Note: Descriptions are shown in the official language in which they were submitted.
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MODAF1NIL COMPOSITIONS
FIELD OF THE INVENTION
The present invention relates to modafinil-containing compositions,
pharmaceutical compositions comprising modafinil, and methods for preparing
the
same.
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
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,
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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
(I).
Modafinil is a chiral molecule due to the chiral S=O group. Therefore,
modafinil exists
as two isomers, R-(-)-modafinil and S-(+)-modafmil. 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 andlor 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 polymorphs and solvates of modafinil can be
obtained. Some of which can have different properties as compared to the free
form of
the API.
Embodiments of the present invention including, but not limited to, 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
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about 90 percent ee). Similarly, 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 another embodiment, the present invention provides the following modafinil
solvates: chloroform, chlorobenzene, ethyl acetate, and acetic acid.
The processes according to the present invention may each comprise a further
step or steps in which a modafinil polymorph or solvate produced thereby is
incorporated into a pharmaceutical composition.
In a further embodiment, the present invention provides a novel polymorph of
R-(-)-modafmil. In a specific embodiment, the present invention provides Forms
III,
IV, and V of R-(-)-modafinil. The present invention also provides a method of
making
a polymorph of R-(-)-modafinil.
In a further embodiment, the present invention provides a method of making a
polymorph of R-(-)-modafinil, comprising:
(a) providing R-(-)-modafinil;
(b) crystallizing the polymorph of R-(-)-modafinil from an appropriate
solvent.
In a further embodiment, a polymorph of R-(-)-modafinil is crystallized from
an
organic solvent. In particular embodiments, the organic solvent can be
acetonitrile,
dimethyl formamide (DMF), methanol, methyl ethyl ketone, N-methyl pyrollidone,
ethanol, isopropanol, isobutanol, formamide, isobutyl acetate, 1,4-dioxane,
tetrahydrofuran (THF), ethyl acetate, o-xylene, isopropyl acetate,
dichloromethane,
propylene glycol, acetic acid, water, acetone, nitromethane, toluene, and
benzyl
alcohol. Both pure solvents and mixed solvents are considered organic solvent,
according to the present invention. In a particular embodiment, the organic
solvent is
ethanol. In another embodiment, a mixed solvent system is used to crystallize
a
polymorph of R-(-)-modafinil. Mixed solvent systems can be, for example,
ethanol and
isopropyl alcohol, or ethyl acetate and ethanol. In a further embodiment, the
crystallization in step (b) is completed via thermal crystallization. In a
further
embodiment, the crystallization in step (b) is completed via evaporation of
the solvent.
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.
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The invention further provides a medicament comprising a polymorph or a
solvate 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 polymorph or solvate 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 polymorph or a solvate of modafinil.
In another embodiment, a method is provided for treating a subject suffering
from one or more of the above mentioned conditions or disorders, including,
but not
limited to sleep disorders such as narcolepsy, comprising administering to the
subject a
therapeutically-effective amount of R-(-)-modafinil Form III, R-(-)-modafinil
Form IV,
or R-(-)-modafmil Form V.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1- PXRD diffractogram of polymorph of 2:1 R-(-)-modafinil:S-(+)-
modafinil.
Figure 2- DSC thermogram of polymorph of 2:1 R-(-)-modafinil:S-(+)-modafinil.
Figure 3- PXRD diffractogram of a polymorph of R-(-)-modafinil (Form III).
Figure 4- DSC thermogram of a polymorph of R-(-)-modafinil (Form III).
Figure 5- PXRD diffractogram of a polymorph of R-(-)-modafinil (Form III).
Figure 6- PXRD diffractogram of a polymorph of R-(-)-modafinil (Form IV).
Figure 7- DSC thermogram of a polymorph of R-(-)-modafinil (Form IV).
Figure 8- PXRD diffractogram of a polymorph of R-(-)-modafinil (Form IV).
Figure 9- PXRD diffractogram of a polymorph of R-(-)-modafinil (Form V).
Figure 10- PXRD diffractogram of a polymorph of R-(-)-modafinil (Form V).
Figure 11- PXRD diffractogram of 2:1 R-(-)-modafinil:S-(+)-modafinil.
Figure 12- DSC thermogram of 2:1 R-(-)-modafinil:S-(+)-modafinil.
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Figure 13- PXRD diffractogram of R-(-)-modafinil form IV.
Figure 14- PXRD diffractogram of R-(-)-modafinil form V.
Figure 15- DSC thermogram of R-(-)-modafinil form V.
Figure 16- PXRD diffractogram of R-(-)-modafinil chloroform solvate.
Figure 17- TGA thermogram of R-(-)-modafinil chloroform solvate.
Figure 18- PXRD diffractogram of R-(-)-modafinil chlorobenzene solvate.
Figure 19- PXRD diffractogram of racemic modafinil ethyl acetate channel
solvate.
Figure 20- TGA thermogram of racemic modafinil ethyl acetate channel solvate.
Figure 21- PXRD diffractogram of R-(-)-modafmil acetic acid solvate.
Figure 22- TGA thermogram of R-(-)-modafinil acetic acid solvate.
Figure 23- DSC thermogram of R-(-)-modafinil acetic acid solvate.
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 (t)-2-[(Diphenylmethyl)
sulfinyl]acetamide.
The isomeric pairs of racemic modafmil are R-(-)-2-[(Diphenylmethyl)
sulfinyl]acetamide or R-(-)-modafmil 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:
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 "modafinil" 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" refers to a
material (e.g., a polymorph or a solvate) which is comprised of an equimolar
mixture of
the enantiomers of modafinil, the solvent, or both. For example, a solvate
comprising
modafinil and a non-stereoisomeric solvent molecule is a "racemic solvate"
only when
there is present an equimolar mixture of the modafinil enantiomers. Similarly,
a
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solvate comprising modafinil and a stereoisomeric solvent molecule is a
"racemic
solvate" only when there is present an equimolar mixture of the modafinil
enantiomers
and of the solvent molecule enantiomers.
As used herein and unless otherwise specified, the term "enantiomerically
pure"
refers to a material which is comprised of modafinil, and optionally, a
stereoisomeric or
non-stereoisomeric solvent molecule, where the enantiomeric excess of the
stereoisomeric species is greater than or equal to about 90 percent ee
(enantiomeric
excess).
For purposes of the present invention, the chemical and physical properties of
modafinil in the form of a solvate or a polymorph 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. 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.
Modafinil and some solvent molecules 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 solvates 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 traps-isomers, R- and S-enantiomers, and (D)- and (L)-
isomers.
Solvates of the present invention can include isomeric forms of either
modafinil or the
solvent molecules or both. Isomeric forms of modafinil and solvent molecules
include,
but are not limited to, stereoisomers such as enantiomers and diastereomers.
In one
embodiment, a solvate comprises racemic modafinil and a solvent molecule. In
another
embodiment, a solvate comprises enantiomerically pure R- or S-modafinil and a
solvent
molecule. In another embodiment, a solvate of the present invention comprises
modafinil and/or a solvent molecule with an enantiomeric excess of about 1
percent, 2
percent, 3 percent, 4 percent, S 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
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percent, 97 percent, 98 percent, 99 percent, greater than 99 percent, or any
intermediate
value. 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 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-(-)-modafmil" 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.
Solvates and polymorphs comprising enantiomerically pure and/or
enantiomerically enriched components (e.g., modafinil or solvent molecule) can
give
rise to chemical and/or physical properties which are modulated with respect
to those of
the corresponding form comprising a racemic component.
Polymorphs and solvates of modafinil can be prepared with racemic modafinil,
enantiomerically pure modafmil, or with any mixture of R-(-)- and S-(+)-
modafinil
(e.g., enriched modafmil) according to the present invention.
In another embodiment, the compositions or medicaments including 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)
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In another embodiment, the present invention provides the following modafinil
solvates: chloroform, chlorobenzene, ethyl acetate, and acetic acid.
Pharmaceutically acceptable forms 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 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
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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 solvates, polymorphs 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;
each of which is incorporated herein by reference. 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, Cali~ 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 polymorphs and
thus
effect controlled delivery of the drug. Examples of specific anion exchangers
include,
but are not limited to, Duolite~ A568 and Duolite~ AP 143 (Rohm & Haas, Spring
House, PA. USA).
One embodiment of the invention encompasses a unit dosage form which
comprises a pharmaceutically acceptable solvate, hydrate, dehydrate,
anhydrous, or
amorphous form thereof, and one or more pharmaceutically acceptable 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 B1;
6,368,626 B1;
6,342,249 B1; 6,333,050 B2; 6,287,295 B1; 6,283,953 B1; 6,270,787 B1;
6,245,357
B1; and 6,132,420; each of which is incorporated herein by reference. 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-PulITM, Delayed
Push-
PulITM, Multi-Layer Push-PulITM, and Push-StickTM Systems, all of which are
well
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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 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
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 OROS~ drug delivery systems cannot be used to effectively deliver
drugs
with low water solubility. Id. at 234.
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 polymorph, or a solvate, hydrate, dehydrate, anhydrous, or
amorphous
form thereof. See U.S. Pat. No. 6,368,626, the entirety of which is
incorporated herein
by reference.
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 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 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
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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 polymorph, or a solvate, hydrate, dehydrate,
anhydrous,
or amorphous form thereof. See U.S. Pat. No. 6,342,249, the entirety of which
is
incorporated herein by reference.
In another embodiment, a pharmaceutical composition or medicament
comprises a mixture of a novel form of modafinil of the present invention
(e.g., a
polymorph or solvate) and racemic 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 racemic modafinil and a
polymorph or a solvate of the present invention.
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 Cm~ due
to R-(-)-modafinil) in plasma concentration and the S-(+)-modafinil provides a
delayed
increase (subsequent C",~ due to S-(+)-modafinil) in plasma concentration. The
delayed increase in Cm~ due to S-(+)-modafinil can be 2, 3, 4, 5, 6 hours or
more after
the initial Cm~ due to R-(-)-modafinil. In another embodiment, the delayed Cm~
is
approximately equal to the initial Cm~. In another embodiment, the delayed Cm~
is
greater than the initial Cm~. In another embodiment, the delayed Cm~ is less
than the
initial C",~. In another embodiment, the delayed Cm~ is due to racemic
modafmil,
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instead of S-(+)-modafinil. In another embodiment, the delayed C",~ is due to
R-(-)-
modafinil, instead of S-(+)-modafinil. In another embodiment, the initial Cm~
is due to
racemic modafinil, instead of R-(-)-modafinil. In another embodiment, the
initial C",
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-(+)-modafmil are present in the form of a
solvate or a
polymorph.
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
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-(+)-modafmil 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.
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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.
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 dehydrate; sucrose-
based
diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium
sulfate
dehydrate; 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 1 O 1 ),
either
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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
to, either individually or in combination, starches, including sodium starch
glycolate
(e.g., ExplotabTM of PenWest) and pregelatinized corn starches (e.g.,
NationalTM 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-SoITM 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
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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; 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 1 S%, 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
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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 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.
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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
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
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WO 2005/077894 PCT/US2005/002782
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
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, malefic 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-
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WO 2005/077894 PCT/US2005/002782
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 SO%, 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
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
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WO 2005/077894 PCT/US2005/002782
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 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 modafmil and an additional API can be prepared. T'he
modafinil and the additional API can 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 Tm~ relative to modafinil) to the dissolution profile
while the
modafinil causes the therapeutic effect to be present for hours after
administration. For
example, the Tm~ 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.
In a further embodiment, the present invention provides a novel polymorph of
R-(-)-modafinil. In a specific embodiment, the present invention provides
Forms III,
IV, and V of R-(-)-modafinil. The present invention also provides a method of
making
a polymorph of R-(-)-modafinil.
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In a further embodiment, the present invention provides a method of making a
polymorph of R-(-)-modafinil, comprising:
(a) providing R-(-)-modafinil; and
(b) crystallizing the polymorph of R-(-)-modafinil from an appropriate
solvent.
In a further embodiment, a polymorph of R-(-)-modafinil is crystallized from
an
organic solvent. In a particular embodiment, the organic solvent is ethanol.
In another
embodiment, a mixed solvent system is used to crystallize a polymorph of R-(-)-
modafmil. Mixed solvent systems can be, for example, ethanol and isopropyl
alcohol,
or ethyl acetate and ethanol. In a further embodiment, the crystallization in
step (b) is
completed via thermal recrystallization. In a further embodiment, the
crystallization in
step (b) is completed via evaporation of the solvent.
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 method is provided for treating a subject suffering
from one or more of the above mentioned conditions or disorders, including,
but not
limited to sleep disorders such as narcolepsy, comprising administering to the
subject a
therapeutically-effective amount of R-(-)-modafinil Form III, R-(-)-modafinil
Form IV,
or R-(-)-modafinil Form V.
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.
EXAMPLES
Analytical Methods
Differential scanning calorimetric (DSC) analysis of the samples was performed
using a Q1000 Differential Scanning Calorimeter (TA Instruments, New Castle,
DE,
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WO 2005/077894 PCT/US2005/002782
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.lE;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 3.1 E;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 NZ, 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.
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-
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WO 2005/077894 PCT/US2005/002782
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/Ka 1.54056 angstroms),
automated x-y-z stage, and O.Smm 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
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 t 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
23
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WO 2005/077894 PCT/US2005/002782
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 Sx microscope objective.
HPLC Method: (adapted from Donovan et al. Therapeutic Drub Monitoring
25:197-202.
Column: Astec Cyclobond I 2000 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
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.O:acetonitrile):
for each liter, mix 700 mL Mobile Phase A and 300 mL of acetonitrile.
24
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WO 2005/077894 PCT/US2005/002782
Sample Prep:
1. Dissolve samples in 90:10 (v/v) 20 mM sodium phosphate, pH 3.O: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 l Ox
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
Ex osure time (s) 2.0
Number of ex osures 10
Laser source wavelen th 785
nm)
Laser ower %) 100
A erture sha a in hole
A erture size (um 100
S ectral ran a 104-3428
Gratin osition Sin 1e
Temperature at acquisition24.0
(degrees C)
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.
CA 02556106 2006-08-03
WO 2005/077894 PCT/US2005/002782
Example 1
2:1 R-(-)-modafinil:S-(+)-modafinil
Anhydrous ammonia gas was bubbled through a solution containing R-
benzhydrylsulfinyl methyl ester (8.62 g, 0.0299 mol, about 80:20 R-isomer:S-
isomer by
weight) in methanol (125 mL) for 10 minutes. The pressure build-up from the
reaction
caused a back flow of sodium bicarbonate from the trap into the reaction
mixture. The
reaction was stopped and the precipitate was collected. The filtrate was
concentrated
under reduced pressure to give a yellow solid residue (2.8 g). The yellow
solid was
passed through a column (silica gel, grade 9385, 230-400, mesh 60 angstroms),
3:1 v/v
ethyl acetate:hexane as eluent). The filtrates were then combined and
concentrated
under reduced pressure to give a slightly yellow solid (most of the yellow
color
remained on the column). The solid was then re-crystallized from ethanol by
heating
the mixture until it was boiling and then cooling to room temperature to give
2:1 R-(-)-
modafinil:S-(+)-modafinil as a colorless solid (580 mg). PXRD and DSC analysis
were
completed on the obtained solid and it was determined that the solid is a pure
form of
R-(-)-modafinil and S-(+)-modafinil in an approximate 2:1 ratio by weight.
The 2:1 R-(-)-modafinil:S-(+)-modafinil solid obtained above 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, 8.97, 10.15, 12.87,
14.15, 15.13,
15.77, 18.19, and 20.39 degrees 2-theta (data as collected).
DSC of the solid described above showed an endothermic transition at about
167 degrees C (See Figure 2).
Example 2
Pol~orphs of R-(-)-modafinil
Several polymorphs of R-(-)-modafinil have been observed, each characterized
by PXRD. Figures 3, 6, and 9 show these PXRD diffractograms (data as
collected) of
polymorphs Form III, Form IV, and Form V.
Recrystallization has proved to be an effective technique for the formation
and
acquisition of the polymorphs of R-(-)-modafinil. Suitable solvents for the
26
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WO 2005/077894 PCT/US2005/002782
crystallization of one or more polymorphs of R-(-)-modafmil include, but are
not
limited to, acetonitrile, dimethyl formamide (DMF), methanol, methyl ethyl
ketone, N-
methyl pyrollidone, ethanol, isopropanol, isobutanol, formamide, isobutyl
acetate, 1,4-
dioxane, tetrahydrofuran (THF), ethyl acetate, o-xylene, isopropyl acetate,
dichloromethane, propylene glycol, acetic acid, water, acetone, nitromethane,
toluene,
and benzyl alcohol. Pure solvents and mixtures of solvents may be used to
crystallize
one or more polymorphs of R-(-)-modafinil.
R-(-)-modafinil Form III
Anhydrous ammonia gas was bubbled through a solution containing R-
benzhydrylsulfinyl methyl ester (8.3 g, 0.0288 mol) in methanol (75 mL) for 10
minutes. The reaction was then stirred in a 5 degrees C ice bath for 1 hour
and
ammonia gas was bubbled through for an additional 10 minutes. Stirring was
continued for an additional 2 hours and ammonia was bubbled through again for
10
minutes. After stirring for another hour a precipitate had formed (575 mg) and
was
collected. The filtrate was then neutralized using conc. HCl and another
precipitate
formed and was collected. The solid residue was then re-crystallized from a
1:1 v/v
mixture of ethanol and isopropyl alcohol by heating the mixture until it was
boiling and
then cooling to room temperature to give R-(-)-modafinil form III as a
colorless solid
(1.01 g).
R-(-)-modafinil Form III can be characterized by any one, any two, any three,
any four, any five, or any six or more of the peaks in Figure 3 including, but
not limited
to, 7.21, 10.37, 17.73, 19.23, 21.17, 21.77 and 23.21 degrees 2-theta (Rigaku
PXRD,
data as collected).
DSC of the R-(-)-modafmil form III characterized in Figure 4 showed an
endothermic transition at about 161 degrees C.
A second batch of R-(-)-modafmil form III was prepared for further analysis
via
thermal microscopy and PXRD. Solubility data was also acquired. These data are
discussed below.
R-(-)-modafinil Form III solubility was equal to about 6.1-7.0 mg/mL. The
solubility was measured from an isopropyl acetate slurry stirred at 25 degrees
C. The
solubility measurement was performed via HPLC. The solid from the solubility
samples were dried under nitrogen and characterized by PXRD and thermal
microscopy. Form conversion was not observed during procedure.
27
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WO 2005/077894 PCT/US2005/002782
Thermal (hotstage) microscopy was used with a heating rate of 10 degrees
C/minute to measure the melting point of R-(-)-modafinil Form III, which was
determined to be about 156-158 degrees C.
R-(-)-modafinil Form III can be characterized by any one, any two, any three,
any four, any five, or any six or more of the peaks in Figure 5 including, but
not limited
to, 7.19, 10.37, 12.11, 14.41, 17.73, 19.17, 21.71, 23.17, 24.39, 25.17,
26.07, and 27.91
degrees 2-theta (Rigaku PXRD, data with background removed).
R-(-)-modafinil Form IV
Anhydrous ammonia gas was bubbled through a solution containing R-
benzhydrylsulfmyl methyl ester (8.3 g, 0.0288 mol) in methanol (75 mL) for 10
minutes. The reaction was then stirred in a 5 degrees C ice bath for 1 hour
and
ammonia gas was bubbled through for an additional 10 minutes. Stirring was
continued for an additional 4 hours. After stirring for another hour a
precipitate had
formed (422 mg) and was collected. The filtrate was then neutralized using
conc. HCl
and another precipitate formed and was collected. The solid material (3 g) was
passed
through a column (silica gel, grade 9385, 230-400, mesh 60 angstroms), 3:1 v/v
ethyl
acetate and hexane as eluent). The column was then flushed with ethyl acetate
(250
mL). The filtrates were combined and concentrated under reduced pressure to
give R-(-
-modafinil form IV as a colorless solid (590 mg).
R-(-)-modafinil Form IV can be characterized by any one, any two, any three,
any four, any five, or any six or more of the peaks in Figure 6 including, but
not limited
to, 7.79, 10.31, 11.77, 16.49, 17.33, 19.47, and 23.51 degrees 2-theta (Rigaku
PXRD,
data as collected).
DSC of the R-(-)-modafinil form IV characterized in Figure 7 showed an
endothermic transition at about 147 degrees C.
A second batch of R-(-)-modafinil form IV was prepared for further analysis
via
thermal microscopy and PXRD. Solubility data was also acquired. These data are
discussed below.
R-(-)-modafinil Form IV solubility was equal to about 3.5-4.0 mg/mL. The
solubility was measured from an isopropyl acetate slurry stirred at 25 degrees
C. The
solubility measurement was performed via HPLC. The solid from the solubility
samples were dried under nitrogen and characterized by PXRD and thermal
microscopy. Form conversion was not observed during procedure.
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WO 2005/077894 PCT/US2005/002782
Thermal (hotstage) microscopy was used with a heating rate of 10 degrees
C/minute to measure the melting point of R-(-)-modafinil Form IV, which was
determined to be about 147-158 degrees C.
R-(-)-modafinil Form IV can be characterized by any one, any two, any three,
any four, any five, or any six or more of the peaks in Figure 8 including, but
not limited
to, 7.77, 10.33, 11.75, 16.53, 19.43, 19.89, 21.87, 23.49, and 26.69 degrees 2-
theta
(Rigaku PXRD, data with background removed).
R-~)-modafinil Form V
R-(-)-modafinil form IV (prepared in procedure above) was heated in a solution
of ethanol until the mixture was boiling and then was cooled to room
temperature. The
solid material was then collected and characterized as R-(-)-modafinil form V.
R-(-)-modafinil Form V can be characterized by any one, any two, any three,
any four, any five, or any six or more of the peaks in Figure 9 including, but
not limited
to, 6.61, 10.39, 13.99, 16.49, 17.73, 19.03, 20.87, 22.31, and 25.99 degrees 2-
theta
(Rigaku PXRD, data as collected).
A second batch of R-(-)-modafinil form V was prepared for further analysis via
thermal microscopy and PXRD. Solubility data was also acquired. These data are
discussed below.
R-(-)-modafinil Form V solubility was equal to about 2.1-2.6 mg/mL. The
solubility was measured from an isopropyl acetate slurry stirred at 25 degrees
C. The
solubility measurement was performed via HPLC. The solid from the solubility
samples were dried under nitrogen and characterized by PXRD and thermal
microscopy. Form conversion was not observed during procedure.
Thermal (hotstage) microscopy was used with a heating rate of 10 degrees
C/minute to measure the melting point of R-(-)-modafinil form V, which was
determined to be about 159 degrees C.
R-(-)-modafinil Form V can be characterized by any one, any two, any three,
any four, any five, or any six or more of the peaks in Figure 10 including,
but not
limited to, 6.53, 10.19, 13.90, 16.56, 17.35, 17.62, 18.99, 20.93, 22.08,
23.36, and
25.91 degrees 2-theta (Broker PXRD, data as collected).
The polymorphs of R-(-)-modafinil are named Forms III, IV, and V based on
similarities in the PXRD diffractograms to those found in the diffractograms
for
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WO 2005/077894 PCT/US2005/002782
corresponding racemic modafinil Forms III, IV, and V in US Patent Application
No.
20020043207, published on April 18, 2002.
Example 3
2:1 R-(-)-modafinil: S-(+)-modafinil
A solution containing R-(-)-modafinil (80.16 mg, 0.293 mmol) and racemic
modafinil (20.04 mg, 0.0366 mmol) in ethanol (2 mL) was prepared. The mixture
was
heated to boiling in order to dissolve the entire solid and was then cooled to
room
temperature (25 degrees C). After remaining at room temperature for 15
minutes, the
solution was placed at 5 degrees C overnight. The solution was then decanted
and the
remaining crystals were dried under a flow of nitrogen gas and characterized
using
HPLC, PXRD, DSC, and thermal microscopy.
The crystals obtained contained between about 63 and about 67 percent R-(-)-
modafinil and the remainder of the crystals was S-(+)-modafinil. HPLC analysis
indicated that the crystals were a 2:1 phase containing two R-(-)-modafinil
molecules
for every one S-(+)-modafinil molecule.
PXRD was completed on a single crystal sample of the 2:1 R-(-)-modafinil:S-
(+)-modafinil. 2:1 R-(-)-modafinil:S-(+)-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 11
including, but not limited to, 8.95, 10.17, 11.87, 14.17, 15.11, 17.39, 18.31,
20.39,
21.09, 24.41, and 26.45 degrees 2-theta (Rigaku PXRD, data as collected).
DSC of the 2:1 R-(-)-modafinil:S-(+)-modafmil characterized in Figure 12
showed an endothermic transition at about 168 degrees C.
Thermal (hotstage) microscopy was used with a heating rate of 5 degrees
C/minute to measure the melting point of 2:1 R-(-)-modafinil:S-(+)-modafinil,
which
was determined to be about 160-166 degrees C.
Example 4
R-(~-modafmil Form IV
105.9 mg of R-(-)-modafinil was slurried in 1.5 mL of ethanol for 2 days. The
liquor was filtered off and then dried under flowing nitrogen gas. The
resultant solid
was analyzed via PXRD and was determined to be R-(-)-modafinil form IV (Figure
13).
CA 02556106 2006-08-03
WO 2005/077894 PCT/US2005/002782
R-(-)-modafinil Form IV can be characterized by any one, any two, any three,
any four, any five, or any six or more of the peaks in Figure 13 including,
but not
limited to, 7.64, 10.17, 11.61, 16.41, 19.34, 21.71, 22.77, and 23.36 degrees
2-theta
(Broker PXRD, data as collected).
R-(-)-modafinil form IV was also recovered via thermal recrystallization from
ethanol and via the slow evaporation of solvent from ethanol.
Example 5
R-(-)-modafinil Form V
107.7 mg of R-(-)-modafmil was dispensed into 3 mL ethyl acetate. The
suspension was heated on a hotplate (60 degrees C) to dissolve the solid.
Approximately one third to one half of the heated solvent was evaporated off
with
flowing nitrogen gas. The mixture was then cooled to room temperature (25
degrees
C). A centrifuge filter was used to separate the solid from the liquid. The
resultant
solid was analyzed via PXRD and DSC and was determined to be R-(-)-modafinil
form
V (Figures 14 and 15).
R-(-)-modafmil Form V can be characterized by any one, any two, any three,
any four, any five, or any six or more of the peaks in Figure 14 including,
but not
limited to, 6.52, 10.23, 13.93, 16.37, 17.61, 18.97, 20.74, 22.21, 23.36, and
25.90
degrees 2-theta (Broker PXRD, data as collected).
DSC of the R-(-)-modafinil form V was completed. Figure 15 showed an
endothermic transition at about 161-162 (161.57) degrees C.
Example 6
R~~)-modafinil Chloroform Solvate
200 microliters chloroform was added to 30.5 mg R-(-)-modafinil. Mixture was
heated at 75 degrees C for 30 minutes, and then an additional 200 microliters
chloroform was added. After an additional 30 minutes, the solid had completely
dissolved. The sample was heated for an additional 2 hours. After heating, the
sample
was cooled to 5 degrees C at a rate of about 1 degree/minute. Upon reaching 5
degress
C, the sample was still a homogeneous liquid solution. The sample was then
placed
under nitrogen flow for one minute causing crystals to begin to form. Sample
was
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WO 2005/077894 PCT/US2005/002782
again incubated at 5 degrees C and more solid crashed out. The sample was then
dried
under nitrogen flow and characterized by PXRD and TGA.
PXRD was completed on the R-(-)-modafinil chloroform solvate. R-(-)-
modafinil chloroform 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 16 including, but
not limited to,
8.97, 12.07, 14.20, 16.91, 17.49, 18.56, 20.87, 21.45, 23.11, and 25.24
degrees 2-theta
(Broker PXRD, data as collected).
TGA of the R-(-)-modafinil chloroform solvate was completed. Figure 17
showed about a 15 percent weight loss between about 25 and about 150 degrees
C.
Example 7
1~~-modafinil Chlorobenzene Solvate
R-(-)-modafmil (102.6 mg, 0.375 mmol) was suspended in chlorobenzene (5
mL) and heated on a 60 degrees C hotplate. The mixture was allowed to cool to
about
25 degrees C. The slurry was then reheated and THF was added until all solids
were
dissolved. The solution was then allowed to cool while being stored at room
temperature for 4 days in a sealed vial. After storage, the resultant solid
was collected
via vacuum filtration and characterized via PXRD.
PXRD was completed on the R-(-)-modafinil chlorobenzene solvate. R-(-)-
modafinil chlorobenzene 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 18 including,
but not
limited to, 4.51, 6.25, 7.77, 10.37, 11.43, 11.97, 16.61, 17.95, 20.19, 20.89,
23.41, and
30.43 degrees 2-theta (Rigaku PXRD, data as collected).
Example 8
Ethyl acetate channel solvate of racemic modafinil
The ethyl acetate channel solvate of racemic modafinil was made from a
solution of racemic modafinil (53.7 mg, 0.196 mmol) and 1-hydroxy-2-naphthoic
acid
(75.5 mg, 0.401 mmol) in 2.4 mL of ethyl acetate, dissolved over a 60 degrees
C
hotplate. Once cooled, the solution was seeded with ground co-crystals of R-(-
)-
modafinil: l-hydroxy-2-naphthoic acid (see Example 17 of Application No.
PCT/US2004/29013).
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PXRD was completed on the ethyl acetate channel solvate of racemic modafinil.
The ethyl acetate channel solvate of racemic 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 19
including, but not limited to, 8.88, 14.09, 19.83, 21.59, 23.04, and 25.94
degrees 2-theta
(Broker PXRD, data as collected).
TGA of the ethyl acetate channel solvate of racemic modafinil was completed.
Figure 20 showed about a 3.6 percent weight loss between about 25 and about
150
degrees C.
Example 9
R-(-)-modafinil Acetic acid Solvate
The R-(-)-modafinil acetic acid solvate was formed by grinding R-(-)-modafinil
(105.5 mg) in 0.066 mL of acetic acid for 10 minutes in stainless steel
cylinder with a
Wig-L-Bug grinder/mixer. The powder was then analyzed by DSC, TGA, and PXRD.
PXRD was completed on the R-(-)-modafinil acetic acid solvate. The 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 21 including, but not limited to, 9.17, 10.20,
16.61, 17.59,
18.90, 21.11, and 24.11 degrees 2-theta (Broker PXRD, data as collected).
TGA of the R-(-)-modafinil acetic acid solvate was completed. Figure 22
showed about an 11 percent weight loss between about 25 and about 125 degrees
C.
DSC of the R-(-)-modafinil acetic acid solvate was completed. Figure 23
showed an endothermic transition at about 56 degrees C.
33
