A process for the preparation of pure amorphous form of pimobendan

Abstract

The present invention relates to a process for the preparation of the pure amorphous form of Pimobendan, as represented by formula (1) More specifically, it pertains to methods for producing the amorphous form of Pimobendan from its methanol solvate. Additionally, it describes methods for obtaining the amorphous form of Pimobendan from its crystalline form.

Description

[0001] "A PROCESS FOR THE PREPARATION OF PURE AMORPHOUS FORM OF PIMOBENDAN"

[0002] FIEED OF THE INVENTION

[0003] The present invention relates to a process for the preparation of the pure amorphous form of Pimobendan, as represented by formula (1). More specifically, it pertains to methods for producing the amorphous form of Pimobendan from its methanol solvate. Additionally, it describes methods for obtaining the amorphous form of Pimobendan from its crystalline form."

[0004] BACKGROUND OF THE INVENTION

[0005] Pimobendan (1), chemically knows as (4,5-dihydro-6-[2-(4-methoxyphenyl)-lH- benzimidazol-5-yl]-5-methyl-3(2H)-pyridazone), is represented by the following chemical structure:

[0006] Pimobendan (1) has been approved by the United States Federal Drug Administration (USFDA) as Vetmedin® Chewable Tablets for oral administration for management of heart failure in dogs, most commonly caused by myxomatous mitral valve disease or dilated cardiomyopathy [Adin, D.B. and Benjamin, E.J., Standard Medical Therapies for Preclinical Heart Disease and Congestive Heart Failure in Dogs]. Research has shown that as a monotherapy, pimobendan (1) increases survival time and improves quality of life of the canine patients afflicted with congestive heart failure secondary to mitral valve disease [Boyle, K.L. and Leech, E., 2012. A review of the pharmacology and clinical uses of Pimobendan. Journal of Veterinary Emergency and Critical Care, 22(4), pp.398- 408}.

[0007] Pimobendan and its hydrochloride salt were first disclosed in U.S. Pat. No.

[0008] 4361563, in which the drug was reported as crystals. The patent EP2199291 disclose a process for the preparation of Pimobendan hydrochloride comprising of the steps (i) suspending Pimobendan in the aqueous solution of hydrochloride acid; (ii) stirring and heating the suspension; (iii) cooling the suspension; and (iv) separating said Pimobendan hydrochloride.

[0009] The patent US20110152283A1 discloses four polymorphic crystalline forms A, B, C and D of Pimobendan and process for the preparation and use thereof. Specifically, the document discloses a process for the preparation of a crystalline forms of Pimobendan.

[0010] The patent WO2011124638 Al discloses a process for of a non-solvated crystalline form of Pimobendan and use thereof.

[0011] Polymorphism is the occurrence of different crystalline forms for a pharmaceutical drug or its complex. It is a property of some solid compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula. Each polymorph exhibits distinct physical properties. Different polymorphs of a drug exhibit distinct physical characteristics like solubility profiles, melting temperatures, X-ray diffraction peaks etc. An amorphous form of the drug is its non-crystalline form, and this form too exhibits different physical characteristics. Since, the solubility of each polymorph may vary, identifying the precise polymorphs of a drug is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.

[0012] Polymorphic forms of a compound can be distinguished by X-ray diffraction spectroscopy and by solid-state infrared spectrometry. Polymorphic forms of the same drug substance / the active pharmaceutical ingredient API, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form). This is well known in the pharmaceutical art to affect, solubility, stability, flowability, tractability and compressibility of drug substances.

[0013] The API, Pimobendan hardly dissolves in water. The resorption of Pimobendan when administered orally is prone to considerable inter- and intra-individual fluctuations if the active substance is incorporated in known or conventional solid oral forms.

[0014] As can be seen from the above, the prior art discloses crystalline forms of Pimobendan or its salts by involving use of expensive solvents and reaction conditions which are not industrially viable for scale-up production at plant level. The prior art does not disclose a amorphous form of Pimobendan (1). Amorphous forms of Pimobendan can possess advantageous properties in terms of their solubility and / or stability and / or bioavailability and / or impurity profile and / or filtration characteristics and / or drying characteristics and / or their ability to be handled and / or micronized and / or preparation of solid oral forms. Thus, there is need to invent amorphous Pimobendan (1) and develop a simple, cost effective and industrially viable process for its preparation.

[0015] Hence, the inventors of the present invention hereby disclose amorphous form of Pimobendan (1) and disclose a new and novel process for its preparation, its preparation. The amorphous form of Pimobendan (1) displays advantageous properties in terms of their solubility and / or stability and / or bioavailability and / or impurity profile and / or filtration characteristics and / or drying characteristics and / or ability to be handled and / or micronized and / or preparation of solid oral forms.

[0016] OBJECTIVE OF THE INVENTION

[0017] One objective of the present invention is to provide a process for the preparation of the amorphous form of Pimobendan, as represented by formula (1). Another objective of the present invention is to provide a novel process for the preparation of a pure amorphous form of Pimobendan, as represented by formula (1), using the Pimobendan methanol solvate.

[0018] A further objective of the present invention is to provide a novel process for the preparation of a pure amorphous form of Pimobendan, as represented by formula (1), using the crystalline form of Pimobendan.

[0019] Yet another objective of the present invention is to provide a process for the preparation of a pure amorphous form of Pimobendan, wherein the obtained form has a purity greater than 99.0% (w / w), preferably greater than 99.5% (w / w), and more preferably greater than 99.9% (w / w), as determined by HPLC.

[0020] SUMMARY OF THE INVENTION

[0021] Accordingly, in one aspect of the present invention, there is provided a novel process for the preparation of the pure amorphous form of Pimobendan, as represented by formula (1).

[0022] In another aspect, the present invention provides a process for the preparation of the pure amorphous form of Pimobendan, as represented by formula (1), from Pimobendan methanol solvate.

[0023] In yet another aspect, the present invention provides a process for the preparation of the pure amorphous form of Pimobendan, as represented by formula (1), from the crystalline form of Pimobendan.

[0024] In another aspect, the present invention provides a process for the preparation of the pure amorphous form of Pimobendan of formula (1), wherein the process comprises the following steps: a) providing a solution of Pimobendan in a solvent or a mixture of solvents; and b) isolating the amorphous Pimobendan of formula (1). In a further aspect, the present invention provides that the starting material for the process may be either Pimobendan methanol solvate or the crystalline form of Pimobendan.

[0025] In a further aspect, the present invention provides a process for the preparation of the pure amorphous form of Pimobendan of formula (1), wherein the obtained form has a purity greater than 99.0% (w / w), preferably greater than 99.5% (w / w), and more preferably greater than 99.9% (w / w), as determined by HPLC.

[0026] BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 illustrates X-Ray Diffraction (XRD) pattern of pure amorphous form of Pimobendan (1) prepared by Example 1.

[0028] Figure 2: X-Ray Diffraction (XRD) pattern of pure amorphous form of Pimobendan (1) prepared by Example 2.

[0029] Figure 3: X-Ray Diffraction (XRD) pattern of pure amorphous form of Pimobendan (1) prepared by Example 3.

[0030] DETAILED DESCRIPTION OF THE INVENTION

[0031] Accordingly, in one embodiment of the present invention, there is provided a novel process for the preparation of the pure amorphous form of Pimobendan, as represented by formula (1).

[0032] In another embodiment, the present invention provides a process for the preparation of the pure amorphous form of Pimobendan, as represented by formula (1), from Pimobendan methanol solvate.

[0033] In another embodiment, the present invention provides a process for the preparation of the pure amorphous form of Pimobendan, as represented by formula (1), from the crystalline form of Pimobendan.

[0034] In another embodiment, the present invention provides a process for the preparation of the pure amorphous form of Pimobendan of formula (1), wherein the process comprises the following steps: a) providing a solution of Pimobendan in a solvent or a mixture of solvents; and b) isolating the amorphous Pimobendan of formula (1).

[0035] The Pimobendan is dissolved in a suitable solvent or a mixture of solvents, with the excess solvent being removed by an appropriate technique, preferably by distillation. The resulting solid is dried, and the amorphous Pimobendan of formula (1) is isolated. The reaction is preferably conducted at room temperature.

[0036] In another embodiment, the present invention provides that the starting material Pimobendan may be either the methanol solvates or the crystalline form.

[0037] In an embodiment, isolating the amorphous form of Pimobendan involves the removal of solvent using suitable techniques, which include, but are not limited to, decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation, or any other suitable technique known in the art.

[0038] In an embodiment, drying the amorphous form of Pimobendan of formula (1) is carried out using suitable drying equipment, such as a tray dryer, vacuum oven, rotary cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying process can be conducted at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperature. The drying can be performed for any period required to obtain the desired quality, such as from about 15 minutes to 10 hours or longer.

[0039] In another embodiment, the amorphous form of Pimobendan of formula (1) obtained according to the present invention is characterized by an XRPD pattern substantially similar to that shown in FIG. 1. In another embodiment, the amorphous form of Pimobendan of formula (1), prepared according to the present invention, is micronized or milled using conventional techniques to achieve the desired particle size for the desired solubility profile, depending on the specific requirements of different pharmaceutical compositions. Techniques that may be used for particle size reduction include, but are not limited to, ball milling, roll milling, hammer milling, and jet milling. Milling or micronization may be performed either before or after the completion of drying the product.

[0040] The stability of the amorphous form of Pimobendan of formula (1), obtained according to the aforementioned method, was determined by storing the samples at temperatures between 2°C and 8°C, as well as at ambient temperature. The samples were analyzed by PXRD. The amorphous form of Pimobendan of formula (1) was found to be stable at both 2°C to 8°C and ambient temperature.

[0041] Therefore, the objective of the present invention was achieved through the preparation of the pure amorphous form of Pimobendan of formula (1), which can be stored at room temperature.

[0042] In an embodiment, the present invention provides a pharmaceutical composition comprising the amorphous form of Pimobendan of formula (1) and one or more pharmaceutically acceptable excipients. The excipients can be selected from those reported in Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems (2006).

[0043] In yet another embodiment, the pharmaceutical composition comprising the amorphous form of Pimobendan of formula (1) is formulated in a manner suitable for the intended route of administration. As used herein, the term "pharmaceutical compositions" includes chewable tablets, palatable tablets, capsules, and powder preparations. In another embodiment, the suitable solvents used in the present invention are selected from a group comprising protic, aprotic solvents, or mixtures thereof. The protic solvents may be selected from a group including water, methanol, ethanol, isopropyl alcohol, isobutyl alcohol, or polar aprotic solvents like dimethyl sulfoxide, N, N-dimethylformamide, and the like. Preferably, methanol was used in the present invention. The aprotic solvents may be selected from a group including acetone, acetonitrile, nitromethane, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, butyl acetate, methyl tertiary butyl ether, hexane, cyclohexane, toluene, tetrahydrofuran, and the like. Preferably, dichloromethane was used in the present invention.

[0044] In a further aspect, the present invention provides a process for the preparation of the pure amorphous form of Pimobendan of formula (1), wherein the obtained form has a purity greater than 99.0% (w / w), preferably greater than 99.5% (w / w), and more preferably greater than 99.9% (w / w), as determined by HPLC.

[0045] In another embodiment, the amorphous form of Pimobendan of formula (1) obtained by any of the above methods has a moisture content of less than 5% (w / w), and more preferably less than 2.0% (w / w).

[0046] In yet another embodiment, the amorphous form of Pimobendan of formula (1) obtained by any of the above methods has an impurity content of less than 0.5% (w / w) by HPLC, preferably less than 0.15% (w / w) by HPLC, and more preferably less than 0.1% (w / w) by HPLC.

[0047] P-XRD Method of Analysis: PXRD analysis of Pimobendan (1) was carried out using a BRUKER / D8 ADVANCE diffractometer with Cu Ka radiation of wavelength 1.5406 A and a continuous scan speed of 0.03° / min.

[0048] The following examples further illustrate the present invention but should not be construed in any way to limit its scope. EXAMPLES:

[0049] Example 1: Preparation of Amorphous Form of Pimobendan of formula (1) 500 g of Pimobendan methanol solvate was dissolved in 20 volumes of 30% methanol in dichloromethane at ambient temperature and stirred for 10 minutes. The resulting solution was passed through a 0.2-micron filter and spray-dried to obtain the amorphous form of Pimobendan of formula (1).

[0050] Yield: 265 g; Purity: 99.91% (w / w) by HPLC. The PXRD pattern of the obtained compound is illustrated in Figure 1.

[0051] Example 2: Preparation of amorphous form of Pimobendan of formula (1) 500 g of Pimobendan methanol solvate was dissolved in 20 volumes of 20% methanol in dichloromethane at ambient temperature and stirred for 10 minutes. The resulting solution was passed through a 0.2-micron filter and spray-dried to obtain the amorphous form of Pimobendan of formula (1). Yield: 260 g; Purity: 99.9% (w / w) by HPLC. The PXRD pattern of the obtained compound is illustrated in Figure 2.

[0052] Example 3: Preparation of amorphous form of Pimobendan of formula (1) 50 g of crystalline Pimobendan was dissolved in 3000 mL of ethanol at room temperature and stirred for 15 minutes. The reaction mixture was then heated to 70- 75°C and stirred. After completion of the reaction, the mixture was filtered. The solvent was completely evaporated, and the mass was degassed for 2-3 hours. The resulting material was scraped and dried to obtain the amorphous form of Pimobendan of formula (1). Yield: 95 g; Purity: 99.9% (w / w) by HPLC. The PXRD pattern of the obtained compound is illustrated in Figure 3.

Claims

We claim:

1. Substantially pure amorphous form of Pimobendan of formula (1).wherein it contains less than 2% of crystalline forms of Pimobendan.

2. A process for the preparation of pure amorphous form of Pimobendan of formula (1),wherein the process comprises the following steps: a) providing a solution of Pimobendan of formula (1) or solvated form in a solvent or a mixture of solvents; and b) isolating the amorphous Pimobendan of formula (1). wherein Pimobendan amorphous form obtained from the above process is having purity at least 99.5% (w / w) by HPLC.

3. The process as claimed in claim 2, wherein the solvent is selected from "alcoholic solvents" such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol, and the like; "chloro solvents" such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform, and the like; and / or mixtures thereof.

4. The process as claimed in claim 2, wherein the solvent is methanol in dichloromethane .

5. The process as claimed in claim 2, wherein the starting material Pimobendan is selected from the methanol solvate or crystalline form.

6. The process as claimed in claim 2, wherein the isolation involves the removal of solvent by suitable techniques, which include but are not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillationunder reduced pressure, distillation using a rotational distillation device such as a Buchi Rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation, or any other suitable techniques.

7. A pharmaceutical composition comprising the amorphous form of Pimobendan of formula (1) as prepared according to claim 2, and one or more pharmaceutically acceptable excipients.

Images