CLIAMS:We Claim:

1. A stable amorphous Regadenoson.

2. The compound of claim 1, wherein said stable amorphous Regadenoson comprises Regadenoson or its combination with a pharmaceutically acceptable carrier.

3. A stable pharmaceutical composition comprising stable amorphous Regadenoson of claim 1 along with one or more pharmaceutically acceptable excipient.

4. A process of preparing a stable amorphous Regadenoson which process comprises removal of solvent from the solution of Regadenoson or its combination with a pharmaceutically acceptable carrier/excipient in a solvent.

5. The process of claim 4, wherein said solvent is methanol, dimethylformamide or a mixture of methanol and dimethylformamide.

6. The process of claim 4, wherein said removal of solvent from the solution by using suitable techniques such as spray drying, freeze drying (lyophilization), agitated thin film drying (ATFD).

Dated this 26 day of March 2013 For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory
,TagSPECI:DESCRIPTION

The present invention provides a stable amorphous Regadenoson and process for preparation. Further, it provides stable pharmaceutical compositions of amorphous Regadenoson along with other pharmaceutically acceptable excipients. The inventors have observed when amorphous Regadenoson is prepared by using spray drying with or without combination of pharmaceutically acceptable excipients, leads to a stable amorphous form which does not get converted to crystalline form.

Regadenoson of Formula I is chemically known as 1-[6-Amino-9-(3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid methylamide, which is a highly selective A2A-Adenosine receptor agonist.

Formula I

Regadenoson is marketed under the trade name Lexiscan by Astellas Pharma in the U.S. and as Rapiscan by GE Healthcare in U.K. and Germany. Lexiscan is available as an intravenous injection, each ml contains 0.08 mg Regadenoson; the dosage being 5 ml (equivalent to 0.4 mg Regadenoson).

Regadenoson has been reported in at least four crystalline forms, namely, Form A, B, C and D and as well as Amorphous form.

Zablocki et al. (WO 200792372 A1 to CV Therapeutics Inc.) have reported the first three morphs and amorphous form of Regadenoson. Form A is a crystalline monohydrate and is the most stable form of Regadenoson. Form B and C have been described as less stable and difficult to reproduce polymorphs. The amorphous Regadenoson, produced by heating Form A polymorph of the material at a temperature of 200 °C, is unstable and forms variable hydrates.

Wooldridge et al. (eliable Biopharmaceutical Corporation) have reported the form D of Regadenoson. This form is synthesized by the reaction of 2-Fluoroadenosine and 4-(N-methylcarboxamido) pyrazole isolated by column chromatography.

Many pharmaceutically active compounds are known to exist in different polymorphic forms. Different polymorphic forms of the same compound may have completely different properties, especially when compared with an amorphous form of the same compound. Amorphous materials have properties that can be of advantage in the preparation of solid dosage forms, such as solubility/dissolution rate, bioavailability, functional mechanics and adhesively. However, the increased reactivity of an amorphous solid, with a consequent high propensity to spontaneously transform to the crystalline state at a certain conditions such as for example relative humidity, force and temperature among others, may negatively affect the physical and chemical stability of the pharmaceutical preparation. The present invention is to provide potential advantage, especially to affect the stability of amorphous form of Regadenoson.

The present invention provides a stable amorphous Regadenoson, which comprises removal of solvent from solution of Regadenoson or in combination with pharmaceutically acceptable excipient in a suitable solvent by Spray drying.

In an aspect, the present invention is to provide a stable amorphous Regadenoson comprising Regadenoson or its combination with pharmaceutically acceptable excipient.

In an embodiment, the present invention provides a stable amorphous Regadenoson, which comprise Regadenoson, prepared by spray drying technique.

In another embodiment, the present invention provides a stable amorphous Regadenoson, which comprises solid dispersion of Regadenoson and pharmaceutically acceptable excipient, prepared by spray drying technique.

The solid dispersion of a stable amorphous Regadenoson has a weight ratio of Regadenoson to the pharmaceutically acceptable excipient from about 1:1 to about 1:10.

Accordingly, the present invention provides a thermodynamically stable amorphous form of Regadenoson having amorphous X-ray powder diffraction pattern. The XRD pattern of the freshly prepared Regadenoson amorphous and after exposure for 7 days to atmospheric conditions are depicted in Figure 1 and Figure 2 respectively.

In another aspect, the present invention provides a process for the preparation of stable amorphous Regadenoson, which comprises removal of solvent from the solution of Regadenoson or its combination with a pharmaceutically acceptable carrier/excipient in a solvent.

A solution of Regadenoson may be provided by dissolving it in a solvent or a mixture of solvents. Any polymorphic form may be used in the preparation of solution, such as crystalline forms including solvates and hydrates.

Regadenoson and the pharmaceutically acceptable excipient may be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture.

Solvents which may be used for dissolving Regadenoson include, but are not limited to, alcohols such as methanol, ethanol, isopropyl alcohol and butanol; aprotic polar solvents like dimethylformamide, dimethyl sulfoxide or dimethylacetamide, and the like; or mixtures thereof. Specific examples of solvents that may be utilized for the present invention include methanol, ethanol, dimethylformamide, dimethyl sulfoxide and mixtures thereof. The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted.

The desired temperatures can range from about 20°C to about 100°C, depending on the solvent used for dissolution. Any other temperature is also acceptable as long as a clear solution of Regadenoson and excipient is provided.

Optionally, the solution obtained above may be filtered to remove any undissolved particles, prior to further processing. The undissolved particles may be removed suitably by filtration, centrifugation, decantation, and other techniques. The solution may be filtered by passing through paper (for example, Whatman filter paper), glass fiber, or other membrane material, or a bed of a clarifying agent such as celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.

The solvent removal is performed by using spray drying technique to provide a stable amorphous Regadenoson with or without pharmaceutically acceptable excipient, or agitated thin film drying (ATFD). The other suitable techniques, which may be used for solvent removal include distillation using a rotational evaporator device such as freeze drying (lyophilization), microwave irradiation, micronization and the like.

Evaporation of the solvent may be conducted under a vacuum at temperatures such as about -20°C to about 170°C. Any temperature and vacuum conditions may be used as long as there is no increase in the impurity levels of the product. For example, spray drying is more suitable for industrial scale production with batch sizes of about 100 g or about 1 Kg, or greater at about 50 °C to 100 °C.

According to the present invention the obtained amorphous form from spray drying, ATFD and lyophilization is quickly dissolved for pharmaceutical compositions.

The amorphous material can be collected from the equipment using techniques such as by scraping, or by shaking the container, or using techniques specific to the particular apparatus, optionally under an inert gas atmosphere.

Optionally, drying of solid product may be carried out under suitable conditions to afford stable Regadenoson in an amorphous form, substantially free of residual solvents.

In an embodiment, the amorphous Regadenoson of present invention is retained its physical stability when stored at different conditions, for example, at 50-55% relative humidity and at room temperature.

The stable amorphous form of Regadenoson of present invention may be utilized for the pharmaceutical composition because of their advantages, for example, its high stability. The effective amount of stable amorphous form of present invention can be used to prepare pharmaceutical composition in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents thereof.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES

Example -1: Preparation of stable amorphous Regadenoson

Crystalline monohydrate Regadenoson (10 gm) was dissolved in a mixture of methanol (2000 ml) at RT and then filtered. The resultant filtrate was subjected lot wise for Spray drying at elevated temperature. After completion of the spray drying, the spray dryer was cooled to RT and then collected amorphous solid under nitrogen atmosphere. The solid was dried under vacuum in vacuum tray dryer to afford the title compound (Formula 1).
Yield: 4.0 to 8.0 gm.
Parameters for spray dryer
Inlet temperature : 85±1.5°C
Outlet temperature : 36±3 °C
Drying gas flow rate (Aspirator) : 36 ±2 m3/hr (100 %)
Feed rate : 1800 ± 10 ml/hr (85%)
Automization pressure (Nitrogen) : 5.5 ± 0.5 Kg/cm2
Vacuum in system : - 65 ± 5 mbar

Example -2: Stable amorphous Regadenoson

The obtained amorphous solid material was exposed to different conditions to ascertain physical stability. The results are summarized with their XRPD pattern in the below table.

Regadenoson Amorphous Initial purity Initial morph Purity after 7 days Morph after 7 days
99.90 amorphous 99.82 amorphous