearance rate of modafinil.
Table VII- PK parameters of racemic modafinil and R-(-)-modafinil from In Vivo
study
Racemic Modafinil (5 m kg IV)
Cmax AUC (inf) t1/2 Vd CL
(ng/mL) (ng/mL x hr) (hr) (mL/kg) (mL/hr x kg)
Mean 8682.83 15117.50 1.05 588.83 341.00
SD 1413.71 2870.24 0.16 96.41 65.63
% CV 16.3 19.0 15.4 16.4 19.2
R-(-)-modafinil (5 mg/kg IV)
Mean 7806.67 15905.17 1.53 646.67 340.33
SD 827.97 4958.47 1.11 68.10 102.39
% CV 10.6 31.2 72.5 10.5 30.1
These results suggest that there is no significant difference between the
pharmacokinetics of R-(-)-modafinil and racemic modafinil following
intravenous
administration.
These results are in contrast to the pharmacokinetics of the isomers when
administered by the oral route (See US Patent No. 4,927,855, which is herein
incorporated by reference in its entirety). In said study, four dogs were
administered
30 mg/kg oral dose of either R-(-)-modafinil (40-982), S-(+)-modafinil (40-
983), or
racemic modafinil (40-476). The AUC values were calculated from plasma
concentration of both forms (40-476) and the sulfone metabolite measured from
2 to 9
hours post-dose administration. Table VIII shows the pharmacokinetic data.
Table VIII- PK parameters of racemic modafinil, R-(-)-modafinil, and S-(+)-
modafinil from In Vivo
study
Compound administered Mean AUC (racemate) Mean AUC (sulfone)
(30 mg/kg) (mg/L x hr) (mg/L x hr)
40-476 (racemate) 46.76 +/- 6.95 35.12 +/- 6.93
40-982 (R-(-)-modafinil) 97.22 +/- 12.58 8.69 +/-1.22
40-983 (S-(+)-modafinil) 50.94 +/- 8.77 83.12 +/- 21.66
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These results suggest striking differences in the metabolism of both isomers
of
modafinil, leading to differences in the formation of the inactive sulfone
metabolite
therefore resulting in higher exposure to the API when administered as R-(-)-
modafinil. The different profile observed between the intravenous and the oral
route
could be explained by the fact that the formation of the sulfone metabolite is
primarily
catalyzed by cytochrome CYP3A4 which is both present at the intestinal and
hepatic
level, and that the affinity of CYP3A4 to S-(+)-modafinil is higher
(stereoselective
metabolism) than that to R-(-)-modafinil. This can result in faster metabolite
formation with S-(+)-modafinil which can reduce the exposure to the API.
Example 39
R-(-)-modafinil Ethanol Solvate
A solution containing R-(-)-modafinil (100 mg, 0.366 mmol, 85.4 percent R-
isomer) and racemic modafinil (40 mg, 0.146 mmol) in ethanol (3 mL) was
prepared.
The mixture was heated to reflux in order to dissolve the entire solid and was
then
cooled to room temperature (25 degrees Q. After remaining at room temperature
for
15 minutes, the solution was placed at 5 degrees C overnight. A solid
precipitate was
observed after 1 day and was collected, dried, and characterized using PXRD
and
TGA (Figures 72 and 73). The solid was determined to be an ethanol solvate of
R-(-)-
modafinil.
R-(-)-modafinil ethanol solvate can be characterized by any one, any two, any
three, any four, any five, or any six or more of the peaks in Figure 72
including, but
not limited to, 6.13, 9.59, 15.69, 17.97, 20.05, 21.55, 22.35, 25.77, and
29.07 degrees
2-theta (Rigaku PXRD, data as collected).
TGA of the R-(-)-modafinil ethanol solvate characterized in Figure 73 showed
about a 5.4 percent weight loss between about 25 and about 140 degrees C.
Example 40
R-(-)-modafinil Benzyl alcohol Solvate
R-(-)-modafinil (100 mg, 0.3 66 mmol) was milled with benzyl alcohol (40
microliters) for 5 minutes. The milled powder was then analyzed by PXRD, DSC,
and TGA (Figures 74, 75, and 76). The powder was determined to be a benzyl
alcohol solvate of R-(-)-modafinil.
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R-(-)-modafinil benzyl alcohol solvate can be characterized by any one, any
two, any three, any four, any five, or any six or more of the peaks in Figure
74
including, but not limited to, 5.77, 7.76, 10.48, 15.78, 17.80, 18.57, 21.53,
22.97, and
27.73 degrees 2-theta (Bruker PXRD, data as collected).
DSC of the R-(-)-modafinil benzyl alcohol solvate characterized in Figure 75
showed an endothermic transition at about 83 degrees C.
TGA of the R-(-)-modafinil benzyl alcohol solvate characterized in Figure 76
showed about a 28.5 percent weight loss between about 25 and about 125 degrees
C.
Example 41
R-(-)-modafinil Isopropanol Solvate
R-(-)-modafinil was slurried overnight in isopropanol. The liquid was filtered
out in a centrifuge filter, then dried under flowing nitrogen gas at 5 degrees
C. The
resulting solid was analyzed via PXRD.
R-(-)-modafinil isopropanol solvate can be characterized by any one, any two,
any three, any four, any five, or any six or more of the peaks in Figure 77
including,
but not limited to, 5.76, 7.77, 10.49, 15.79, 18.58, 21.53, 25.76, and 27.74
degrees 2-
theta (Bruker PXRD, data as collected).
Example 42
R-(-)-modafinil Acetonitrile Solvate
100 mg of R-(-)-modafinil was slurrie in acetonitrile for 2 days. The solid
was
filtered from the suspension and analyzed by PXRD.
R-(-)-modafinil acetonitrile solvate can be characterized by any one, any two,
any three, any four, any five, or any six or more of the peaks in Figure 78
including,
but not limited to, 5.29, 6.17, 8.16, 10.19, 11.19, and 21.86 degrees 2-theta
(Bruker
PXRD, data as collected).
Example 43
R-(-)-Modafinil:Glutaric acid Co-crystal
R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and glutaric
acid (15-20 mg) were ground together in the presence of one drop of benzyl
alcohol.
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The resultant solid was characterized by PXRD (See Figure 79) and may
comprise a co-crystal. The R-(-)-modafinil:glutaric acid co-crystal can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 79 including, but not limited to, 4.30, 8.67, 9.78, 17.99,
18.92,
19.74, 20.50, 21.36, 22.25, 23.87, 27.16, 29.24, and 32.46 degrees 2-theta
(Bruker
PXRD, data as collected).
Wet grinding was also used with acetone and with water, both of which
resulted in the formation of the co-crystal.
Example 44
R-(-)-Modafinil:Citric acid Co-crystal
R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and citric
acid
monohydrate (15-20 mg) were ground together in the presence of one drop of
benzyl
alcohol.
The resultant solid was characterized by PXRD (See Figure 80) and may
comprise a co-crystal. The R-(-)-modafinil:citric acid co-crystal can be
characterized
by any one, any two, any three, any four, any five, or any six or more of the
peaks in
Figure 80 including, but not limited to, 5.23, 7.06, 9.10, 12.43, 13.18,
14.37, 17.34,
17.95, 20.85, 21.39, 22.03, 22.96, 23.54, and 24.93 degrees 2-theta (Bruker
PXRD,
data as collected).
Wet grinding was also used with acetone which resulted in the formation of
the co-crystal.
Example 45
R-(-)-Modafinil:L-tartaric acid Co-crystal
R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and L-tartaric
acid (15-20 mg) were ground together in the presence of one drop of benzyl
alcohol.
The resultant solid was characterized by PXRD (See Figure 81) and may
comprise a co-crystal. The R-(-)-modafinil:L-tartaric acid co-crystal can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 81 including, but not limited to, 4.56, 10.33, 14.45,
17.29, 19.91,
21.13, 23.10, 24.10, and 26.76 degrees 2-theta (Bruker PXRD, data as
collected).
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Wet grinding was also used with acetone and with water, both of which
resulted in the formation of the co-crystal.
Example 46
R-(-)-Modafinil:Oxalic acid Co-crystal
R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and oxalic
acid (15-20 mg) were ground together in the presence of one drop of benzyl
alcohol.
The resultant solid was characterized by PXRD (See Figures 82A and 82B)
and may comprise one or more co-crystals. The R-(-)-modafinil:oxalic acid
(Form I)
co-crystal can be characterized by any one, any two, any three, any four, any
five, or
any six or more of the peaks in Figure 82A including, but not limited to,
5.99, 14.73,
16.59, 17.38, 18.64, 25.66, and 28.85 degrees 2-theta (Bruker PXRD, data as
collected). The R-(-)-modafinil:oxalic acid (Form II) co-crystal can be
characterized
by any one, any two, any three, any four, any five, or any six or more of the
peaks in
Figure 82B including, but not limited to, 5.66, 14.76, 17.20, 17.63, 19.60,
24.90, and
28.84 degrees 2-theta (Bruker PXRD, data as collected).
Wet grinding was also used with acetone and with water, both of which
resulted in the formation of the co-crystal.
Example 47
R-(-) Modafinil:Palmitic acid Co-crystal
R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and palmitic
acid (15-20 mg) were ground together in the presence of one drop of benzyl
alcohol.
The resultant solid was characterized by PXRD (See Figure 83) and may
comprise a co-crystal. The R-(-)-modafinil:palmitic acid co-crystal can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 83 including, but not limited to, 3.80, 6.55, 7.66, 10.24,
11.49,
19.48, 21.09, 21.74, 22.20, 22.97, and 23.99 degrees 2-theta (Bruker PXRD,
data as
collected).
Example 48
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R-(-)-Modafinil:L- roline Co-crystal
R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and L-proline
(15-20 mg) were ground together in the presence of one drop of benzyl alcohol.
The resultant solid was characterized by PXRD (See Figure 84) and may
comprise a co-crystal. The R-(-)-modafinil:L-proline co-crystal can be
characterized
by any one, any two, any three, any four, any five, or any six or more of the
peaks in
Figure 84 including, but not limited to, 6.52, 8.53, 10.25, 14.69, 19.06,
19.71, 20.75,
22.29, 22.75, 25.08, and 26.27 degrees 2-theta (Bruker PXRD, data as
collected).
Wet grinding was also used with acetone and with methanol, both of which
resulted in the formation of the co-crystal.
Example 49
R-(-)-Modafinil:Salicylic acid Co-crystal
R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and salicylic
acid (15-20 mg) were ground together in the presence of one drop of benzyl
alcohol.
The resultant solid was characterized by PXRD (See Figure 85) and may
comprise a co-crystal. The R-(-)-modafinil:salicylic acid co-crystal can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 85 including, but not limited to, 8.92, 10.85, 12.18,
14.04, 17.07,
17.59, 18.81, 21.24, 23.32, 25.22, and 28.59 degrees 2-theta (Bruker PXRD,
data as
collected).
Example 50
R-(-)-Modafinil:Lauric acid Co-crystal
R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and lauric
acid (15-20 mg) were ground together in the presence of one drop of benzyl
alcohol.
The resultant solid was characterized by PXRD (See Figure 86) and may
comprise a co-crystal. The R-(-)-modafinil:lauric acid co-crystal can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 86 including, but not limited to, 3.12, 6.55, 10.24,
13.97, 16.40,
17.62, 19.02, 20.05, 21.38, 22.24, 23.81, and 25.96 degrees 2-theta (Bruker
PXRD,
data as collected).
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Wet grinding was also used with acetone and with methanol, both of which
resulted in the formation of the co-crystal.
Example 51
R-(-)-Modafinil:L-malic acid Co-crystal
R-(-)-modafinil (20 to 30 mg, greater than 98 percent R-isomer) and L-malic
acid (15-20 mg) were ground together in the presence of one drop of acetone.
The resultant solid was characterized by PXRD (See Figure 87) and may
comprise a co-crystal. The R-(-)-modafinil:L-malic acid co-crystal can be
characterized by any one, any two, any three, any four, any five, or any six
or more of
the peaks in Figure 87 including, but not limited to, 4.62, 9.32, 10.32,
15.83, 16.71,
17.38, 19.30, 19.93, 21.48, 23.07, 24.26, and 27.25 degrees 2-theta (Broker
PXRD,
data as collected).
Example 52
Preparation of benzhdrylthioacetic acid from benzhydrol
To a solution of benzhydrol (100 g, 0.542 mol) in trifluoroacetic acid (300
mL) at room temperature (about 22 degrees C) was added thioglycolic acid (50
g,
0.542 mol) drop wise over 20 minutes. Reaction progress was monitored by thin
layer chromatography (TLC). The reaction was complete within one hour at which
point water (1000 mL) was added slowly into the reaction mixture causing the
product to precipitate. The resulting precipitate was filtered, washed with
water and
dried overnight under high vacuum to give benzhydrylthioacetic acid (139.3 g,
99.3%) as a pale yellow solid. (See Prisinzano, T. et al, Tetrahedron Asymm.,
2004,
15, 1053-1058)
Example 53
Preparation of benzhdrylthioacetic acid from bromodiphenylmethane (One Pot
Procedure
To a solution of thiourea (30.4 g, 0.399 mol) in water (200 mL) was added
bromodiphenylmethane (98.8 g, 0.399 mol) at 42 degrees C. The mixture was
heated
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gradually to reflux for 10 minutes. The reaction mixture was then cooled to 50
degrees C and 5 N NaOH (200 mL) was subsequently added. The reaction mixture
was then heated to reflux (101-102 C) for 30 minutes and subsequently cooled
to 60
degrees C. To this reaction mixture was slowly added a solution of
chloroacetic acid
(53.4 g, 0.565 mol) and NaOH (22.2 g) in water (150 mL) over 45 minutes. The
reaction mixture was stirred for another 30 minutes. The reaction was then
cooled to
room temperature and washed with t-butylmethylether (200 ml) to remove any non
carboxylic acid impurities. The aqueous layer was acidified (pH 2.0) using
concentrated HCl (50 mL). The resulting precipitate was filtered, washed with
water
(2 x 200 mL) and heptane (200 mL) and allowed to air dry to give
benzhydrylthioacetic acid (116.8 g, 100%) as a colorless solid. (See US Patent
No.
4,066,686)
Example 54
Preparation of benzhdry1thioacetic acid from benzhydrol using trifluoroacetic
acid in
dichloromethane
To a solution of benzhydrol (90 g, 0.488 mol) and trifluoroacetic acid (90 mL)
in dichloromethane (300 mL) was added thioglycolic acid (40 g, 0.488 mol) in
dichloromethane (60 mL) drop wise over 20 minutes. The reaction was completed
in
one hour. The solvent was removed in vacuo to give a crude solid, which was
dried
overnight under high vacuum. The solid was treated with 2 N NaOH (1.0 L) and
washed with t-butylmethylether (200 ml) to remove non carboxylic acid
impurities.
The aqueous solution was then acidified with concentrated HCl and the
resulting
precipitate was collected, washed with water and dried to give
benzhydrylthioacetic
acid (128.5 g) as a colorless solid.
Example 55
Preparation of benzhydrylsulfinyiacetic acid from benzhdrylthioacetic acid
To a suspension of benzhydrylthioacetic acid (63.7 g, 0.246 mol) in methanol
(250 mL) was added a solution of concentrated H2S04 (1.6 mL) in isopropyl
alcohol
(65 mL) at room temperature (about 22 degrees C). To this suspension was added
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30% H202 in water (65 mL) drop wise over 25 minutes. The reaction was
monitored
by TLC and was completed within 2 hours. The solution was diluted with a
solution
of NaHSO3 (125 mg) in water (700 mL). The resulting precipitate was filtered,
washed with water, then methanol: water (1:1), and dried to give
benzhydrylsulfinylacetic acid (47.6 g). 'H-NUR indicated the desired product
was
obtained along with -10 percent starting material and some impurities. The
compound was triturated with ethanol (100 mL), filtered and dried to give pure
benzhydrylsulfinylacetic acid (33.4 g, 49.4%) as a colorless solid. (See
Prisinzano, T.
et al, Tetrahedron Asymm., 2004, 15, 1053-1058)
Example 56
Oxidation of benzhdrylthioacetic acid
A 50 L three-necked round bottom flask equipped with a mechanical stirrer, a
21 dropping funnel, a nitrogen inlet and an internal temperature probe was
charged
with benzhydrylthioacetic acid (3.5 kg, 13.54 mol), methanol (14 L) and H2SO4
(72 g)
solution in isopropyl alcohol (6.5 L). To this mixture was added 30% H202
solution
in water (3.75 L) drop wise over 80 minutes maintaining the temperature below
30
degrees C. Reaction mixture was further stirred for 7 hours, which resulted in
formation of a crystalline solid. The reaction was monitored using TLC and
HPLC.
The resulting solid was filtered and washed with water (4.0 L) to give
benzhydrylsulfinylacetic acid (2.5 kg) as a colorless solid. The peroxide was
quenched with a NaHSO3 solution.
Example 57
Resolution of benzhydrylsulfinylacetic acid using S-(-)-a-meth l~ylamine
To a solution of ( )-benzhydrylsulfinylacetic acid (62.4 g, 0.227 mol) in
water
(300 mL) at 80 degrees C was added S-(-)-a-methylbenzyl amine (30 mL, 0.236
mol)
and stirred at reflux (101-102 degrees C) for 10 minutes. The solution was
gradually
cooled to 40 degrees C and the resulting precipitate was filtered, washed with
water
and dried to give a colorless solid (71.4 g). The salt was re-crystallized in
water (500
ml) to give another colorless solid (53.5 g). The salt was then suspended in
water
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(200 mL), acidified with concentrated HCl (50 mL), and stirred for 10 minutes.
The
resulting suspension was filtered and washed with water to give R-(-)-
benzhydrylsulfinylacetic acid (21.5 g) as a colorless solid. Chiral purity as
determined
by HPLC was >99.9% ee. (See US Patent No. 4,927,855)
Example 58
Amidation of R-(-) benzhydrylsulfinylacetic acid to give R-(-)-modafinil using
NN
carbonyl diimidazole
A 50 L, three-necked round bottom flask equipped with a mechanical stirrer, a
nitrogen inlet and an internal temperature probe was charged with R-(-)-
benzhydrylsulfinylacetic acid (1.32 kg, 4.81 mol) and tetrahydrofuran (7.0 L).
To this
slurry was added NN-carbonyl diimidazole (1.215 kg, 7.49 mol) in
tetrahydrofuran (7
L), which gave a clear solution. The solution was then stirred for 30 minutes
and NH3
gas (191 g, 2.5 eq.) was then bubbled through the reaction mixture for 3.5
hours.
After that time, the volatiles were removed in vacuo to give a crude solid,
which was
triturated with a 20% methanol solution in t-butylmethylether (7.0 L)
overnight. The
solid material was then collected and purified further by refluxing of the
solid in a 1:1
mixture of ethanol and t-butylmethylether (3 L). The reaction was then cooled
to
room temperature and the solid material was filtered and dried to give R-(-)-
modafinil
(501 g, 99.6% chemical purity and 100% ee) as a colorless solid.
Example 59
Preparation of Racemic Modafinil via activation using NN-CarbonylDiimidazole
CDI
To a suspension of ( )-benzhydrylsulfinylacetic acid (10.0 g, 0.036 mol) in
tetrahydrofuran (100 mL) was added NN-carbonyl diimidazole (7.1 g, 0.043 mol)
resulting in a clear solution. The solution was stirred for 10 minutes and a
precipitate
formed upon evolution of CO2. NH3 gas was then bubbled through the reaction
mixture for 10 minutes raising the reaction temperature from 16 to 33 degrees
C. The
reaction mixture was then diluted with water and extracted with ethyl acetate
(3 x 50
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mL). The organic layers were combined, washed with water, brine and dried over
Na2SQ4. The organic layer was then concentrated in vacuo to give crude
modafinil
(11.5 g). Recrystallization from 60 % aqueous methanol gave pure modafinil
(6.0 g)
as a colorless solid.
Example 60
Synthesis of ( )Modafinil from benzhvdrol
To a solution of benzhydrol (30 g, 0.162 mol) and trifluoroacetic acid (15 mL)
in dichloromethane (120 ml) was added a solution of methyl thioglycolate
(0.178
mol) in dichloromethane (30 ml) drop wise over 20 minutes. The reaction was
stirred
at room temperature for 1 hour and a saturated NaHCO3 solution was added
slowly.
The organic layer was separated and concentrated in vacuo to give crude
benzhydrylthioacetate (38.2 g, 89%).
To a solution of NH4Cl (0.29 mol, 2.0 eq) and NH4OH (300 ml) in methanol
(200 mL) was added a solution of benzhydrylthioacetate (38.2 g, 0.145 mol) in
methanol (50 ml) maintaining the temperature below 20 T. The reaction was
stirred
for 1 hour and diluted with water (100 ml) resulting in the formation of a
precipitate.
The precipitate was collected, washed with water and dried to give
benzhydrylthioacetamide (31 g) as colorless solid.
Racemic modafinil was obtained from oxidation of benzhydrylthiacetamide
using H202 following the same method used in the oxidation of
benzhydrylthioacetic
acid in the preparation of R-(-)-modafinil.
