DESC:FIELD OF THE INVENTION

The present invention relates to crystalline Acotiamide hydrochloride hydrates. More particularly the present invention relates to crystalline Acotiamide hydrochloride monohydrate and the process for the preparation thereof. The present invention also includes the pharmaceutical composition of crystalline Acotiamide hydrochloride monohydrate.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

Acotiamide is an active pharmaceutical substance with an empirical formula of C21H30N4O5S and molecular weight of 450.55 g/mol. Acotiamide is the international common accepted name for N-{2-[bis(1-methylethyl)amino]ethyl}-2-{[(2-hydroxy-4,5-dimethoxyphenyl)carbonyl]amino}-1,3-thiazole-4-carboxamide, which is represented in Formula I.

Formula (I)

Acotiamide (YM-443, Z-338) is an experimental acetylcholinesterase inhibitor undergoing clinical trials for the treatment of functional dyspepsia. The drug modulates upper gastrointestinal motility to alleviate abdominal symptoms resulting from hypomotility and delayed gastric emptying. It exerts its activity in the stomach via muscarinic receptor inhibition, resulting in enhanced acetylcholine release and inhibition of acetylcholinesterase activity. Unlike other prokinetic drugs that are utilized in the management of functional dyspepsia, acotiamide shows little/no affinity for serotonin or dopamine D2 receptors. Acotiamide is the world's first approved treatment for functional dyspepsia diagnosed by Rome III criteria, with its first approval occurring in Japan.

U.S. Patent No. 5,981,557 (the ‘557 patent) discloses the acotiamide and the process for preparation thereof. Example 38 of the ‘557 patent describes the preparation of acotiamide in hydrochloride trihydrate form. According to the descriptions of the above described patent, acotiamide is produced through the following procedure. 2-Hydroxybenzoic acid serving as a raw material is subjected to condensation reaction with 2-amino -4-alkoxycarbonyl-1, 3-thiazole. Subsequently, the alkoxycarbonyl group of the thiazole ring is further subject to amidation, the reaction scheme is illustrated as follows:

Formula (II)
U.S. Patent No. 6,197,970 (the ‘970 patent) discloses the preparation of acotiamide hydrochloride by reacting condensed compound of 2-hydroxybenzoic acid and 2-amino-4-alkoxycarbonyl-1,3-thiazole with secondary or tertiary amine in presence of polar solvent.

U.S. Patent No. 8,586,761(the ‘761 patent) and its Indian family equivalent IN 253632 discloses the preparation of acotiamide by demethylating the 2-methoxy group of an aromatic carboxylic acid and amidation reaction with 2-amino thiazole. The ‘761 also discloses the preparation of acotiamide hydrochloride trihydrate.

U.S. Patent application No. 2013/0253222 discloses the preparation of 2-bromo-4, 5-dialkoxybenzoic acid which is useful as intermediate in the preparation of acotiamide.

Due to different crystal forms, variation of some basic physical properties like, solubility, dissolution rate, melting behavior, and certain micrometric properties or performance characteristics, e.g. tablet compressibility, mechanical strength, powder flow provide alternatives to select form that provides suitable balance critical properties for development into drug product. As usual in the course of pharmaceutical research and development, investigations to discover new forms of drug are going-on, with the aim to identify the most suitable form of this drug substance for various pharmaceutical uses and formulations.

The present invention encompasses the novel crystalline monohydrate Form-Z of the compound N-{2-[bis (1-methylethyl) amino] ethyl}-2-{[(2-hydroxy-4, 5-dimethoxyphenyl) carbonyl] amino}-1,3-thiazole-4-carboxamide hydrochloride, which compound is represented by the following Formula (III):

Formula (III)

The present invention also encompasses the pharmaceutical composition of crystalline acotiamide hydrochloride monohydrate.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a novel crystalline Form-Z of acotiamide hydrochloride monohydrate.

In another general aspect, there is provided a crystalline Form-Z of acotiamide hydrochloride monohydrate characterized by X-ray powder diffraction pattern, differential scanning calorimetric endothermic curve and thermo gravimetric analysis curve.

In another general aspect, the acotiamide hydrochloride monohydrate is characterized by elemental analysis (CHNS).

In another general aspect, there is provided process for the preparation of crystalline Form-Z of acotiamide hydrochloride monohydrate comprising the steps of:
i. dissolving the acotiamide hydrochloride trihydrate in a polar solvent;
ii. heating the mixture to 25°C to reflux temperature to yield a solution;
iii. cooling down the resulting solution to 0°C to 25°C and optionally filtering the said solution to obtain the crystalline acotiamide hydrochloride monohydrate.
In another general aspect, there is provided process for the preparation of crystalline Form-Z of acotiamide hydrochloride monohydrate comprising the steps of:
i. dissolving acotiamide in isopropyl alcohol to yield solution;
ii. precipitating the said solution by adding isopropanolic HCl solution;
iii. filtering the said solution to obtain solid; and
iv. recrystallizing from ethanol to obtain crystalline Form-Z of acotiamide hydrochloride monohydrate

In another general aspect, there is provided crystalline Form-Z1 of acotiamide hydrochloride trihydrate characterized by X-ray powder diffraction pattern, differential scanning calorimetric endothermic curve.

In another general aspect, there is provided process for the preparation of crystalline form Z1 of acotiamide hydrochloride trihydrate comprising the steps of:
i. dissolving acotiamide in a mixture of isopropyl alcohol and water;
ii. heating the mixture to 25°C to 80°C optionally under stirring to yield a solution;
iii. optionally filtering the said solution;
iv. cooling down the said solution to 0° to 25°C ;
v. precipitating the said solution by adding IPA-HCl solution; and
vi. isolating the crystalline Form–Z1 of acotiamide hydrochloride trihydrate.

In another general aspect, there is provided a pharmaceutical composition comprising therapeutically effective amount of crystalline Form-Z of acotiamide hydrochloride monohydrate together with one or more of pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWINGS

FIG.1 provides a powder XRD pattern of crystalline Form-Z of acotiamide hydrochloride monohydrate.
FIG.2 provides a DSC thermogram of crystalline Form-Z of acotiamide hydrochloride monohydrate.
FIG.3 provides a TGA thermogram of crystalline Form-Z of acotiamide hydrochloride monohydrate.
FIG.4 provides a powder XRD pattern of crystalline Form-Z1 of acotiamide hydrochloride
FIG.5 provides a DSC thermogram of crystalline Form-Z1 of acotiamide hydrochloride

DETAILED DESCRIPTION OF THE INVENTION

All ranges recited herein include the endpoints, including those that recite a range “between” two values. Terms such as “about”, “general”, “substantially” and the like are 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 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.

The present invention can comprise (open ended) or consist essentially of the components of the present invention as well as other ingredients or elements described herein. As used herein, “comprising” means the elements recited, or their equivalent 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 suggest otherwise.

In general, the term “obtaining” means removal of solvent medium to obtain the product. Herein removal of solvent may be done by a technique which includes, for example, filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.

The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a hot air oven, tray drier, dried under vacuum and/or in a Fluid Bed Drier.

The term “acotiamide hydrochloride trihydrate” used herein means N-{2-[bis (1-methylethyl) amino] ethyl}-2-{[(2-hydroxy-4, 5-dimethoxyphenyl) carbonyl] amino}-1, 3-thiazole-4-carboxamide hydrochloride trihydrate compound of Formula (II).

In one general aspect, there is provided a novel crystalline Form-Z of acotiamide hydrochloride monohydrate.

In another general aspect, there is provided a crystalline Form-Z of acotiamide hydrochloride monohydrate characterized by, X-ray powder diffraction pattern, differential scanning calorimetric endothermic curve and thermo gravimetric analysis curve.

In general, acotiamide hydrochloride monohydrate is characterized by Elemental analysis (CHNS). The elemental analysis of the compound of formula (III) revealed that the compound is present in monohydrate form. The elemental analysis data obtained with the above compound are shown below:
C % - 49.62
H % - 6.39
N% - 10.97
S % - 6.41

In general, the crystalline Form-Z of acotiamide hydrochloride monohydrate is characterized by X-ray powder diffraction pattern having characteristic peaks at about 6.08°, 9.52°, 10.96°, 12.26°, 14.27°, 14.64°, 15.02°, 15.95°, 18.02°, 19.19°, 19.77°, 20.52°, 21.36°, 22.96°, 23.56°, 24.68°, 26.08°, 27.14°, 27.68°, 28.96° ±0.2° 2?.

The crystalline Form-Z of acotiamide hydrochloride monohydrate is characterized by X-ray powder diffraction pattern substantially as depicted in FIG.1

The crystalline Form-Z of acotiamide hydrochloride monohydrate is characterized by differential scanning calorimetry endothermic peak at 173.46°C with an onset at about 155.30 °C.

The crystalline Form-Z of acotiamide hydrochloride monohydrate is characterized by differential scanning calorimetry endotherm as depicted in FIG.2.

The crystalline Form-Z of acotiamide hydrochloride monohydrate is characterized by thermo gravimetric analysis curve as depicted in FIG.3.

In another general aspect, there is provided crystalline Form-Z1 of acotiamide hydrochloride as depicted in FIG.4.

In another general aspect, the crystalline Form-Z1 of acotiamide hydrochloride is characterized by differential scanning calorimetry endothermic endotherm as depicted in FIG.5

In general, recrystallization is a simple and inexpensive method for scaling up the drug developments to a commercial level. Significant advances in the different pharmaceutical dosage form technologies renders drug recrystallization as a green technique due to saving of costs, time, energy and less machinery as fewer personnel. In general, production of another crystalline form of a drug and also purification are the two major sets of applications for drug recrystallization processes.

In another general aspect, there is provided a process for preparation of crystalline Form-Z of acotiamide hydrochloride monohydrate, the process comprising:
i. dissolving the acotiamide hydrochloride trihydrate in a polar solvent;
ii. heating the mixture to 25°C to reflux temperature to yield a solution;
iii. cooling down the resulting solution to 0°C to 25°C and optionally filtering the said solution to obtain the crystalline acotiamide hydrochloride monohydrate.

In another general aspect, acotiamide hydrochloride trihydrate is recrystallized from one or more of:
? Polar protic solvent: C1-C4 alcohols, formic acid, acetic acid, nitro methane;
? Polar aprotic solvent: dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethyl formamide, acetonitrile, dimethyl sulfoxide.

In particular embodiment, acotiamide hydrochloride is recrystallized from C1-4 alcohols selected from isopropanol, n-butanol, ethanol, n-propanol, and methanol.

In more particular embodiment, the acotiamide hydrochloride is recrystallized from ethanol.

In particular embodiment, wherein step (i) solution is heated to 25°C to 80°C.

In particular embodiment, wherein step (ii) solution is cooled at a temperature of between 0°C to 5°C.

In another general aspect, there is provided process for the preparation of crystalline form Z1 of acotiamide hydrochloride monohydrate comprising the steps of:
i. dissolving acotiamide in isopropyl alcohol to yield solution;
ii. precipitating the said solution by adding isopropanolic HCl solution;
iii. filtering the said solution to obtain solid; and
iv. recrystallizing from ethanol to obtain crystalline Form-Z of acotiamide hydrochloride monohydrate

In another general aspect, there is provided for the preparation of crystalline form Z1 of acotiamide hydrochloride trihydrate comprising the steps of:
i. dissolving acotiamide in a mixture of isopropyl alcohol and water;
ii. heating the mixture to 25°C to 80°C optionally under stirring to yield a solution;
iii. optionally filtering the said solution;
iv. cooling the said solution to 0°C to 25°C;
v. precipitating the said solution by adding IPA-HCl solution; and
vi. isolating the crystalline Form–Z1 of acotiamide hydrochloride trihydrate.

In particular embodiment, the precipitation temperature is 0°C to 30°C.

In more particular embodiment, the precipitation temperature is 15°C to 20°C.

In another general aspect, there is provided pharmaceutical composition comprising a therapeutically effective amount of Form-Z of acotiamide hydrochloride monohydrate obtained according to the present invention, together with one or more pharmaceutically acceptable excipients.

In another aspect, there is provided pharmaceutical composition comprising therapeutically effective amount of Form-Z of acotiamide hydrochloride monohydrate obtained according to the present invention having particle size distribution D (90) < 50 microns, D (50) < 20 microns and D (10) < 10 microns and one or more of pharmaceutically acceptable carriers, excipients, or diluents.

In another general aspect, there is provided pharmaceutical composition comprising a therapeutically effective amount of Form-Z1 of acotiamide hydrochloride trihydrate obtained according to the present invention, together with one or more pharmaceutically acceptable excipients.

The particle size distribution may be performed by Malvern Laser Diffraction, using the Mastersizer instrument or by image analysis measuring instruments.

Powder X-ray diffraction of acotiamide forms can be obtained under following conditions.

The X-ray powder diffraction spectrum was measured under the following experimental conditions:

Instrument : X-Ray Diffractometer, PANalytical XPERT-PRO
Make : PHILIPS
X- Ray : Cu/40kv/40mA
Minimum Step Size : 2 Theta: 0.001
Minimum Step Size Omega: 0.001
Sample Stage : Spinner PW 3064
Scan Mode : Continuous
Scan Axes : Two Theta / Theta
Scan Range : 2.0000 to 40.0000

In another general aspect, the starting material in the synthesis of the instant monohydrate compound, the corresponding trihydrate form of the compound represented by Formula (II), can be made by the process disclosed in U.S. Patent No’s. 5,981,557 or 6,197,970.

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example-1:
Preparation of crystalline Form-Z of acotiamide hydrochloride monohydrate
N-{2-[bis (1-methylethyl) amino] ethyl}-2-{[(2-hydroxy-4, 5-dimethoxyphenyl) carbonyl] amino}-1, 3-thiazole-4-carboxamide hydrochloride trihydrate (100 g) was dissolved in ethanol (700mL). The reaction mass was heated at reflux temperature with stirring and filtered. The reaction mass was gradually cooled to 0-5°C and filtered to obtain the solid. The obtained solid was washed with ethanol and dried in vacuum.
Yield: 90%

Example-2:
Preparation of acotiamide hydrochloride monohydrate:
To the solution of 2-[N-(2, 4, 5-trimethoxybenzoyl) amino]-4-methoxycarbonyl-1, 3-thiazole (100g) in dimethylacetamide (200 mL), N, N-isopropyl ethylene diamine (190.96g) was added and reaction mass was heated. To the reaction mass, methylene dichloride (1000 mL) and water (1500 mL) was added and stirred, then add 5% NaOH solution and the layers were separated. To the organic layer, 5% NaOH solution was added, stir the reaction mass and layers were separated. Aqueous alkaline layers were combined and adjusted the pH with conc. HCl and extracted with methylene dichloride (2×500 mL). Sodium sulfate was added to the organic layer and filtered through hyflow bed. The organic layer was distilled under vacuum till the residual volume of solvent. To the residue, isopropanol (469mL) was added and adjusted the pH with IPA-HCl, filtered the reaction mass to obtain solid. The obtained compound was recrystallized using ethanol to obtain the title compound.
Yield: 60%

Example-3:
Preparation of crystalline Form-Z1 of acotiamide hydrochloride trihydrate:
Isopropylalcohol (80mL) and acotiamide hydrochloride monohydrate (10g) were heated to reflux, filtered and the filtrate is cooled gradually to 0-5°C. The resultant mass is filtered and washed with ethanol and dried to get the titled compound.

Example-4:
Preparation of crystalline Form-Z1 of acotiamide hydrochloride trihydrate:
Acotiamide (80 g) was added to mixture of isopropyl alcohol and water. The mixture was heated to 75° C to 80°C to yield solution. Activated carbon (8 g) was added at the same temperature and stirred for 30 minutes. The reaction mixture is cooled to 25°C. The pH of the reaction mixture is adjusted with isopropanolic HCl solution at 25°C to precipitate the solid and further cooled the reaction mixture to 15°C. The reaction mixture was filtered and washed with mixture of isopropyl alcohol and water to obtain crystalline Form-Z1 of acotiamide hydrochloride trihydrate.
Yield: 91.6 %
,CLAIMS:We claim:

1. The crystalline Form-Z of acotiamide hydrochloride monohydrate characterized by data selected from:
i. X-ray powder diffraction pattern having characteristic peaks at about 6.08°, 9.52°, 10.96°, 12.26°, 14.27°, 14.64°, 15.02°, 15.95°, 18.02°, 19.19°, 19.77°, 20.52°, 21.36°, 22.96°, 23.56°, 24.68°, 26.08°, 27.14°, 27.68°, 28.96° ± 0.2° 2?; and
ii. differential scanning calorimetry endothermic peak at 173.46°C with an onset at about 155.30°C

2. The process for the preparation of crystalline Form-Z of acotiamide hydrochloride monohydrate as claimed in claim 1 comprising the steps of:
i. dissolving the acotiamide hydrochloride trihydrate in a polar solvent;
ii. heating the mixture to 25°C to reflux temperature to yield a solution;
iii. cooling down the resulting solution to 0°C to 25°C and optionally filtering the said solution to obtain the crystalline acotiamide hydrochloride monohydrate.

3. The process as claimed in claim 2, wherein the polar solvent is selected from the group consisting of C1-C4 alcohols, formic acid, acetic acid, nitromethane, dichloroethane, tetrahydrofuran, ethyl acetate, acetone, dimethyl formamide, acetonitrile, dimethyl sulfoxide, or any mixtures thereof.

4. The process as claimed in claim 2, wherein the polar solvent is ethanol.

5. The process as claimed in claim 2, wherein step (i) solution is heated at a temperature of between 25°C to 80°C.
6. The process as claimed in claim 2, wherein step (ii) solution is cooled at a temperature of between 0°C to 5°C.

7. The process for the preparation of crystalline Form-Z of acotiamide hydrochloride monohydrate as claimed in claim 1 comprising the steps of:
i. dissolving acotiamide in isopropyl alcohol to yield solution;
ii. precipitating the said solution by adding isopropanolic HCl solution;
iii. filtering the said solution to obtain solid;
iv. recrystallizing from ethanol to obtain crystalline Form-Z of acotiamide hydrochloride monohydrate

8. The process for the preparation for the preparation of crystalline form Z1 of acotiamide hydrochloride trihydrate comprising the steps of:
i. dissolving acotiamide in a mixture of isopropyl alcohol and water;
ii. heating the mixture to 25°C to 80°C optionally under stirring to yield a solution;
iii. optionally filtering the said solution;
iv. cooling the said solution to 25°C ;
v. precipitating the said solution by adding IPA-HCl solution; and
vi. isolating the crystalline Form –Z1 of acotiamide hydrochloride trihydrate.

9. The process as claimed in claim 8, wherein the precipitation temperature is 0°C to 30°C.

10. The process as claimed in claim 8, wherein the precipitation temperature is 15°C to 20°C.

Dated this the 23rd day of December 2014.
(H. SUBRAMANIAM)
Of SUBRAMANIAM & ASSOCIATES
Attorneys for the Applicants