Novel co-crystal of saroglitazar with poly(d-glucosamine)

Abstract

The present invention relates to novel Poly(D-glucosamine) co-crystals of Saroglitazar. Specifically, the present invention provides co-crystal of Saroglitazar of formula (I) and Chitosan, process for the preparation of said co-crystal, use thereof and pharmaceutical compositions comprising the same.

Description

[0001] TITLE: NOVEL CO-CRYSTAL OF SAROGLITAZAR WITH POLY(D- GLUCOSAMINE)

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to novel Poly(D-glucosamine) co-crystals of Saroglitazar. Specifically, the present invention provides co-crystal of Saroglitazar of formula (I) and Chitosan, process for the preparation of said co-crystal, use thereof and pharmaceutical compositions comprising the same.

[0004] BACKGROUND OF THE INVENTION

[0005] Saroglitazar, (S) 2-Ethoxy-3-(4-{2-[2-methyl-5-(4-methylthiophenyl)-pyrrol-l- yl] -ethoxy} -phenyl)-propionic acid, shown below as formula (I), is a peroxisome proliferator-activated receptor (PPAR) agonist. Its synthesis was first described in WO 03009841.

[0006] 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 also for non-cirrhotic non-alcoholic steatohepatitis (NASH). It is also approved as an add-on therapy to metformin for treatment of type 2 diabetes mellitus in India.

[0007] WO 03009841 discloses compounds of the following general formula:

[0008] These compounds are reported to be hypolipidemic agents which also include Saroglitazar of formula (I).

[0009] formula (I)

[0010] 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. However, most of these efforts have not been successful in obtaining the acid in a stable solid form for further commercial development. Thus, there is a continuing need to obtain solid form of Saroglitazar of formula (I) having improved physical and / or chemical properties. The present invention satisfies this need by providing novel co-crystals of Saroglitazar of formula (I).

[0011] As described above, the Saroglitazar as disclosed in W003009841 was always obtained in liquid form. When its stability studies were conducted, it was found to be less suitable for further development due to its purity as well as stability concerns as shown below tabular form:

[0012]

[0013] The experimental data in above table shows there is a rise in impurity even after 6 and 17 days for the Saroglitazar free acid (compound of formula (I)). Further, the Saroglitazar was found to be less stable at room temperature conditions and hence could not be developed further. Hence there is unmet need for additional solid stable forms of Saroglitazar that are stable upon storage to allow the potential of Saroglitazar to be fully explored.

[0014] WO2012104869 discloses Saroglitazar Magnesium salt being effective in the treatment of lipohypertrophy, lipoatrophy and metabolic abnormalities in HIV patients.

[0015] 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.

[0016] Certain pre-mixes have been disclosed in W02020183379. However, none of them suitable in obtaining the acid in a stable solid form for further commercial development. W02025115040 discloses novel co-crystals of Saroglitazar and Saroglitazar mg salt. Surprisingly, inventors of the present application found more stable and efficacious co-crystal of Saroglitazar.

[0017] Although therapeutic efficacy is the primary concern for an active pharmaceutical ingredient (API), the chemical composition and solid-state form (i.e., the crystalline or amorphous form) of the API 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. The differences in physical properties exhibited by a novel solid-state forms (such as, for example, a polymorph of the API or a co-crystal containing the API, discussed further below) 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). For example, 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. Because 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.

[0018] 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. It may be possible to achieve more desirable properties of a particular API by forming a co-crystal of the API. 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). 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. For example, 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.

[0019] Unlike salts, which possess a neutral net charge, but which are comprised of charge-balanced components, co-crystals are comprised of neutral species. Thus, 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 co-crystal.

[0020] Without limiting the disclosed invention to any particular definition because others may define the term differently, the term ‘co-crystal’ may be thought of as a multi-component crystal composed of neutral molecules. These multicomponent 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, affect aqueous solubility and / or dissolution rates, increase stability and improve bioavailability of active pharmaceutical ingredients.

[0021] This is because a co-crystal form may have improved dissolution or solubility properties or advantageous storage stability, melting point, hygroscopicity, etc. For a pharmaceutical co-crystal 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.

[0022] The Saroglitazar Chitosan co-crystal may be present either in substantially crystalline or amorphous forms or may be present as partially crystalline forms. In another embodiment, the Saroglitazar Chitosan co-crystal may be present in non- solvated / unsolvated form or in a solvent free form. In another embodiment, the Saroglitazar Chitosan co-crystal is present in solvated / hydrated form. In yet another embodiment the Saroglitazar Chitosan co-crystal is present in anhydrous form.

[0023] OBJECT OF THE INVENTION:

[0024] In one embodiment of the present invention, there is provided a co-crystals of Saroglitazar of formula (I) and Chitosan.

[0025] In yet another embodiment is provided a pharmaceutical composition comprising, the therapeutically effective amount of a Saroglitazar Chitosan co-crystals, prepared according to the present invention, along with at least one suitable pharmaceutically acceptable excipient.

[0026] In a still further embodiment is provided a Saroglitazar Chitosan co-crystal for use as a medicament preferably for the treatment of dyslipidemia or hyperglycemia.

[0027] In a further embodiment is provided a process for the preparation of Saroglitazar Chitosan co-crystal. Ill an embodiment, the invention relates to a Saroglitazar Chitosan co-crystal in a ratio (1:1).

[0028] In a further embodiment, the invention relates to a Saroglitazar Chitosan cocrystal in a ratio (3:2).

[0029] In yet another embodiment relates to a co-crystal of Saroglitazar with low molecular weight of Chitosan in a ratio (1: 1).

[0030] BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG. 1 shows an XRPD diagram of the co-crystal of Saroglitazar with Chitosan (1 :1)

[0032] FIG. 2 shows differential scanning calorimetry (DSC) trace of the co-crystal of Saroglitazar with Chitosan (1 :1)

[0033] FIG. 3 shows an IR diagram of the co-crystal of Saroglitazar with Chitosan (1: 1)

[0034] FIG. 4 shows an XRPD diagram of the co-crystal of Saroglitazar with Chitosan (3:2)

[0035] FIG. 5 shows differential scanning calorimetry (DSC) trace of the co-crystal of Saroglitazar with Chitosan (3:2)

[0036] FIG. 6 shows an IR diagram of the co-crystal of Saroglitazar with Chitosan (3:2)

[0037] FIG. 7 shows an XRPD diagram of the co-crystal of Saroglitazar with low molecular weight Chitosan (1: 1)

[0038] FIG. 8 shows differential scanning calorimetry (DSC) trace of the co-crystal of Saroglitazar with low molecular weight Chitosan (1 :1)

[0039] FIG. 9 shows an IR diagram of the co-crystal of Saroglitazar with low molecular weight Chitosan (1:1)

[0040] FIG. 10 shows an UPLC diagram of initial stability data of Saroglitazar co-crystal with low molecular weight Chitosan (1 :1)

[0041] FIG. 11 shows an UPLC diagram of 6 months stability data of Saroglitazar cocrystal with low molecular weight Chitosan (1: 1) DETAILED DESCRIPTION OF THE INVENTION:

[0042] As herein used the term 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: formula (I)

[0043] In such embodiment the molar ratio of Saroglitazar to Chitosan can take any value depending on the Chitosan, for example, 1 to 5 : 1 to 3.

[0044] The molar ratio of Saroglitazar to Chitosan can take any value depending on the Chitosan, for example, 1 :0.5 to 1 : 1, 1.5: 1 to 1.5:2, 2:1 to 2:1.5, 3: 1 to 3:2 preferably 1: 1 or 3:2.

[0045] In some embodiments, the Chitosan may elute from the crystal lattice of the cocrystal under certain conditions, thereby rendering Saroglitazar supersaturated and increasing its solubility.

[0046] In such a case, Chitosan is insoluble in water and organic solvents but becomes soluble in dilute aqueous acidic solutions, Chitosan dissolves in weak acidic solutions, such as dilute acetic acid (1% acetic acid is a preferable)

[0047] In another embodiment, the Chitosan is a molecule that is solid at ambient temperature (20°C to 25°C) and normal pressure (100 kPa). In the present specification, the term "organic acid" is not particularly limited as long as it is an organic compound exhibiting acidity and that can form a co-crystal with Saroglitazar, and includes, for example, carboxylic acids and phenols.

[0048] "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.

[0049] In this specification, "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.

[0050] In certain embodiments, the non-volatile organic acid is a water-soluble organic acid. Preferably it is a carboxylic acid. More preferred is 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.

[0051] As used herein, "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.

[0052] In this specification, "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.

[0053] In the present specification, "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.

[0054] (Poly(D-glucosamine (Chitosan) is a linear polysaccharide composed of randomly distributed 0-(l— >4)-linked D-glucosamine (deacetylated unit) and A-acetyl-D- glucosamine (acetylated unit) or Poly(D-glucosamine is a linear polysaccharide polymer of D-glucosamine.

[0055] Suitable solvent is selected from a polar protic solvent(s) such as those 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 solvents used is selected from di chloromethane, chloroform, tetrahydrofuran, 1, 4 -dioxane or suitable mixtures thereof.

[0056] In one embodiment of the present invention, there is provided Chitosan co-crystal of Saroglitazar which are in amorphous form.

[0057] In one embodiment of the present invention, there is provided Chitosan co-crystal of Saroglitazar which are in crystalline form.

[0058] In one embodiment of the present invention, there is provided Chitosan co-crystal of Saroglitazar which are in at least partially crystalline form.

[0059] In particular, the invention relates to a Saroglitazar chitosan co-crystals in ratio of (1 :1), Saroglitazar low molecular weight Chitosan co-crystals (1: 1) and Saroglitazar Chitosan co-crystals in ratio of (3:2)

[0060] The Saroglitazar Chitosan co-crystals of the present invention, its preparation and its characterization are described in the examples below and shown in the figures. The invention also relates to pharmaceutical compositions containing a therapeutically effective amount of a Saroglitazar chitosan co-crystal 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 chitosan cocrystals of the invention, or a pharmaceutical composition containing it, for that treatment. The invention further provides the use of Saroglitazar chitosan cocrystals. Chitosan co-crystals of Saroglitazar of the invention in the manufacture of a medicament for use in the treatment of the diseases, disorders, and conditions are also described herein.

[0061] In a further embodiment of the invention is disclosed Saroglitazar Chitosan cocrystal (1: 1) which has the following characteristics: i) A powder X-ray diffraction pattern substantially in accordance with Figure

[0062] 1; ii) A powder X-ray diffraction having an amorphous pattern; iii) The differential scanning calorimetry (DSC) trace as per Figure 2; iv) The differential scanning calorimetry (DSC) trace, Figure, shows a single endotherm with an onset temperature of 54.96° C. and a peak maximum of 64.45° C; v) IR frequency substantially in accordance with Figure 3; vi) IR frequency having peaks at about 3365, 2914, 1573, 1510, 1433, 1409,

[0063] 1311, 1244, 1095, 1045, 821, 759cm’1;

[0064] In a further embodiment of the invention disclosed Saroglitazar Chitosan cocrystals (3:2) which has the following characteristics: i) A powder X-ray diffraction pattern substantially in accordance with Figure

[0065] 4; ii) A powder X-ray diffraction having amorphous pattern; iii) The differential scanning calorimetry (DSC) trace as per Figure 5; iv) The differential scanning calorimetry (DSC) trace, Figure, shows a single endotherm with an onset temperature of 33.93° C. and a peak maximum of 80.80° C; v) IR frequency substantially in accordance with Figure 6; ii) IR frequency having peaks at about 3342, 2893, 1581, 1510, 1409, 1311, 1242, 1161, 1029, 894, 758 cm’1; In a further embodiment of the invention is disclosed Saroglitazar with low molecular weight Chitosan co-crystals (1: 1) which has the following characteristics: i) A powder X-ray diffraction pattern substantially in accordance with Figure

[0066] 7; ii) A powder X-ray diffraction having amorphous pattern; iii) The differential scanning calorimetry (DSC) trace as per Figure 8; iv) The differential scanning calorimetry (DSC) trace, Figure, shows a single endotherm with an onset temperature of 32.03° C. and a peak maximum of 88.60°C; v) IR frequency substantially in accordance with Figure 9; vi) IR frequency having peaks at about 2920, 1722, 1612, 1512, 1471, 1438,

[0067] 1409, 1311,

[0068] 1244, 1114, 1045, 823, 758 cm’1

[0069] Therapeutic Uses of Saroglitazar Co-crystals

[0070] As discussed above Saroglitazar is known in the art to be useful in the treatment of various diseases, disorders, and conditions. The Saroglitazar Chitosan cocrystals of the invention, specifically, Saroglitazar Chitosan co-crystal in a ratio (1 :1), Saroglitazar with low molecular weight chitosan co-crystals (1 :1) and Saroglitazar chitosan co-crystal in a ratio (3:2) 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 chitosan 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 Bihary Cholangitis (PBC), Fibrosis, Polycystic ovary syndrome (PCOS), Lipodystrophy, Diabetic retinopathy, Alcoholic liver diseases, Insulin-sensitizing and metabolic related disorders, anti-inflammatory, atherogenesis, renal dysfunction, autoimmune diseases, inflammatory bowel disease (IBD), autoimmune myocarditis, autoimmune encephalomyelitis, multiple sclerosis, Accordingly, 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 Chitosan co-crystal of the invention or of administering to a patient in need thereof a therapeutic composition containing an Saroglitazar Chitosan co-crystal of the invention.

[0071] The term "treatment" or "treating" 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. Therefore, as used herein 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.

[0072] Pharmaceutical compositions Containing Saroglitazar Chitosan co-crystals

[0073] The present invention also provides a pharmaceutical composition, which contains the Sarogliazar Chitosan co-crystal and a 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.

[0074] The pharmaceutical compositions according to this invention can exist in various forms. In some embodiments, the pharmaceutical composition is in the form of a powder or solution. In some other embodiments, 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. Non-limiting example of such a compatible reconstitution diluent include water.

[0075] The pharmaceutical compositions according to this invention can exist in various forms. In some embodiments, the pharmaceutical composition is in the form of a powder or solution. In some other embodiments, 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. Non-limiting example of such a compatible reconstitution diluent include water.

[0076] The pharmaceutical 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. For example, 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, stabilizer etc. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice.

[0077] Examples of 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.

[0078] Examples of 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.

[0079] Examples of 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.

[0080] Examples of glidants include colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc.

[0081] Examples of disintegrants 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.

[0082] The stable pharmaceutical composition may be made by direct compression, wet granulation or dry granulation methods by techniques known to persons skilled in the art. Thus, for example,

[0083] In wet granulation process, the drug is mixed with one or more pharmaceutical excipients and granulated with suitable binding solution as described earlier, to form wet granules, the wet granules are dried and optionally sieved. The dried granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules.

[0084] In direct compression process, the drug is mixed with all the pharmaceutical excipients required and then is either compressed into tablets or filled in capsules.

[0085] In dry granulation process the drug is mixed with one or more pharmaceutical excipients and compressed into slugs and these slugs are passed through required sieve. The sieved granules are mixed with one or more suitable excipients from those described elsewhere and then compressed into tablets or filled into capsules.

[0086] One or more solvents used in the formulation are selected from acetone, chloroform, dichloromethane, ethyl alcohol, ethyl acetate, methyl alcohol, isopropyl alcohol and combinations thereof and other such materials known to those of ordinary skill in the art.

[0087] In another embodiment of the present invention, is a described process for the preparation of a stable pharmaceutical composition of Saroglitazar Chitosan cocrystal, including:

[0088] (a) Prepared the homogenous solution of Saroglitazar in a suitable solvent and a suitable base;

[0089] (b) Prepared a mixture of Chitosan in a suitable solvent;

[0090] (c) Added mixture obtained from step (b) to the homogenous solution of Saroglitazar step(a);

[0091] (d) The co-crystal is filtered and dried under reduced pressure.

[0092] Suitable solvent used in step (a) and step (b) is 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 solvents used is selected from dichloromethane, chloroform, tetrahydrofuran, 1, 4 -dioxane or suitable mixtures thereof.

[0093] Suitable base used in step (a) is selected from sodium hydroxide, potassium hydroxide, ammonium hydroxide or suitable mixtures thereof.

[0094] Compared with Saroglitazar, the Saroglitazar Chitosan 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.

[0095] Following characterization methods were used to confirm synthesis of novel cocrystal.

[0096] Analytical methods:

[0097] 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:

[0098] X-ray: Cu / 40kv / 30mA, Diverging slit: lo, Scattering slit: lo, Receiving slit: 0.15 mm, Monochromator RS: 0.8 mm, Counter: Scintillation counter.

[0099] 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

[0100] Differential scanning calorimetric analysis was carried out in a DSC-60 model from Shimadzu (S / W: TA-60WS Acquisition version 2.1.0.0) by keeping following parameters,

[0101] Sample Size: Approx. l-2mg, Sample Pans: Hermetic / Crimping Pans,

[0102] Start Temperature: 50°C, End Temperature: 300°C, Rate of Heating: 10 °C / min., Purge Gas: Nitrogen, Flowrate: 20 ml / min 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.

[0103] Table 1 provides initial stability data of Saroglitazar co-crystal with low molecular weight Chitosan (as per Figure 10):

[0104] Table no. 1:

[0105] Table 2 provides 6 months stability data of Saroglitazar co-crystal with low molecular weight Chitosan: (as per Figure 11):

[0106] Table no. 2:

[0107] The above stability data shows that the co-crystal of Saroglitazar with low molecular weight Chitosan is stable.

[0108] The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention’s scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of a person skilled in the art.

[0109] EXAMPLES

[0110] Example 1

[0111] Co-crystal of Saroglitazar and Chitosan (1:1)

[0112] Step 1: Sodium salt of (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)- 1 H-pyrrol- 1 -yl)ethoxy)phenyl)propanoate.

[0113] To a solution of (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-lH- pyrrol-l-yl)ethoxy)phenyl)propanoic acid (1.6 g, 3.64 mmol) in methanol (20 ml), sodium hydroxide (0.146 g, 3.64 mmol) was added and the reaction mixture was stirred at 30 °C for 2 hours. Then reaction mixture was concentrated under reduced pressure to yield sodium (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4- (methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)phenyl)propanoate (1.680 gm, 100 % yield) as a yellowish crystalline solid.

[0114] Step 2: Co-crystal of (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-

[0115] 1 H-pyrrol- 1 -yl)ethoxy)phenyl)propanoic acid with Chitosan.

[0116] To a suspension of sodium (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4- (methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)phenyl)propanoate (1.65 g, 3.57 mmol) in 1% acetic acid (20 ml), Chitosan (1.886 g, 3.57 mmol) was added and the reaction mixture was stirred at 30°C for 20-30 minute. Then in this 1% sodium citrate solution (20.00 ml) was added and the reaction mixture was continue to stirred at 30 °C for 2.0 hours. Separated solid was filtered, washed with water and dried over phosphorous pentoxide under vacuum to yield off white solid. (Yield: 3.1 gm).

[0117] Example 2

[0118] Co-crystal of Saroglitazar and Chitosan (3:2)

[0119] Step 1: Sodium salt of (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)- 1 H-pyrrol- 1 -yl)ethoxy)phenyl)propanoate.

[0120] To a solution of (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-lH- pyrrol-l-yl)ethoxy)phenyl)propanoic acid (4.0 g, 9.10 mmol) in methanol (20 ml), sodium hydroxide (0.364 g, 9.10 mmol) was added and the reaction mixture was stirred at 30 °C for 2 hours. Then reaction mixture was concentrated under reduced pressure to yield sodium (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4- (methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)phenyl)propanoate (4.20 gm, 100 % yield) as a yellowish crystalline solid.

[0121] Step 2: Co-crystal of (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-

[0122] 1 H-pyrrol- 1 -yl)ethoxy)phenyl)propanoic acid with Chitosan .

[0123] To a suspension of sodium (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4- (methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)phenyl)propanoate (1.5 g, 3.25 mmol) in 1% acetic acid (30 ml), Chitosan (1.142 g, 2.164 mmol) was added and the reaction mixture was stirred at 30°C for 20-30 minute. Then in this 1% sodium citrate solution (30.00 ml) was added and the reaction mixture was continue to stirred at 30 °C for 2.0 hours. Separated solid was filtered, washed with water and dried over phosphorous pentoxide under vacuum to yield off white solid. (Yield: 3.10 gm).

[0124] Example 3

[0125] Co-crystal of Saroglitazar and Low molecular weight Chitosan (1:1)

[0126] Step 1: Sodium salt of (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)- 1 H-pyrrol- 1 -yl)ethoxy)phenyl)propanoate. To a solution of (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)-lH- pyrrol-l-yl)ethoxy)phenyl)propanoic acid (2.5 g, 5.69 mmol) in methanol (20 ml), sodium hydroxide (0.250 g, 6.26 mmol) was added and the reaction mixture was stirred at 30 °C for 24 hours. Then reaction mixture was concentrated under reduced pressure to yield sodium (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4- (methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)phenyl)propanoate (2.63 gm, 100 % yield) as a yellowish crystalline solid.

[0127] Step 2: Co-crystal of (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4-(methylthio)phenyl)- lH-pyrrol-l-yl)ethoxy)phenyl)propanoic acid with Low molecular weight Chitosan.

[0128] To a suspension of sodium (S)-2-ethoxy-3-(4-(2-(2-methyl-5-(4- (methylthio)phenyl)-lH-pyrrol-l-yl)ethoxy)phenyl)propanoate (1.4 g, 3.03 mmol) in 1% acetic acid (30 ml), Low molecular weight Chitosan (1.600 g, 3.03 mmol) was added and the reaction mixture was stirred at 30°C for 20-30 minute. Then in this 1% sodium citrate solution (30.00 ml) was added and the reaction mixture was continued to stirred at 30 °C for 2.0 hours. Separated solid was filtered, washed with water and dried over phosphorous pentoxide under vacuum to yield yellowish solid. (Yield: 2.87 gm).

[0129] Pharmacological data:

[0130] Comparative efficacy study (triglyceride lowering effects) of Compound I as free acid form with its different co-crystals in Swiss albino mice model.

[0131] The in-vivo efficacy (triglyceride lowering activity) 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.

[0132] In this experiment, 9-10 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 95 to 228 mg / dl and divided into various treatment groups (Table no. 3) 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.

[0133] Table no. 3- Treatment groups and dose levels

[0134] Test compounds were formulated at specified doses in MiliQ water as vehicle. 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.

[0135] On Day 6, one hour after dose administration, approximately 0.25 ml of blood was collected from the retro-orbital sinus of anesthetized animals. Serum was separated by centrifugation and subsequently analyzed for triglyceride levels using the Mindray BS-240 biochemical analyzer and the Mindray TG estimation kit. The percentage change and reduction in serum triglyceride levels were calculated using Microsoft Excel as presented in Table 4. Result:

[0136] Oral administration of Compound (I) as a free acid for six days at a dose of 1.0 mg / kg resulted in a significant 26% reduction in serum triglyceride levels. In comparison, its co-crystal forms produced reductions of 48%, 73%, and 50%, respectively, relative to the vehicle-treated group, as shown in Table no. 4. The triglyceride-lowering activity of L-proline co-crystal, LMW chitosan co-crystal and chitosan co-crystal forms was significantly greater than that of the free acid form. Notably, the co-crystal with low molecular weight (LMW) chitosan demonstrated a significantly higher reduction in serum triglyceride levels compared to the co-crystal with chitosan and L-proline co-crystal following six days of oral administration.

[0137] Table no. 4- Effect on serum triglyceride levels

[0138] * Significantly different from the vehicle control group at p< 0.05, and **** significantly different from the vehicle control group at p< 0.0001, # significantly different from Compound (I) as free acid (1.0 mg / kg,p.o.) at p< 0.01 using One way ANOVA followed by Dunnett’s multiple comparison method. Conclusion:

[0139] In conclusion, the co-crystal forms of Saroglitazar acid with L-proline, Low Molecular Weight (LMW) Chitosan and standard Chitosan, demonstrated superior triglyceride-lowering efficacy compared to the free acid form. The co-crystal with low molecular weight Chitosan showed statistically superior efficacy compared to the standard Chitosan co-crystal and L-proline co-crystal in the Swiss albino mice model.

Claims

We claim:

1. A co-crystal comprising: a) saroglitazar of formula 1, andFormula (I) b) chitosan.

2. The co-crystal as claimed in claim 1 wherein the molar ratio ofSaroglitazar and Chitosan is 1 to 5 : 1 to 3.

3. The co-crystal as claimed in claim 2 wherein the molar ratio ofSaroglitazar and Chitosan is 1:0.5 to 1: 1, 1.5:1 to 1.5:2, 2: 1 to 2: 1.5, 3: 1 to 3:2.

4. The co-crystal as claimed in claim 2 wherein the molar ratio of Saroglitazar and Chitosan is 1 :1 or 3:2.

5. The co-crystal as claimed in claim 1 is in amorphous form or in crystalline form or in partially crystalline form.

6. The co-crystal as claimed in claim 1, wherein Saroglitazar Chitosan cocrystal in ratio (1 :1) is in amorphous form characterized by a powder X- ray diffraction pattern as per figure 1; the differential scanning calorimetry (DSC) trace of Saroglitazar chitosan co-crystals in ratio (1: 1) shows a single endotherm with an onset temperature of 54.96° C. and a peak maximum of 64.45° C as per figure 2.

7. The co-crystal as claimed in claim 1 wherein Saroglitazar chitosan cocrystal in ratio (3:2) is in amorphous form characterized by a powder X-ray diffraction pattern as per figure 4; the differential scanning calorimetry (DSC) trace of Saroglitazar chitosan co-crystals in ratio (1: 1) shows a single endotherm with an onset temperature of 33.93° C. and a peak maximum of 80.80° C as per figure 5.

8. The co-crystal as claimed in claim 1 wherein Saroglitazar and low molecular weight Chitosan co-crystal is in amorphous form characterized by a powder X-ray diffraction pattern of as per figure 7; the differential scanning calorimetry (DSC) trace of Saroglitazar and low molecular weight chitosan co-crystals in ratio (1 :1) shows a single endotherm with an onset temperature of 32.03° C. and a peak maximum of 88.60°C as per figure 8.

9. The pharmaceutical composition of co-crystal as claimed in claim 1 comprises one or more suitable pharmaceutically acceptable carrier or excipient.

10. The use of pharmaceutical composition of co-crystal as claimed in claim 1 for the treatment of dyslipidemia or hyperglycemia.

11. The process for the preparation of co-crystal of Saroglitazar with chitosan as claimed in claim 1 comprising: a) Prepare the homogenous solution of Saroglitazar in a suitable solvent and suitable base; b) Prepare the mixture of Chitosan in a suitable solvent; c) Adding mixture of Chitosan to the homogenous solution of Saroglitazar; d) The co-crystal is filtered and dried under reduced pressure.

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