Description:CRYSTALLINE FORM I OF ETHACIZINE HYDROCHLORIDE

FIELD OF THE INVENTION
The present invention relates to crystalline form I of Ethacizine hydrochloride. The present invention also relates to a purification process for preparing crystalline form I of Ethacizine hydrochloride.

BACKGROUND OF THE INVENTION
Ethacizine hydrochloride (ethacyzine) is a class Ic antiarrhythmic agent, related to moracizine. It is used in Russia and some other CIS countries for the treatment of severe and/or refractory ventricular and supraventricular arrhythmias, especially those accompanied by organic heart disease. It is also indicated as a treatment of refractory tachycardia associated with Wolff–Parkinson–White syndrome. It is manufactured under the brand name Ethacizin (Этацизин) by Latvian pharmaceutical company Olainfarm. Ethacizine only approved in Russia. In Russia Ethacizin tablets 50 mg (Olainfarm). Ethacizine is chemically known as ethyl N-[10-[3-(diethylamino)propanoyl]phenothiazin-2-yl]carbamate of formula (I) has the following structure.

RU 2098412 C1 (State Scientific Center of the Russian Federation "NIOPIK") reported process for preparation of Ethacizine hydrochloride. Ethacizine hydrochloride is obtained in ‘412 patent by precipitates out to obtain a Ethacizine hydrochloride melting at 200-202ºC, literary at 200-210ºC.

A.P. Chemical Pharmaceutical Journal, 1986, N 4, p. 485-488 reported process for preparation of Ethacizine hydrochloride. Ethacizine hydrochloride is obtained by isolated by the addition of an absolute ethanol solution of hydrogen chloride to obtain a Ethacizine hydrochloride melting at 200-202ºC.
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 Ethacizine hydrochloride. 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 Ethacizine hydrochloride, which it enhance in pharmaceutical composition.

SUMMARY OF THE INVENTION
The present invention relates to crystalline form I of Ethacizine hydrochloride and also relates to a purification process for preparing crystalline form I of Ethacizine hydrochloride.

In one aspect of the present invention, it provides a crystalline form I of Ethacizine hydrochloride characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about
8.01, 11.15, 15.06, 21.95, 24.94 and 25.57±0.2 degrees 2θ.

In another aspect of the present invention, it provides a process for the preparation of crystalline form I of Ethacizine hydrochloride, comprising:
a. Crude Ethacizine hydrochloride was dissolved in a suitable organic solvent or mixture of 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 Ethacizine hydrochloride.

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

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1: X-ray powder diffraction (PXRD) crystalline form I of Ethacizine hydrochloride.
Figure 2: Differential scanning calorimetry (DSC) crystalline form I of Ethacizine hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates crystalline form I of Ethacizine hydrochloride and its process for the preparation.

In one embodiment of the present invention, the crystalline form I of Ethacizine hydrochloride 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 Ethacizine hydrochloride characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 8.01, 11.15, 15.06, 21.95, 24.94 and 25.57±0.2 degrees 2θ.

According to the embodiment of the crystalline form I of Ethacizine hydrochloride is further characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 14.30, 16.00, 16.33, 16.86, 18.31, 22.29, 23.97, 24.15, 25.35 and 28.99±0.2 degrees 2θ.

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

In another aspect of the present invention, it provides a process for the preparation of crystalline form I of Ethacizine hydrochloride, comprising:
a. Crude Ethacizine hydrochloride was dissolved in a suitable organic solvent or mixture of 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 Ethacizine hydrochloride.

According to the embodiment of the present invention, crude Ethacizine hydrochloride was dissolved in a suitable organic solvent or mixture of organic solvent. The reaction mixture was heated to 60-80º C for 10-40 min. The obtained reaction mixture was cooled to 20-35°C and again cool the reaction mass to 0-5°C. The resultant solid was filtered, washed with suitable organic solvent and dried at 70-85°C for 10-16 hrs to obtained crystalline form I of Ethacizine hydrochloride.

According to an embodiment of the present invention provides crystalline Form I of Ethacizine hydrochloride having HPLC purity ≥ 99.8%.

According to the embodiment of the present invention, the organic solvent is selected from group consisting of methanol, ethanol, isopropanol/isopropyl alcohol and/or mixture thereof.

Another embodiment of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of Ethacizine hydrochloride 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 Ethacizine hydrochloride having particle size distribution D90 less than 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
Purification crystalline form I of Ethacizine hydrochloride:
Example - 1:
Taken crude Ethacizine hydrochloride (100gms) into RBF and charge methanol (150 ml) & isopropanol (150ml) at 25-35°C. The reaction mass was raised temperature to 65-75°C and stir for 20-30 min at same temperature. The resultant reaction mass charge with isopropanol (150 ml) at 65-75°C and stir for 20-30 min at same temperature. The obtained reaction mass was allowed to cool at 25-35°C and stir for 1-2 hrs. The obtain reaction mass was again allowed to cool at 0-5°C and stir for 30-60 min at 0-5°C. Filter the solid and wet solid wash with isopropanol (25 ml). Suck dry the wet solid for 20-30 min and then unload the wet material, Dry the wet material in hot air oven for 12-14 hrs. at 75-80°C to obtain pure crystalline form I of Ethacizine hydrochloride.
Yield: 85% (85 gm)
Purity: ≥ 99.8%.

Example - 2:
Taken crude Ethacizine hydrochloride (100gms) into RBF and charge ethanol (160 ml) & isopropanol (150ml) at 25-35°C. The reaction mass was raised temperature to 65-75°C and stir for 20-30 min at same temperature. The resultant reaction mass charge with isopropanol (150 ml) at 65-75°C and stir for 20-30 min at same temperature. The obtained reaction mass was allowed to cool at 25-35°C and stir for 1-2 hrs. The obtain reaction mass was again allowed to cool at 0-5°C and stir for 30-60 min at 0-5°C. Filter the solid and wet solid wash with isopropanol (25 ml). Suck dry the wet solid for 20-30 min and then unload the wet material, Dry the wet material in hot air oven for 12-14 hrs. at 75-80°C to obtain pure crystalline form I of Ethacizine hydrochloride.
Yield: 84% (84gm)
Purity: ≥ 99.8%.

, Claims:

WE CLAIM:
1. Crystalline form I of Ethacizine hydrochloride.

2. A crystalline form I of Ethacizine hydrochloride as claimed in claim 1, characterized by an X-ray powder diffraction pattern (XRPD) spectrum having peak reflection at about 8.01, 11.15, 15.06, 21.95, 24.94 and 25.57±0.2 degrees 2θ.

3. A crystalline form I of Ethacizine hydrochloride as claimed in claim 2, further characterized by an X-ray powder diffraction pattern (XRPD) spectrum having peak reflections at about 14.30, 16.00, 16.33, 16.86, 18.31, 22.29, 23.97, 24.15, 25.35 and 28.99±0.2 degrees 2θ.

4. A crystalline form I of Ethacizine hydrochloride 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 Ethacizine hydrochloride 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 Ethacizine hydrochloride comprising:
a. Crude Ethacizine hydrochloride was dissolved in a suitable organic solvent or mixture of 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 Ethacizine hydrochloride.

7. The process as claimed in claim 6, step b) wherein the heating reaction is carried out at 60-80º C.

8. The process as claimed in claim 6, wherein the organic solvent is selected from group consisting of methanol, ethanol, isopropanol/isopropyl alcohol and/or mixture thereof

9. The crystalline form I of Ethacizine hydrochloride as claimed in claim 1, wherein the particle size distribution D90 less than 250 μm.