CA3059815C - Acid addition salts of an orally available gonadotropin-releasing hormone receptor antagonist, elagolix - Google Patents
Acid addition salts of an orally available gonadotropin-releasing hormone receptor antagonist, elagolix Download PDFInfo
- Publication number
- CA3059815C CA3059815C CA3059815A CA3059815A CA3059815C CA 3059815 C CA3059815 C CA 3059815C CA 3059815 A CA3059815 A CA 3059815A CA 3059815 A CA3059815 A CA 3059815A CA 3059815 C CA3059815 C CA 3059815C
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- CA
- Canada
- Prior art keywords
- elagolix
- acid
- addition salt
- acid addition
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000003839 salts Chemical class 0.000 title claims abstract description 138
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- 238000011835 investigation Methods 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
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- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
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- 235000010355 mannitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
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- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
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- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
Abstract
The invention relates to non-deliquescent acid addition salts of elagolix with strong acids, for example selected from the group consisting of 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.
Description
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-methoxy pheny1)-3- [[2-fluoro-6-(tri fluoromethyl)phenyllmethyll -3 ,6-di hy dro-4-methyl-
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-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 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)-
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 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 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
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.
-3a-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
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 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
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.
-3a-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
4 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.
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
.. 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.
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
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
- 6 - PCT/EP2018/059218 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
"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
7 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) F3C (I) with a strong acid, which acid addition salt is non-deliquescent.
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) F3C (I) with a strong acid, which acid addition salt is non-deliquescent.
- 8 - PCT/EP2018/059218 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.
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.
9 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
(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
- 10 - PCT/EP2018/059218 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
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
- 11 - PCT/EP2018/059218 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
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
- 12 - PCT/EP2018/059218 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),
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),
- 13 - PCT/EP2018/059218 (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,
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,
- 14 - PCT/EP2018/059218 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.
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.
- 15 - PCT/EP2018/059218 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
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
- 16 - PCT/EP2018/059218 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
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 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 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.
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 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.
Claims
2) The acid addition salt of elagolix according to claim 1, characterized by having a molar ratio of elagolix : acid in the range of from 1.0 : 0.8 to 1.0 : 1.2.
3) The acid addition salt of elagolix according to claim 1 or 2, wherein the acid is 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 or benzenesulfonic acid.
4) The acid addition salt of elagolix according to any one of claims 1 to 3, wherein the acid is sulfuric acid or hydrochloric acid.
5) The acid addition salt of elagolix with sulfuric acid of claim 4, which is crystalline.
6) The crystalline acid addition salt of elagolix with sulfuric acid according to claim 5 characterized by having a powder X-ray diffractogram comprising reflections at 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)°;
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.
7) The acid addition salt of elagolix with hydrochloric acid of claim 4, which is amorphous.
8) The acid addition salt of elagolix with hydrochloric acid of claim 4 or 7, which 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-Kalpha1,2 radiation having a wavelength of 0.15419 nm.
9) A process for the preparation of the acid addition salt of elagolix as defined in any one of claims 1 to 8 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.
10) The process according to claim 9, wherein the reaction mixture further comprises water.
11) Use of the acid addition salt of elagolix as defined in any one of claims 1 to 8 for the preparation of a base addition salt of elagolix.
12) The use according to claim 11 wherein the base addition salt of elagolix is elagolix sodium.
13) Use of the acid addition salt of elagolix as defined in any one of claims 1 to 8 for the preparation of a pharmaceutical composition.
14) A pharmaceutical composition comprising the acid addition salt of elagolix as defined in any one of claims 1 to 8 and one or more pharmaceutically acceptable excipient(s).
15) The acid addition salt of elagolix as defined in any one of claims 1 to 8 for use in the treatment of endometriosis or uterine fibroids.
16) The pharmaceutical composition of claim 14 for use in the treatment of endometriosis and uterine fibroids.
17) Use of the acid addition salt of elagolix as defined in any one of claims 1 to 8 or the pharmaceutical composition of claim 14 for the treatment of endometriosis or uterine fibroids.
18) Use of the acid addition salt of elagolix as defined in any one of claims
1 to 8 or the pharmaceutical composition of claim 14 for the manufacture of a medicament for the treatment of endometriosis or uterine fibroids.
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| EP17166263 | 2017-04-12 | ||
| EP17166263.8 | 2017-04-12 | ||
| EP17166501.1A EP3388421B1 (en) | 2017-04-13 | 2017-04-13 | Acid addition salts of an orally available gonadotropin-releasing hormone receptor antagonist |
| EP17166501.1 | 2017-04-13 | ||
| PCT/EP2018/059218 WO2018189212A1 (en) | 2017-04-12 | 2018-04-11 | Acid addition salts of an orally available gonadotropin-releasing hormone receptor antagonist |
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| WO2021016929A1 (en) * | 2019-07-31 | 2021-02-04 | 深圳仁泰医药科技有限公司 | Cocrystal form a of elagolix and pyrimethamine, preparation method therefor and use thereof |
| CN113527213B (en) * | 2020-04-20 | 2023-01-03 | 上海英诺富成生物科技有限公司 | Gonadotropin releasing hormone receptor antagonists and uses thereof |
| CN113912552A (en) * | 2020-07-09 | 2022-01-11 | 成都苑东生物制药股份有限公司 | Preparation method of amorphous form of oxalagogri sodium |
| CN114835649A (en) * | 2021-02-01 | 2022-08-02 | 上海漠澳浩医药科技有限公司 | Oxagolide salt, crystal, preparation method and application thereof |
| US11273128B1 (en) | 2021-04-15 | 2022-03-15 | Sandoz Ag | Elagolix formulation |
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| WO2009062087A1 (en) | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| US10881659B2 (en) * | 2013-03-15 | 2021-01-05 | Abbvie Inc. | Methods of treating heavy menstrual bleeding |
| US9949973B2 (en) | 2015-07-07 | 2018-04-24 | Abbvie Inc. | Acoustic mixing for auto granulation |
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