Amorphous vibegron and process for preparation thereof

Abstract

The present invention provides amorphous form of Vibegeon (1) and process for the preparation thereof.

Description

[0001] TITLE OF THE INVENTION

[0002] AMORPHOUS VIBEGRON AND PROCESS FOR PREPARATION THEREOF

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to amorphous form of Vibegron (I) and the process for preparation thereof.

[0005] Vibegron (I)

[0006] BACKGROUND OF THE INVENTION

[0007] (6S)-N-(4-(((2S,5R)-5-((R)-Hydroxyphenylmethyl)pyrrolidin-2-yl)methyl)phenyl)- 4-oxo-4,6,7,8-tetrahydropyrrolo(l,2-a)pyrimidine-6-carboxamide (herein

[0008] “Vibegron”) also known as Gemtesa®, has a CAS number of 1190389-15-1, a molecular formula of C26H28N4O3 and the molecular weight is 444.538 g / mol.

[0009] Gemtesa is a beta-3 adrenergic agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.

[0010] U.S. Patent No. 8,247,415 B2 discloses Vibegron and process for preparation of Vibegron wherein crystallization is in presence of methanol and acetonitrile gives crystalline white solid Vibegron. US, 415 is silent about any specific polymorphic form of Vibegron.

[0011] European patent no. 3,597,737 Al discloses anhydrous form-I of Vibegron and process for preparation thereof in presence of Isopropanol and water. The process described in the prior art reports novel crystalline forms of Vibegron. The prior art methods do not describe the process for the preparation of an amorphous form of Vibegron. Hence, the need was felt to develop process for preparation of pure amorphous form of Vibegron.

[0012] Polymorphism is the ability of a solid material to exist in more than one form or crystal structure. Amorphous solids consist of disordered arrangement of molecules and do not possess a distinguishable crystal lattice. The amorphous form is generally more soluble than the crystalline form and thus contributes more in the bioavailability.

[0013] An important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient’s stomach fluid may have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered pharmaceutical compound may reach the patient’s bloodstream. The rate of dissolution is a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.

[0014] It has been disclosed in the art that the amorphous forms of a number of pharmaceutical compounds exhibit superior dissolution characteristics and in some cases different bioavailability patterns compared to crystalline forms [Konno T., Chem. Pharm. Bull., 38, 2003 (1990)]. For some therapeutic indications, one bioavailability pattern may be favored over another.

[0015] Solvent medium and mode of isolation play important roles in obtaining one polymorphic form over another.

[0016] Hence, there is a need in the art for highly pure and stable amorphous form of Vibegron, a process for its preparation and a pharmaceutical composition thereof. The advantages of the process include simplicity, eco-friendliness and suitability for commercial use.

[0017] OBJECTS OF THE INVENTION

[0018] An object of the invention is to provide amorphous form of Vibegron (I).

[0019] Another object of the invention is to provide processes for the preparation of amorphous form of Vibegron (1).

[0020] SUMMURY OF THE INVENTION:

[0021] The present invention provides an amorphous form of Vibegron (I).

[0022] The present invention provides a process for the preparation of amorphous form of Vibegron (I).

[0023] According to another embodiment, the present invention provides a process for preparation of the amorphous form of Vibegron (I), the said process comprising: a. providing solution of Vibegron in a solvent; and b. removing the said solvent for isolating the amorphous form of Vibegron (I).

[0024] BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Fig-1 : provides the representative XRPD pattern of sample (a) of amorphous form of Vibegron (I) prepared as per Example 1 ; and

[0026] Fig-2: provides the representative XRPD pattern of sample (b) of amorphous form of

[0027] Vibegron (I) prepared as per Example 1.

[0028] Wherein,

[0029] Sample (a) is the amorphous form of Vibegron (I) prepared as per Example 1 analyzed on same day of Experiment; and

[0030] Sample (b) is the amorphous form of Vibegron (I) prepared as per Example 1 analyzed after 1 month of Experiment. DETAILED DESCRIPTION OF THE INVENTION

[0031] Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only and is not intended to limit the scope of the present invention.

[0032] Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and “the like”, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed in the embodiments are merely exemplary methods of the invention, which may be embodied in various forms.

[0033] As used herein in the present application, the term "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure. The term "substantially free of' means that a contaminant substance can be controlled or cannot be detected as per respective guidelines in the compound and / or composition by methods known to those skilled in the art at the time of the filing of this application.

[0034] The term “Nitrosamine free” means that a nitrosamine impurity can be controlled or cannot be detected as per respective guidelines in the compound and / or composition by methods known to those skilled in the art at the time of the filing of this application.

[0035] One of the embodiments of the present invention provides amorphous form of Vibegron (I).

[0036] Amorphous materials do not exhibit the three-dimensional long-range order found in crystalline materials but are structurally more similar to liquids where the arrangement of molecules is random. Amorphous solids are not crystalline and therefore do not give a definitive x-ray diffraction pattern (XRD), in addition they do not give rise to a melting point and tend to liquefy at some point beyond the glass transition point.

[0037] Another embodiment of the present invention provides a process for preparation of the amorphous form of Vibegron (I), the said process comprising: a. providing solution of Vibegron (I) in a solvent; and b. removing the said solvent for isolating the amorphous form of Vibegron (I).

[0038] According to another embodiment of the present invention, Vibegron (I) used in step (a) can be either in semi-solid form, crystalline form, or mixture of crystalline and amorphous form, solvates form or hydrates form thereof. The solution of Vibegron (I) may be obtained by dissolving Vibegron (I) in a suitable solvent, or such a solution may be obtained directly from a reaction in which Vibegron (I)is formed.

[0039] In a preferred embodiment, the solvent used in step (a) is selected from the group comprising of esters such as alkyl acetate including but not limited to ethyl acetate, isopropyl acetate; aliphatic hydrocarbons such as but not limited to cyclohexane, n- hexane, n-heptane, and pentane; aromatic hydrocarbons such as but not limited to toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons such as but not limited to dichloromethane, chloroform, and ethylene dichloride; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, di-methyl ether, and methyl butyl ether; cyclic ethers such as but not limited to tetrahydrofuran, and 1,4-di oxane; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran; alcohols such as but not limited to methanol, ethanol, isopropanol, butanol, ethylene glycol, and diethylene glycol; ketones such as but not limited to acetone, methyl ethyl ketone, and methyl isobutyl ketone; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides such as but not limited to N,N-dimethyl acetamide; cyclic amides such as but not limited to V-methyl-2-pyrrolidinone; nitriles such as but not limited to acetonitrile, and propionitrile; water; or mixtures thereof. Preferably, the solvent used in step (a) is alcohol, water or mixtures thereof.

[0040] The removal of the solvent in step (b) may be affected at an increased temperature, preferably at reflux temperature, and / or reduced pressure.

[0041] The removal of solvent is carried out by distillation, evaporation, atmospheric distillation, distillation under vacuum such as rotary evaoprator, lyophilization, Freeze drying, spray drying, Agitated thin film drying (ATFD). Preferably, carried out by distillation, spray drying.

[0042] The solid residue obtained after solvent removal may be isolated and dried using conventional methods such as Air tray drier (ATD), Vacuum Tray Drier (VTD), Fluidized bed drier (FBD), Spin Flash Drier (SFD), Flash Drier (FD).

[0043] Isolation of Amorphous Vibegron (I) may be carried out by the process known in skilled art which involves steps such as quenching of reaction mass, washings of aqueous acid, followed by washings of aqueous basic solutions, followed by water washings, distillation, filtration, solvent-antisolvent technique, dissolution technique, acid-base, precipitation, recrystallization etc. Preferably, carried out by dissolution technique, distillation.

[0044] Isolation of Amorphous Vibegron (I) may be carried out by dissolution technique, distillation in presence of hydrocarbon solvents.

[0045] According to another embodiment of this invention, the Vibegron (I) used in step (a) may be prepared by novel or improved or known prior art process.

[0046] According to another embodiment of this invention, the amorphous form of Vibegron (I) prepared in this invention may be used in pharmaceutical composition or formulation.

[0047] Amorphous Vibegron (I) obtained from the process of the present invention is substantially free of Nitrosamine impurities, process related impurities, by products, carry over impurities and degradation impurities. Amorphous Vibegron (I) obtained from the process of the present invention is substantially pure. BEST MODE OR EXAMPLES FOR WORKING OF THE INVENTION

[0048] The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.

[0049] Example 1: Preparation of Amorphous Vibegron

[0050] To a clean and dry round-bottom flask was charged (R)-((2R,5S)-5-(4- aminobenzyl)pyrrolidin-2-yl)(phenyl)methanol (100g) in a mixture of isopropanol (400mL) and water (240mL) at a temp, of about 25-30 °C. To the resulting mixture was added ((6S)-4-oxo-4,6,7,8-tetrahydropyrrolo[l,2-a]pyrimidine-6-carboxylic acid (63.80g), and the reaction mass was stirred for about 20 min. The pH of the reaction mixture was adjusted to a range about 2-3 using dil. HC1, and stirring was continued until complete dissolution of the solids was achieved. Thereafter, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC HC1, 99.43 g) was added to the reaction mixture, and stirring was maintained for around 10 hrs. at the same temp. (25-30°C). Upon completion of the reaction, the reaction mixture was treated with activated carbon for decolorization. Subsequently, the pH of the mixture was adjusted to a range of about 9-10 using aqueous ammonia, and the reaction mass was stirred at ambient temperature to obtain wet solid.

[0051] Further, the wet solid obtained was charged into MeOH (1800 mL) and the mixture was heated to a temp, of about 65-70°C, with continued stirring for around 30 minutes to achieve complete dissolution. The reaction mixture was subsequently cooled to a temperature of about 25-30°C, followed by the gradual addition of water (10 vol). The resulting mixture was stirred to facilitate the distillation of methanol and water until a residue was obtained. The residue was then subjected to isolation by the addition of n-heptane (500 mL), followed by heating the mixture to a temperature of about 70-75°C and subsequent cooling to ambient temperature. The precipitated solid was collected by filtration and washed with n-heptane (100 mL) to afford the Amorphous Vibegron (I). Yield: 65%; Purity(HPLC): 99.75%.

Claims

We claim,1. Amorphous form of Vibegron (I).

2. A process for preparation of the amorphous form of Vibegron (I), the said process comprising: a. providing solution of Vibegron (I) in a solvent; and b. removing the said solvent for isolating the amorphous form of Vibegron (I).

3. The process as claimed in claim 2, wherein the solvent used in step (a) is selected from the group comprising of esters such as alkyl acetate including but not limited to ethyl acetate, isopropyl acetate; aliphatic hydrocarbons such as but not limited to cyclohexane, n-hexane, n-heptane, and pentane; aromatic hydrocarbons such as but not limited to toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons such as but not limited to dichloromethane, chloroform, and ethylene dichloride; dialkylformamides such as but not limited to dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, di-methyl ether, and methyl butyl ether; cyclic ethers such as but not limited to tetrahydrofuran, and 1,4-di oxane; substituted cyclic ethers such as but not limited to 2-methyl tetrahydrofuran; alcohols such as but not limited to methanol, ethanol, isopropanol, butanol, ethylene glycol, and diethylene glycol; ketones such as but not limited to acetone, methyl ethyl ketone, and methyl isobutyl ketone; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides such as but not limited to N,N-dimethyl acetamide; cyclic amides such as but not limited to A-methyl-2-pyrrolidinone; nitriles such as but not limited to acetonitrile, and propionitrile; water; or mixtures thereof.

4. The process claimed in claim 2, wherein isolation of Amorphous Vibegron (I) is carried out by the process known in skilled art which involves steps such as such as but not limited to quenching of reaction mass, washings of aqueous acid, followed by washings of aqueous basic solutions, followed by water washings, distillation,filtration, solvent-antisolvent technique, dissolution technique, acid-base, precipitation, recrystallization.

5. The process claimed in claim 2, wherein isolation of Amorphous Vibegron (I) is carried out by dissolution technique, distillation in presence of hydrocarbon solvents.

6. The process claimed in claim 2, wherein Vibegron (I) used in step (a) is either in semi-solid form, crystalline form, or mixture of crystalline and amorphous form, solvates form or hydrates form thereof.

7. The process claimed in claim 2, wherein the solution of Vibegron (I) is obtained by dissolving Vibegron (I) in a suitable solvent, or such a solution may be obtained directly from a reaction in which Vibegron (I) is formed.

8. The process claimed in claim 2, wherein the removal of the solvent in step (b) is affected at an increased temperature, preferably at reflux temperature, and / or reduced pressure.

9. The process claimed in claim 2, wherein the removal of solvent is carried out by distillation, evaporation, atmospheric distillation, distillation under vacuum such as rotary evaoprator, lyophilization, Freeze drying, spray drying, Agitated thin film drying, etc. The solid residue obtained after solvent removal may be isolated and dried using conventional methods such as Air tray drier, Vacuum Tray Drier, Fluidized bed drier, Spin Flash Drier, Flash Drier.

10. The process claimed in claim 2, wherein Vibegron (I) used in step (a) is prepared by novel or improved or known prior art process.

Images