DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL CRYSTALLINE FORMS OF ACORAMIDIS HYDROCHLORIDE AND PROCESSES FOR PREPARATION

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to a novel crystalline forms of Acoramidis hydrochloride and process for the preparation thereof.

BACKGROUND OF THE INVENTION

Acoramidis hydrochloride, chemically known as 3-(3-(3-5-dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzoic acid hydrochloride (compound of Formula 1), which is a promising candidate to treat TTR amyloid related diseases such as TTR amyloid cardiomyopathy.

Formula 1

Acoramidis (1) along with its pharmaceutically acceptable salts was disclosed in US 9,169,214. The ‘214 patent also disclosed a process for the preparation of Acoramidis.
US 10,513,497 disclosed crystalline forms of Acoramidis including six hydrochloride salt forms such as Type A, Type B, Type E, Type H, Type I, Type J and two freebase forms including Type C and Type G and two unidentified forms Type D and Type F . Forms of Type A, B & E were identified to be anhydrates. Type I was identified to be a hydrate. Type H and J were identified to be a methanol solvate and Dimethylacetamide solvate, respectively.

Considering the importance of Acoramidis hydrochloride, nevertheless, besides the known solid forms of Acoramidis hydrochloride, there is still the need for further polymorphs, which are, stable in formulation, reproducible, and a process which involves the use of reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, and/or provide a product of higher purity.

In view of the above, our inventors have developed Crystalline Acoramidis hydrochloride Form ACR-1 and Crystalline Acoramidis hydrochloride Form ACR-2 which are stable in formulation, reproducible and process for the preparation thereof.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a crystalline Forms of Acoramidis hydrochloride and a process for the preparation thereof.

SUMMARY OF THE INVENTION

The present invention is directed to Benzyl alcohol solvate of Acoramidis hydrochloride, designated as crystalline Acoramidis hydrochloride Form ACR-1 and DMSO solvate of Acoramidis hydrochloride, designated as crystalline Acoramidis hydrochloride Form ACR-2.

The present invention further directed to a process for the preparation of crystalline Acoramidis hydrochloride Form ACR-1 and crystalline Acoramidis hydrochloride Form ACR-2.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: PXRD pattern of crystalline Acoramidis hydrochloride Form ACR-1.
Figure 2: DSC pattern of crystalline Acoramidis hydrochloride Form ACR-1.
Figure 3: PXRD pattern of crystalline Acoramidis hydrochloride Form ACR-2.
Figure 4: DSC pattern of crystalline Acoramidis hydrochloride Form ACR-2.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides Benzyl alcohol solvate of Acoramidis hydrochloride, designated as crystalline Acoramidis hydrochloride Form ACR-1.

In another embodiment, the present invention provides crystalline Acoramidis hydrochloride Form ACR-1 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 5.2, 9.9, 12.5, 13.2 and 15.8 ± 0.2° 2?. The present invention provides crystalline Acoramidis hydrochloride Form ACR-1 characterized by its PXRD pattern having additional peaks at about 10.5, 16.5, 19.8, 20.9 and 26.4 ± 0.2° 2?.

In another embodiment the present invention provides a process for the preparation of the crystalline Acoramidis hydrochloride Form ACR-1,
which comprises;
a) dissolving Acoramidis hydrochloride in benzyl alcohol to obtain a solution;
b) adding a solvent to the above solution; and
c) obtaining the crystalline Acoramidis hydrochloride Form ACR-1.

In another embodiment, the present invention provides a crystalline Acoramidis hydrochloride Form ACR-1 having a Powder X-ray Diffraction (PXRD) pattern shown in Figure-1.

In another embodiment, the present invention provides a crystalline Acoramidis hydrochloride Form ACR-1 characterized by DSC thermogram comprising an endotherm Peak at 104.09ºC, 207.66ºC and Broad endotherm peak at 147.05°C as shown in Figure 2.

In another embodiment, the present invention provides Dimethyl sulfoxide (DMSO) solvate of Acoramidis hydrochloride, designated as crystalline Acoramidis hydrochloride Form ACR-2.

In another embodiment, the present invention provides crystalline Acoramidis hydrochloride Form ACR-2 characterized by its powder X-ray diffraction (PXRD) pattern having peaks at about 7.0, 11.3, 12.4, 14.0 and 16.7 ± 0.2° 2?. The present invention provides crystalline Acoramidis hydrochloride Form ACR-2 characterized by its PXRD pattern having additional peaks at 8.2, 14.8, 15.5, 19.0 and 25.8 ± 0.2° 2?.

In another embodiment the present invention provides a process for the preparation of the crystalline Acoramidis hydrochloride Form ACR-2
Which comprises;
a) dissolving Acoramidis hydrochloride in dimethyl sulfoxide to obtain a solution;
b) adding a suitable solvent to the above solution; and
c) obtaining the crystalline Acoramidis hydrochloride Form ACR-2.

In another embodiment, the present invention provides a crystalline Acoramidis hydrochloride Form ACR-2 having a Powder X-ray Diffraction (PXRD) pattern shown in Figure-3.

In another embodiment, the present invention provides a crystalline Acoramidis hydrochloride Form ACR-2 characterized by DSC thermogram comprising an endotherm onset peak temperature at 95.93ºC and broad endothermic peak at 209.86°C as shown in Figure 4.

The suitable solvent(s) used in present invention comprising the group of esters comprises ethyl acetate, and isopropyl acetate; aliphatic hydrocarbons comprises cyclohexane, n-hexane, n-heptane, and pentane; aromatic hydrocarbons comprises toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons comprises dichloromethane, chloroform, and ethylene dichloride; dialkyl formamides comprises dimethyl formamide; ethers comprises methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, dimethyl ether, and methyl butyl ether; cyclic ethers comprises tetrahydrofuran, and 1 ,4-dioxane; substituted cyclic ethers comprises 2-methyl tetrahydrofuran; alcohols comprises methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, ethylene glycol, and diethylene glycol; ketones comprises acetone, methyl ethyl ketone, and methyl isobutyl ketone; dialkylsulfoxides comprises dimethyl sulfoxide; dialkylacetamides comprises N,N-dimethyl acetamide; nitriles comprises acetonitrile, and propionitrile; water and/or mixtures thereof.

The Powder X-ray diffraction (PXRD) pattern measured on an X-ray diffractometer (instrument name Bruker D8 advance-Eco with lynex detector equipped with Cu source ?=1.58Å) measured using CuKa radiation. Methodology of X-ray diffraction is as follows:
Scanning Type: Continuous scan; Scan range: at least 3-40° 2theta; Step size: 0.8°; Time/Step: 0.05 sec; Divergence slit: V20; Rotation: 30 rpm
The Differential Scanning Calorimetry (DSC) thermograms were obtained on a TA Q2000 DSC. Methodology of DSC is as follows:
Mass flow: 50.0 ± 10 mL/min; Equilibrate: 30.00°C; Ramp: 10.00°C/min to 300.00°C.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES:
Example 1: Preparation of crystalline Acoramidis hydrochloride Form ACR-1.
In a 10mL Round bottom flask, 50 mg. Acoramidis hydrochloride and 0.8 ml. benzyl alcohol were added and dissolved at 55-60ºC, stirred for 5-10 minutes. The solution was cooled to 0-5ºC and 2 ml methyl tert-butyl ether (MTBE) was added and stirred for 25-30 minutes and cooled to -8 to -5ºC and stirred for 10-15 minutes. The obtained solid was filtered and washed with 0.5 ml chilled methyl tert-butyl ether (MTBE) and suck dried under vacuum for 45-60 minutes at 40ºC to get 40mg of crystalline Acoramidis hydrochloride Form ACR-1 with yield 80%. Dried material analyzed by PXRD.

Example 2: Preparation of crystalline Acoramidis hydrochloride Form ACR-2
In a 10mL Round bottom flask, 50 mg. Acoramidis hydrochloride and 0.8 ml. dimethyl sulfoxide were added and dissolved at 55-60ºC, stirred for 5-10 minutes. The solution was added to 2 ml methyl tert-butyl ether (MTBE) and stirred for 25-30 minutes and cooled to -8 to -5ºC and stirred for 10-15 minutes. The obtained solid was filtered and washed with 0.5 ml chilled methyl tert-butyl ether (MTBE) and suck dried under vacuum for 45-60 minutes at 40ºC to get 42mg of crystalline Acoramidis hydrochloride Form ACR-2 with yield of 84%. Dried material analyzed by PXRD. ,CLAIMS:WE CLAIM:

1. A Crystalline Acoramidis Hydrochloride Form ACR-1 characterized by XRPD pattern having 2? values at about 5.2, 9.9, 12.5, 13.2 and 15.8 (± 0.2 degrees 2 theta).

2. The Crystalline form according to claim 1, characterized by XRPD pattern having 2? values at about 5.2, 9.9, 10.5, 12.5, 13.2, 14.8, 15.7, 16.5, 19.1, 19.8, 20.9, 21.8, 22.2, 24.8 and 26.4 (± 0.2 degrees 2 theta).

3. The Crystalline form according to claim 1, characterized by XRPD pattern depicted in Figure 1.

4. A process for the preparation of the Crystalline Acoramidis Hydrochloride Form ACR-1, which comprises;
a) dissolving Acoramidis hydrochloride in benzyl alcohol to obtain a solution;
b) adding a solvent to the above solution; and
c) obtaining the crystalline Acoramidis hydrochloride Form ACR-1.

5. A Crystalline Acoramidis Hydrochloride Form ACR-2 characterized by XRPD pattern having 2? values at about 7.0, 11.3, 12.4, 14.0 and 16.7 (± 0.2 degrees 2 theta).

6. The Crystalline form according to claim 6, characterized by XRPD pattern having 2? values at about 7.0, 8.2, 11.3, 12.4, 12.8, 13.0, 14.0, 14.8, 15.5, 16.7, 18.7, 19.0, 20.7, 21.1, 21.3, 21.7, 22.2, 22.8,24.1, 25.8, 27.1 and 28.6 (± 0.2 degrees 2 theta).

7. The Crystalline form according to claim 5, characterized by XRPD pattern depicted in Figure 3.
8. A process for the preparation of the Crystalline Acoramidis Hydrochloride Form ACR-2, which comprises;
a) dissolving Acoramidis hydrochloride in dimethyl sulfoxide to obtain a solution;
b) adding a solvent to the above solution; and
c) obtaining the crystalline Acoramidis hydrochloride Form ACR-2.

9. The process according to claim 4 and 8, wherein the solvent comprises methyl tertiary butyl ether, diisopropyl ether and diethyl ether.