Field of the Invention

The present invention provides a novel crystalline form of irinotecan hydrochloride, process for its preparation and pharmaceutical compositions comprising it.

Background of the Invention

Irinotecan hydrochloride is chemically, (S)-4,l l-diethyl-3,4,12,14-tetrahydro-4- hydroxy-3,14-dioxo-lH-pyrano[3',4':6,7]-indolizino[l,2-6]qui nolin-9-yl[l ,4'- bipiperidine]-l-carboxylate hydrochloride and has the structural formula:

.HC1

Irinotecan hydrochloride is an antineoplastic agent of the topoisomerase I inhibitor class. Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, and alkaloid extract from plants such as Camptotheca acuminata. Irinotecan hydrochloride is approved by the Food and Drug Administration as a component of first- line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum. It is also approved for treating patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. Irinotecan hydrochloride is commercially available in injection form under the trade name Camptosar ^® . Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).

Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.

Irinotecan hydrochloride can exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

Irinotecan hydrochloride was disclosed in U.S. patent no. 4,604,463. According to the patent, irinotecan hydrochloride (example 37) was obtained as an amorphous solid (form A).

Crystalline form of irinotecan hydrochloride trihydrate (Form B) was reported in Sawada et al., Chem. Pharm. Bull. Vol. 39, No. 6, 1446-54 (1991).

U.S. patent publication no. 2006/0046993 disclosed irinotecan hydrochloride crystalline form C. According to the patent application, irinotecan hydrochloride form C can be prepared by stirring a suspension of irinotecan hydrochloride form A or irinotecan hydrochloride form B in acetonitrile or acetone.

U.S. patent no. 7,435,818 (herein after referred to as the '818 patent) disclosed crystalline form I, form II, form III and form IV of irinotecan hydrochloride trihydrate. According to the '818 patent, crystalline form I of irinotecan hydrochloride trihydrate can be prepared by crystallization of irinotecan acetate from ethanol, n-heptane and hydrochloric acid.

According to the '818 patent, crystalline form II of irinotecan hydrochloride trihydrate can be prepared by crystallization of irinotecan acetate from ethanol and hydrochloric acid.

According to the '818 patent, crystalline form III of irinotecan hydrochloride trihydrate can be prepared by crystallization of irinotecan acetate from methanol, ethyl acetate and hydrochloric acid.

According to the '818 patent, crystalline form IV of irinotecan hydrochloride trihydrate can be prepared by crystallization of irinotecan acetate from ethanol, ethyl acetate and hydrochloric acid.

EP patent publication no. 2189461 described irinotecan hydrochloride crystalline form H. According to the patent application, irinotecan hydrochloride crystalline form H can be prepared by crystallization of irinotecan hydrochloride from dichloromethane.

Thus there is a need for stable and reproducible crystalline forms of irinotecan hydrochloride.

We have discovered novel crystalline form of irinotecan hydrochloride. The novel form has been found to be stable over the time and reproducible and so, suitable for pharmaceutical preparations.

Thus, an object of the present invention is to provide a novel crystalline form of irinotecan hydrochloride, process for its preparation and pharmaceutical compositions comprising it.

Summary of the invention

In one aspect, the present invention provided a crystalline form of irinotecan hydrochloride designated as form HI characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.3, 6.2, 8.3, 8.5, 10.1, 1 1.3, 14.8, 15.9, 19.7 and 23.8 ± 0.2 degrees.

In another aspect, the present invention provided a process for the preparation of irinotecan hydrochloride crystalline form HI, which comprises crystallizing irinotecan hydrochloride from a solvent system comprising alcohol solvent, chlorinated solvent and ketonic solvent and isolating irinotecan hydrochloride crystalline form HI .

In yet another aspect, the present invention provided a pharmaceutical composition comprising irinotecan hydrochloride crystalline form HI and a pharmaceutically acceptable excipient.

Brief Description of the Drawing

Figure 1 is X-ray powder diffraction spectrum of irinotecan hydrochloride crystalline form HI .

X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X- ray powder diffractometer having a copper-Κα radiation. Approximately 1 gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 degrees to theta per step and a step of 10.4 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 V and current 35 mA.

Detailed Description of the Invention

According to another aspect of the present invention, there is provided a crystalline form of irinotecan hydrochloride designated as form HI characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.3, 6.2, 8.3, 8.5, 10.1 , 1 1.3, 14.8, 15.9, 19.7 and 23.8 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of irinotecan hydrochloride crystalline form HI is shown in figure 1.

Irinotecan hydrochloride crystalline form HI may contain water content. The water content of the irinotecan hydrochloride crystalline form HI may be in between 3.0 to 13.0% by weight and typically may be in between 4.0 to 8.0% by weight.

According to another aspect of the present invention, there is provided a process for the preparation of irinotecan hydrochloride crystalline form HI , which comprises crystallizing irinotecan hydrochloride from a solvent system comprising alcohol solvent, chlorinated solvent and ketonic solvent and isolating irinotecan hydrochloride crystalline form H 1 . Irinotecan hydrochloride used in the process may preferably be irinotecan _. hydrochloride obtained by the known process.

The alcohol solvent used in the process may preferably be a solvent or mixture of solvents selected from methanol, ethanol and isopropyl alcohol, and more preferable alcohol solvent is methanol.

The chlorinated solvent used in the process may preferably be a solvent or mixture of solvents selected from methylene chloride, chloroform, carbontetrachloride and ethylene dichloride, and more preferable chlorinated solvent is methylene dichloride.

The ketonic solvent used in the process may preferably be a solvent or mixture of solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone, and more preferable ketonic solvent is acetone.

Isolation of irinotecan hydrochloride crystalline form HI in the process may preferably be performed by conventional techniques such as centrifugation and filtration.

According to another aspect of the present invention, there is provided a pharmaceutical composition that comprises irinotecan hydrochloride crystalline form HI and pharmaceutically acceptable carriers, diluents or excipients and optionally other therapeutic ingredients. The irinotecan hydrochloride crystalline form HI may preferable be formulated into tablets, capsules, suspensions, dispersions, injectables and other pharmaceutical forms.

The invention will now be further described by the following examples, which are illustrative rather than limiting.

Examples

Reference example 1 :

Preparation of Irinotecan

Triphosgene (45 gm) was added to methylene dichloride (500 ml) at room temperature and then cooled to 0 to 10°C. A solution of 4-piperidinopiperidine (50 gm) in methylene dichloride (500 ml) was added to the reaction mass for 2 hours 30 minutes at 0 to 10°C. The temperature of the reaction mass was raised to room temperature, stirred for 1 hour and then added sodium bicarbonate (50 gm). The reaction mass was stirred for 1 hour at room temperature and the mass was filtered through hi-flow bed. To the mixture of 7-ethyl- 10-hydroxy camptothecin (50 gm) in pyridine (1250 ml) was added filtrate obtained above slowly for 2 hours at room temperature. The reaction mass was stirred for 20 hours at 35 to 40°C and the solvent was distilled off completely under reduced pressure at 45°C to obtained residue. To the residue was added methylene dichloride at room temperature. The organic layer was separated and dried over sodium sulfate. The solvent was distilled off completely under reduced pressure at 45°C and co- distilled with hexane. The reaction mass was cooled to room temperature and then added hexane (1000 ml). The reaction mass was stirred for 30 minutes at room temperature and filtered. To the wet solid obtained was added acetonitrile (1000 ml) and stirred for 30 minutes at room temperature. The solid obtained was collected by filtration and dried at room temperature for 8 hours to obtain 63 gm of irinotecan.

Reference example 2:

Preparation of irinotecan hydrochloride trihydrate

Irinotecan (50 gm) as obtained in reference example 1 was dissolved in water (550 ml) at room temperature and then added concentrated hydrochloric acid (10 gm). The contents were heated to 40 to 45°C and stirred for 1 hour at 40 to 45°C. The reaction mass was treated with charcoal at 40 to 45°C. The reaction mass was cooled to room temperature and the mass was filtered through hi-flow bed. The hi-flow bed washed with water and again washed with ethyl acetate. 50 percent of the solvent was distilled off under reduced pressure at 45°C and filtered. To the filtrate was added concentrated hydrochloric acid (1.65 gm) and water (3.3 ml) at room temperature. The reaction mass was stirred for 18 hours at room temperature and then added acetone (500 ml). The reaction mass was stirred for 2 hours at room temperature and filtered. The solid obtained was dried under reduced pressure at 35 to 40°C for 16 hours to obtain 34 gm of irinotecan hydrochloride trihydrate.

Example 1 :

Preparation of irinotecan hydrochloride crystalline form HI

Irinotecan hydrochloride trihydrate (10 gm) as obtained in reference example 2 was dissolved in a mixture of methanol (50 ml) and methylene dichloride (50 ml) under stirring at room temperature. About 80 percent of the solvent was distilled off under vacuum at below 40°C to obtain a residual mass. The residual mass was stirred for 18 hours at room temperature to form solid. To the solid was added acetone (60 ml) and stirred for 2 hour at room temperature. The solid obtained was collected by filtration and dried under vacuum at below 40°C for 15 hours to obtain 7.5 gm of irinotecan hydrochloride crystalline form HI .

Example 2:

Preparation of irinotecan hydrochloride crystalline form HI

Irinotecan hydrochloride trihydrate (10 gm) was dissolved in a mixture of methanol (30 ml) and methylene dichloride (30 ml) under stirring at room temperature. About 80 percent of the solvent was distilled off under vacuum at below 40°C to obtain a residual mass. The residual mass was stirred for 18 hours at room temperature to form solid. To the solid was added acetone (50 ml) and stirred for 2 hour at room temperature. The solid obtained was collected by filtration and dried under vacuum at below 40°C for 17 hours to obtain 7.2 gm of irinotecan hydrochloride crystalline form HI .

Example 3 :

Preparation of irinotecan hydrochloride crystalline form HI

Irinotecan hydrochloride trihydrate (10 gm) was dissolved in a mixture of methanol (60 ml) and methylene dichloride (40 ml) under stirring at room temperature. About 80 percent of the solvent was distilled off under vacuum at below 40°C to obtain a residual mass. The residual mass was stirred for 18 hours at room temperature to form solid. To the solid was added acetone (50 ml) and stirred for 2 hour at room temperature. The solid obtained was collected by filtration and dried under vacuum at below 40°C for 16 hours to obtain 7 gm of irinotecan hydrochloride crystalline form HI .

Example 4:

Preparation of irinotecan hydrochloride crystalline form HI

Irinotecan hydrochloride trihydrate (10 gm) was dissolved in a mixture of methanol (50 ml) and methylene dichloride (50 ml) under stirring at room temperature. About 80 percent of the solvent was distilled off under vacuum at below 40°C to obtain a residual mass. The residual mass was added acetone (60 ml) and stirred for 18 hour at room temperature, filtered. The solid obtained dried under vacuum at below 40°C for 15 hours to obtain 7.2 gm of irinotecan hydrochloride crystalline form HI .

Example 5:

Preparation of irinotecan hydrochloride crystalline form HI

Irinotecan hydrochloride trihydrate (5 gm) was dissolved in a mixture of methanol (25 ml) and methylene dichloride (25 ml) under stirring at room temperature. To the solution was added (30 ml) and the mass was stirred for 18 hour at room temperature. The separated solid was filtered and dried under vacuum at below 40°C for 14 hours to obtain 3.5 gm of irinotecan hydrochloride crystalline form HI .

Example 6:

Preparation of irinotecan hydrochloride crystalline form HI

Irinotecan hydrochloride trihydrate crystalline form I (10 gm) was dissolved in a mixture of methanol (50 ml) and methylene dichloride (50 ml) under stirring at room temperature. About 80 percent of the solvent was distilled off under vacuum at below 40°C to obtain a residual mass. The residual mass was stirred for 18 hours at room temperature to form solid. To the solid was added acetone (60 ml) and stirred for 2 hour at room temperature. The solid obtained was collected by filtration and dried under vacuum at below 40°C for 16 hours to obtain 7 gm of irinotecan hydrochloride crystalline form HI . Example 7:

Preparation of irinotecan hydrochloride crystalline form HI

Example 6 was repeated using irinotecan hydrochloride trihydrate crystalline form II instead of irinotecan hydrochloride crystalline trihydrate form I to obtain irinotecan hydrochloride crystalline form HI .

Example 8: Preparation of irinotecan hydrochloride crystalline form HI

Example 6 was repeated using irinotecan hydrochloride trihydrate crystalline form III instead of irinotecan hydrochloride crystalline trihydrate form I to obtain irinotecan hydrochloride crystalline form HI .

Example 9:

Preparation of irinotecan hydrochloride crystalline form HI

Example 6 was repeated using irinotecan hydrochloride trihydrate crystalline form IV instead of irinotecan hydrochloride crystalline trihydrate form I to obtain irinotecan hydrochloride crystalline form HI .