KOTTUR MOHAN KUMAR (IN)
EDA VISHNU VARDHANA VEMA REDDY (IN)
SEN SAIKAT (IN)
CHAKRABORTY SHAUNAK (IN)
KALLEM DIVYA JYOTHI (IN)
NEKKANTI SATISH CHOWDARY (IN)
THIRUNAHARI SATYANARAYANA (IN)
| WO2018133705A1 | 2018-07-26 |
| We claim: 1. A crystalline form of elafibranor selected from: a) Form A of elafibranor, characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 8, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta at about 9.44, 18.99, and 20.99 ±0.2°, and combination thereof; b) Form B of elafibranor, characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 9, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2- theta, at about 10.33, 11.12 and 13.22 ±0.2°, and combination thereof; c) Form C of elafibranor, characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 10, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta at about 13.36, 15.52 and 18.21±0.2°, and combination thereof; d) Form D of elafibranor, characterized by data selected from: : a X-Ray powder diffraction pattern substantially the same as shown in Figure 11, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta at about 13.28, 16.02 and 17.11 ±0.2°, and combination thereof; e) Form E of elafibranor, characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 12, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta at about 17.77, 19.27 and 24.45 ±0.2°, and combination thereof; f) Form F of elafibranor, characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 13, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta at about 13.30, 15.70 and 24.63 ±0.2°, and combination thereof; g) Form G of elafibranor, characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 14, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta at about 9.77, 13.03, and 16.31 ±0.2°, and combination thereof; h) Form H of elafibranor, characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 15, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta at about 10.72, 14.30 and 24.05 ±0.2°, and combination thereof; i) Form J of elafibranor, characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 16, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta at about 19.72, 20.58 and 22.23 ±0.2°, and combination thereof. j) Form M of elafibranor, characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 19, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta at about 19.93, 25.43 and 29.97 ±0.2°, and combination thereof; k) Form N of elafibranor, characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 20, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta at about 8.65, 12.94 and 21.53 ±0.2°, and combination thereof; l) Form O of elafibranor, characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 21, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2- theta, at about 8.15, 17.03 and 21.81 ±0.2°, and combination thereof; m) Form Q of elafibranor, characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 23, a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2- theta, at about 8.15, 17.03 and 21.81 ±0.2°, and combination thereof. 2. A hemihydrate Form O of elafibranor. 3. A process for preparing Form H of elafibranor, the process comprising the steps of: a) providing elafibranor in formic acid or 1, 4 dioxane; and b) isolating Form H of elafibranor. 4. A process for preparing Form H of elafibranor, the process comprising the steps of: a) providing elafibranor in ethyl acetate or water; b) seeding with Form H of elafibranor; c) isolating Form H of elafibranor. 5. A process for preparing Form O of elafibranor, the process comprising the steps of: a) heating Elafibranor Form J; b) isolating Form O of Elafibranor. 6. An amorphous form of elafibranor. 7. An amorphous elafibranor-syloid admixture. 8. A solid dispersion of elafibranor and copovidone. 9. A solid dispersion of elafibranor selected from: a) a solid dispersion of elafibranor and hydroxy propyl methyl cellulose (HPMC); b) a solid dispersion of elafibranor and povidone; c) a solid dispersion of elafibranor and hydroxy propyl cellulose (HPC). 10. A co-crystal of elafibranor selected from: a) a co-crystal of elafibranor with urea; b) a co-crystal of elafibranor with L-proline; c) a co-crystal of elafibranor with saccharine. |
FIELD OF THE INVENTION
The present invention provides various solid state forms of elafibranor, more particularly, amorphous, solid dispersions, co-crystals, admixture and crystalline forms of elafibranor.
BACKGROUND OF THE INVENTION AND DISCLOSURE OF PRIOR ART
The drug compound“Elafibranor” has the chemical name: (E)-2-(2, 6-dimethyl -4-(3- (4-(methylthio)phenyl)-3-oxoprop-l-en-l-yl)phenoxy)-2-methyl propanoic acid; and the structure as depicted in Formula I.
Genfit SA is currently evaluating elafibranor, in a pivotal phase 3 study, for the treatment of nonalcoholic steatohepatitis or“NASH”.
W02004005233A1 & W02005005369A1 reported the synthesis of elafibranor. However, these patents do not disclose any polymorphic form of the product obtained by the disclosed process therein.
IP.com Journal, Volume: 18, Issue: 2B, Pages: 1-10, Journal; Patent, 2018, Accession Number: 2018:436647, reproduced synthesis of elafibranor, according to the general synthesis method described in W02004005233A1 and W02005005369A1. The obtained elafibranor was found to be in crystalline nature with a reported X-ray powder diffraction.
W02018060372A1 reported the salts of elafibranor with choline, ethanolamine, diethanolamine, L-lysine, piperazine, calcium or tromethamine. W02018060373A1 reported the metformin salt of Elafibranor. W02020025789A1 reported fifteen salts of elafibranor.
W02018060372A1 & W02018060373A1, in example 1, step 3 reported the synthesis of elafibranor having a melting point of 144-145° C and an appearance as amorphous yellow solid powder. Further, no other physical characteristic of elafibranor was disclosed therein. It has been now found that the elafibranor obtained by the reproduction of example 1, step 3 of W02018060372A1 & W02018060373A1 is in crystalline form. CN106674069B, W02019025017A1 & W02020039297A1 reported synthetic processes for the preparation of elafibranor. WO2018133705A1, WO2019099761A1 & W02019186410A1 reported solid state forms of elafibranor.
Discovering new solid state forms/ polymorphic forms, solvates and solid dispersion of a pharmaceutical product can provide materials having desirable physicochemical properties. New polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. Solid dispersions of drugs are generally known to improve the stability and solubility of drug products.
In view of the above, it is therefore, desirable to prepare stable solid state forms of elafibranor, more particularly, amorphous, solid dispersions, co-crystals, admixture and crystalline forms of elafibranor. The amorphous form, admixture and solid dispersions provided herein is at least stable under ordinary stability conditions with respect to purity, storage and is a free flowing powder and therefore useful for producing pharmaceutical compositions. Moreover, the present invention provides novel polymorphic forms and solvates having desired physicochemical properties that would enhance its suitability for pharmaceutical composition.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides an amorphous form of elafibranor.
In another embodiment, the present invention provides an amorphous elafibranor- Syloid admixture.
In another embodiment, the present invention provides a solid dispersion comprising elafibranor and one or more pharmaceutically acceptable excipients. In yet another embodiment, the present invention provides a solid dispersion of: elafibranor and hydroxy propyl methyl cellulose (HPMC), elafibranor and copovidone, elafibranor and povidone & elafibranor and hydroxy propyl cellulose (HPC).
In another embodiment present invention provides crystalline forms of elafibranor. In yet another embodiment present invention provides: Form A of elafibranor, Form B of elafibranor, Form C of elafibranor, Form D of elafibranor, Form E of elafibranor, Form F of elafibranor, Form G of elafibranor, Form H of elafibranor, Form J of elafibranor, Form M of elafibranor, Form N of elafibranor, Form O of elafibranor and Form Q of elafibranor. In another embodiment, present invention provides co-crystal of elafibranor. In yet another embodiment, present invention provides co-crystal of elafibranor with urea, co crystal of elafibranor with L-proline and co-crystal of elafibranor with saccharin.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustration of powder X-ray diffraction pattern of amorphous form of elafibranor.
Figure 2 is an illustration of powder X-ray diffraction pattern of amorphous form of elafibranor.
Figure 3 is an illustration of powder X-ray diffraction pattern of amorphous elafibranor- Syloid admixture.
Figure 4 is an illustration of powder X-ray diffraction pattern of solid dispersion comprising elafibranor and hydroxy propyl methyl cellulose (HPMC).
Figure 5 is an illustration of powder X-ray diffraction pattern of solid dispersion comprising elafibranor and copovidone.
Figure 6 is an illustration of powder X-ray diffraction pattern of solid dispersion comprising elafibranor and povidone.
Figure 7 is an illustration of powder X-ray diffraction pattern of solid dispersion comprising elafibranor and hydroxy propyl cellulose (HPC).
Figure 8 is an illustration of powder X-ray diffraction pattern of Form A of Elafibranor.
Figure 9 is an illustration of powder X-ray diffraction pattern of Form B of Elafibranor.
Figure 10 is an illustration of powder X-ray diffraction pattern of Form C of Elafibranor.
Figure 11 is an illustration of powder X-ray diffraction pattern of Form D of Elafibranor.
Figure 12 is an illustration of powder X-ray diffraction pattern of Form E of Elafibranor.
Figure 13 is an illustration of powder X-ray diffraction pattern of Form F of Elafibranor.
Figure 14 is an illustration of powder X-ray diffraction pattern of Form G of Elafibranor.
Figure 15 is an illustration of powder X-ray diffraction pattern of Form H of Elafibranor.
Figure 16 is an illustration of powder X-ray diffraction pattern of Form J of Elafibranor. Figure 17 is an illustration of powder X-ray diffraction pattern of co-crystal of elafibranor with urea.
Figure 18 is an illustration of powder X-ray diffraction pattern of co-crystal of elafibranor with L-proline.
Figure 19 is an illustration of powder X-ray diffraction pattern of Form M of Elafibranor.
Figure 20 is an illustration of powder X-ray diffraction pattern of Form N of Elafibranor. Figure 21 is an illustration of powder X-ray diffraction pattern of Form O of Elafibranor. Figure 22 is an illustration of powder X-ray diffraction pattern of co-crystal of elafibranor with saccharin.
Figure 23 is an illustration of powder X-ray diffraction pattern of Form Q of Elafibranor. Figure 24 is an illustration of thermo gravimetric analysis (TGA) of Form O of Elafibranor.
DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides an amorphous form of elafibranor. An amorphous form of elafibranor is characterized by X-ray powder diffraction patterns as illustrated by Figure 1 and Figure 2. In one embodiment, the present invention provides a stable amorphous form which is substantially pure and without any crystalline peak.
In yet another embodiment, the present invention provides a process for preparing an amorphous form of elafibranor, the process comprising the steps of:
a) providing elafibranor in acetone, dichloromethane, tetrahydrofuran or suitable mixture thereof;
b) isolating amorphous elafibranor.
Step (a) may involve mixture of acetone, dichloromethane or tetrahydrofuran with suitable solvent. Suitable solvent which can be used in step (a) is selected from the group comprising of: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol, ethylene glycol, propylene glycol and the like; hydrocarbons such as n-hexane, n- heptane, cyclohexane, toluene and the like; halogenated hydrocarbons such as 1, 2- dichloroethane, dichloromethane (DCM), chloroform, carbon tetrachloride and the like; ketones such as, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1,4-dioxane, methyl tert-butyl ether (MTBE) and the like; nitriles such as acetonitrile, propionitrile and the like; organic acids such as formic acid, acetic acid and the like; water; and any mixtures of two or more thereof.
In another embodiment, the present invention provides an amorphous elafibranor- Syloid admixture. An amorphous elafibranor-Syloid admixture is characterized by X-ray powder diffraction pattern as illustrated by Figure 3. The present inventor found that admixture of amorphous elafibranor and Syloid is stable and no crystalline peak was observed up to 7 days at ambient conditions of temperature and humidity. In another embodiment, the present invention provides a process for preparing amorphous elafibranor-Syloid admixture, the process comprising the step of physical mixing of amorphous elafibranor with Syloid.
In another embodiment, the present invention provides a solid dispersion comprising elafibranor and one or more pharmaceutically acceptable excipients.
In another embodiment, the present invention provides a solid dispersion of: elafibranor and hydroxy propyl methyl cellulose (HPMC), elafibranor and copovidone, elafibranor and povidone & elafibranor and hydroxy propyl cellulose (HPC).
In yet another embodiment, the present invention provides a solid dispersion comprising elafibranor and hydroxy propyl methyl cellulose (HPMC). In preferred embodiment, solid dispersion comprising elafibranor and hydroxy propyl methyl cellulose (HPMC) is characterized by X-ray powder diffraction pattern as illustrated by Figure 4.
In yet another embodiment, the present invention provides a solid dispersion comprising elafibranor and copovidone. In preferred embodiment, solid dispersion comprising elafibranor and copovidone is characterized by X-ray powder diffraction pattern as illustrated by Figure 5. The present inventor found that solid dispersion of elafibranor with copovidone is physically and chemically stable in ICH accelerated, long term and cold conditions for 3 months.
In yet another embodiment, the present invention provides a solid dispersion comprising elafibranor and povidone. In preferred embodiment, solid dispersion comprising elafibranor and povidone is characterized by X-ray powder diffraction pattern as illustrated by Figure 6.
In yet another embodiment, the present invention provides a solid dispersion comprising elafibranor and hydroxy propyl cellulose (HPC). In preferred embodiment, solid dispersion comprising elafibranor and hydroxy propyl cellulose (HPC) is characterized by X- ray powder diffraction pattern as illustrated by Figure 6.
In another embodiment, the present invention provides a method for preparing a solid dispersion comprising elafibranor and one or more pharmaceutically acceptable excipients, the process comprising the steps of:
a) providing a mixture of elafibranor and one or more pharmaceutically acceptable excipients in solvent; and
b) isolating solid dispersion comprising elafibranor and one or more pharmaceutically acceptable excipients. Suitable solvent which can be used in step (a) for the preparation of solid dispersion of elafibranor is selected from the group comprising of: alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol, ethylene glycol, propylene glycol and the like; hydrocarbons such as n-hexane, n-heptane, cyclohexane, toluene and the like; halogenated hydrocarbons such as, 1, 2-dichloroethane, dichloromethane, chloroform, carbon tetrachloride and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, 1,4- dioxane, methyl tert-butyl ether (MTBE) and the like; nitriles such as acetonitrile, propionitrile and the like; organic acids such as formic acid, acetic acid and the like; water; and any mixtures of two or more thereof.
Suitable pharmaceutically acceptable excipients which can be used in step (a) for the preparation of solid dispersion of Elafibranor include but are not limited to: polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, Copovidone VA 64, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methyl cellulose, methacrylic acid copolymer, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (FfPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(FfPC-SSL), hydroxypropyl cellulose SL(FfPC-SL), hydroxypropyl cellulose L (FfPC-L), hydroxyethyl cellulose, Hydroxy Propyl cellulose NF FfPC-L, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-P VAc- PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethylcellulose and the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present invention. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. The preferred pharmaceutically acceptable excipient which can be used in step (a) for the preparation of solid dispersion of Elafibranor can be selected from hydroxy propyl methyl cellulose, copovidone, povidone or hydroxy propyl cellulose.
In an aspect of the present invention, providing in step a) may be carried out by 1) mixing of elafibranor and at least one pharmaceutically acceptable excipient; 2) dissolving elafibranor and at least one pharmaceutically acceptable excipient in a suitable solvent or 3) dissolving elafibranor and at least one pharmaceutically acceptable excipient separately in a suitable solvent to form individual solutions and combining those solutions later.
In an aspect of the present invention, solution of elafibranor and the excipient may be prepared at any suitable temperatures, such as about 20°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an aspect of present invention, the amount of Elafibranor in the solid dispersions of the present invention ranges from about 0.1% to about 90% by weight of the solid dispersion; or from about 10% to about 70% by weight of the solid dispersion; or from about 20% to about 60% by weight of the solid dispersion; or from about 20% to about 40% by weight of the solid dispersion; or about 30% by weight of the solid dispersion.
In an aspect of present invention, solid dispersion comprising elafibranor and one or more pharmaceutically acceptable excipient comprises elafibranor having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
In another embodiment present invention provides crystalline forms of elafibranor. In yet another embodiment present invention provides: Form A of elafibranor, Form B of elafibranor, Form C of elafibranor, Form D of elafibranor, Form E of elafibranor, Form F of elafibranor, Form G of elafibranor, Form H of elafibranor, Form J of elafibranor, Form M of elafibranor, Form N of elafibranor, Form O of elafibranor and Form Q of elafibranor.
FORM A OF ELAFIBRANOR:
In one embodiment, the present invention provides Form A of elafibranor.
In yet another embodiment, Form A of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 8; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 9.44, 18.99, and 20.99 ±0.2°; and combination thereof. The Form A of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 10.43, 12.43, 17.01, 25.23, and 26.35 ±0.2°.
In yet another embodiment, the present invention provides a process for preparing Form A of elafibranor, the process comprising the steps of:
a) providing elafibranor in ketone solvent; and
b) isolating Form A of elafibranor.
Suitable ketone solvents which can be used in step (a) for the preparation of Form A of elafibranor include but are not limited to: acetone, ethyl methyl ketone, methyl isobutyl ketone or the like;
In yet another embodiment, solvates are prepared or formed during the process described herein above. In preferred embodiment, Form A of elafibranor is acetone solvate.
FORM B OF ELAFIBRANOR:
In one embodiment, the present invention provides Form B of elafibranor.
In yet another embodiment, Form B of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 9; a X- Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 10.33, 11.12 and 13.22 ±0.2°; and combination thereof. The Form B of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 6.62, 12.50, 16.25, 23.52 and 26.41 ±0.2°.
In yet another embodiment, the present invention provides a process for preparing Form B of elafibranor, the process comprising the steps of:
a) providing elafibranor in acetic acid; and
b) isolating Form B of elafibranor.
In yet another embodiment, solvates are prepared or formed during the process described herein above. In preferred embodiment, Form B of Elafibranor is acetic acid solvate.
FORM C OF ELAFIBRANOR:
In one embodiment, the present invention provides Form C of elafibranor.
In yet another embodiment, Form C of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 10; a X- Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 13.36, 15.52 and 18.21±0.2°; and combination thereof. The Form C of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 12.18, 14.67, 17.00, and 28.62 ±0.2°;
In yet another embodiment, the present invention provides a process for preparing Form C of elafibranor, the process comprising the steps of:
a) providing elafibranor in N,N-dimethylformamide (DMF); and
b) isolating Form C of elafibranor.
In yet another embodiment, solvates are prepared or formed during the process described herein above. In preferred embodiment of present invention, Form C of Elafibranor is N,N-dimethylformamide solvate.
FORM D OF ELAFIBRANOR:
In one embodiment, the present invention provides Form D of elafibranor.
In yet another embodiment, Form D of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 11; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 13.28, 16.02 and 17.11 ±0.2°; and combination thereof. The Form D of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 15.11, 18.99, 23.12 and 25.23 ±0.2°;
In yet another embodiment, the present invention provides a process for preparing Form D of elafibranor, the process comprising the steps of:
a) providing elafibranor in N,N-dimethylacetamide (DMAc); and
b) isolating Form D of elafibranor.
In yet another embodiment of present invention, solvates are prepared or formed during the process described herein above. In preferred embodiment of present invention, Form D of elafibranor is N,N-dimethylacetamide (DMAc) solvate.
FORM E OF ELAFIBRANOR:
In one embodiment, the present invention provides Form E of elafibranor.
In yet another embodiment, Form E of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in FIGURE 12; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 17.77, 19.27 and 24.45 ±0.2°; and combination thereof. The Form E of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 11.83, 14.62, 15.44, 18.23 and 23.13 ±0.2; In yet another embodiment, the present invention provides a process for preparing Form E of elafibranor, the process comprising the steps of:
a) providing elafibranor in formamide; and
b) isolating Form E of elafibranor.
In yet another embodiment, solvates are prepared or formed during the process described herein above. In preferred embodiment of present invention, Form E of elafibranor is formamide solvate.
FORM F OF ELAFIBRANOR:
In one embodiment, the present invention provides Form F of elafibranor.
In yet another embodiment, Form F of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 13; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 13.30, 15.70 and 24.63 ±0.2°; and combination thereof. The Form F of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 12.67, 14.72, 16.91 and 18.96 ±0.2;
In yet another embodiment, the present invention provides a process for preparing Form F of elafibranor, the process comprising the steps of:
a) providing elafibranor in N-methylpyrrolidone (NMP); and
b) isolating, Form F of elafibranor.
In yet another embodiment, solvates are prepared or formed during the process described herein above. In preferred embodiment of present invention, Form F of Elafibranor is N-methylpyrrolidone (NMP) solvate.
FORM G OF ELAFIBRANOR:
In one embodiment, the present invention provides Form G of elafibranor.
In another embodiment, Form G of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 14; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 9.77, 13.03, and 16.31 ±0.2°; and combination thereof. The Form G of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 6.51, 13.9, 14.92 and 22.85±0.2.
In yet another embodiment, the present invention provides process for preparing Form G of elafibranor, the process comprising the steps of: a) providing elafibranor in DMSO; and
b) isolating Form G of elafibranor.
In yet another embodiment, solvates may be prepared or formed during the process described herein above. In preferred embodiment of present invention, Form G of elafibranor is DMSO solvate.
FORM H OF ELAFIBRANOR:
In one embodiment, the present invention provides Form H of elafibranor.
In another embodiment, Form H of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 15; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 10.72, 14.30 and 24.05 ±0.2°; and combination thereof. The Form H of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 8.88, 12.23, 17.52, 19.23 and 20.49 ±0.2.
In yet another embodiment, the present invention provides a process for preparing Form H of elafibranor, the process comprising the steps of:
a) providing elafibranor in formic acid or 1, 4 dioxane; and
b) isolating Form H of elafibranor.
In one aspect of present invention, step a) of a process for preparing Form H of Elafibranor may involve slurring or dissolving of Elafibranor in formic acid. The suitable temperature for dissolving the elafibranor can be selected between 50 °C to 100 °C.
In yet another embodiment, the present invention provides a process for preparing Form H of elafibranor, the process comprising the steps of:
a) providing elafibranor in ethyl acetate or water;
b) seeding with form H of elafibranor;
c) isolating Form H of elafibranor.
In one aspect of present invention, step a) may use any polymorphic form of elafibranor other than Form H.
In another embodiment, the present invention provides a process for preparation of Form H of Elafibranor, the process comprising ball milling of Elafibranor with formic acid or 1,4 dioxane.
In yet another aspect of present invention may involve isolation of Form H of Elafibranor from ball mill in solid form. A ball mill used in the present invention consists of a cylindrical vessel and grinding media composed typically of spherical ceramic or steel balls. Ball milling was performed using a Retsch mixer-mill MM-400 equipped with a 5 ml stainless steel milling jar and stainless steel balls of 10 mm as milling media. The milling vibrational frequency was 25 Hz or 1500 min 1 .
FORM J OF ELAFIBRANOR:
In one embodiment, the present invention provides Form J of elafibranor.
In another embodiment, Form J of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 16; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 19.72, 20.58 and 22.23 ±0.2°; and combination thereof. The Form J of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 12.79, 13.24, 21.63, and 28.28 ±0.2°.
In yet another embodiment, the present invention provides a process for preparing Form J of elafibranor, the process comprising the steps of:
a) providing elafibranor in suitable solvent;
b) adding anti-solvent; and
c) isolating Form J of Elafibranor.
Suitable solvents which can be used in step (a) is selected from the group comprising of: alcohols such as, methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, tert- Butyl alcohol, pentanol, hexanol and the like; ketones such as, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t- butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di -isopropyl ether, 1,4- dioxane, tetrahydrofuran, water and the like or suitable mixtures thereof.
In another aspect, the solution/slurry obtained in step a) is added into suitable anti solvent.
In another aspect of step b), the suitable anti-solvent is pre-cooled. The suitable temperature for pre-cooled solvent lies between -80 °C to 5°C, more specifically between - 80°C to -50°C. The suitable anti-solvent can be selected from n-hexane, n-heptane, cyclohexane, toluene and the like.
In preferred embodiment, the present invention provides a process for preparing Form J of elafibranor, the process comprising the steps of:
a) providing elafibranor in methanol, water or suitable mixture thereof;
b) adding anti-solvent, wherein anti-solvent is selected from n-hexane, n-heptane, cyclohexane and toluene;
c) isolating Form J of Elafibranor. In another aspect, the solution/slurry obtained in step a) is added into suitable anti solvent. In another aspect of step b), the suitable anti-solvent is pre-cooled. The suitable temperature for pre-cooled solvent lies between -80 °C to 5°C, more specifically between - 80°C to -50°C.
FORM M OF ELAFIBRANOR:
In one embodiment, the present invention provides Form M of elafibranor.
In another embodiment, Form M of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 19; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 19.93, 25.43 and 29.97 ±0.2°; and combination thereof. The Form M of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 11.79, 12.05, 17.21 and 22.46 ±0.2°;
In yet another embodiment, the present invention provides a process for preparing Form M of elafibranor, the process comprising the steps of:
a) providing elafibranor in suitable solvent;
b) adding anti-solvent; and
c) isolating Form M of elafibranor.
Suitable solvents which can be used in step (a) is selected from the group comprising of: nitromethane; alcohols such as, methanol, ethanol, propanol, isopropanol, n-butanol, 2- butanol, tert-Butyl alcohol, pentanol, hexanol and the like; water; ketones such as, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di -isopropyl ether, 1,4-dioxane, tetrahydrofuran, water and the like or suitable mixtures thereof.
In yet another embodiment preferred suitable solvent is selected from nitromethane, tetrahydrofuran, water or suitable mixtures thereof.
In an aspect of step a), elafibranor provided into nitromethane to give solution and then tetrahydrofuran is added into it.
In another aspect, the solution/slurry obtained in step a) is added into suitable anti solvent.
In an aspect of step b), the suitable anti-solvent is pre-cooled. The suitable temperature for pre-cooled solvent lies between -90 °C to 5°C, more specifically between - 85°C to -50°C. The suitable anti-solvent can be selected from n-hexane, n-heptane, cyclohexane, toluene and the like.
In preferred embodiment, the present invention provides a process for preparing Form M of elafibranor, the process comprising the steps of:
a) providing elafibranor in nitromethane, tetrahydrfuran, water or suitable mixture thereof;
b) adding anti-solvent; wherein anti-solvent is selected from n-hexane, n-heptane, cyclohexane and toluene;
c) isolating Form M of elafibranor.
In another aspect, the solution/slurry obtained in step a) is added into suitable anti solvent. In an aspect of step b), the suitable anti-solvent is pre-cooled. The suitable temperature for pre-cooled solvent lies between -90 °C to 5°C, more specifically between - 85°C to -50°C.
FORM N OF ELAFIBRANOR:
In one embodiment, the present invention provides Form N of elafibranor.
In another embodiment, Form N of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 20; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 8.65, 12.94 and 21.53 ±0.2°; and combination thereof. The Form N of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 17.41, 19.68, 23.65 and 27.73 ±0.2°.
In yet another embodiment, the present invention provides a process for preparing Form N of elafibranor, the process comprising steps of:
a) providing elafibranor in ethanol solvent;
b) isolating Form N of elafibranor.
In preferred embodiment, Form N of elafibranor is ethanol solvate.
FORM O OF ELAFIBRANOR:
In one embodiment, the present invention provides Form O of elafibranor.
In another embodiment, Form O of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 21; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 8.15, 17.03 and 21.81 ±0.2°; and combination thereof. The Form N of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 11.47, 15.50, 28.27, and 34.76 ±0.2°.
In yet another embodiment, the present invention provides process for preparing Form O of Elafibranor, the process comprising steps of:
a) heating elafibranor Form J;
b) isolating Form O of elafibranor.
In an aspect of the present invention, step a) can be performed in open or close heating system. The suitable close heating system can be selected from DSC instrument, sealed tube heating instrument, or a system known to skilled person in the art. In an aspect of present invention, Form O of elafibranor is hemihydrate. The hemihydrate Form O of elafibranor is stable at 40 degrees centigrade under 75% RH and at 25 degrees centigrade under 75% RH up to 24 hours.
FORM O OF ELAFIBRANOR:
In one embodiment, the present invention provides Form Q of elafibranor.
In another embodiment, Form Q of elafibranor is characterized by data selected from: a X-Ray powder diffraction pattern substantially the same as shown in Figure 23; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 8.15, 17.03 and 21.81 ±0.2°; and combination thereof. The Form Q of elafibranor may be further characterized by an X-ray powder diffraction pattern having additional peaks at 11.47, 15.50, 28.27, and 34.76 ±0.2°.
In yet another embodiment, the present invention provides process for preparing Form Q of Elafibranor, the process comprising steps of:
a) heating Elafibranor Form N;
b) isolating Form Q of elafibranor.
In an aspect of the present invention, step a) can be performed in open or close heating system. The suitable close heating system can be selected from DSC instrument, sealed tube heating instrument, or a system known to skilled person in the art.
In one embodiment, present invention provides co-crystal of elafibranor. In yet another embodiment, present invention provides co-crystal of elafibranor with urea, co crystal of elafibranor with L-proline and co-crystal of elafibranor with saccharin.
CO-CRTSTAL OF ELAFIBRANOR WITH UREA:
In one embodiment, the present invention provides co-crystal of elafibranor with urea. In another embodiment, co-crystal of Elafibranor with urea is characterized by data comprising of: a X-Ray powder diffraction pattern substantially the same as shown in Figure 17; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 8.25, 11.6 and 14.32 ±0.2°; and combination thereof. The co-crystal of elafibranor with urea may be further characterized by an X-ray powder diffraction pattern having additional peaks at about 16.53, 17.17, 20.65 and 26.94 ±0.2°.
In yet another embodiment, the present invention provides a process for preparing co crystal of Elafibranor with urea, the process comprising the steps of:
a) providing Elafibranor and urea in suitable solvent; and
b) isolating co-crystal of elafibranor with urea.
Suitable solvents which can be used in step (a) is selected from the group comprising of: alcohols such as, methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, tert- Butyl alcohol, pentanol, hexanol and the like; ketones such as, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t- butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di -isopropyl ether, 1,4- dioxane, tetrahydrofuran and the like or suitable mixtures thereof.
CO-CRTSTAL OF ELAFIBRANOR WITH L-PROLINE:
In one embodiment, the present invention provides co-crystal of elafibranor with L-proline.
In another embodiment, co-crystal of Elafibranor with L-proline is characterized by data comprising of: a X-Ray powder diffraction pattern substantially the same as shown in FIGURE 18; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 5.54, 13.93 and 17.58 ±0.2°; and combination thereof. The co crystal of Elafibranor with L-proline may be further characterized by an X-ray powder diffraction pattern having additional peaks at about 6.58, 10.97, 19.77 and 22.14±0.2°.
In yet another embodiment, the present invention provides a process for preparing co crystal of elafibranor with L-proline, the process comprising the steps of:
a) providing elafibranor and L-proline in suitable solvent; and
b) isolating co-crystal of elafibranor with L-proline.
Suitable solvents which can be used in step (a) is selected from the group comprising of: alcohols such as, methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, tert- Butyl alcohol, pentanol, hexanol and the like; ketones such as, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t- butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di -isopropyl ether, 1,4- dioxane, tetrahydrofuran and the like or suitable mixtures thereof.
CO-CRTSTAL OF ELAFIBRANOR WITH SACCHARIN:
In one embodiment, the present invention provides co-crystal of elafibranor with saccharin.
In another embodiment, co-crystal of Elafibranor with saccharin is characterized by data comprising of: a X-Ray powder diffraction pattern substantially the same as shown in Figure 22; a X-Ray powder diffraction pattern with characteristic peaks in terms of degrees 2-theta, at about 9.60, 15.51, 17.65 and 19.18 ±0.2°; and combination thereof. The co-crystal of Elafibranor with saccharin may be further characterized by an X-ray powder diffraction pattern having additional peaks at about 13.28, 18.49, 21.64 and 25.04°.
In yet another embodiment, the present invention provides a process for preparing co crystal of elafibranor with saccharin, the process comprising the steps of:
a) providing elafibranor and saccharin in suitable solvent; and
b) isolating co-crystal of elafibranor with saccharin.
Suitable solvents which can be used in step (a) is selected from the group comprising of: alcohols such as, methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, tert- Butyl alcohol, pentanol, hexanol and the like; ketones such as, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t- butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, di -isopropyl ether, 1,4- dioxane, tetrahydrofuran and the like or suitable mixtures thereof.
In one aspect present invention optionally involves, filtration step to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, micron filter, centrifugation, decantation, and any other techniques known in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
In one aspect present invention involves, isolation of elafibranor by removing solvent. Suitable techniques which can be used for the removal of solvent include but are not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin- film drying (e.g., agitated thin-film drying (ATFD)), agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer (RVPD) or any other suitable technique known in the art. In an aspect of present invention provides pharmaceutical composition comprising solid state forms of elafibranor, more particularly, amorphous, solid dispersions, co-crystals, admixture & crystalline forms of elafibranor and one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are useful in the present invention include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like.
DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise. Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula. “Amorphous form” as used herein refers to a solid state wherein the amorphous content within the said solid state is at least about 35% or at least about 40% or at least about 45% or at least about 50% or at least about 55% or at least about 60% or at least about 65% or at least about 70% or at least about 75% or at least about 80% or at least about 85% or at least about 90% or at least about 95% or at least about 96% or at least about 97% or at least about 98% or at least about 99% or about 100%.
All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25°C and normal pressure unless otherwise designated. The present disclosure can comprise the components discussed in the present disclosure as well as other ingredients or elements described herein. As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
The compound of this invention is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. X-ray powder diffraction (PXRD) data reported herein was obtained using CuKa radiation, having the wavelength 1.5406 A and were obtained using a PANalytical X’Pert PRO instruments.
TGA data reported herein was obtained from TGA Q 500 V20.13 Build 39.
As used herein, the term "room temperature" refers to a temperature of from about 20°C to about 35°C, from about 25°C to about 35°C, from about 25°C to about 30°C, or for example, about 25°C.
Terms such as "about" or "substantially" is to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify, as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
As used herein, the term "room temperature" refers to a temperature of from about 20°C to about 35°C, from about 25°C to about 35°C, from about 25°C to about 30°C, or for example, about 25°C.
Certain specific aspects and embodiments of the present invention will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the invention in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
EXAMPLES
EXAMPLE 1: Preparation of amorphous elafibranor Elafibranor (250 mg) and 6 mL of dichloromethane were charged into a flask at room temperature. The resulting mixture was stirred to get a clear solution and filtered to remove undissolved particles. The resultant solution was subjected to fast solvent evaporation under reduced pressure at about 45 ° C to afford the solid compound. The said solid was dried under vacuum at about 45 ° C to afford 200 mg of pale yellow amorphous elafibranor and characterized by X-ray powder diffraction according to Figure 1.
EXAMPLE 2: Preparation of amorphous elafibranor
Elafibranor (250 mg) and 8 mL of dichloromethane-acetone mixture (1 : 1) were charged into a flask at room temperature. The resulting mixture was stirred to get a clear solution and filtered to remove undissolved particles. The resultant solution was subjected to fast solvent evaporation under reduced pressure at about 45 ° C to afford the solid compound. The said solid was dried under vacuum at about 45 ° C to afford 200 mg of pale yellow amorphous elafibranor and characterized by X-ray powder diffraction according to Figure 1.
EXAMPLE 3: Preparation of amorphous elafibranor
Elafibranor (250 mg) and 8 mL of dichloromethane-MTBE mixture (1 : 1) were charged into a flask at room temperature. The resulting mixture was stirred to get a clear solution and filtered to remove undissolved particles. The resultant solution was subjected to fast solvent evaporation under reduced pressure at about 45 ° C to afford the solid compound. The said solid was dried under vacuum at about 45 ° C to afford 200 mg of pale yellow amorphous elafibranor and characterized by X-ray powder diffraction according to Figure 1.
EXAMPLE 4: Preparation of amorphous elafibranor
Elafibranor (500 mg) and 35 mL of acetone were charged into a flask at room temperature. The resulting mixture was stirred to get a clear solution and filtered to remove undissolved particles. The resultant solution was subjected to evaporation under reduced pressure at about 40 ° C to afford the solid compound. The said solid was dried under vacuum to afford 369 mg of pale yellow amorphous elafibranor and characterized by X-ray powder diffraction according to Figure 2.
EXAMPLE 5: Preparation of amorphous elafibranor
Elafibranor (250 mg), THF (10 mL) and DI water (10 mL) were charged into a flask at room temperature. The resulting mixture was stirred to get a clear solution and filtered to remove undissolved particles. The resultant solution was freezed in a dry ice and acetone and lyophilized to afford 228 mg of pale yellow amorphous elafibranor and characterized by X- ray powder diffraction according to Figure 1.
EXAMPLE 6: Preparation of Elafibranor-Syloid Admixture:
Amorphous elafibranor (150 mg) and Syloid (150 mg) was mixed to obtain an admixture of amorphous elafibranor and Syloid. It is found that the admixture of amorphous elafibranor and Syloid is stable and no crystalline peak was observed up to 7 days at ambient conditions of temperature and humidity. Elafibranor- syloid admixture is characterized by X- ray powder diffraction according to Figure 3.
EXAMPLE 7: Preparation of solid dispersion of elafibranor with hydroxy propyl methyl cellulose
Elafibranor (500 mg) and hydroxy propyl methyl cellulose AS (250 mg) were dissolved in acetone (60 mL) at room temperature. The resulting mixture was stirred to get a clear solution and filtered to remove undissolved particles. The resultant solution was subjected to fast solvent evaporation under reduced pressure at about 40 ° C to afford the solid compound. The said solid was dried under vacuum to afford 638 mg. The resulting dispersion was found to be amorphous by X-ray powder diffraction according to Figure 4.
EXAMPLE 8: Preparation of solid dispersion of elafibranor with copovidone
Elafibranor (500 mg) and copovidone VA 64 (250 mg) were dissolved in acetone (60 mL) at room temperature. The resulting mixture was stirred to get a clear solution and filtered to remove undissolved particles. The resultant solution was subjected to fast solvent evaporation under reduced pressure at about 40 ° C to afford the solid compound. The said solid was dried under vacuum to afford 662 mg. The resulting dispersion was found to be amorphous by X-ray powder diffraction according to Figure 5. Solid dispersion of elafibranor with copovidone (1 :0.5) was loaded for stability and it is found to be physically and chemically stable in ICH accelerated, long term and cold conditions for 3 months.
EXAMPLE 9: Preparation of solid dispersion of elafibranor with povidone
Elafibranor (500 mg) and povidone K 30 (250 mg) were dissolved in acetone (60 mL) and DCM (20 mL) at room temperature. The resulting mixture was stirred to get a clear solution and filtered to remove undissolved particles. The resultant solution was subjected to fast solvent evaporation under reduced pressure at about 40 ° C to afford the solid compound. The said solid was dried under vacuum to afford 649 mg. The resulting dispersion was found to be amorphous by X-ray powder diffraction according to Figure 6. EXAMPLE 10: Preparation of solid dispersion of elafibranor with hydroxy propyl cellulose
Elafibranor (500 mg) and hydroxy propyl cellulose NF HPC-L (250 mg) were dissolved in acetone (60 mL) and DCM (20 mL) at room temperature. The resulting mixture was stirred to get a clear solution and filtered to remove undissolved particles. The resultant solution was subjected to fast solvent evaporation under reduced pressure at about 40 ° C to afford the solid compound. The said solid was dried under vacuum to afford 705 mg. The resulting dispersion was found to be amorphous by X-ray powder diffraction according to Figure 7.
EXAMPLE 11: Preparation of Form A of elafibranor
Elafibranor (2 g) and 3 mL of acetone were charged into a flask at room temperature. The resulting mixture was stirred to get slurry. The resultant slurry was filtered under reduced pressure to afford the solid compound. The said solid was dried under vacuum to afford 1.89 gm. The resulting solid was found to be Form A of Elafibranor by X-ray powder diffraction according to Figure 8.
EXAMPLE 12: Preparation of Form B of elafibranor
Elafibranor (2 g) and 3 mL of acetic acid were charged into a flask at room temperature. The resulting mixture was stirred to get slurry. The resultant slurry was filtered under reduced pressure to afford the solid compound. The said solid was dried under vacuum to afford 1.83 gm. The resulting solid was found to be Form B of Elafibranor by X-ray powder diffraction according to Figure 9.
EXAMPLE 13: Preparation of Form C of elafibranor
Elafibranor (2 g) and 2 mL of DMF were charged into a flask at room temperature. The resulting mixture was stirred to get slurry. The resultant slurry was filtered under reduced pressure to afford the solid compound. The said solid was dried under vacuum to afford 2.21 gm. The resulting solid was found to be Form C of Elafibranor by X-ray powder diffraction according to Figure 10.
EXAMPLE 14: Preparation of Form D of elafibranor
Elafibranor (2 g) and 2 mL of DMAc were charged into a flask at room temperature. The resulting mixture was stirred to get slurry. The resultant slurry was filtered under reduced pressure to afford the solid compound. The said solid was dried under vacuum to afford 1.82 gm. The resulting solid was found to be Form D of Elafibranor by X-ray powder diffraction according to Figure 11.
EXAMPLE 15: Preparation of Form E of elafibranor Elafibranor (2 g) and 2 mL of Formamide were charged into a flask at room temperature. The resulting mixture was stirred to get slurry. The resultant slurry was filtered under reduced pressure to afford the solid compound. The said solid was dried under vacuum to afford 2.2 gm. The resulting solid was found to be Form E of Elafibranor by X-ray powder diffraction according to Figure 12.
EXAMPLE 16: Preparation of Form F of elafibranor
Elafibranor (2 g) and 2 mL of NMP were charged into a flask at room temperature. The resulting mixture was stirred to get slurry. The resultant slurry was filtered under reduced pressure to afford the solid compound. The said solid was dried under vacuum to afford 2.2 gm. The resulting solid was found to be Form F of Elafibranor by X-ray powder diffraction according to Figure 13.
EXAMPLE 17: Preparation of Form G of elafibranor
Elafibranor (200 mg) and 0.2 mL of DMSO were charged into a flask at room temperature. The resulting mixture was stirred to get slurry. The resultant slurry was filtered under reduced pressure to afford the solid compound. The said solid was dried under vacuum to afford 180 mg. The resulting solid was found to be Form G of Elafibranor by X-ray powder diffraction according to Figure 14.
EXAMPLE 18: Preparation of Form H of elafibranor
Elafibranor (65 mg) and 0.1 mL of formic acid were charged into a flask at room temperature. The resulting mixture was heated to get a clear solution. The resultant solution was filtered and solvent was removed by evaporation to get solid form. The resulting solid was dried under vacuum to afford 55 mg. The resulting solid was found to be Form H of Elafibranor by X-ray powder diffraction according to Figure 15.
EXAMPLE 19: Preparation of Form H of elafibranor
Elafibranor (500 mg) and 0.2 mL of formic acid were charged into a ball mill at room temperature and subjected for milling process. After milling, solid form of 426 mg was obtained. The resulting solid was found to be Form H of Elafibranor by X-ray powder diffraction according to Figure 15.
EXAMPLE 20: Preparation of Form H of elafibranor
Elafibranor (200 mg) and 0.1 mL of 1, 4 dioxane were charged into a ball mill at room temperature and subjected for milling process. After milling, solid form of 170 mg was obtained. The resulting solid was found to be Form H of Elafibranor by X-ray powder diffraction according to Figure 15.
EXAMPLE 21: Preparation of Form H of elafibranor Elafibranor (200 mg) and 0.5 mL of 1, 4 dioxane were charged into a flask at room temperature. The resultant slurry was filtered to get solid form. The resulting solid was dried under vacuum to afford 190 mg (yield). The resulting solid was found to be Form H of Elafibranor by X-ray powder diffraction according to Figure 15.
EXAMPLE 22: Preparation of Form H of elafibranor
Elafibranor (300 mg) and Elafibranor Form H (50 mg) and 1 mL DM water were charged into a flask at room temperature. The resulting mixture was stirred and dried to get solid form of 340 mg. The resulting solid was found to be Form H of Elafibranor by X-ray powder diffraction according to Figure 15.
EXAMPLE 23: Preparation of Form H of elafibranor
Elafibranor (1.023 g) and 1.5 mL ethyl acetate were charged into a flask at room temperature. The resultant mixture was stirred and seeded with Form H of elafibranor (50 mg). The resultant slurry was stirred and dried to afford lOOOmg. The resulting solid was found to be Form H of Elafibranor by X-ray powder diffraction according to Figure 15.
EXAMPLE 24: Preparation of Form J of elafibranor
Elafibranor (250 mg) and 1.5 mL of methanol were charged into a flask at room temperature. The resulting mixture was heated at 60°C to get a clear solution. The resultant solution was poured in pre-cool ed (about -78°C) 10 mL cyclohexane solvent. The resultant slurry was dried to afford 200 mg of Elafibranor. The resulting solid was found to be Form J of Elafibranor by X-ray powder diffraction according to Figure 16.
EXAMPLE 25: preparation of co-crystal of elafibranor with urea
Elafibranor (384 mg) and urea (60 mg) were charged into mortar and 0.5 mL of methanol was added into it. The resulting mixture was grinded with a pestle. The resulting solid of 400 mg was found to be co-crystal of elafibranor with urea and can be characterized by X-ray powder diffraction according to Figure 17.
EXAMPLE 26: Preparation of co-crystal of elafibranor with L-proline
Elafibranor (500 mg) and L-proline (270 mg) were charged into mortar and 0.5 mL of methanol was added into it. The resulting mixture was grinded with a pestle. The resultant solid was dissolved in mixture of 20 mL acetonitrile and 20 mL methanol. The resultant solution was subjected to rotary evaporator apparatus under reduced pressure at about 60 ° C to afford the solid compound. The resulting solid of 400 mg was found to be co-crystal of elafibranor with L-proline and can be characterized by X-ray powder diffraction according to Figure 18.
EXAMPLE 27: Preparation of Form M of elafibranor Elafibranor (200 mg) and 1 mL of nitromethane were charged into a flask at room temperature and kept on sonicator. 0.5 mL of tetrahydrfuran was added to get a clear solution. The resultant solution was poured in pre-cooled (about -80°C) 2 mL n-heptane solvent. The resultant slurry was filtered and dried to afford 120 mg of Elafibranor. The resulting solid was found to be Form M of Elafibranor by X-ray powder diffraction according to Figure 19. EXAMPLE 28: Preparation of Form N of elafibranor
Elafibranor (250 mg) and 1.5 mL of ethanol were charged into a flask at room temperature. The resulting mixture was heated at 65°C to get a clear solution. The resultant solution was cooled to room temperature. The yellow crystal was grown in solution over two hours. The resultant crystal was filtered and dried to afford 200 mg of Elafibranor. The resulting solid was found to be Form N of Elafibranor by X-ray powder diffraction according to Figure 20.
EXAMPLE 29: Preparation of Form O of elafibranor
Elafibranor form J (20 mg) was loaded on DSC pan and sealed. The loaded pan was heated at 105 °C on a DSC instrument for 3 minutes. The resulting solid was found to be Form O of Elafibranor by X-ray powder diffraction according to FIGURE 21. Form O of elafibranor is found to be stable at 40 degrees centigrade under 75% RH and at 25 degrees centigrade under 75% RH upto 24 hours.
EXAMPLE 30: Preparation of co-crystal of elafibranor with saccharin
Elafibranor (770 mg) and saccharin (366 mg) were charged into mortar and 2 mL of methanol was added into it. The resulting mixture was grinded with a pestle and dried. The resulting solid of 1100 mg was found to be co-crystal of elafibranor with saccharin and can be characterized by X-ray powder diffraction according to Figure 22
EXAMPLE 31: Preparation of Form Q of elafibranor
Elafibranor form N (20 mg) was loaded on DSC pan and sealed. The loaded pan was heated at 105 °C on a DSC instrument for two minutes. The resulting solid was found to be Form Q of Elafibranor by X-ray powder diffraction according to Figure 23.