Note: Descriptions are shown in the official language in which they were submitted.
- 1 -
ACID ADDITION SALTS OF AN ORALLY AVAILABLE GONADOTROPIN-
RELEASING HORMONE RECEPTOR ANTAGONIST, ELAGOLIX
FIELD OF THE INVENTION
The invention relates to acid addition salts of elagolix with strong acids,
such as sulfuric
acid and hydrochloric acid, to processes for their preparation and to a
pharmaceutical
composition comprising one of said salts, preferably in an effective and/or
predetermined
amount, wherein the pharmaceutical composition can be used as a medicament, in
particular
for the treatment of endometriosis and uterine fibroids.
BACKGROUND OF THE INVENTION
Elagolix is an orally available gonadotropin-releasing hormone (GnRH) receptor
antagonist
currently under investigation in clinical phase III trials for the treatment
of endometriosis
and uterine fibroids. The chemical name of elagolix is 4-[[(1R)-2-[5-(2-fluoro-
3-
methoxy pheny1)-3- [[2-fluoro-6-(tri fluoromethyl)phenyllmethyll -3 ,6-di hy
dro-4-methyl-
2,6-dioxo-1(2H)-pyrimidiny11-1-phenylethyllaminolbutanoic acid. Elagolix is an
uracil
derivative which can be represented by the chemical structure according to
Formula (I)
titt
"
Fsc (1)
WO 2005/007165 Al discloses pyrimidine-2,4-dione derivatives as gonadotropin
releasing
hormone receptor antagonists. The publication mentions on page 12 that said
compounds
may generally be used as the free acid or free base or alternatively in form
of acid or base
addition salts followed by a long list of potentially suitable acids and
bases. The compound
elagolix is disclosed as one example of pyrimidine-2,4-dione derivatives. In
Example 1H of
said
Date Recue/Date Received 2020-06-03
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application elagolix free acid was formed as an intermediate during production
of the elagolix
sodium salt and was described as a white gel after extraction with ethyl
acetate and evaporation
of the solvent. The gel was passed through a DOWEX MSC-1 macroporous strong
cation-
exchange column to convert the acid to the sodium salt. Finally,
lyophilization gave the sodium
salt of elagolix as a white solid.
According to Chen C. et al. "Discovery of Sodium R-(+)-4- {245-(2-Fluoro-3-
methoxypheny1)-
3 -(2-fluoro -6- [trifluoromethyl]benzy1)-4-methyl-2,6-dioxo-3,6-dihydro-2H-
pyrimidin-l-yll-
1-phenylethylaminolbutyrate (Elagolix), a Potent and Orally Available
Nonpeptide Antagonist
of the Human Gonadotropin-Releasing Hormone Receptor" J. Med. Chenz., 2008, 51
(23),
in 7478-7485 elagolix free acid was either obtained as white foam or as gel
after extraction with
ethyl acetate and subsequent evaporation of the solvent. As already previously
described in
WO 2005/007165 Al the gel was passed through a DOWEX MSC-1 macroporous strong
cation-exchange column to convert it to the sodium salt, which was obtained as
white solid after
lyophilization.
WO 2009/062087 Al describes processes for the preparation of uracil
derivatives, a class of
gonadotropin-releasing hormone receptor antagonists including elagolix.
Elagolix free acid
(Example 4, final product of step 4B) and its sodium salt (Example 5, final
product of step 5B
and alternate step 5B) were both obtained as off-white solids. On page 6, the
application
describes the compounds of the application as amorphous solids and goes on to
suggest that the
compounds of the application are formulated as amorphous cosolutions, for
example by spray-
drying with excipients such as PVP (polyvinyl pyrrolidone, Kollidons) or HPMC
(hydroxypropylmethylcellulose). Amorphous elagolix sodium is described as
preferred for that
purpose and in Example 9 a solid amorphous mixture was prepared from elagolix
sodium and
polymers such as HPMC and Kollidon, wherein an excess of polymer at a weight
ratio of 1:3
has been used.
The drug substance elagolix is described to be an amorphous hygroscopic solid
on page 10 of
WO 2017/007895 Al. In Examples 1 and 2 of said application, elagolix drug
substance was
employed in form of its sodium salt.
Extensive solid-form screening of a new drug is an important step during
pharmaceutical
development. It is noteworthy that elagolix or its pharmaceutically acceptable
salts have not
been obtained as crystalline materials so far during pharmaceutical
development of elagolix
despite what must have been considerable efforts. Even worse, elagolix sodium
is highly
- 3 -
hygroscopic and was found to deliquesce upon moisture contact. Such properties
requiring
special care and precautionary measures, such as controlled atmosphere during
pharmaceutical processing, which renders manufacturing cumbersome and
expensive. The
solid dispersion of elagolix sodium with HPMC, which is disclosed in WO
2009/062087
Al, introduces the 3-fold amount of polymer in relation to the active
substance, which
significantly increases the weight and therefore also the volume of an oral
solid dosage
form such as a tablet or a capsule. Such formulations may negatively influence
patients'
compliance, in particular for elderly people having troubles swallowing.
It was thus an objective of the present invention to provide improved solid
forms of
elagolix, which address some or all of the above-mentioned problems of the
elagolix
sodium salt.
SUMMARY OF THE INVENTION
The present invention provides pharmaceutically acceptable non-deliquescent
acid addition
salts of elagolix with strong acids, such as acids selected from the group
consisting of
sulfuric acid and hydrochloric acid, wherein the acid addition salt is
amorphous or
crystalline. It was surprisingly found that salts of elagolix with strong
acids, in particular
wherein the stoichiometry of elagolix : anion is about 1:1, can be obtained
which do not
deliquesce and /or show unexpected low hygroscopicity, in particular when
compared to
the widely used salts of elagolix with a base, like the elagolix sodium salt.
They therefore
demonstrate physicochemical properties making them suitable for various
purposes in the
pharmaceutical field, in particular for storage and/or for the preparation of
a pharmaceutical
composition.
In an embodiment, there is provided a non-deliquescent acid addition salt of
elagolix,
wherein the acid is a strong acid having a pKa in water of at most 1.0, which
addition
salt is crystalline or amorphous.
Also provided is a process for the preparation of an acid addition salt of
elagolix
described herein, comprising:
(i) reacting elagolix with a strong acid in the presence of an organic
solvent; and
(ii) separating the elagolix acid addition salt obtained in step (i) from the
reaction
mixture.
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Also provided is an acid addition salt of elagolix described herein for the
preparation
of a base addition salt of elagolix.
Also provided is an acid addition salt of elagolix described herein for the
preparation
of a pharmaceutical composition.
Also provided pharmaceutical composition comprising an acid addition salt of
elagolix described herein and one or more pharmaceutically acceptable
excipient(s).
Also provided is an acid addition salt of elagolix described herein for use in
the
treatment of endometriosis or uterine fibroids.
Also provided is a pharmaceutical composition as described herein for use in
the
treatment of endometriosis and uterine fibroids.
Also provided is a use of an acid addition salt of elagolix described herein
or a
pharmaceutical composition described herein for the treatment of endometriosis
or
uterine fibroids.
Also provided is a use of an acid addition salt of elagolix described herein
or a
pharmaceutical composition described herein for the manufacture of a
medicament for
the treatment of endometriosis or uterine fibroids.
Abbreviations
PXRD powder X-ray diffractogram
RH relative humidity
RT room temperature
w-% weight percent
Definitions
In the context of the present invention the following definitions have the
indicated
meaning, unless explicitly stated otherwise:
The term "elagolix" as used herein refers to the compound with the chemical
name 4-
R(JR)-245-(2-fluoro-3-methoxypheny1)-3-[[2-fluoro-6-
(trifluoromethypphenyl]methyl]-
3,6-dihydro-4-methyl-2,6-dioxo-l(211)-pyrimidiny1]-1-
phenylethyl]amino]butanoic acid,
which is
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represented by the chemical structure as depicted in Formula (I) of the
present invention. In the
present invention "elagolix" indicates the free acid form, where the hydrogen
atom of the
carboxylic acid group is not substituted by another kind of atom, for example
by sodium
or potassium.
.. As used herein, the term "strong acid" refers to an acidic compound having
a pKa in water at a
temperature of 25 C of at most 1.0, more preferably of at most 0.0, such as at
most -1Ø With
regard to the definition of pKa and pharmaceutically acceptable salts of
strong acids, reference
is made to Stahl, P. H., & Wermuth, C. G. (2002): Handbook of pharmaceutical
salts:
Properties, selection, and use. Weinheim: Wiley-VCH.
As used herein, the term "an acid addition salt of a compound with sulfuric
acid" can be a
hydrogen sulfate salt or a sulfate salt of a compound, preferably a sulfate
salt of a compound.
Thus, when applied to elagolix, the term "an acid addition salt of elagolix
with sulfuric acid"
can be a hydrogen sulfate salt or a sulfate salt of elagolix, preferably a
sulfate salt of elagolix.
As used herein, the term "an acid addition salt of a compound with
hydrochloric acid" is a
hydrochloride salt of a compound, preferably a monohydrochloride salt of a
compound. Thus,
when applied to elagolix, the term -an acid addition salt of elagolix with
hydrochloric acid" is
a hydrochloride salt, preferably a monohydrochloride salt of elagolix.
As used herein the term "room temperature" refers to a temperature in the
range of from 20 to
30 C, preferably to a temperature in the range of from 22 to 27 C, more
preferably to a
temperature in the range of from 23 to 26 C.
As used herein, the term "measured at a temperature in the range of from 20 to
30 C" refers to
a measurement under standard conditions. Typically, standard conditions mean a
temperature
in the range of from 20 to 30 C, i.e. at room temperature. A preferred
temperature for
measurements is 22 C. Typically, standard conditions additionally mean a
measurement at
20% to 75% RH, with about 40% RH being a preferred controlled humidity value
for a
measurement.
As used herein the term "amorphous" refers to a solid form of a compound that
is not crystalline.
An amorphous compound possesses no long-range order and does not display a
definitive X-
ray diffraction pattern with reflections.
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The term "reflection" with regards to powder X-ray diffraction as used herein,
means peaks in
an X-ray diffractogram, which are caused at certain diffraction angles (Bragg
angles) by
constructive interference from X-rays scattered by parallel planes of atoms in
solid material,
which are distributed in an ordered and repetitive pattern in a long-range
positional order. Such
5 a solid material is classified as crystalline material, whereas amorphous
material is defined as
solid material, which lacks long-range order and only displays short-range
order, thus resulting
in broad scattering. According to literature, long-range order e.g. extends
over approximately
103 to 1020 atoms, whereas short-range order is over a few atoms only (see
"Fundamentals of
Powder Diffraction and Structural Characterization of Materials" by Vitalij K.
Pecharsky and
Peter Y. Zavalij, Kluwer Academic Publishers, 2003, page 3).
The term "essentially the same" with reference to powder X-ray diffraction
means that
variabilities in peak positions and relative intensities of the peaks need to
be taken into account.
For example, a typical precision of the 2-Theta values is in the range of +
0.2 2-Theta,
preferably in the range of + 0.1 2-Theta. Thus, a diffraction peak that
usually appears at 8.6
2-Theta for example can appear between 8.4 and 8.8 2-Theta, preferably
between 8.5 and
8.7 2-Theta on most X-ray di ffractometers under standard conditions.
Furthermore, one skilled
in the art will appreciate that relative peak intensities will show inter-
apparatus variability as
well as variability due to degree of crystallinity, preferred orientation,
sample preparation and
other factors known to those skilled in the art and should be taken as
qualitative measure only.
The term "physical form" or "solid form", which may be used interchangeably
herein, refers to
any crystalline and amorphous phase of a compound.
A "predetermined amount" as used herein with regard to an acid addition salt
of elagolix of the
present invention refers to a defined amount of said acid addition salt of
elagolix to be used for
the preparation of a unit dose of a pharmaceutical composition.
The term "effective amount" as used herein with regard to an acid addition
salt of elagolix of
the present invention encompasses an amount of said acid addition salt of
elagolix, which
causes a desired therapeutic and/or prophylactic effect.
An acid addition salt of elagolix may be referred to herein as being
characterized by graphical
data "as shown in" a figure. Such data include, for example, powder X-ray
diffractograms. The
person skilled in the art understands that factors such as variations in
instrument type, response
and variations in sample directionality, sample concentration and sample
purity may lead to
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small variations for such data when presented in graphical form, for example
variations relating
to the exact peak positions and intensities.
"Impurities" as used herein are organic impurities as defined in the ICH
tripartite guideline
"Impurities in new drug substances" Q3A(R2), step4 version dated 25.10.2006.
In any given
sample, this means the organic components of a sample comprising elagolix or
an acid addition
salt thereof that is not elagolix or an acid addition salt thereof. Briefly,
organic impurities can
arise during the manufacturing process and/or storage of an active
pharmaceutical ingredient.
They can include starting materials, by-products, intermediates, degradation
products, reagents,
ligands and catalysts.
As used herein the term "deliquescent" means the property of a solid form of a
compound to
readily absorb moisture form the surrounding atmosphere until it deliquesces
and forms a
solution upon storage for 14 days at 40 C, atmospheric pressure and 75%
relative humidity.
As used herein the term "moderately hygroscopic" refers to a solid form of a
compound which
shows a water uptake of at most 8.0 w-% in the sorption cycle when measured
with gravimetric
moisture sorption at a relative humidity in the range of from 0% to 80% and a
temperature of
25.0 0.1 C, based on the weight of the compound.
As used herein, the term -about" means within a statistically meaningful range
of a value. Such
a range can be within an order of magnitude, typically within 10%, more
typically within 5%,
even more typically within 1% and most typically within 0.1% of the indicated
value or range.
Sometimes, such a range can lie within the experimental error, typical of
standard methods used
for the measurement and/or detemiination of a given value or range.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: illustrates a representative F'XRD of the crystalline acid addition
salt of elagolix with
sulfuric acid of the present invention. The x-axis shows the scattering angle
in 2-Theta, the y-
axis shows the intensity of the scattered X-ray beam in counts of detected
photons.
Figure 2: illustrates a representative PXRD of the amorphous acid addition
salt of elagolix with
hydrochloric acid of the present invention. The x-axis shows the scattering
angle in 2-Theta,
the y-axis shows the intensity of the scattered X-ray beam in counts of
detected photons.
DETAILED DESCRIPTION OF THE INVENTION
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The present invention relates to non-deliquescent acid addition salts of
elagolix with strong
acids, for example an acid addition salt of elagolix with sulfuric acid or
with hydrochloric acid,
for example wherein the molar ratio of elagolix and acid is in the range of
from 1.0 : 0.8 to 1.0
: 1.2. The acid addition salt of elagolix with a strong acid may be amorphous
or crystalline.
Preferably the acid addition salt of elagolix with a strong acid are only
moderately hygroscopic.
The present inventors have found that elagolix can form non-deliquescent acid
addition salts
with strong acids. This is in contrast to the elagolix salts with bases, such
as the elagolix sodium
salt, which are deliquescent and take up so much water upon two weeks storage
at 40 C and
70% relative humidity that these salts dissolve in that water. The non-
deliquescent acid addition
salts of the present invention have the advantage that they are particularly
suitable for storage
and/or for the preparation of a pharmaceutical composition. In addition, the
crystalline acid
addition salt of elagolix with sulfuric acid of the present invention is a
solid form of elagolix,
which is more convenient to handle during pharmaceutical processing, for
example which is
easier to handle during the formulation of a drug product, in particular
during the formulation
of an oral solid dosage form such as a capsule or a tablet. A further
advantage of the crystalline
acid addition salt of elagolix with sulfuric acid of the present invention is
that it can be used to
efficiently deplete impurities from elagolix.
Different aspects of the invention are described below in further detail by
embodiments, without
being limited thereto. Each aspect of the invention may be described by one
embodiment or by
combining two or more of the embodiments.
A first aspect of the present invention concerns an acid addition salt of
elagolix of Formula (I)
0
0
HO 0
F3C (I)
with a strong acid, which acid addition salt is non-deliquescent.
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Strong acids which form pharmaceutically acceptable acid addition salts with
elagolix are
preferred, such as hydrobromic acid, hydrochloric acid, naphthalene-1,5-
disulfonic acid,
sulfuric acid, ethane-1,2-disulfonic acid, cyclamic acid, p-toluenesulfonic
acid, thiocyanic acid,
nitric acid, methanesulfonic acid, dodecylsulfuric acid, naphthalene-2-
sulfonic acid and
benzenesulfonic acid, with hydrobromic acid, hydrochloric acid, sulfuric acid,
ethane-1,2-
disulfonic acid, p-toluenesulfonic acid and methanesulfonic acid being even
more preferred.
Acid addition salts which are only moderately hygroscopic are particularly
preferred.
In a preferred embodiment the present invention relates to a non-deliquescent
salt of elagolix
with sulfuric acid, in particular wherein the acid addition salt of elagolix
with sulfuric acid is
crystalline.
The crystalline acid addition salt of elagolix with sulfuric acid of the
present invention may be
characterized by analytical methods well known in the field of the
pharmaceutical industry for
characterizing solids. A preferred method for characterizing said crystalline
solid is for example
powder X-ray diffraction.
In one embodiment, the present invention relates to the crystalline acid
addition salt of elagolix
with sulfuric acid characterized by having a PXRD comprising reflections at 2-
Theta angles of:
(7.6 0.2) , (8.6 0.2) and (10.0 0.2) ; or
(7.6 0.2) , (8.6 0.2) , (10.0 0.2) and (15.5 0.2) ; or
(7.6 0.2) , (8.6 0.2) , (10.0 0.2) , (15.5 0.2) and (18.1 0.2) ; or
(7.6 0.2) , (8.6 0.2) , (10.0 0.2) , (15.5 0.2) , (18.1 0.2) and
(20.1 0.2) ; or
(7.6 0.2) , (8.6 0.2) , (9.1 0.2) , (10.0 0.2) , (15.5 0.2) , (18.1
0.2) and (20.1
0.2) ; or
(7.6 + 0.2) , (8.6 + 0.2) , (9.1 + 0.2) , (10.0 + 0.2) , (14.2 0.2) , (15.5
+ 0.2) , (18.1 + 0.2)
and (20.1 0.2)", or
(7.6 0.2) , (8.6 0.2) , (9.1 0.2) , (10.0 0.2) , (14.2 0.2) , (15.5
0.2) , (18.1 0.2) ,
(19.0 0.2) and (20.1 0.2) ; or
(7.6 0.2) , (8.6 0.2) , (9.1 0.2) , (10.0 0.2) , (14.2 0.2) , (14.8
0.2) , (15.5 0.2) ,
(18.1 0.2) , (19.0 0.2) and (20.1 0.2) ;
when measured at a temperature in the range of from 20 to 30 C with Cu-
Kalphai,2 radiation
having a wavelength of 0.15419 nm.
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In another embodiment, the present invention relates to the crystalline acid
addition salt of
elagolix with sulfuric acid characterized by having a PXRD comprising
reflections at 2-Theta
angles of:
(7.6 0.1) , (8.6 0.1) and (10.0 0.1) ; or
(7.6 0.1) , (8.6 0.1) , (10.0 0.1) and (15.5 0.1) ; or
(7.6 0.1) , (8.6 0.1) , (10.0 0.1) , (15.5 0.1) and (18.1 0.1) ; or
(7.6 0.1) , (8.6 0.1) , (10.0 0.1) , (15.5 0.1) , (18.1 0.1) and
(20.1 0.1) ; or
(7.6 0.1) , (8.6 0.1) , (9.1 0.1) , (10.0 0.1) , (15.5 0.1) , (18.1
0.1) and (20.1
0.1) ; or
(7.6 0.1) , (8.6 0.1) , (9.1 0.1) , (10.0 0.1) , (14.2 OA) , (15.5
0.1) , (18.1 0.1)
and (20.1 0.1) ; or
(7.6 0.1) , (8.6 0.1) , (9.1 0.1) , (10.0 0.1) , (14.2 0.1) , (15.5
0.1) , (18.1 0.1) ,
(19.0 0.1) and (20.1 0.1) ; or
(7.6 0.1) , (8.6 0.1) , (9.1 0.1) , (10.0 0.1) , (14.2 0.1) , (14.8
0.1) , (15.5 0.1) ,
(18.1 0.1) , (19.0 0.1) and (20.1 0.1) ;
when measured at a temperature in the range of from 20 to 30 C with Cu-
Kalpha1,2radiation
having a wavelength of 0.15419 nm.
In still another embodiment, the present invention relates to the crystalline
acid addition salt of
elagolix with sulfuric acid characterized by having a PXRD essentially the
same as shown in
Figure 1 of the present invention, when measured at a temperature in the range
of from 20 to
C with Cu-Kalphal,2 radiation having a wavelength of 0.15419 nm.
In a further aspect, the invention refers to a non-deliquescent acid addition
salt of elagolix of
Formula (I) with hydrochloric acid.
In a preferred embodiment, the acid addition salt of elagolix with
hydrochloric acid is
25 amorphous.
In one embodiment, the acid addition salt of elagolix with hydrochloric acid
is characterized by
having a powder X-ray diffractogram comprising no reflection in the range of
from 2 to 40 2-
Theta, when measured at a temperature in the range of from 20 to 30 C with Cu-
Kalphai,2
radiation having a wavelength of 0.15419 nm.
30 In a further embodiment, the acid addition salt of elagolix with
hydrochloric acid is
characterized by having a PXRD essentially the same as shown in Figure 2 of
the present
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invention, when measured at a temperature in the range of from 20 to 30 C
with Cu-Kalpha1,2
radiation having a wavelength of 0.15419 nm.
In a particular embodiment, the acid addition salts of elagolix with the
strong acid, in particular
with a pharmaceutically acceptable acid such as sulfuric acid or hydrochloric
acid, is
characterized by having a molar ratio of elagolix and acid in the range of
from 1.0 : 0.8 to 1.0:
1.2, preferably of from 1.0: 0.9 to 1.0 :1.1 and most preferably the molar
ratio is 1.0: 1Ø
Surprisingly, the acid addition salts of elagolix of the present invention,
such as the crystalline
acid addition salt of elagolix with sulfuric acid and the amorphous acid
addition salt of elagolix
with hydrochloric acid, do not deliquesce upon moisture contact but preserve
their solid form
even under accelerated stress conditions of 40 C/75% RH. This is
advantageous, since there is
no need for precautionary measures in order to protect the salts of the
present invention during
drug product manufacturing from moisture and there is also no need for
expensive packaging
material, which protects the final drug product comprising the salts of the
present invention
from humid atmospheres during storage.
In contrast, elagolix sodium and other tested base addition salts of elagolix
deliquesced fairly
quickly, when they were subjected to the above described accelerated stress
conditions. Said
property requires moisture protection during pharmaceutical processing,
special formulation
strategies, such as solid dispersions, thereby adding further excipients to
the formulation and
making the so formulated pharmaceutical dosage form larger than necessary or
desired, and/or
special packaging for storage. The results of the accelerated stress test are
summarized in
Example 2.
In a further aspect, the present invention relates to a process for the
preparation of the elagolix
acid addition salts as defined above, said process comprising the steps of:
(i) reacting elagolix with a strong acid, such as selected from the group
consisting
of sulfuric acid or hydrochloric acid, in the presence of an organic solvent
and
(ii) separating the elagolix acid addition salt obtained in step (i) from the
reaction
mixture.
El agolix provided in step (i) can be prepared according to the teaching of WO
2009/062087 Al
Example 4 yielding amorphous material.
A suitable organic solvent, in which the acid base reaction of step (i) may be
carried out is
selected from the group consisting of acetonitrile, C3-05 ketones, Ci-C2
halogenated
hydrocarbons, C3-C4 alcohols, C2-C6 ethers, C3-05 esters or a combination of
two or more
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thereof. Preferably, the solvent is selected from the group consisting of
dichloromethane,
chloroform, tetrahydrofiiran, 2-methyltetrahydrofuran, 2-propanol, ethyl
acetate, isopropyl
acetate, acetone, acetonitrile or mixtures of two or more thereof More
preferably, the solvent
is selected from the group consisting of ethyl acetate, acetonitrile or a
mixture thereof Even
more preferably the reaction mixture comprises one or more of the above listed
organic
solvent(s) and additionally water. Most preferably, the reaction mixture
comprises acetonitrile
and water or ethyl acetate and water.
The temperature of the reaction mixture is kept in the range of from 0 to 30
C, more preferably
in the range of from 2 to 25 C, for example in the range of from 20 to 25 C
and preferably the
reaction is carried out at ambient pressure. The acid may be applied as
aqueous solution
containing 37 to 97 w-% acid as described in Example 1 herein. The molar ratio
of elagolix and
acid applied is in the range of from 1.0 : 0.8 to 1.0 : 1.2, preferably of
from 1.0 : 0.9 to 1.0 : 1.1
and most preferably the molar ratio is 1.0 : 1Ø
The reaction mixture obtained in step (i) is stirred, shaken or allowed to
stand at a temperature
in the range of from 0 to 30 C, preferably in the range of from 2 to 25 C,
for example in the
range of from 20 to 25 C, typically for a period of time in the range of from
0.1 to 24 hours in
order to promote the formation of the el agolix acid addition salt. Once the
reaction is complete,
the acid addition salt may remain in solution, precipitate as amorphous
material or crystallize.
If the acid addition salt remains in solution it may be separated from the
reaction mixture by
removing the solvent for example by lyophilization, spray drying, vacuum
drying or
evaporation. In a spray drying process, the solution is pumped through an
atomizer into a drying
chamber thereby removing the solvent to form the solid acid addition salt. A
drying process
uses hot gases, such as air, nitrogen, nitrogen-enriched air or argon, to dry
the particles. The
solution can be atomized by conventional means well known in the art, such as
a two-fluid
.. sonication nozzle and a two-fluid non-sonication nozzle. Preferably, the
solvent is removed by
lyophilization or spray drying. If the solvent is removed by lyophilization,
the sample
temperature during lyophilization may be varied or held essentially constant
and is preferably
in the range of from 20 to 40 C, more preferably in the range of from 25 to
35 C.
If the acid addition salt precipitates as amorphous material or crystallizes,
the obtained
suspension can optionally be further kept at a temperature in the range of
from 0 to 20 C,
preferably in the range of from 2 to 10 C to increase the process yield
before the acid addition
salt is separated from the reaction mixture by any conventional method such as
filtration or
centrifugation, most preferably by filtration. Optionally, the isolated solid
material may be
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washed with a solvent. Preferably, the solvent comprises ethyl acetate and
most preferably, the
solvent is ethyl acetate. Finally, the elagolix acid addition salt may
optionally be dried at a
temperature in the range of from 20 to 60 C, more preferably of from 20 to 40
C and most
preferably the elagolix acid addition salt is dried at RT. Drying may be
performed for a period
of time in the range of from about 1 to 72 hours, preferably from about 2 to
48 hours, more
preferably from about 4 to 24 hours and most preferably from about 6 to 18
hours. Drying may
be performed at ambient pressure and/or under vacuum preferably at about 100
mbar or less,
more preferably at about 50 mbar or less and most preferably at about 30 mbar
or less.
In order to promote the crystallization of the acid addition salt of elagolix
with sulfuric acid,
seed crystals of acid addition salt of elagolix with sulfuric acid as defined
hereinabove can
optionally be added to the reaction mixture of step (i). Seed crystals can be
prepared according
to Example 1.1 disclosed herein. The amount of seed crystals employed may
range from about
0.1 to 20 w-%, preferably from about 0.5 to 10 w-% and most preferably from
about 1 to 5 w-
%, based on the weight of applied clagolix starting material.
As already mentioned above, the crystalline acid addition salt of elagolix
with sulfuric acid of
the present invention efficiently depletes impurities from elagolix and is
obtained in high
chemical purity. Hence, the crystalline acid addition salt of elagolix with
sulfuric acid may also
be used as a means for purification of elagolix and may be further used for
the preparation of a
base addition salt of elagolix.
Therefore, in a further aspect, the invention relates to the use of the
crystalline acid addition
salt of elagolix with sulfuric acid as described herein for the preparation of
a pharmaceutically
acceptable base addition salt of elagolix. In a particular embodiment the
pharmaceutically
acceptable base addition salt is selected from the group consisting of
elagolix sodium,
potassium, magnesium, calcium, lithium, zinc, ammonium, ethylenediamine,
meglumine and
.. lysine. Preferably, the pharmaceutically acceptable base addition salt is
selected from elagolix
sodium and elagolix potassium, most preferably it is elagolix sodium
In a further aspect, the invention relates to a method for the preparation of
a pharmaceutically
acceptable base addition salt of elagolix, said method comprising the steps
of:
(a) providing an acid addition salt of elagolix with a strong acid, such as
the acid
addition salt of elagolix with sulfuric acid as described herein,
(b) converting the acid addition salt to elagolix of Formula (I),
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(c) reacting elagolix obtained in step (b) with a pharmaceutically acceptable
base,
such as sodium hydroxide, in the presence of an organic solvent and
(d) separating the pharmaceutically acceptable base addition salt of elagolix,
such
as elagolix sodium, obtained in step (c) from the reaction mixture.
In another aspect, the present invention relates to the non-deliquescent acid
addition salts of
elagolix with a strong acid, such as sulfuric acid or hydrochloric acid, as
described herein for
the preparation of a pharmaceutical composition.
In another aspect, the present invention relates to a non-deliquescent
amorphous acid addition
salt of elagolix with a strong acid, such as sulfuric acid or hydrochloric
acid, for the preparation
of a pharmaceutical composition.
In another aspect, the present invention relates to a non-deliquescent
crystalline acid addition
salt of elagolix with a strong acid, such as sulfuric acid or hydrochloric
acid, for the preparation
of a pharmaceutical composition.
In a further aspect, the present invention relates to a pharmaceutical
composition comprising
one of the non-deliquescent acid addition salts of elagolix with a strong
acid, such as sulfuric
acid or hydrochloric acid as defined herein, preferably in a predetermined
and/or effective
amount and one or more pharmaceutically acceptable excipient(s). The acid
addition salt of
elagolix with a strong acid can be amorphous or crystalline.
In a preferred embodiment, the predetermined and/or effective amount of the
acid addition salt
of elagolix of the pharmaceutical composition as defined above is selected
from the group
consisting of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225
mg, 250
mg, 275 mg and 300 mg calculated as elagolix.
In a further preferred embodiment, the one or more pharmaceutically acceptable
excipient(s) of
the pharmaceutical composition as defined above is/are one or more diluent(s).
Preferably, the
one or more diluent(s) is/are selected from the group consisting of
carbohydrates such as sugars,
sugar alcohols, starches and celluloses. In another embodiment, the sugar may
be selected from
the group consisting of lactose, e.g. lactose monohydrate, anhydrous lactose
or spray dried
lactose, sucrose, dextrose, fructose, glucose, maltose and maltodextrin. In
still another
embodiment, the sugar alcohol may be selected from the group consisting of
mannitol, sorbitol,
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xylitol and inositol. In a further embodiment the starches may be selected
from corn starch and
potato starch, whereas the starches are preferably pre-gelatinized or
hydrolyzed. In yet another
embodiment the celluloses may be selected from the group consisting of
powdered cellulose,
microcrystalline cellulose and silicified cellulose. In another preferred
embodiment the one or
more diluent(s) may also be selected from inorganic materials such as but not
limited to calcium
phosphate, calcium carbonate, calcium sulfate, calcium lactate, sodium
chloride, magnesium
oxide and magnesium carbonate.
In still another preferred embodiment, the pharmaceutical composition of the
present invention
is an oral solid dosage form such as a tablet or a capsule and most preferably
the pharmaceutical
composition is a tablet.
The pharmaceutical composition as defined above may be prepared by
pharmaceutical standard
procedures e.g. by wet or dry processing methods. In certain embodiments the
pharmaceutical
composition is prepared by wet processing methods, such as, but not limited
to, wet granulation
methods. Suitable wet granulation methods comprise high-shear granulation or
fluid bed
granulation. In another embodiment the pharmaceutical composition is prepared
by dry
processing methods, such as, but not limited to, direct compression or dry
granulation methods.
An example of dry granulation is roller compaction. The pharmaceutical
composition obtained
by dry or wet processing methods are preferably compressed into tablets or
encapsulated.
The present invention also relates to the pharmaceutical composition as
defined above for use
as a medicament.
The present invention also relates to the pharmaceutical composition as
defined above for the
treatment of endometriosis and uterine fibroids.
The present inventors have found that acid addition salts of elagolix with
strong acids, such as
hydrochloric acid or sulfuric acid, can be obtained as solid forms which are
non-deliquescent.
This is contrary to the base addition salts which are widely used for
elagolix. This makes acid
addition salts of elagolix with strong acids, such as hydrochloric acid or
sulfuric acid, attractive
for storage and/or shipment, for example as an intermediate for elagolix
sodium production.
The present invention therefore also relates to the use of an acid addition
salt of elagolix with a
strong acid, such as hydrochloric acid or sulfuric acid, for shipment and/or
storage.
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The present invention also relates to a method for the transport of elagolix,
wherein an acid
addition salt of elagolix with a strong acid, such as hydrochloric acid or
sulfuric acid, is
moved from one place to another. Transport can mean transport from one
reaction vessel to
another. But in particular transport means long-distance transport, where an
acid addition salt
of elagolix with a strong acid is transported for a distance of more than one
kilometer, or even
shipped between countries and/or continents.
EXAMPLES
The following analytical method and parameters have been applied for the
generation of the
powder X-ray data disclosed in the present invention:
Powder X-ray diffraction
Powder X-ray diffraction was performed with a PANalytical X'Pert PRO
diffractometer
equipped with a theta/theta coupled goniometer in transmission geometry, Cu-
Kalphai,2
radiation (wavelength 0.15419 nm) with a focusing mirror and a solid state
Meet detector.
.. Diffractograms were recorded at a tube voltage of 45 kV and a tube current
of 40 mA, applying
a stepsize of 0.013 2-Theta with 40s per step (255 channels) in the angular
range of 2 to 40
2-Theta at ambient conditions.
Gravimetric Moisture Sorption
Moisture sorption and desorption curves are recorded with an SPSx-1u moisture
sorption
analyzer (ProUmid, Ulm).
The measurement cycle is started at ambient relative humidity (RH) of 30%. RH
is then
decreased to 0% in 5% steps. Afterwards RH is increased from 0% to 80% in a
sorption cycle.
The time per step is set to a minimum of 2 hours and a maximum of 6 hours. If
an equilibrium
condition with a constant mass of 0.01% within 1 hour is reached before the
maximum time
for all examined samples the sequential humidity step is applied before the
maximum time of
6 hours If no equilibrium is achieved the consecutive humidity step is applied
after the
maximum time of 6 hours. The temperature is 25 0.1 C.
The following non-limiting examples are illustrative for the disclosure and
shall not limit the
scope of the invention.
Example 1: Preparation of elagolix acid addition salts
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Example 1.1: Crystalline acid addition salt of elagolix with sulfuric acid
Amorphous elagolix (200 mg, for example prepared according to the procedure
disclosed in
WO 2009/062087 Al, example 4B) was dissolved in 3.0 naL ethyl acetate,
followed by filtration
with the aid of a syringe filter (pore size 0.45 microns). Sulfuric acid (95-
97 w-% aqueous
.. solution, 1.05 mol equivalent, 18.8 microliter) was diluted with 1.0 mL
ethyl acetate and added
dropwise to the elagolix solution under stirring. The thus obtained mixture
was further stirred
at room temperature for 18 hours, leading to the formation of a homogeneous
suspension. The
solid material was collected by filtration, washed with a little amount of
ethyl acetate and dried
under vacuum (30 mbar) at room temperature for 16 hours, yielding the acid
addition salt of
.. elagolix with sulfuric acid as a white solid. The obtained material was
crystalline as confirmed
by the PXRD depicted in Figure 1 herein. The corresponding reflection list is
provided in Table
1 below.
Angle Relative Intensity Angle Relative Intensity
[ 2-Theta] [%] [ 2-Theta] [%]
7.6 41 21.0 13
8.6 100 21.3 20
9.1 17 22.1 15
10.0 62 22.5 5
11.7 2 22.9 11
12.1 6 23.5 4
13.8 7 24.1 11
14.2 28 24.4 19
14.8 18 25.0 17
15.5 71 25.2 17
16.5 16 25.5 27
16.7 8 26.0 14
17.6 6 26.4 7
18.1 48 27.6 13
18.6 10 28.1 4
19.0 21 28.7 9
19.5 3 29.0 6
20.1 33 29.7 4
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Table 1: PXRD reflections and corresponding relative intensities of the
crystalline acid addition salt of
elagolix with sulfuric acid prepared according to Example 1.1 in the range of
from 2 to 300 2-Theta; A
typical precision of the 2-Theta values is in the range of + 0.2 2-Theta,
preferably of 0.1 2-Theta.
Example 1.2: Amorphous acid addition salt of clagolix with hydrochloric acid
Amorphous elagolix (300 mg, for example prepared according to the procedure
disclosed in
WO 2009/062087 Al, example 4B) was dissolved in 4.2 mL acetonitrile/water
(volume ratio
1:1). Hydrochloric acid fuming (37 w-% aqueous solution, 1.0 mol equivalent,
39.4 microliter)
was diluted with 1.5 mL acetonitrile/water (volume ratio 1:1) and added to the
elagolix solution.
The thus obtained solution was shaken at room temperature and afterwards
allowed to stand
without shaking for about 10 min before it was filtered with the aid of a
syringe filter (pore size
0.45 microns). The homogeneous solution was frozen in a bath of liquid
nitrogen and
lyophilized at room temperature and a pressure below 2 mbar, yielding acid
addition salt of
elagolix with hydrochloric acid as a white solid. The obtained material was
amorphous as
confirmed by the PXRD depicted in Figure 2 herein.
Example 2: Accelerated stress test at 40 C/ 75% RH with elagolix acid
addition salts vs.
base addition salts
The physical stability of different elagolix salts against moisture and
temperature stress has
been tested. For this purpose, the clagolix salts were open stored at
accelerated stress conditions
of 40 C and 75% RH for 1, 3 and 8 weeks respectively. The physical stability
has been
investigated by means of powder X-ray diffraction and the consistency of the
samples was
visually controlled. The results are summarized in Table 2 below.
Salts of 1 week at 3 weeks at 8 weeks at
Initial sample
elagolix with 40 C/75% RH 40 C/75% RH 40 C/75% RH
sulfuric acid crystalline solid crystalline solid crystalline
solid crystalline solid
HC1 amorphous solid amorphous solid amorphous solid
amorphous solid
NaOH amorphous solid deliquescence
KOH amorphous solid deliquescence
L-arginine amorphous solid deliquescence
cholinc amorphous solid deliquescence
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meglumine amorphous solid deliquescence
L-lysine amorphous solid deliquescence
Table 2: Results of comparative stress test with different elagolix salts
As can be seen from Table 2, those acid addition salts of elagolix prepared
with strong acids,
such as sulfuric acid or hydrochloric acid remained solid throughout the whole
stress test. In
addition, these salts did not undergo any solid form transformations. The
amorphous acid
addition salt of elagolix with hydrochloric acid remained amorphous and the
crystalline acid
addition salt of elagolix with sulfuric acid preserved its crystal structure,
which was confirmed
by the unchanged powder X-ray diffractograms measured before and after the
stress test.
In stark contrast, all tested salts of elagolix with a base including elagolix
sodium deliquesced
fairly quickly, when they were subjected to the above described stress
conditions.
Consequently, the stress test for these salts was already discontinued at the
first check point
after one week.
