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WO2025115040A1 - Nouveaux co-cristaux de saroglitazar et de sel de saroglitazar mg - Google Patents

Nouveaux co-cristaux de saroglitazar et de sel de saroglitazar mg Download PDF

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Publication number
WO2025115040A1
WO2025115040A1 PCT/IN2024/052314 IN2024052314W WO2025115040A1 WO 2025115040 A1 WO2025115040 A1 WO 2025115040A1 IN 2024052314 W IN2024052314 W IN 2024052314W WO 2025115040 A1 WO2025115040 A1 WO 2025115040A1
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Prior art keywords
acid
saroglitazar
crystal
proline
ratio
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Inventor
Harikishore Pingali
Kaushik BANERJEE
Pandurang Zaware
Sanjay Kumar
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Zydus Lifesciences Ltd
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Zydus Lifesciences Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide

Definitions

  • the present invention relates to co-crystal of Saroglitazar of formula (I) and Saroglitazar magnesium of formula (la), processes for the preparation of these novel co-crystal, use thereof and pharmaceutical composition comprising the same.
  • Saroglitazar was approved by the Drug Controller General of India for the treatment of diabetic dyslipidemia and hypertriglyceridemia that is not controlled by statin and non-cirrhotic nonalcoholic steatohepatitis (NASH).
  • WO 03009841 discloses compounds of the following general formula:
  • Saroglitazar of formula (I).
  • formula (I) WO2012104869 discloses Saroglitazar Magnesium salt. Saroglitazar magnesium was approved by the Drug Controller General of India for the treatment of Diabetic Dyslipidemia, a condition in which a patient has diabetes and has elevated levels of the total cholesterol, the bad LDL cholesterol and triglycerides and a decrease in good HDL cholesterol in blood, and non-cirrhotic non-alcoholic steatohepatitis (NASH).
  • NASH non-cirrhotic non-alcoholic steatohepatitis
  • the Saroglitazar of formula (I) is a thick liquid which is difficult to isolate, purify and develop into a pharmaceutical formulation. It is therefore necessary to isolate the acid in a form that is easy to purify, handle, scale up and develop into suitable pharmaceutical formulation.
  • Several attempts have been made to purify, stabilize the acid and obtain it in a solid form. Such efforts are reported in W02020183379. However, most of these efforts have not been successful in obtaining the acid in a stable solid form for further commercial development.
  • the present invention satisfies this need by providing novel cocrystal of Saroglitazar of formula (I).
  • WO2012104869 discloses Saroglitazar Magnesium salt being effective in the treatment of lipohypertrophy, lipoatrophy and metabolic abnormalities in HIV patients.
  • WO2014174524 discloses the use of Saroglitazar and its pharmaceutically acceptable salts for the treatment of Non-alcoholic Fatty Liver Diseases (NAFLD) & Nonalcoholic Steatohepatitis (NASH).
  • W02016181409 discloses the use of Saroglitazar and its pharmaceutically acceptable salts for the treatment of Chylomicronemia.
  • WO2017089979 discloses the use of the Saroglitazar and its pharmaceutically acceptable salts for the treatment of diabetic nephropathy.
  • WO2017089980 discloses the use of the Saroglitazar and its pharmaceutically acceptable salts for the treatment of diabetic retinopathy.
  • Disclosed herein are the use of the Saroglitazar or its pharmaceutically acceptable salts for the treatment of polycystic ovarian syndrome (PCOS).
  • PCOS polycystic ovarian syndrome
  • compositions and solid-state forms i.e., the crystalline or amorphous form
  • the chemical composition and solid-state form can be critical to its pharmacological properties, such as bioavailability, and to its development as a viable drug candidate.
  • Compositions and crystalline forms of some API's have been used to alter the API's physicochemical properties. Each composition or crystalline form can have different solid state (physical and chemical) properties.
  • a novel solid-state forms may affect pharmaceutical and pharmacological properties such as storage stability, compressibility and density (important in formulation and product manufacturing), and/or solubility and dissolution rates (important factors in determining bioavailability).
  • pharmaceutical and pharmacological properties such as storage stability, compressibility and density (important in formulation and product manufacturing), and/or solubility and dissolution rates (important factors in determining bioavailability).
  • the rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it impacts the rate at which an orally administered active ingredient may reach the patient's bloodstream.
  • these practical properties are influenced by the solid-state properties, e.g. the crystalline form of the API, they can impact the selection of a particular compound as an API, the ultimate pharmaceutical dosage form, the optimization of manufacturing processes, and absorption in the body.
  • Physical properties of an API also have a major influence on the ability to deliver a drug by a desired method. For example, if a drug is delivered by inhalation physical properties relating to the API as a particle, such as morphology, density, surface energy, charge, hygroscopicity, stability, dispersive properties and/or agglomeration, can come into play.
  • the solid-state form of the API, and as described below, co-crystals of the API provide opportunities to address, engineer and/or improve upon one or more of such properties and thereby upon methods of delivery.
  • a co-crystal of an API is a distinct chemical composition of the API and coformer(s) and generally possesses distinct crystallographic and spectroscopic properties when compared to those of the API and coformer(s) individually. Crystallographic and spectroscopic properties of crystalline forms are typically measured by X-ray powder diffraction (XRPD) and single crystal X-ray crystallography, among other techniques. Co-crystals often also exhibit distinct thermal behavior. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC).
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • Co-crystals often possess more favorable solid state, physical, chemical, pharmaceutical and/or pharmacological properties or be easier to process than known forms or formulations of the API.
  • a co-crystal may have different dissolution and/or solubility properties than the API and can therefore be more effective in therapeutic delivery. Formation of a co- crystal can be used as a way to avoid polymorph formation of the drug.
  • New pharmaceutical compositions comprising a co-crystal of a given API may therefore have different or superior properties as compared to its existing drug formulations.
  • co-crystals are comprised of neutral species.
  • charge balance unlike a salt, one cannot determine the stoichiometry of a co-crystal based on charge balance. Indeed, one can often obtain co-crystals having stoichiometric ratios of drug to coformer of greater than or less than 1: 1.
  • the stoichiometric ratio of an API to coformer is a generally unpredictable feature of a cocrystal.
  • co-crystal may be thought of as a multi-component crystal composed of neutral molecules. These multi-component assemblies are continuing to excite and find usefulness, particularly within the pharmaceutical field, for their ability to alter physicochemical properties. More specifically, co-crystals have been reported to alter melting point, make a compound in liquid to solid form, aqueous solubility and/or dissolution rates, increase stability and improve bioavailability of active pharmaceutical ingredients.
  • a co-crystal form may have improved dissolution or solubility properties or advantageous storage stability, melting point, hygroscopicity, etc.
  • a pharmaceutical cocrystal of Saroglitazar to be used as an alternative marketed form of Saroglitazar it is important that the coformer used is ‘inactive’ and that it possesses regulatory acceptability for use in a pharmaceutical formulation.
  • co-crystals may be present either in substantially crystalline or amorphous forms or may be present as partially crystalline forms. In another embodiment, the co-crystal are present in non-solvated/unsolvated form or in a solvent free form. In another embodiment, the co-crystals are present in solvated/hydrated form. In yet another embodiment the co-crystal are present in their anhydrous form.
  • a pharmaceutical composition comprising, the therapeutically effective amount of a co-crystal of Saroglitazar of formula (I), prepared according to the present invention, along with at least one suitable pharmaceutically acceptable excipient known in the art for the treatment of dyslipidemia or hyperglycemia.
  • invention is further relates Saroglitazar isonicotinamide co-crystals.
  • the invention relates to a Saroglitazar isonicotinamide co-crystals in ratio (1: 1), a Saroglitazar isonicotinamide co-crystals in ratio (1:2) and a Saroglitazar isonicotinamide co-crystals in ratio (1 :3).
  • invention is further relates to Saroglitazar L-proline co-crystal.
  • the invention relates to a Saroglitazar L-proline co-crystals in ratio (1: 1), a Saroglitazar L-proline co-crystals in ratio (1:2) and a Saroglitazar L-proline co-crystals in ratio (1:3).
  • a co-crystal of Saroglitazar magnesium of formula (la) with a suitable one or more coformer in yet another embodiment, there is provided a co-crystal of Saroglitazar magnesium of formula (la) with a suitable one or more coformer.
  • a pharmaceutical composition comprising, the therapeutically effective amount of a co-crystal of Saroglitazar magnesium of formula (la), prepared according to the present invention, along with at least one suitable pharmaceutically acceptable excipient known in the art for the treatment of dyslipidemia or hyperglycemia.
  • invention is further relates Saroglitazar magnesium Isonicotinamide cocrystals.
  • invention is further relates Saroglitazar magnesium nicotinamide co-crystals.
  • invention is further relates to Saroglitazar magnesium L-proline co-crystal.
  • FIG.1 shows a DSC trace for the co-crystal of Saroglitazar with Isonicotinamide (1.5:1)
  • FIG.2 shows a DSC trace for the co-crystal of Saroglitazar with L-proline (1: 1)
  • FIG.3 shows an XRPD diagram of the co-crystal of Saroglitazar with L-proline (1: 1)
  • FIG.4 shows an IR diagram of the co-crystal of Saroglitazar with L-proline (1 :2)
  • FIG.5 shows a DSC trace for the co-crystal of Saroglitazar with L-proline (1:3)
  • FIG.6 shows an XRPD diagram of the co-crystal of Saroglitazar with L-proline (1:3)
  • FIG.7 shows a DSC trace for the Co-crystal of Saroglitazar with L-proline (1:4)
  • FIG.8 shows an XRPD diagram of the co-crystal of Saroglitazar with L-proline (1:4)
  • FIG 9. shows a DSC trace for the Co-crystal of Saroglitazar with L-proline (1 :5)
  • FIG 10. shows an XRPD diagram of the co-crystal of Saroglitazar with L-proline (1:5)
  • FIG 11. shows a DSC trace for the Co-crystal of Saroglitazar with L-proline (1:6)
  • FIG 12. shows an XRPD diagram of the co-crystal of Saroglitazar with L-proline (1:6)
  • FIG 13. shows a DSC trace for the Co-crystal of Saroglitazar with L-proline (1:7)
  • FIG 14. shows an XRPD diagram of the co-crystal of Saroglitazar with L-proline (1:7)
  • FIG 15. shows a DSC trace for the Co-crystal of Saroglitazar with L-proline (1:8)
  • FIG 16. shows an XRPD diagram of the co-crystal of Saroglitazar with L-proline (1:8)
  • FIG 17. shows an XRPD diagram of the Co-crystal of s Saroglitazar magnesium with L-proline (1: 1)
  • FIG 18. shows a DSC trace for the Co-crystal of Saroglitazar magnesium with L-proline (1: 1)
  • FIG 19. shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with L-proline (1:2)
  • FIG 20 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with L-proline (1:2)
  • FIG 21 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with L-proline (1:3)
  • FIG 22 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with L-proline (1:3)
  • FIG 23 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with L-proline (1:4)
  • FIG 24 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with L-proline (1:4)
  • FIG 25 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with L-proline (1:5)
  • FIG 26 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with L-proline (1:5)
  • FIG 27 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with Isonicotinamide (1: 1)
  • FIG 28. shows a DSC trace for the Co-crystal of Saroglitazar magnesium with Isonicotinamide (1: 1)
  • FIG 29. shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with Isonicotinamide (1:2)
  • FIG 30 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with Isonicotinamide (1:2)
  • FIG 31 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with Isonicotinamide (1:3)
  • FIG 32 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with Isonicotinamide (1:3)
  • FIG 33 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with Isonicotinamide (1:4)
  • FIG 34 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with Isonicotinamide (1:4)
  • FIG 35 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with Isonicotinamide (1:5)
  • FIG 36 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with Isonicotinamide (1:5)
  • FIG 37 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with Nicotinamide (1: 1)
  • FIG 38 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with Nicotinamide (1: 1)
  • FIG 39 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with Nicotinamide (1:2)
  • FIG 40 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with Nicotinamide (1:2)
  • FIG 41 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with
  • FIG 42 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with Nicotinamide (1:3)
  • FIG 43 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with
  • FIG 44 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with Nicotinamide (1:4)
  • FIG 45 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with
  • FIG 46 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with Nicotinamide (1:5)
  • FIG 47 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with Benzamide (1:3)
  • FIG 48 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with Benzamide (1:3)
  • FIG 49 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with Acetamide (1:3)
  • FIG 50 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with Acetamide (1 :3)
  • FIG 51. shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with Nicotinic acid (1:3)
  • FIG 53 shows an XRPD diagram of the Co-crystal of Saroglitazar magnesium with (E)-3-(4- hy dr oxy-3 -methoxyphenyl)acrylic acid (1 :3)
  • FIG 54 shows a DSC trace for the Co-crystal of Saroglitazar magnesium with (E)-3-(4-hydroxy- 3-methoxyphenyl)acrylic acid (1 :3)
  • Saroglitazar or Saroglitazar free acid or Saroglitazar base or (S) 2- Ethoxy-3-(4- ⁇ 2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-l-yl]-ethoxy ⁇ -phenyl)-propionic acid or formula (I) in acid form is the compound having the following formula
  • the present invention provides novel co-crystal of Saroglitazar.
  • Co-crystal of Saroglitazar comprising; a) Saroglitazar and; b) Suitable one or more coformers.
  • a "coformer” is a non-ionized molecule that can form a co-crystal with Saroglitazar.
  • the molar ratio of Saroglitazar to coformer can take any value depending on the coformer, for example, 1 to 2 : 1 to 15.
  • the molar ratio of Saroglitazar to coformer can take any value depending on the coformer, for example, 1:0.5 to 1:15, 1.5:1 to 1.5: 15, 1: 1.5 to 1:5, 1:3 to 1:8 preferably 1:3.
  • the molar ratio of Saroglitazar to conformer is selected from 1: 1, 1 :2, 1:3, 1:4, 1 :5, 1:6, 1:7, 1:8, 1:9, 1: 10, 1.5: 1, 1.5:2, 1.5:3, 1.5:4, 1.5:5.
  • the molar ratio of coformer to Saroglitazar can take any value depending on the coformer, for example, 1:0.5 to 1:15, 1.5:1 to 1.5: 15, 1: 1.5 to 1:5, 1 :3 to 1:8 preferably 1:3.
  • the molar ratio of conformer to Saroglitazar is selected from 1: 1, 1 :2, 1:3, 1:4, 1 :5, 1:6, 1:7, 1:8, 1:9, 1: 10, 1.5: 1, 1.5:2, 1.5:3, 1.5:4, 1.5:5.
  • the coformer may elute from the crystal lattice of the co-crystal under certain conditions, thereby rendering Saroglitazar supersaturated and increasing its solubility.
  • the coformer is preferably water-soluble.
  • the coformer is a molecule that is solid at ambient temperature (15 °C - 25 °C) and normal pressure.
  • organic acid is not particularly limited as long as it is an organic compound exhibiting acidity that can form a co-crystal with Saroglitazar, and includes, for example, carboxylic acids and phenols.
  • Carboxylic acid is not particularly limited as long as it is an organic compound having at least one carboxyl group (-COOH) that can form a co-crystal with Saroglitazar, but examples include chain carboxylic acid, aromatic carboxylic acids and heterocyclic carboxylic acids.
  • non-volatile organic acid is not particularly limited as long as it is an organic acid that can form a co-crystal with Saroglitazar; Examples include organic acids.
  • the non-volatile organic acid is a water-soluble organic acid.
  • it is a carboxylic acid.
  • a benzoic acid compound which may be substituted at least one of the o-, m- or p-positions with a group selected from the group consisting of hydroxy, amino and carboxyl. More preferred are 2, 5-dihydroxybenzoic acid or salicylic acid.
  • amino acid is not particularly limited as long as it is an organic compound having both amino and carboxyl functional groups, and includes natural amino acids and unnatural amino acids.
  • amine is not particularly limited as long as it is a compound in which the hydrogen atom of ammonia is replaced with a hydrocarbon group or an aryl group, and includes aliphatic amines and aromatic amines.
  • amide is not particularly limited as long as it is a compound obtained by dehydration condensation of an oxoacid and ammonia or a primary or secondary amine, and examples thereof include carboxylic acid amide.
  • Suitable specific coformers used in the invention are selected from L-proline, L-proline monohydrate, L-proline tetrahydrate, DL-proline, D-proline, D-alanine, histidine, threonine, glutamic acid, arginine, valine, cysteine, leucine, lysine, tyrosine, isoleucine, asparagine, phenylalanine, glutamine, tryptophan, methionine, serine, glycine, trimethyl glycine, L- pyroglutamic acid, isonicotinamide, nicotinamide, acetamide, pyrazinamide, malonamide, picolinamide, anthranilamide, benzamide, succinamide, caprolactum, salicylic acid, cinnamic acid, ferulic acid, hydroxy-2-naphthoic acid, nicotinic acid, p-aminobenzoic acid, 4-
  • Suitable solvent is selected from polar protic solvent used selected from methanol, ethanol, n- propanol, n-butanol, acetic acid and mixture thereof.
  • Dipolar aprotic solvents used are selected from acetone, ethyl acetate, dimethyl sulfoxide, acetonitrile, dimethyl formamide and mixture thereof.
  • Nonpolar solvents used are selected from dichloromethane, chloroform, tetrahydrofuran, 1, 4 -dioxane or suitable mixtures thereof.
  • Saroglitazar co-crystal which are in amorphous form.
  • Saroglitazar co-crystal which are in crystalline form.
  • Saroglitazar co-crystals which are in at least partially crystalline form.
  • invention is further relates to Saroglitazar isonicotinamide co-crystal.
  • the Saroglitazar isonicotinamide co-crystal vary in ratio from 1 :1 to 1: 15 Saroglitazar to isonicotinamide or isonicotinamide to Saroglitazar.
  • the invention relates to a Saroglitazar isonicotinamide co-crystals in ratio (1.5:1), a Saroglitazar isonicotinamide co-crystals in ratio (1 :2) and a Saroglitazar isonicotinamide cocrystals in ratio (1:3).
  • invention is further relates to Saroglitazar L-proline co-crystal.
  • the Saroglitazar L-proline co-crystal vary in ratio from 1 :1 to 1: 15 Saroglitazar to L-proline or L- proline to Saroglitazar.
  • the invention relates to a Saroglitazar L-proline co-crystals in ratio (1: 1), a Saroglitazar L-proline co-crystals in ratio (1:2), Saroglitazar L-proline co-crystals in ratio (1 :3), a Saroglitazar L-proline co-crystals in ratio (1:4), Saroglitazar L-proline co-crystals in ratio (1 :5), a Saroglitazar L-proline co-crystals in ratio (1:6), Saroglitazar L-proline co-crystals in ratio (1 :7), and a Saroglitazar L-proline co-crystals in ratio (1:8).
  • the invention relates to pharmaceutical compositions containing a therapeutically effective amount of a Saroglitazar L-proline co-crystal or Isonicotinamide cocrystal of the invention and a pharmaceutically acceptable carrier.
  • the invention also relates to methods of treatment for the diseases, disorders and conditions described herein and the use of a therapeutically effective amount of Saroglitazar L-proline co-crystals or Isonicotinamide cocrystal of the invention, or a pharmaceutical composition containing it, for that treatment.
  • the invention further provides the use of Saroglitazar L-proline co-crystals or Isonicotinamide cocrystal.
  • Saroglitazar L-proline co-crystal or Isonicotinamide co-crystal which are in amorphous form.
  • Saroglitazar L-proline co-crystal or Isonicotinamide co-crystal which are in crystalline form.
  • Saroglitazar L-proline co-crystals or Isonicotinamide co-crystal which are in at least partially crystalline form.
  • L-proline co-crystal or Isonicotinamide co-crystal of Saroglitazar of the invention in the manufacture of a medicament for use in the treatment of the diseases, disorders, and conditions described herein.
  • Saroglitazar Isonicotinamide co-crystal (1.5: 1) which has the following characteristics: i) The differential scanning calorimetry (DSC) trace, Figure 1, shows a single endotherm with an onset temperature of 295.99 °C and a peak maximum of 302.01 °C.
  • Saroglitazar L-proline co-crystal (1: 1) which has at least one of the following characteristics: i) A powder X-ray diffraction pattern substantially in accordance with Figure 3; ii) A powder X-ray diffraction having amorphous pattern; iii) Saroglitazar L-proline co-crystal characterized by a melting point 53 °C ⁇ 2 °C; iv) The differential scanning calorimetry (DSC) trace as per Figure 2; v) IR frequency having peaks at about 2972, 2920, 2877, 1720, 1610, 1510, 1408, 1311, 1238, 1111, 1043, 821, 758, 669, 542 cm’ 1 ;
  • Saroglitazar L-proline co-crystals (1:2) which has the following characteristics: i) IR frequency substantially in accordance with Figure 4; ii) IR frequency having peaks at about 3053, 2976, 2920, 2873, 1720, 1610, 1560, 1510, 1406, 1377, 1311, 1296, 1238, 1112, 1095, 1035, 821, 759, 638, 542 cm’ 1 ;
  • Saroglitazar co-crystals (1:3) which has at least one of the following characteristics: i) A powder X-ray diffraction pattern substantially in accordance with Figure 6; ii) A powder X-ray diffraction pattern having peaks at about 14.953, 17.843, 18.199, 19.327, 22.472, 24.540, 33.772 ⁇ 0.2 degrees 2-theta; iii) A powder X-ray diffraction pattern having additional peaks at about 12.168, 20.683, 25.673, 26.768, 30.091, 30.287, 31.920, 34.562, 35.229, 36.263, 37.319, 38.521, 39.499 ⁇ 0.2 degrees 2-theta; iv) Saroglitazar L-proline co-crystal characterized by a melting point 194.8 °C ⁇ 2 °C; v) The differential scanning calorimetry (DSC) trace, Figure 5, shows a single endotherm with
  • Saroglitazar co-crystals (1:4) which has at least one of the following characteristics: i) A powder X-ray diffraction pattern substantially in accordance with Figure 8; ii) A powder X-ray diffraction pattern having peaks at about 15.000, 17.886, 18.230, 19.382,
  • Saroglitazar co-crystals which has at least one of the following characteristics: i) A powder X-ray diffraction pattern substantially in accordance with Figure 10; ii) A powder X-ray diffraction pattern having peaks at about 15.005, 17.990, 18.299, 19.398, 22.550, 24.618, 33.839 ⁇ 0.2 degrees 2-theta; iii) A powder X-ray diffraction pattern having additional peaks at about 20.753, 25.752, 26.878, 30.408, 32.013, 24.634, 26.365, 39.606 ⁇ 0.2 degrees 2-theta; iv) The differential scanning calorimetry (DSC) trace, Figure 9, shows a single endotherm with an onset temperature of 200.82 °C and a peak maximum of 208.73 °C; v) IR frequency having peaks at about 3055, 2981, 1720, 1610, 1556, 1510, 1448
  • Saroglitazar co-crystals which has at least one of the following characteristics: i) A powder X-ray diffraction pattern substantially in accordance with Figure 12; ii) A powder X-ray diffraction pattern having peaks at about 14.986, 17.876, 18.264, 19.374, 22.515, 24.584, 33.813 ⁇ 0.2 degrees 2-theta; iii) A powder X-ray diffraction pattern having additional peaks at about 20.715, 25.719, 26.844, 30.056, 30.375, 31.978, 34.593, 36.344, 37.410, 39.571 ⁇ 0.2 degrees 2-theta; iv) The differential scanning calorimetry (DSC) trace, Figure 11, shows a single endotherm with an onset temperature of 203.13 °C and a peak maximum of 212.33 °C; v) IR frequency having peaks at about 3051, 2981, 1720, 1610, 1556,
  • Saroglitazar co-crystals (1:7) which has at least one of the following characteristics: i) A powder X-ray diffraction pattern substantially in accordance with Figure 14; ii) A powder X-ray diffraction pattern having peaks at about 14.973, 17.856, 18.182, 19.352,
  • Saroglitazar co-crystals (1:8) which has at least one of the following characteristics: i) A powder X-ray diffraction pattern substantially in accordance with Figure 16; ii) A powder X-ray diffraction pattern having peaks at about 14.963, 17.847, 18.237, 19.349,
  • the invention also provides a method for preparing the co-crystal, including:
  • Dipolar aprotic solvents used is selected from acetone, ethyl acetate, dimethyl sulfoxide, acetonitrile, dimethyl formamide and mixture thereof.
  • Non polar solvents used is selected from di chloromethane, chloroform, tetrahydrofuran, 1, 4 -dioxane or suitable mixtures thereof. b) The solvent was allowed to evaporate slowly under grinding at ambient temperature. c) The co-crystal is dried under reduced pressure for 3 days.
  • Method 2 a) Prepared the homogenous solution of Saroglitazar and suitable coformers such as L-proline, L-proline monohydrate, L-proline tetrahydrate, DL-proline, D-proline, D-alanine, histidine, threonine, glutamic acid, arginine, valine, cysteine, leucine, lysine, tyrosine, isoleucine, asparagine, phenylalanine, glutamine, tryptophan, methionine, serine, glycine, trimethyl glycine, L-pyroglutamic acid, isonicotinamide, nicotinamide, acetamide, pyrazinamide, malonamide, picolinamide, anthranilamide, benzamide, succinamide, caprolactum, salicylic acid, cinnamic acid, ferulic acid, hydroxy-2-naphthoic acid, nicotinic acid,
  • Dipolar aprotic solvents used is selected from acetone, ethyl acetate, dimethyl sulfoxide, acetonitrile, dimethyl formamide and mixture thereof.
  • Non polar solvents used is selected from di chloromethane, chloroform, tetrahydrofuran, 1, 4 -dioxane or suitable mixtures thereof.
  • the present invention also provides another method for preparing the co-crystal, including:
  • Dipolar aprotic solvents used is selected from acetone, ethyl acetate, dimethyl sulfoxide, acetonitrile, dimethyl formamide and mixture thereof.
  • Non polar solvents used is selected from dichloromethane, chloroform, tetrahydrofuran, 1, 4 dioxane or suitable mixtures thereof manually or mechanically, for a fixed period of time.
  • Saroglitazar is known in the art to be useful in the treatment of various diseases, disorders, and conditions.
  • the Saroglitazar co-crystals of the invention specifically, 1.5: 1 Saroglitazar Isonicotinamide co-crystal, 1:1 Saroglitazar L-proline co-crystal, and 1:2 Saroglitazar L-proline co-crystal and 1 :3 Saroglitazar L-proline co-crystal and pharmaceutical compositions containing them may then also be used to treat such diseases, disorders, and conditions.
  • the diseases, disorders, or conditions which may treated with an Saroglitazar cocrystal of the invention include, but are not limited to: treatment of dyslipidemia and hypercholesterolemia, nonalcoholic steatohepatitis (NASH), Non-alcoholic fatty liver disease (NAFLD), Primary Biliary Cholangitis (PBC), Fibrosis, Polycystic ovary syndrome (PCOS), Lipodystrophy, Diabetic retinopathy, Insulin-sensitizing and metabolic related disorders, anti-inflammatory, atherogenesis, renal dysfunction, autoimmune diseases, inflammatory bowel disease (IBD), autoimmune myocarditis, autoimmune encephalomyelitis, multiple sclerosis.
  • NASH nonalcoholic steatohepatitis
  • NAFLD Non-alcoholic fatty liver disease
  • PBC Primary Biliary Cholangitis
  • PCOS Polycystic ovary syndrome
  • Lipodystrophy Diabetic retinopathy
  • Insulin-sensitizing and metabolic related disorders
  • the invention relates to the method of treating such a disease, disorder, or condition comprising the step of administering to a patient in need thereof a therapeutically effective amount of a Saroglitazar co-crystal of the invention or of administering to a patient in need thereof a therapeutic composition containing an Saroglitazar co-crystal of the invention.
  • treatment means any treatment of a disease, disorder, or condition in a mammal, including: preventing or protecting against the disease, disorder, or condition, that is, causing the clinical symptoms not to develop; inhibiting the disease, disorder, or condition, that is, arresting or suppressing the development of clinical symptoms; and/or relieving the disease, disorder, or condition (including the relief of discomfort associated with the condition or disorder), that is, causing the regression of clinical symptoms. It will be understood by those skilled in the art that in human medicine, it is not always possible to distinguish between “preventing” and “suppressing” since the ultimate inductive event or events may be unknown, latent, or the patient is not ascertained until well after the occurrence of the event or events.
  • the term “prophylaxis” is intended as an element of “treatment” to encompass both “preventing” and “suppressing” the disease, disorder, or condition.
  • the term “protection” is meant to include “prophylaxis.”
  • Another aspect of the invention relates to the use of a Saroglitazar co-crystal of the invention in the treatment of diseases, disorders, and conditions discussed above. Accordingly, the invention further relates to the manufacture of a medicament for use in the treatment of such diseases, disorders, and conditions.
  • compositions Containing Saroglitazar co-crystals Containing Saroglitazar co-crystals
  • the present invention also provides a pharmaceutical composition, which contains the co-crystal and one or more pharmaceutically acceptable carrier or excipient.
  • the co-crystal of Saroglitazar of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • compositions according to this invention can exist in various forms.
  • the pharmaceutical composition is in the form of a powder or solution.
  • the pharmaceutical compositions according to the invention are in the form of a powder that can be reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration.
  • a compatible reconstitution diluents include water.
  • compositions are prepared and formulated according to conventional methods, such as those disclosed in standard reference texts and are well within the scope of a skilled person.
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tableting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing variable quantities of fillers, binding agent, lubricants, glidants, disintegrants, etc. Such operations are of course conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • binding agents include acacia, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, dextrates, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinised starch, sodium alginate, sorbitol, starch, syrup, tragacanth.
  • fillers include calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol.
  • lubricants include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate.
  • disintegrants examples include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, polacrilin potassium, Pregelatinized starch, sodium alginate, sodium lauryl sulphate, sodium starch glycollate.
  • Saroglitazar co-crystal for the treatment of dyslipidemia or hyperglycemia.
  • the Saroglitazar co-crystal prepared by the invention has better stability, is convenient for storage and use, can be directly used in the preparation of solid preparations, and has good powder properties.
  • the complete x-ray powder spectrum was recorded with a Rigaku D/Max 2200 VPC X-ray powder diffractometer model using copper radiation.
  • the X-ray diffraction pattern was recorded by keeping the instrument parameters as below:
  • X-ray Cu/40kv/30mA
  • Diverging slit lo
  • Scattering slit lo
  • Receiving slit 0.15 mm
  • Monochromator RS 0.8 mm
  • Counter Scintillation counter.
  • Scan mode Continuous, Scan speed: 3.000o/min., Sampling width: 0.020o, Scan axes: 2 theta vs CPS, Scan range: 2o to 40. Oo, Theta offset: 0.000
  • the infrared (IR) spectrum has been recorded on a Shimadzu FTIR-8400 model spectrophotometer, between 450 cm-1 and 4000 cm-1, with a resolution of 4 cm-1 in a KBr pellet.
  • test compound The in-vivo efficacy of test compound was evaluated in Swiss albino mice.
  • Anti-dyslipidemic drugs have been reported to lower circulating levels of triglyceride in mice through their effect on genes involved in the peroxisomal fatty acid beta oxidation via PPAR alpha agonism. Therefore, this species is preferred for evaluation of their efficacy in lowering circulating triglyceride (TG) levels.
  • TG circulating triglyceride
  • mice seven to eight weeks old male Swiss albino mice were used after acclimatization. Near the end of the acclimatization period, animals judged to be suitable for testing were bled under light anesthesia and serum samples were analyzed for serum triglyceride levels. Animals were selected according to triglyceride levels in the range of 59 to 152 mg/dl and divided into various treatment groups (Table no.1) of 6 animals each such that the average TG levels of animals in each group were not significantly different from the others and each group. Table no.l- Treatment groups and dose levels
  • Test compounds were formulated at specified doses in vehicle (MiliQ Water). The animals were dosed orally, once daily in the morning during six days, starting from next day of grouping, with vehicle or test compound. The animals were weighed prior to dosing and based on these weights; the volume of administration was calculated. The volume of formulation administered orally to each mouse was 10 ml/kg body weight.
  • L-proline co-crystal form showed greater efficacy than Magnesium salt form of
  • Saroglitazar or Saroglitazar free acid or (S) 2-Ethoxy-3-(4- ⁇ 2-[2-methyl- 5-(4-methylthiophenyl)-pyrrol-l-yl] -ethoxy ⁇ -phenyl)-propionic acid or formula (I) in acid form is the compound having the following formula and Saroglitazar magnesium as shown in formula (la)
  • the present invention provides novel co-crystal of Saroglitazar magnesium.
  • Co-crystal of Saroglitazar magnesium comprising; a) Saroglitazar magnesium and; b) Suitable one or more coformers.
  • a "coformer” is a non-ionized molecule that can form a co-crystal with Saroglitazar.
  • organic acids examples include organic acids, amino acids, amines, and amides, with nonvolatile organic acids or amino acids being preferred.
  • the molar ratio of Saroglitazar to coformer can take any value depending on the coformer, for example, 1 to 2 : 1 to 15.
  • the molar ratio of Saroglitazar magnesium to coformer can take any value depending on the coformer, for example, 1 :0.5 to 1: 15, 1.5: 1 to 1.5: 15, 1 :1.5 to 1:5, 1:3 to 1 :8 preferably 1 :3.
  • the molar ratio of Saroglitazar magnesium to conformer is selected from 1: 1, 1 :2, 1:3, 1 :4, 1:5, 1:6, 1:7, 1 :8, 1:9, 1:10, 1.5:1, l.:2, 1.5:3, 1.5:4, 1.5:5.
  • the molar ratio of coformer to Saroglitazar magnesium can take any value depending on the coformer, for example, 1 :0.5 to 1: 15, 1.5: 1 to 1.5: 15, 1 :1.5 to 1:5, 1:3 to 1 :8 preferably 1 :3.
  • the molar ratio of conformer to Saroglitazar magnesium is selected from 1: 1, 1 :2, 1:3, 1:4, 1:5, 1:6, 1:7, 1 :8, 1:9, 1:10, 1.5:1, 1.5:2, 1.5:3, 1.5:4, 1.5:5.
  • the coformer may elute from the crystal lattice of the co-crystal under certain conditions, thereby rendering Saroglitazar magnesium supersaturated and increasing its solubility.
  • the coformer is preferably water-soluble.
  • the coformer is a molecule that is solid at ambient temperature (15 °C - 25 °C) and normal pressure.
  • Suitable specific coformers used in the invention are selected from L-proline, L-proline monohydrate, L-proline tetrahydrate, DL-proline, D-proline, D-alanine, histidine, threonine, glutamic acid, arginine, valine, cysteine, leucine, lysine, tyrosine, isoleucine, asparagine, phenylalanine, glutamine, tryptophan, methionine, serine, glycine, trimethyl glycine, L- pyroglutamic acid, Isonicotinamide, nicotinamide, acetamide, pyrazinamide, malonamide, picolinamide, anthranilamide, benzamide, succinamide, caprolactum, salicylic acid, cinnamic acid, ferulic acid, hydroxy-2-naphthoic acid, nicotinic acid, p-aminobenzoic acid, 4-
  • Suitable solvent is selected from polar protic solvent used selected from methanol, ethanol, n- propanol, n-butanol, acetic acid and mixture thereof.
  • Dipolar aprotic solvents used is selected from acetone, ethyl acetate, dimethyl sulfoxide, acetonitrile, dimethyl formamide and mixture thereof.
  • Non polar solvent used is selected from dichloromethane, chloroform, tetrahydrofuran, 1, 4 -dioxane or suitable mixtures thereof.
  • Saroglitazar magnesium co-crystal which are in amorphous form.
  • Saroglitazar magnesium co-crystal which are in crystalline form.
  • Saroglitazar magnesium cocrystals which are in at least partially crystalline form.
  • invention is further relates to Saroglitazar magnesium L-proline co-crystal.
  • the Saroglitazar magnesium L-proline co-crystal vary in ratio from 1:1 to 1 :15 Saroglitazar magnesium to L-proline or L-proline to Saroglitazar magnesium.
  • invention is further relates to Saroglitazar magnesium Isonicotinamide cocrystal.
  • the Saroglitazar magnesium Isonicotinamide co-crystal vary in ratio from 1: 1 to 1:15 Saroglitazar magnesium to Isonicotinamide or Isonicotinamide to Saroglitazar magnesium.
  • invention is further relates to Saroglitazar magnesium Nicotinamide cocrystal.
  • the Saroglitazar magnesium Nicotinamide co-crystal vary in ratio from 1 :1 to 1 :15 Saroglitazar magnesium to Nicotinamide or nicotinamide to Saroglitazar magnesium.
  • the invention relates to pharmaceutical compositions containing a therapeutically effective amount of a Saroglitazar magnesium L-proline co-crystal, nicotinamide co-crystal or Isonicotinamide cocrystal of the invention and a pharmaceutically acceptable carrier.
  • the invention also relates to methods of treatment for the diseases, disorders and conditions described herein and the use of a therapeutically effective amount of Saroglitazar magnesium L-proline co-crystals, nicotinamide co-crystal or Isonicotinamide co-crystal of the invention, or a pharmaceutical composition containing it, for that treatment.
  • the invention further provides the use of Saroglitazar magnesium L-proline co-crystals, nicotinamide co-crystal or Isonicotinamide co-crystal.
  • Saroglitazar magnesium L-proline co-crystals, nicotinamide co-crystals or Isonicotinamide co-crystal which are in crystalline form.
  • Saroglitazar magnesium L-proline co-crystals, nicotinamide co-crystals or Isonicotinamide co-crystals which are in at least partially crystalline form.
  • L-proline co-crystal, nicotinamide co-crystal or Isonicotinamide co-crystal of Saroglitazar magnesium of the invention in the manufacture of a medicament for use in the treatment of the diseases, disorders, and conditions described herein.
  • Saroglitazar magnesium L-proline (1 :1) cocrystals which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 17; ii. A powder X-ray diffraction pattern having amorphous pattern; iii. Saroglitazar magnesium L-proline (1: 1) co-crystal characterized by a melting point 68.7 °C ⁇ 2 °C; iv.
  • Saroglitazar magnesium L-proline co-crystals (1:2) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 19; ii. A powder X-ray diffraction pattern having amorphous pattern; iii. DSC of the 1:2 Saroglitazar magnesium L-Proline co-crystal, The differential scanning calorimetry (DSC) trace, Figure 20 shows a single endotherm with an onset temperature of 110.33° C. and a peak maximum of 121.82° C; iv.
  • DSC differential scanning calorimetry
  • IR frequency of the 1 :2 Saroglitazar magnesium L-Proline co-crystal having peaks at about 2968, 2922, 1606, 1510, 1406, 1311, 1238, 1176, 1093, 1043, 821, 759 cm ;
  • Saroglitazar magnesium L-proline co-crystals (1:3) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 21; ii. A powder X-ray diffraction pattern having peaks at about 15.064, 17.996, 18.387, 19.465, 22.626, 24.690, 33.952 ⁇ 0.2 degrees 2-theta; iii. A powder X-ray diffraction pattern having additional peaks at about 17.454, 29.821, 30.470, 32.075 ⁇ 0.2 degrees 2-theta; iv.
  • DSC of the 1:3 Saroglitazar magnesium L-Proline co-crystal The differential scanning calorimetry (DSC) trace, Figure 22 shows a single endotherm with an onset temperature of 187.21 °C and a peak maximum of 202.11 °C; v. IR frequency of the 1 :3 Saroglitazar magnesium L-Proline co-crystal, having peaks at about 3057, 2966, 1602, 1510, 1377, 1238, 1176, 1093, 1037, 821, 758 cm 4 .
  • DSC of the 1:4 Saroglitazar magnesium L-Proline co-crystal The differential scanning calorimetry (DSC) trace, Figure 24 shows a single endotherm with an onset temperature of 199.38 °C and a peak maximum of 207.22 °C; V. IR frequency of the 1 :4 Saroglitazar magnesium L-Proline co-crystal, having peaks at about 3049, 2980, 1610, 1558, 1436, 1377, 1240, 1170, 1093, 1035, 821, 759 cm’ 1 ;
  • Saroglitazar magnesium L-proline co-crystals (1:5) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 25; ii. A powder X-ray diffraction pattern having peaks at about 15.091, 17.989, 18.402, 19.487, 22.647, 24.715, 33.958 ⁇ 0.2 degrees 2-theta; iii. A powder X-ray diffraction pattern having additional peaks at about 20.846, 26.970, 30.506, 32.112, 34.741, 36.478 ⁇ 0.2 degrees 2-theta; iv.
  • DSC of the 1:5 Saroglitazar magnesium L-Proline co-crystal The differential scanning calorimetry (DSC) trace, Figure 26, shows a single endotherm with an onset temperature of 202.84 °C and a peak maximum of 212.03 °C. v. IR frequency of the 1 :5 Saroglitazar magnesium L-Proline co-crystal, having peaks at about 3047, 2983, 1614, 1556, 1406, 1377, 1242, 1170, 1085, 1035, 821, 759 cm’ 1 ;
  • Saroglitazar magnesium Isonicotinamide cocrystal (1: 1) which has at least one of the following characteristics: i) A powder X-ray diffraction pattern substantially in accordance with Figure 27; ii) A powder X-ray diffraction pattern having peaks at about 4.351, 7.688, 8.834, 14.051, 15.771, 16.344, 17.618, 18.676, 19.426, 19.766, 20.486, 21.030, 22.077, 22.728, 22.909, 23.292, 28.335 ⁇ 0.2 degrees 2-theta; iii) A powder X-ray diffraction pattern having additional peaks at about 24.851, 26.805, 30.463, 32.322, 34.691, 35.673 ⁇ 0.2 degrees 2-theta; iv) Saroglitazar magnesium Isonicotinamide co-crystal (1: 1) characterized by a melting point 198.2 °C ⁇ 2 °C; v) The differential scanning
  • Saroglitazar magnesium Isonicotinamide cocrystal (1:2) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 29; ii. A powder X-ray diffraction pattern having peaks at about 14.499, 18.459, 22.120 ⁇ 0.2 degrees 2-theta; iii. A powder X-ray diffraction pattern having additional peaks at about 4.449, 18.603, 18.871, 21.617, 24.240, 25.402, 32.105 ⁇ 0.2 degrees 2-theta; iv.
  • DSC of the 1:2 Saroglitazar magnesium Isonicotinamide co-crystal The differential scanning calorimetry (DSC) trace, Figure 30, shows a single endotherm with an onset temperature of 142.01 °C and a peak maximum of 148.22 °C; v. IR frequency of the 1 :2 Saroglitazar magnesium Isonicotinamide co-crystal, having peaks at about 3327, 3057, 1676, 1610, 1554, 1508, 1394, 1238, 1002, 821, 758 cm’ 1 ;
  • Saroglitazar magnesium Isonicotinamide cocrystal (1:3) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 31 ; ii. A powder X-ray diffraction pattern having peaks at about 14.497, 18.439, 22.117, 22.931, 23.347 ⁇ 0.2 degrees 2-theta; iii. A powder X-ray diffraction pattern having additional peaks at about 4.392, 14.139, 18.643, 18.875, 19.807, 20.727, 21.627, 24.222, 24.863, 28.471, 32.113 ⁇ 0.2 degrees 2- theta; iv.
  • DSC of the 1:3 Saroglitazar magnesium Isonicotinamide co-crystal The differential scanning calorimetry (DSC) trace, Figure 32, shows a single endotherm with an onset temperature of 150.54 °C and a peak maximum of 154.10 °C; v. IR frequency of the 1 :3 Saroglitazar magnesium Isonicotinamide co-crystal, having peaks at about 3321, 3051, 1678, 1614, 1552, 1510, 1396, 1224, 1062, 1002, 819, 759 cm’ 1 ;
  • Saroglitazar magnesium Isonicotinamide cocrystal (1:4) which has at least one of the following characteristics: i.
  • DSC of the 1:4 Saroglitazar magnesium Isonicotinamide co-crystal The differential scanning calorimetry (DSC) trace, Figure 34, shows a single endotherm with an onset temperature of 151.58 °C and a peak maximum of 154.81 °C; v. IR frequency of the 1 :4 Saroglitazar magnesium Isonicotinamide co-crystal, having peaks at about 3327, 3059, 1680, 1614, 1552, 1510, 1394, 1002, 819, 758 cm’ 1 .
  • Saroglitazar magnesium Isonicotinamide cocrystal (1:5) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 35; ii. A powder X-ray diffraction pattern having peaks at 14.536, 18.488, 22.166, 22.976, 23.392, 24.269 ⁇ 0.2 degrees 2-theta; iii. A powder X-ray diffraction pattern having additional peaks at about 4.441, 1.165, 18.696, 19.853, 20.779, 21.669, 24.942, 25.434, 28.483, 32.154 ⁇ 0.2 degrees 2-theta; iv.
  • DSC of the 1:5 Saroglitazar magnesium Isonicotinamide co-crystal The differential scanning calorimetry (DSC) trace, Figure 36, shows a single endotherm with an onset temperature of 152.01 °C. and a peak maximum of 154.56 °C. v. IR frequency of the 1:5 Saroglitazar magnesium Isonicotinamide Co-crystal, having peaks at about 3325, 3057, 1678, 1614, 1552, 1508, 1394, 1224, 1002, 819, 758 cm’ 1 ;
  • Saroglitazar magnesium nicotinamide cocrystal (1: 1) which has at least one of the following characteristics: i) A powder X-ray diffraction pattern substantially in accordance with Figure 37; ii) A powder X-ray diffraction pattern having peaks at about 4.372, 7.723, 8.841, 14.620,
  • Saroglitazar magnesium nicotinamide cocrystal (1:2) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 39; ii. A powder X-ray diffraction pattern having peaks at about 4.491, 14.707, 17.111, 17.401, 19.419, 23.264, 24.487, 25.287, 25.745, 27.214 ⁇ 0.2 degrees 2-theta; iii. A powder X-ray diffraction pattern having additional peaks at about 7.824, 9.016, 16.191, 17.966, 19.797, 23.656, 26.486, 32.497 ⁇ 0.2 degrees 2-theta; iv.
  • DSC of the 1:2 Saroglitazar magnesium nicotinamide co-crystal The differential scanning calorimetry (DSC) trace, Figure 40, shows a single endotherm with an onset temperature of 121.64 °C and a peak maximum of 125.77 °C; v. IR frequency of the 1:2 Saroglitazar magnesium nicotinamide co-crystal, having peaks at about 3367, 3155, 1678, 1614, 1510, 1402, 1238, 1028, 821, 759 cm’ 1 ;
  • Saroglitazar magnesium nicotinamide cocrystal (1:3) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 41; ii. A powder X-ray diffraction pattern having peaks at about 14.738, 22.161, 23.297, 25.319, 29.779, 27.247 ⁇ 0.2 degrees 2-theta; iii. A powder X-ray diffraction pattern having additional peaks at about 4.507, 11.272, 19.455, 19.836 ⁇ 0.2 degrees 2-theta; iv.
  • DSC of the 1:2 Saroglitazar magnesium nicotinamide co-crystal The differential scanning calorimetry (DSC) trace, Figure 42, shows a single endotherm with an onset temperature of 123.31 °C and a peak maximum of 126.76 °C; v. IR frequency of the 1:3 Saroglitazar magnesium nicotinamide co-crystal, having peaks at about 3363, 3159, 1676, 1612, 1421, 1394, 1238, 1028, 827, 759 cm’ 1 .
  • Saroglitazar magnesium nicotinamide cocrystal (1:4) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 43; ii. A powder X-ray diffraction pattern having peaks at about 14.706, 22.123, 23.272, 25.299, 25.753, 27.226 ⁇ 0.2 degrees 2-theta; iii. A powder X-ray diffraction pattern having additional peaks at about 11.240, 19.418, 22.613 ⁇ 0.2 degrees 2-theta; iv.
  • DSC of the 1:4 Saroglitazar magnesium nicotinamide co-crystal The differential scanning calorimetry (DSC) trace, Figure 44, shows a single endotherm with an onset temperature of 124.15 °C and a peak maximum of 128.19 °C; v. IR frequency of the 1:4 Saroglitazar magnesium nicotinamide co-crystal, having peaks at about 3361, 3147, 1674, 1614, 1510, 1394, 1240, 1028, 827, 765 cm’ 1 .
  • Saroglitazar magnesium nicotinamide cocrystal (1:5) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 45; ii. A powder X-ray diffraction pattern having peaks at about 14.704, 22.119, 23.241, 25.273, 25.728, 27.202 ⁇ 0.2 degrees 2-theta; iii. A powder X-ray diffraction pattern having additional peaks at about 11.237, 19.418, 22.604, 30.871 ⁇ 0.2 degrees 2-theta. iv.
  • DSC of the 1:5 Saroglitazar magnesium nicotinamide co-crystal The differential scanning calorimetry (DSC) trace, Figure 46, shows a single endotherm with an onset temperature of 124.57 °C and a peak maximum of 127.70 °C; v. IR frequency of the 1 : 5 Saroglitazar magnesium nicotinamide co-crystal, having peaks at about 3360, 3151,1676, 1612, 1394, 1242, 1028, 827, 763 cm’ 1 .
  • Saroglitazar magnesium Benzamide cocrystal (1:3) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 47; ii. A powder X-ray diffraction pattern having peaks at about 7.747, 15.627, 16.402, 17.927, 19.831, 20.790, 22.408, 26.358, 28.356, 28.605 ⁇ 0.2 degrees 2-theta; iii. A powder X-ray diffraction pattern having additional peaks at about 4.390, 19.202, 23.723, 23.920, 25.391, 30.708, 33.274, 35.682 ⁇ 0.2 degrees 2-theta; iv.
  • Saroglitazar magnesium benzamide co-crystal characterized by a melting point 113.7 °C ⁇ 2 °C; v. DSC of the 1 :3 Saroglitazar magnesium benzamide co-crystal,
  • the differential scanning calorimetry (DSC) trace, Figure 48 shows a single endotherm with an onset temperature of 104.60 °C and a peak maximum of 116.27 °C; vi. IR frequency of the 1:3 Saroglitazar magnesium benzamide co-crystal, having peaks at about 3365, 3169, 1654, 1614, 1577, 1508, 1402, 1242, 1120, 810, 765 cm’ 1 .
  • Saroglitazar magnesium Acetamide cocrystal (1:3) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 49; ii. A powder X-ray diffraction pattern having peaks at about 4.453, 7.779, 8.957 ⁇ 0.2 degrees 2-theta; iii. Saroglitazar magnesium Acetamide co-crystal characterized by a melting point 131.3 °C ⁇ 2 °C; iv.
  • DSC of the 1 :3 Saroglitazar magnesium Acetamide co-crystal The differential scanning calorimetry (DSC) trace, Figure 50, shows a single endotherm with an onset temperature of 54.68 °C and a peak maximum of 58.31 °C; v. IR frequency of the 1:3 Saroglitazar magnesium Acetamide co-crystal, having peaks at about 3356, 3386, 1660, 1608, 1510, 1392, 1240, 1112, 821, 758 cm’ 1 .
  • Saroglitazar magnesium Nicotinic acid cocrystal (1:3) which has at least one of the following characteristics: i.
  • DSC of the 1 :3 Saroglitazar magnesium Nicotinic acid co-crystal substantially in accordance with Figure 52; vi. IR frequency of the 1:3 Saroglitazar magnesium Nicotinic acid co-crystal, having peaks at about 2972, 2918, 1707, 1608, 1510, 1413, 1321, 1298, 1240, 1176, 1039, 812 cm’ 1 .
  • Saroglitazar magnesium (E)-3-(4-hydroxy-3- methoxyphenyl)acrylic acid co-crystal (1:3) which has at least one of the following characteristics: i. A powder X-ray diffraction pattern substantially in accordance with Figure 53; ii. A powder X-ray diffraction pattern having peaks at about 8.874, 10.332, 12.661, 15.474, 17.255, 17.960, 20.297, 20.974, 21.472, 22.893, 24.482, 25.792, 26.280, 27.317, 29.302 ⁇ 0.2 degrees 2-theta; iii.
  • IR frequency of the 1:3 Saroglitazar magnesium (E)-3 -(4-hy dr oxy-3 - methoxyphenyl)acrylic acid co-crystal having peaks at about 3345, 1689, 1618, 1598, 1510, 1431, 1267, 1201, 1033, 945, 850, 802 cm’ 1 .
  • the invention also provides a method for preparing the co-crystal, including:
  • Dipolar aprotic solvents used is selected from acetone, ethyl acetate, dimethyl sulfoxide, acetonitrile, dimethyl formamide and mixture thereof.
  • Non polar solvents used is selected from di chloromethane, chloroform, tetrahydrofuran, 1, 4 -dioxane or suitable mixtures thereof. b) The solvent was allowed to evaporate slowly under grinding at ambient temperature. c) The co-crystal are dried under reduced pressure for 3 days.
  • Method 2 a) Prepared the homogenous solution of Saroglitazar magnesium and suitable coformers such as L-proline, L-proline monohydrate, L-proline tetrahydrate, DL-proline, D-proline, D-alanine, histidine, threonine, glutamic acid, arginine, valine, cysteine, leucine, lysine, tyrosine, isoleucine, asparagine, phenylalanine, glutamine, tryptophan, methionine, serine, glycine, trimethyl glycine, L-pyroglutamic acid, Isonicotinamide, nicotinamide, acetamide, pyrazinamide, malonamide, picolinamide, anthranilamide, benzamide, succinamide, caprolactum, salicylic acid, cinnamic acid, ferulic acid, hydroxy-2-naphthoic acid, nicotinic acid,
  • Dipolar aprotic solvents used is selected from acetone, ethyl acetate, dimethyl sulfoxide, acetonitrile, dimethyl formamide and mixture thereof.
  • Non polar solvents used is selected from di chloromethane, chloroform, tetrahydrofuran, 1, 4 -dioxane or suitable mixtures thereof.
  • the present invention also provides another method for preparing the co-crystal, including:
  • Dipolar aprotic solvents used is selected from acetone, ethyl acetate, dimethyl sulfoxide, acetonitrile, dimethyl formamide and mixture thereof.
  • Non polar solvents used is selected from di chloromethane, chloroform, tetrahydrofuran, 1, 4 dioxane or suitable mixtures thereof manually or mechanically, for a fixed period of time.
  • Saroglitazar magnesium is known in the art to be useful in the treatment of various diseases, disorders, and conditions.
  • the Saroglitazar magnesium co-crystals of the invention specifically, Saroglitazar magnesium Isonicotinamide co-crystal, Saroglitazar magnesium L-proline co-crystal, and 1:2 Saroglitazar magnesium nicotinamide co-crystal and pharmaceutical compositions containing them may then also be used to treat such diseases, disorders, and conditions.
  • the diseases, disorders, or conditions which may treated with an Saroglitazar magnesium co-crystal of the invention include, but are not limited to: treatment of dyslipidemia and hypercholesterolemia, nonalcoholic steatohepatitis (NASH), Non-alcoholic fatty liver disease (NAFLD), Primary Biliary Cholangitis (PBC), Fibrosis, Polycystic ovary syndrome (PCOS), Lipodystrophy, Diabetic retinopathy, Insulin-sensitizing and metabolic related disorders, anti-inflammatory, atherogenesis, renal dysfunction, autoimmune diseases, inflammatory bowel disease (IBD), autoimmune myocarditis, autoimmune encephalomyelitis, multiple sclerosis.
  • NASH nonalcoholic steatohepatitis
  • NAFLD Non-alcoholic fatty liver disease
  • PBC Primary Biliary Cholangitis
  • PCOS Polycystic ovary syndrome
  • Lipodystrophy Diabetic retinopathy
  • the invention relates to the method of treating such a disease, disorder, or condition comprising the step of administering to a patient in need thereof a therapeutically effective amount of a Saroglitazar magnesium co-crystal of the invention or of administering to a patient in need thereof a therapeutic composition containing an Saroglitazar magnesium co-crystal of the invention.
  • compositions Containing Saroglitazar magnesium co-crystals Containing Saroglitazar magnesium co-crystals
  • the present invention also provides a pharmaceutical composition, which contains the co-crystal and a pharmaceutically acceptable carrier or excipient.
  • the co-crystal of Saroglitazar magnesium of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • compositions according to this invention can exist in various forms.
  • the pharmaceutical composition is in the form of a powder or solution.
  • the pharmaceutical compositions according to the invention are in the form of a powder that can be reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration.
  • suitable reconstitution diluents include water.
  • compositions are prepared and formulated according to conventional methods, such as those disclosed in standard reference texts and are well within the scope of a skilled person.
  • solid oral compositions may be prepared by conventional methods of blending, filling or tableting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing variable quantities of fillers, binding agent, lubricants, glidants, disintegrants, etc. Such operations are of course conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • binding agents include acacia, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, dextrates, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinised starch, sodium alginate, sorbitol, starch, syrup, tragacanth.
  • fillers include calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol.
  • lubricants include calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate.
  • glidants include colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc.
  • disintegrants examples include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, polacrilin potassium, Pregelatinized starch, sodium alginate, sodium lauryl sulphate, sodium starch glycollate.
  • Saroglitazar magnesium co-crystal for the treatment of dyslipidemia or hyperglycemia.
  • the Saroglitazar magnesium co-crystal prepared by the invention has better stability, is convenient for storage and use, can be directly used in the preparation of solid preparations, and has good powder properties.
  • the complete x-ray powder spectrum was recorded with a Rigaku D/Max 2200 VPC X-ray powder diffractometer model using copper radiation.
  • the X-ray diffraction pattern was recorded by keeping the instrument parameters as below:
  • X-ray Cu/40kv/30mA
  • Diverging slit lo
  • Scattering slit lo
  • Receiving slit 0.15 mm
  • Monochromator RS 0.8 mm
  • Counter Scintillation counter.
  • Scan mode Continuous, Scan speed: 3.000o/min., Sampling width: 0.020o, Scan axes: 2 theta vs CPS, Scan range: 2o to 40. Oo, Theta offset: 0.000
  • Sample Size Approx. l-2mg
  • Sample Pans Hermetic/Crimping Pans

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Abstract

La présente invention concerne un co-cristal de saroglitazar de formule (I) et de saroglitazar magnésium de formule (Ia), des procédés de préparation de ces nouveaux co-cristaux, leur utilisation et une composition pharmaceutique les comprenant.
PCT/IN2024/052314 2023-12-01 2024-11-30 Nouveaux co-cristaux de saroglitazar et de sel de saroglitazar mg Pending WO2025115040A1 (fr)

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IN202321081837 2023-12-01
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012104869A1 (fr) * 2011-01-31 2012-08-09 Cadila Healthcare Limited Traitement de la lipodystrophie
WO2018167103A1 (fr) * 2017-03-13 2018-09-20 Genfit Compositions pharmaceutiques pour polythérapie
US20220071954A1 (en) * 2018-12-18 2022-03-10 Cadila Healthcare Limited Saroglitazar for the treatment of hepatocellular carcinoma

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012104869A1 (fr) * 2011-01-31 2012-08-09 Cadila Healthcare Limited Traitement de la lipodystrophie
WO2018167103A1 (fr) * 2017-03-13 2018-09-20 Genfit Compositions pharmaceutiques pour polythérapie
US20220071954A1 (en) * 2018-12-18 2022-03-10 Cadila Healthcare Limited Saroglitazar for the treatment of hepatocellular carcinoma

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"DOCTORAL DISSERTATION", 11 October 2018, INSTITUTE OF PHARMACY, NIRMA UNIVERSITY, A'BAD, India, article UPADHYAY, JAGAT: "Design Synthesis and Biological Evaluation of Heterocycles Targeting Dipeptidyl Peptidase 4 DPP 4 for Management of Type 2 Diabetes", pages: 1 - 206, XP009564322 *

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