Claims:1. Crystalline form I of Bucillamine.

2. A crystalline form I of Bucillamine as claimed in claim 1, characterized by an X-ray powder diffraction pattern (XRPD) spectrum having peak reflection at about 10.4, 13.5, 14.4, 16.8, 17.2, 17.5, 21.9, 22.7, 28.0, 29.3, 30.0 and 30.45 ±0.2 degrees 2?.

3. A crystalline form I of Bucillamine as claimed in claim 2 and 3, further characterized by an X-ray powder diffraction pattern (XRPD) spectrum having peak reflections at about 10.4, 13.5, 14.4, 16.8, 17.2, 17.5, 20.1, 20.9, 21.9, 22.7, 23.5, 28.0, 28.7, 29.3, 30.0, 30.45, 32.1, 37.8 and 38.6 ±0.2 degrees 2?.

4. A crystalline form I of Bucillamine as claimed in claim 1, having a powder X-ray powder diffraction pattern substantially in accordance with Figure-1.

5. A crystalline form I of Bucillamine as claimed in claim 1, having a differential scanning calorimetry (DSC) substantially in accordance with Figure-2.

6. A process for preparing crystalline form I of Bucillamine comprising:

a. Crude Bucillamine was dissolved in a suitable organic solvent,
b. heating the obtained suspension at suitable temperature,
c. cooling the obtained solution in step b),
d. isolating the crystalline form I of Bucillamine.

7. The process as claimed in claim 6, step b) wherein the heating reaction is carried out at 70-75º C.

8. The process as claimed in claim 6, wherein the suitable organic solvent is selected from group consisting of ethyl acetate, methyl acetate, isopropyl acetate, cyclohexane and water or mixture thereof.

9. The crystalline form I of Bucillamine as claimed in claim 1, wherein the particle size distribution D90 less than about 250 µm.
, Description:FIELD OF THE INVENTION

The present invention relates to crystalline form I of Bucillamine. The present invention also relates to a purification process for preparing crystalline form I of Bucillamine.

BACKGROUND OF THE INVENTION

Bucillamine (INN; trade names Rimatil; Tiobutarit) is an antirheumatic agent developed from tiopronin. It is mainly used in Japan and Korea. Bucillamine only approved in Japan and Korea. In japan Rimati tablets 50 mg and 100 mg (Santen pharmaceuticals Co., Ltd.,) and others for patients with a history of hypersensitivity to ingredients of this drug. Activity is mediated by the two thiol groups that the molecule contains. Research done in USA showed positive transplant preservation properties. It is under Phase 2 trial in patients with Cystinuria in US. Revive Therapeutics Announces US FDA Grants Orphan Drug Designation for Bucillamine for the Treatment of Cystinuria. Bucillamine is chemically known as N-(2-mercaptoisobutyryl)-L-cysteine of formula (I) has the following structure.

US 4,305,958 (Santen pharmaceutical.,) reported Bucillamine and its process for preparation. Bucillamine is obtained in ‘958 patent by recrystallization / purification with ethyl acetate to obtain a pure Bucillamine melting at 139-140ºC.

IN 202041006187 of Optimus reported crystalline form of Bucillamine and its process for the preparation. Crystalline form of Bucillamine is obtained in ‘187 patent application by crystallization / purification with ethyl acetate and cyclohexane melting at 135.99ºC.

In literature, there is not mentioned anything about different crystalline forms of Bucillamine.

Many pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of drug substance to exist in two or more crystalline phases that have different arrangement and/or conformations of the molecule in the crystal lattice. Polymorphism refers to occurrence of different crystalline form of the same drug substance. The different crystalline forms have different physical properties like melting point, x - ray diffraction pattern,
infrared spectra and solid state NMR spectrum.

The difference in physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid. Accordingly, the polymorphs are distinct solids sharing the same molecular formulae, yet having different physical properties compared to other crystalline forms of the same compound.

The different polymorphs, pseudo polymorphs or the amorphous form differ in their physical properties such as melting point, solubility etc and hence may affect pharmaceutical properties such as dissolution rate and bioavailability of the drug substance. Hence, the discovery of new or different polymorphs is essential. Since a new polymorph may aide in the manufacture of the drug product formulation which may prove to be more effective absorption in gastrointestinal tract.

We have found a crystalline form I of Bucillamine. The crystalline form I has been found to be stable over the time and reproducible. Hence it is suitable for pharmaceutical preparations.

The object of the present invention to prepare a novel crystalline form I of Bucillamine, which it enhance in pharmaceutical composition.

SUMMARY OF THE INVENTION

The present invention relates to crystalline form I of Bucillamine and also relates to a purification process for preparing crystalline form I of Bucillamine.

In one aspect of the present invention, it provides a crystalline form I of Bucillamine characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 10.4, 13.5, 14.4, 16.8, 17.2, 17.5, 21.9, 22.7, 28.0, 29.3, 30.0 and 30.45 ±0.2 degrees 2?.

In another aspect of the present invention, it provides a process for the preparation of crystalline form I of Bucillamine, comprising:

a. Crude Bucillamine was dissolved in a suitable organic solvent,
b. heating the obtained suspension at suitable temperature,
c. cooling the obtained solution in step b),
d. isolating the crystalline form I of Bucillamine.

In yet another aspect of the present invention, a pharmaceutical composition comprising a therapeutically effective amount crystalline form I of Bucillamine having particle size distribution D90 less than about 250 µm.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1: X-ray powder diffraction (PXRD) crystalline form I of Bucillamine.

Figure 2: Differential scanning calorimetry (DSC) crystalline form I of Bucillamine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates crystalline form I of Bucillamine and it’s process for the preparation.

In one embodiment of the present invention, the crystalline form I of Bucillamine is characterized by X-Ray powder diffraction spectrum as depicted in Figure 1.

In an embodiment of the present invention provides the crystalline form I of Bucillamine characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 10.4, 13.5, 14.4, 16.8, 17.2, 17.5, 21.9, 22.7, 28.0, 29.3, 30.0 and 30.45 ±0.2 degrees 2?.

According to the embodiment of the crystalline form I of Bucillamine is further characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 10.4, 13.5, 14.4, 16.8, 17.2, 17.5, 20.1, 20.9, 21.9, 22.7, 23.5, 28.0, 28.7, 29.3, 30.0, 30.45, 32.1, 37.8 and 38.6 ±0.2 degrees 2?.

According to the embodiment of the present invention, the crystalline form I of Bucillamine differential scanning calorimetry (DSC) as depicted in Figure 2.

Another embodiment of the present invention provides a process for the preparation of crystalline form I of Bucillamine, comprising:

a. Crude Bucillamine was dissolved in a suitable organic solvent,
b. heating the obtained suspension at suitable temperature,
c. cooling the obtained solution in step b),
d. isolating the crystalline form I of Bucillamine.

According to the embodiment of the present invention, crude Bucillamine was dissolved in an suitable organic solvent and the mixture was heated to 70-75º C for 1-2 hrs. The obtained reaction mixture was cooled to 25-30°C. The resultant solid was filtered, washed with cyclohexane and dried at 50-60°C for 3-4 hrs to obtained crystalline form I of Bucillamine.

According to the embodiment of the present invention, the organic solvent is selected from group consisting of ethyl acetate, methyl acetate, isopropyl acetate, cyclohexane and water or mixture thereof.

Another embodiment of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of Bucillamine crystalline form I in combination with a pharmaceutically acceptable carrier and along with pharmaceutically acceptable excipients, and at least one pharmaceutically acceptable excipient or pharmaceutically acceptable carrier may preferably be formulated into cream, tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.

In yet another embodiment of the present invention provides, a pharmaceutical composition comprising a therapeutically effective amount crystalline form I of Bucillamine having particle size distribution D90 less than about 250 µm.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
EXAMPLES

Example - 1:

Purification crystalline form I of Bucillamine:

To stirred solution of crude Bucillamine (20 g) in ethyl acetate at room temperature, and heat the reaction mass to 70-75°C (clear solution was observed), cooled the clear solution to 25-30°C and stir for 1-2 hrs and further cool the mass to 0-5°C and stir for 1-2 hrs. The resultant solid was filtered, washed with cyclohexane and dry under oven at 50-60°C for 3-4 hrs to afford pure Bucillamine as off white solid.

Yield: 20 gm & Purity: 99.8%

Example – 2:

Purification crystalline form I of Bucillamine:

To stirred solution of crude Bucillamine (20 g) in isopropyl acetate at room temperature, heat to reflux to get clear solution (clear solution was observed) and stir for 1-2 hrs. Cool to 25-30°C for 1-2 hrs, The resultant solid was filtered, washed with isopropyl acetate and dry under oven at 40-45°C for 3-4 hrs to afford pure Bucillamine as off white solid.

Yield: 15 gm & Purity: 99.5%.

Example – 3:

Purification crystalline form I of Bucillamine:

To stirred solution of crude Bucillamine (20 g) in cyclohexane at room temperature and slowly heated to 40-45°C (clear solution was observed) and maintain for 1-2 hrs. The reaction mass was slowly cooled to less than 15°C and stir for additionally 1-2 hrs. The resultant solid was filtered, washed with cyclohexane and dry under oven at 40-45°C for 3-4 hrs to afford Bucillamine as off white solid.

Yield: 17 gm & Purity: 99.8%.