FIELD OF INVENTION

The present invention relates to novel pseudopolymorphs of Prasugrel hydrochloride and processes for the preparation thereof. The present invention also relates to novel processes for the conversion of these pseudopolymorphs into crystalline Prasugrel hydrochloride.

BACKGROUND OF THE INVENTION

Prasugrel is an oral antiplatelet agent that belongs to the thienopyridine family. It is designed to prevent platelet activation by blocking adenosine diphosphate (ADP) P2Y12 receptors on the platelet surface.

Prasugrel Hydrochloride, chemically known as 5-[(lRS)-2-cyclopropyl-l-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate hydrochloride and is structurally represented as Formula I. Prasugrel hydrochloride marketed under the brand name of EFFIENT.

Prasugrel and its pharmaceutical^ acceptable salts are claimed in US 5,288,726.
Specifically Prasugrel hydrochloride and maleate salts were claimed in US 6,693,115. Further, it discloses crystal A, Crystal Bl and crystal B2 of Prasugrel Hydrochloride.

PCT publication WO 2009/098142 discloses acid addition salts of Prasugrel which exhibit improved physical and pharmaceutical properties namely with sulfuric acid and sulfonic acid. This invention also relates to pharmaceutical compositions comprising pharmaceutically effective amount of one or more acid addition salt of Prasugrel with sulfuric acid and sulfonic acid.

Many pharmaceutically active organic compounds can crystallize in more than one type of molecular packing with more than one type of internal crystal lattice. That is, the compounds crystallize in different crystalline forms. The resulting crystal structures (forms) can have, for example, different unit cells. This phenomenon—identical chemical structure but different internal structure—is referred to as polymorphism and the species having different lattice structures are referred to as polymorphs.

Many pharmaco10gically active organic compounds can also crystallize in crystalline forms such that second, foreign molecules, especially solvent molecules, are regularly incorporated into the crystal structure of the principal pharmaco10gically active compound. This phenomenon is sometimes referred to as pseudopolymorphism and the resulting structures as pseudopolymorphs. When the second molecule is a solvent molecule, the pseudopolymorphs can be referred to as solvates. Dissolution rate of Pseudopolymorphs is significantly higher than the hydrates and polymorphs, because of these superior dissolution characteristics can be used in the preparation of a variety of pharmaceutical preparations.

OBJECT OF THE INVENTION

Principle object of the present invention is to provide novel pseudopolymorphs of Prasugrel hydrochloride.

Another object of the present invention is to provide formic acid pseudopolymorph of Prasugrel Hydrochloride and processes for the preparation of the same.
Yet another object of the present invention is to provide acetic acid pseudopolymorph of Prasugrel Hydrochloride and processes for the preparation of the same.
One more object of the present invention is to provide Nitromethane pseudopolymorph of Prasugrel hydrochloride and processes for the preparation of the same.
Another object of the present invention is to provide conversion of above mentioned pseudopolymorphs of Prasugrel hydrochloride to crystalline Prasugrel hydrochloride.

SUMMARY OF THE INVENTION

Main aspect of the present invention is to provide novel pseudopolymorphs of Prasugrel hydrochloride namely formic acid pseudopolymorph of Prasugrel Hydrochloride, acetic acid pseudopolymorph of Prasugrel Hydrochloride and Nitromethane pseudopolymorph of Prasugrel Hydrochloride.

In one aspect the present invention provides, Formic acid pseudopolymorph of Prasugrel Hydrochloride and process for the preparation comprising the steps of:

a) dissolving Prasugrel hydrochloride in Formic acid;
b) adding an anti solvent to the clear solution; and
c) isolating crystalline Formic acid pseudopolymorph of Prasugrel Hydrochloride.

In another aspect of the present invention provides, alternative process for the preparation of Formic acid pseudopolymorph of Prasugrel Hydrochloride comprising the steps of:

a) dissolving Prasugrel free base and Formic acid in a solvent;
b) adding aq HC1 to the clear solution;
c) adding an antisolvent to the solution; and
d) isolating crystalline Formic acid pseudopolymorph of Prasugrel Hydrochloride.

In another aspect the present invention provides, Acetic acid pseudopolymorph of Prasugrel Hydrochloride and process for the preparation comprising the steps of:

a) dissolving Prasugrel hydrochloride in acetic acid;
b) adding an anti solvent to the clear solution; and
c) isolating crystalline Acetic acid pseudopolymorph of Prasugrel Hydrochloride.

In another aspect of the present invention provides, alternative process for the preparation of Acetic acid pseudopolymorph of Prasugrel Hydrochloride comprising the steps of:

a) dissolving Prasugrel free base and Acetic acid in a solvent;
b) adding aq HC1 to the clear solution;
c) adding an anti solvent to the solution; and
d) isolating crystalline Acetic acid pseudopolymorph of Prasugrel Hydrochloride.

In another aspect the present invention provides, Nitromethane pseudopolymorph of Prasugrel Hydrochloride and process for the preparation comprising the steps of:

a) dissolving Prasugrel hydrochloride in Nitromethane;
b) adding an anti solvent to the clear solution; and
c) isolating crystalline Nitromethane pseudopolymorph of Prasugrel Hydrochloride.

In another aspect of the present invention provides, alternative process for the preparation of Nitromethane pseudopolymorph of Prasugrel Hydrochloride comprising the steps of:

a) dissolving Prasugrel hydrochloride in Nitromethane;
b) cooling the reaction temperature; and
c) isolating crystalline Nitromethane pseudopolymorph of Prasugrel Hydrochloride.

In another aspect the present invention provides, process for the preparation of crystalline Prasugrel hydrochloride comprising the steps of:

a) treating the acetic acid, formic acid or nitromethane pseudopolymorph of Prasugrel hydrochloride in a solvent; and
b) isolating crystalline Prasugrel hydrochloride.

BRIEF DESCRIPTION OF THE FIGURES

FIGURE 1 shows the X-Ray diffractogram of Formic acid pseudopolymorph of Prasugrel
hydrochloride.

FIGURE 2 shows the DSC thermogram of Formic acid pseudopolymorph of Prasugrel
hydrochloride.

FIGURE 3 shows the TGA/DTA thermogram of Formic acid pseudopolymorph of Prasugrel
hydrochloride.

FIGURE 4 shows the IR spectrum of Formic acid pseudopolymorph of Prasugrel
hydrochloride.

FIGURE 5 shows the NMR spectrum of the Formic acid pseudopolymorph of Prasugrel
hydrochloride.

FIGURE 6 shows the X-Ray diffractogram of Acetic acid pseudopolymorph of Prasugrel
hydrochloride.

FIGURE 7 shows the DSC thermogram of Acetic acid pseudopolymorph of Prasugrel
hydrochloride.

FIGURE 8 shows the TGA/DTA thermogram of Acetic acid pseudopolymorph of Prasugrel
hydrochloride.
FIGURE 9 shows the IR spectrum of Acetic acid pseudopolymorph of Prasugrel
hydrochloride.

FIGURE 10 shows the NMR spectrum of the Acetic acid pseudopolymorph of Prasugrel
hydrochloride.

FIGURE 11 shows the X-Ray diffractogram of Nitromethane pseudopolymorph of Prasugrel
hydrochloride.

FIGURE 12 shows the DSC thermogram of Nitromethane pseudopolymorph of Prasugrel
hydrochloride.

FIGURE 13 shows the TGA/DTA thermogram of Nitromethane pseudopolymorph of
Prasugrel hydrochloride.

FIGURE 14 shows the IR spectrum of the Nitromethane pseudopolymorph of Prasugrel
hydrochloride.

FIGURE 15 shows the NMR spectrum of the Nitromethane pseudopolymorph of the
Prasugrel hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to pseudopolymorphs of Prasugrel hydrochloride namely Prasugrel hydrochloride formic acid pseudopolymorph, Prasugrel hydrochloride acetic acid pseudopolymorphs and Prasugrel hydrochloride nitromethane pseudopolymorph. Present invention also directs to process for the preparation of said pseudopolymorphs of Prasugrel hydrochloride. The present invention also relates to further conversion of respective pseudopolymorphs of Prasugrel hydrochloride to crystalline Prasugrel hydrochloride.
In one embodiment the present invention provides, crystalline Formic acid pseudopolymorph of Prasugrel hydrochloride.

According to the present invention, crystalline Formic acid pseudopolymorph of Prasugrel hydrochloride is characterized by X-ray diffraction pattern as shown in FIGURE 1 having peaks at about 8.52, 16.33, 18.91, 25.35, 26.77 ±0.20°.

According to the present invention, crystalline Formic acid pseudopolymorph of Prasugrel hydrochloride is further characterized by X-ray diffraction having peaks at about 8.52, 10.35, 12.51, 13.33, 14.05, 14.56, 16.33, 17.78, 18.91, 23.97, 25.35, 26.77 ±0.26°.

According to the present invention, crystalline Formic acid pseudopolymorph of Prasugrel hydrochloride is further characterized by PXRD pattern as shown in FIGURE 1.

According to the present invention, crystalline Formic acid pseudopolymorph of Prasugrel hydrochloride is further characterized by DSC as shown in FIGURE 2.

According to the present invention, crystalline Formic acid pseudopolymorph of Prasugrel hydrochloride is further characterized by TGA/DTA as shown in FIGURE 3.

According to the present invention, crystalline Formic acid pseudopolymorph of Prasugrel hydrochloride is further characterized by IR as shown in FIGURE 4.

According to the present invention, crystalline Formic acid pseudopolymorph of Prasugrel hydrochloride is further characterized by NMR as shown in FIGURE 5.

According to the present invention the characterization data (TGA, NMR and HPLC method) shows the crystalline Formic acid pseudopolymorph is preferably a monosolvate.
In one more embodiment, the present invention provides, process for the preparation of
crystalline Formic acid pseudopolymorph of Prasugrel hydrochloride comprising

a) dissolving Prasugrel hydrochloride in Formic acid;
b) adding an anti-solvent to the clear solution; and
c) isolating crystalline Formic acid pseudopolymorph of Prasugrel
Hydrochloride.

As per the present invention, Prasugrel hydrochloride is dissolved in Formic acid at room temperature and stirred to obtain clear solution. To the clear solution anti-solvent is added. Anti-solvent is selected from non-polar solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, dimethyl ether, diethyl ether, isopropyl ether, diisopropyl ether, THF, dioxane, methyl tertiary butyl ether, preferably diisopropyl ether or methyl tertiary butyl ether. The solid obtained is filtered and washed with said antisolvent and dried to give crystalline Formic acid pseudopolymorph of Prasugrel Hydrochloride.

In one embodiment, the present invention provides alternative process for the preparation of Formic acid pesudopolymorph of Prasugrel Hydrochloride comprising: a) dissolving prasugrel free base and Formic acid in an organic solvent; b) adding aq HC1 to the clear solution; c) adding an anti solvent to the solution; and d) isolating crystalline formic acid pseudopolymorph of Prasugrel hydrochloride.

As per the present invention, Prasugrel free base is dissolved in polar solvent and Formic acid at room temperature and stirred to obtain clear solution. The polar solvent is selected form ketones such as acetone, Methyl ethyl ketone, diethyl ketone, Methyl isobutyl ketone; preferably acetone. To the resulting clear solution aqueous HC1 is added; stirred and an anti solvent is added to the solution. Anti-solvent is selected form non-polar solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, dimethyl ether, diethyl ether, isopropyl ether, diisopropyl ether, THF, dioxane, methyl tertiary butyl ether, preferably diisopropyl ether. The obtained solid is filtered and dried to give crystalline Formic acid pseudopolymorph of Prasugrel Hydrochloride.

In one embodiment, the present invention provides, crystalline Acetic acid pseudopolymorph of Prasugrel hydrochloride.

According to the present invention, crystalline Acetic acid pseudopolymorph of Prasugrel hydrochloride is characterized by X-ray diffraction pattern as shown in FIGURE 6, having peaks at about 16.16, 18.79, 23.89, 24.72, 26.17 ± 0.29°.

According to the present invention, crystalline Acetic acid pseudopolymorph of Prasugrel hydrochloride is further characterized by X-ray diffraction having peaks at about 8.67, 10.46, 12.54, 14.17, 14.37, 16.16, 17.58, 18.79, 19.08, 23.89, 24.72, 26.17, 26.82 ± 0.20°.
According to the present invention, crystalline Acetic acid pseudopolymorph of Prasugrel hydrochloride is further characterized by PXRD pattern as shown in FIGURE 6.

According to the present invention, crystalline Acetic acid pseudopolymorph of Prasugrel hydrochloride is further characterized by DSC as shown in FIGURE 7.

According to the present invention, crystalline Acetic acid pseudopolymorph of Prasugrel hydrochloride is further characterized by TGA/DTA as shown in FIGURE 8.

According to the present invention, crystalline Acetic acid pseudopolymorph of Prasugrel hydrochloride is further characterized by IR as shown in FIGURE 9.

According to the present invention, crystalline Acetic acid pseudopolymorph of Prasugrel hydrochloride is further characterized by NMR as shown in FIGURE 10.

According to the present invention the characterization data (TGA, NMR and HPLC method) shows the crystalline acetic acid pseudopolymorph is preferably a monosolvate.

In another embodiment, the present invention provides, process for the preparation of
crystalline Acetic acid pseudopolymorph of Prasugrel Hydrochloride comprising:

a) dissolving Prasugrel hydrochloride in acetic acid;
b) adding an anti solvent to the clear
solution; and
c) isolating crystalline Acetic acid pseudopolymorph of Prasugrel
Hydrochloride.

As per the present invention, Prasugrel hydrochloride is dissolved in acetic acid at room temperature and stirred to obtain clear solution. To the clear solution anti solvent is added. Anti-solvent is selected from non-polar solvents such as n-pentane, n-hexane, n-heptane,
cyclohexane, dimethyl ether, diethyl ether, isopropyl ether, diisopropyl ether, THF, dioxane, methyl tertiary butyl ether, preferably diisopropyl ether or methyl tertiary butyl ether. The solid obtained is filtered and washed with said anti solvent and dried to give crystalline Acetic acid pseudopolymorph of Prasugrel Hydrochloride.

In another embodiment, the present invention provides alternative process for the preparation of Acetic acid pesudopolymorph of Prasugrel Hydrochloride comprising: a) dissolving prasugrel free base and Acetic acid in an organic solvent; b) adding aq HC1 to the clear solution; c) adding an antisolvent to the solution; and d) isolating crystalline Acetic acid pseudopolymorph of Prasugrel hydrochloride.

As per the present invention, Prasugrel free base is dissolved in polar solvent and Acetic acid at room temperature and stirred to obtain clear solution. The polar solvent is selected form ketones such as acetone, Methyl ethyl ketone, diethyl ketone, Methyl isobutyl ketone; preferably acetone. To the resulting clear solution aqueous HC1 is added; stirred and an anti solvent is added to the solution. Antisolvent is selected form non-polar solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, dimethyl ether, diethyl ether, isopropyl ether, diisopropyl ether, THF, dioxane, methyl tertiary butyl ether, preferably diisopropyl ether. The obtained solid is filtered and dried to give crystalline Acetic acid pseudopolymorph of Prasugrel Hydrochloride.

In one more embodiment, the present invention provides, crystalline Nitromethane pseudopolymorph of Prasugrel hydrochloride.

According to the present invention, crystalline Nitromethane pseudopolymorph of Prasugrel
hydrochloride is characterized by X-ray diffraction pattern as shown in FIGURE 11, having
peaks at bout 8.35,13.82,16.25,18.75,23.80,25.42,26.76 ± 0.29°.

According to the present invention, crystalline Nitromethane pseudopolymorph of Prasugrel hydrochloride is further characterized by having peaks at about 8.35, 10.18, 12.37, 13.31, 13.82, 14.54, 16.25, 16.72, 17.74, 18.75, 19.14, 21.76, 23.80, 24.07, 24.49, 25.42, 26.76, ' 27.45 ± 0.20°.

According to the present invention, crystalline Nitromethane pseudopolymorph of Prasugrel hydrochloride is further characterized by PXRD pattern as shown in FIGURE 11.

According to the present invention, crystalline Nitromethane pseudopolymorph of Prasugrel hydrochloride is further characterized by DSC as shown in FIGURE 12.

According to the present invention, crystalline Nitromethane pseudopolymorph of Prasugrel hydrochloride is further characterized by TGA/DTA as shown in FIGURE 13.

According to the present invention, crystalline Nitromethane pseudopolymorph of Prasugrel hydrochloride is further characterized by IR as shown in FIGURE 14.

According to the present invention, crystalline Nitromethane pseudopolymorph of Prasugrel hydrochloride is further characterized by NMR as shown in FIGURE 15.

According to the present invention the characterization data (TGA, NMR and HPLC method) shows the crystalline Nitromethane pseudopolymorph is preferably a monosolvate.
In one embodiment, the present invention provides, process for the preparation of crystalline Nitromethane pseudopolymorph of Prasugrel Hydrochloride comprising: a) dissolving Prasugrel hydrochloride in Nitromethane; b) adding an antisolvent to the clear solution; and c) isolating crystalline Nitromethane pseudopolymorph of Prasugrel Hydrochloride.

As per the present invention Prasugrel hydrochloride is dissolved in nitromethane at room temperature and stirred to obtain clear solution. To the clear solution antisolvent is added. Anti-solvent is selected from non-polar solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, dimethyl ether, diethyl ether, isopropyl ether, diisopropyl ether, THF, dioxane, methyl tertiary butyl ether, preferably diisopropyl ether. The solid obtained is filtered and washed with diisopropyl ether and dried to give crystalline Nitromethane pseudopolymorph of Prasugrel Hydrochloride.

In another embodiment, the present invention provides an alternative process for the preparation of Nitromethane pseudopolymorph of Prasugrel Hydrochloride comprising: a) dissolving Prasugrel hydrochloride in Nitromethane; b) cooling the reaction temperature; and b) isolating crystalline Nitromethane pseudopolymorph of Prasugrel hydrochloride.
As per the present invention, Prasugrel hydrochloride is dissolved in nitromethane at room temperature and cooled to low temperatures preferably 10 °C to -30 °C, more preferably 5 to -25 °C. The solid obtained is filtered and dried to give nitromethane pseudopolymorph of Prasugrel hydrochloride.

In one more embodiment, the present invention provides, process for the preparation of crystalline Prasugrel hydrochloride comprising the steps of: a) treating the acetic acid, formic acid or nitromethane pseudopolymorph of Prasugrel hydrochloride in a solvent; and b) isolating crystalline Prasugrel hydrochloride.

As per the present invention, acetic acid, formic acid or nitromethane pseudopolymorph of Prasugrel hydrochloride is treated with polar solvent. The polar solvent is selected form ketones such as acetone, Methyl ethyl ketone, diethyl ketone, Methyl isobutyl ketone; preferably acetone. The obtained solid is filtered and dried to give crystalline Prasugrel hydrochloride.

The physical and chemical stability of the Prasugrel hydrochloride formic acid pseudopolymorph is studied as given under examples 12 & 14. It is stable under lab stress conditions (drying, milling, humidity and slurry) as mentioned in Table 1. From indicative stability data it appears that the formic acid solvate is physically and chemically stable up to six months (Table 3).

The physical and chemical stability of the Prasugrel hydrochloride acetic acid pseudopolymorph is studied as given under examples 13 & 15. It is stable under lab stress conditions (drying, milling, humidity and slurry) as mentioned in Table 2. From indicative stability data it appears that the acetic acid solvate is physically and chemically stable up to six months (Table 4).

Instrumentation

Powder X-ray Diffraction (PXRD)

The said formic acid solvate of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on Bruker AXS D8 Discover powder X-ray diffractometer equipped with a goniometer of 9/20 configuration, Variol monochromator and Lynx-Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 25 seconds step time.

Differential Scanning Calorimetry (DSC)

The DSC measurements were carried out on TA Q1000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-200°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.

Thermo gravimetric Analysis (TGA)

TGA/DTA was recorded using the instrument TA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25ml/min.

Infrared (IR) spectroscopy

Fourier transform infrared (FT-IR) spectra were recorded with a Perkin-Elmer spectrum one spectrometer. The samples were prepared as 1 mm thickness and 13 mm diameter KBr glassy discs by triturating 1 to 3 mg of sample with 300 mg to 400 mg of KBr and applying pressure of about 1000 lbs/sq inch. Then these discs were scanned in the spectral range of 4000 to 650 cm" with a resolution of 4 cm".

Nuclear Magnetic Resonance (NMR) spectroscopy

The HNMR experiments were performed on Bruker 300MHz Avance NMR spectrometer
equipped with 5mm BBO probe in CDCI3. The data collected and processed by XWIN-NMR
software.

The following non-limiting examples illustrate specific embodiments of the present invention. The examples are not intended to be limiting the scope of present invention in any way.

EXAMPLES

Example-1: Crystalline Prasugrel Hydrochloride-Formic acid pseudopolymorph.

10g of Prasugrel Hydrochloride was dissolved in 15ml of formic acid at room temperature and stirred for 20 minutes. To the resulting clear solution was added 100mL of diisopropyl ether and stirring was continued for 4hrs. The solid obtained was filtered, washed with diisopropyl ether and suck-dried to get 8g of crystalline Prasugrel hydrochloride formic acid pseudopolymorph.

Example-2: Crystalline Prasugrel Hydrochloride-Formic acid pseudopolymorph

10g of Prasugrel Hydrochloride was dissolved in 15ml of formic acid at room temperature and stirred for 20 minutes. To the resulting clear solution was added 100mL of methyl tertiary butyl ether and stirring was continued for 4hrs. The obtained solid was filtered, washed with methyl tertiary butyl ether and suck-dried to get 8 g of crystalline Prasugrel hydrochloride formic acid pseudopolymorph.

Example-3: Crystalline Prasugrel Hydrochloride-Formic acid pseudopolymorph

2g of Prasugrel free base was dissolved in 12mL of acetone and 4mL of Formic acid at room temperature and stirred for 30 minutes. To the resulting clear solution, added 540 mg of aqueous HC1 and stirring was continued for 30 minutes. 20mL of diisopropyl ether was
added slowly at room temperature and maintained for further 30 minutes. The obtained solid was filtered and suck-dried to get 2g of crystalline PrasUgrel hydrochloride Formic acid pseudopolymorph.

Example-4: Crystalline Prasugrel Hydrochloride-Acetic acid pseudopolymorph
10g of Prasugrel Hydrochloride was dissolved in 35ml of acetic acid and stirred for 20 minutes. To the resulting clear solution was added 100 mL of diisopropyl ether and stirring was continued for 4hrs. The obtained solid was filtered, washed with diisopropyl ether and suck-dried to get 9g of crystalline Prasugrel hydrochloride acetic acid pseudopolymorph.
Example 5: Crystalline Prasugrel Hydrochloride-Acetic acid pseudopolymorph.
10g of Prasugrel Hydrochloride was dissolved in 35 ml of acetic acid and stirred for 20 minutes. . To the resulting clear solution was added 100 ml of methyl tertiary butyl ether and stirring was continued for 4 firs. The obtained solid was filtered, washed with methyl tertiary butyl ether and dried to get 8g of crystalline Prasugrel hydrochloride acetic acid pseudopolymorph.

Example 6: Crystalline Prasugrel Hydrochloride-Acetic acid pseudopolymorph.

2g of Prasugrel free base was dissolved in 12 mL of acetone and 4 mL of Acetic acid at room temperature and stirred for 30 minutes. To the resulting clear solution, added 540 mg of aqueous HC1 and stirring was continued for 30 minutes. 20 mL of diisopropyl ether was added slowly at room temperature and maintained for further 30 minutes. The obtained solid was filtered and suck-dried to get 2 g of crystalline Prasugrel hydrochloride acetic acid pseudopolymorph.

Example 7: Crystalline Prasugrel Hydrochloride-Nitromethane pseudopolymorph

10g of Prasugrel Hydrochloride was dissolved in 150ml of nitromethane at room temperature. To the resulting clear solution was added 200ml of diisopropyl ether and stirring was continued for 4 hrs. The obtained solid was filtered, washed with diisopropyl ether and suck-dried to get crystalline Prasugrel hydrochloride nitromethane pseudopolymorph.

Example 8: Crystalline Prasugrel Hydrochloride-Nitromethane pseudopolymorph
10 g of Prasugrel hydrochloride was dissolved in 150ml of nitromethane and the resulting clear solution was stirred at -20 °C for 4 hrs. The obtained solid was filtered and suck-dried to get 9g of crystalline Prasugrel hydrochloride nitromethane pseudopolymorph.

Example 9: Crystalline Prasugrel Hydrochloride-Nitromethane pseudopolymorph

10 g of Prasugrel hydrochloride was dissolved in 150ml of nitromethane and the resulting clear solution was stirred at 0-5°C for 4 hrs. The obtained solid was filtered and suck-dried to get 7g of crystalline Prasugrel hydrochloride nitromethane pseudopolymorph.

Example 10: Preparation of Crystalline Prasugrel Hydrochloride

0.2 g of Prasugrel hydrochloride-formic acid pseudo-polymorph was slurred in 4 ml of acetone for 15 h at room temperature. The resulting suspension was filtered and suck-dried to get crystalline Prasugrel hydrochloride.

Example 11: Preparation of Crystalline Prasugrel Hydrochloride

0.2 g of Prasugrel hydrochloride-acetic acid pseudo-polymorph was slurred in 4 ml of acetone for 15 h at room temperature. The resulting suspension was filtered and suck-dried to get crystalline Prasugrel hydrochloride.

Example 12: Physical stability of Prasugrel hydrochloride formic acid pseudopolymorph
Approximately 1.0 g of the sample was subjected to different stress conditions; drying, exposure to relative humidity, milling and slurry conversion. The samples were analyzed by PXRD. The novel form is stable under these conditions (Table 1).

Table 1

Example 13: Physical stability of Prasugrel hydrochloride acetic acid pseudopolymorph
Approximately 1.0 g of the sample was subjected to different stress conditions; drying, exposure to relative humidity, milling and slurry conversion. The samples were analyzed by PXRD. The novel form is stable under these conditions (Table 2).

Table 2.

Example 14: Indicative stability of Prasugrel hydrochloride formic acid pseudopolymorph

The physical stability and chemical stability of the Prasugrel hydrochloride formic acid pseudopolymorph was monitored by storing the samples at both long term (25°C and 60%

Relative Humidity) and accelerated stability (40°C and 75% Relative Humidity) conditions up to six months. The samples were tested by PXRD and HPLC and observed to be stable (Table 3).

Table 3

Example 15: Indicative stability of Prasugrel hydrochloride acetic acid pseudopolymorph
The physical stability and chemical stability of the Prasugrel hydrochloride acetic acid pseudopolymorph was monitored by storing the sample at both long term (25 °C and 60% Relative Humidity) and accelerated stability (40°C and 75% Relative Humidity) conditions upto six months. The samples were tested by PXRD and HPLC and observed to be stable (Table 4).
Table 4

We claim:

1. A process for preparation of formic acid pseudopolymorph of Prasugrel
hydrochloride comprising the steps of:

a) dissolving Prasugrel hydrochloride in formic acid;
b) adding an anti solvent; and
c) isolating crystalline formic acid pseudopolymorph of Prasugrel hydrochloride.

2. A process for preparation of formic acid pseudopolymorph of Prasugrel
hydrochloride comprising the steps of:

a) dissolving Prasugrel free base and formic acid in a solvent;
b) adding aq HC1 to the clear solution;
c) adding an antisolvent to the solution; and
d) isolating crystalline formic acid pseudopolymorph of Prasugrel Hydrochloride.

3. A process for preparation of acetic acid pseudopolymorph of Prasugrel hydrochloride
comprising the steps of:

a) dissolving Prasugrel hydrochloride in acetic acid;
b) adding an anti solvent; and
c) isolating crystalline acetic acid pseudopolymorph of Prasugrel hydrochloride.

4. A process for preparation of acetic acid pseudopolymorph of Prasugrel hydrochloride
comprising the steps of:

a) dissolving prasugrel free base and acetic acid in a solvent;
b) adding aq HC1 to the clear solution;
c) adding an anti solvent to the solution; and
d) isolating crystalline acetic acid pseudopolymorph of Prasugrel hydrochloride

5. A process for preparation of nitromethane pseudopolymorph of Prasugrel
Hydrochloride comprising the steps of:

a) dissolving Prasugrel hydrochloride in nitromethane;
b) adding an anti solvent; and
c) isolating crystalline nitromethane pseudopolymorph of Prasugrel hydrochloride.

6. A process for preparation of nitromethane pseudopolymorph of Prasugrel
Hydrochloride comprising the steps of:

a) dissolving Prasugrel hydrochloride in nitromethane;
b) cooling the reaction temperature; and
c) isolating crystalline nitromethane pseudopolymorph of prasugrel hydrochloride.

7. A process for the preparation of Prasugrel HC1 comprising the steps of:

a) treating the pseudopolymorph of prasugrel hydrochloride in a solvent; and
b) isolating crystalline Prasugrel hydrochloride.

8. The process according to claim 7, wherein the solvent is selected from polar solvent.

9. The process according to the claim 8. wherein the polar solvent is a ketone.

10. The process according to the claim 8, wherein polar solvent is acetone.