ILAPRAZOLE

Field of the invention:

The present invention relates to the process for preparation of crystalline form L of ilaprazole.

The present invention further relates to the novel crystalline form L of ilaprazole.

The present invention further relates to the novel crystalline form L of ilaprazole formed by said process.

Background of the invention:

Ilaprazole is a proton pump inhibitor (PPI) used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease and duodenal ulcer.

Ilaprazole is chemically known as 2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]- 6-(lH-pyrrol-l-yl)-lH-benzimidazole havin following structure

There are very few patent documents related to crystallization of ilaprazole.

The example 2 of Indian Patent No. 183088 describes crystallization of ilaprazole from mixture of ethyl acetate and ether.

Indian patent application No. 3607/DELNP/2009 discloses various crystalline forms: A, B, E, F, I of ilaprazole and process for their preparation. The crystalline form B of ilaprazole is obtained by crystallization from acetone/triethylamine in a refrigerator for 11 days. The form B is characterized by peaks at 12.6 and 18.1 degree 2Θ in X-ray powder differactogram. Another Indian patent application No. 3634/DELNP/2009 discloses various solvates of ilaprazole, these are crystalline form C (1,4-dioxane hemisolvate), D (tetrahydrofuran hemisolvate), G (methanol solvate), K (hydrate) of ilaprzole and process for their preparation.

International Patent Publication No. WO 2011/071314 discloses process for the preparation of Form A and Form B. The process for the preparation of Form A involves conversion of ilaprazole to its inorganic salt followed by neutralization with suitable acid in a solvent. The process for preparation of Form B requires use of multiple solvents for the crystallization.

The earlier processes crystallization of ilaprazole has following disadvantages:

i) process is laborious due to concentration of solvent carried out several times;

ii) difficult to obtain the pharmaceutically acceptable purity; and

iii) time consuming.

The physical or chemical properties of a drug can vary depending on the crystalline form of the drug, and such physical and chemical properties can greatly influence a suitable dosage form of the drug, the optimization of a process for preparing the drug, and the in vivo absorption of the drug. The discovery of the most appropriate crystalline form of a drug in a procedure for developing the drug enables the development time and cost to be reduced. Summary of the Invention:

The present invention relates to the process for preparation of crystalline form L of ilaprazole comprising steps of:

i) heating the mixture of ilaprazole in aliphatic ketone containing tertiary organic amine, ii) cooling the mixture,

iii) optionally seeding with form L and

iv) isolating solid. Brief description of drawings:

Figure 1 : X-ray powder differactogram of form L.

Figure 2: IR spectrum of form L.

Figure 3: DSC thermogram of form L.

Detailed description of the invention:

According to one embodiment of the present invention there is provided a process for preparation of crystalline form L of ilaprazole comprising steps of:

i) heating the mixture of ilaprazole in aliphatic ketone containing tertiary organic amine, ii) cooling the mixture,

iii) optionally seeding with form L and

iv) isolating solid.

Ilaprazole used for crystallization may be crude, pure or exist in any polymorphic form or mixtures thereof.

The aliphatic ketone is selected from acetone, 2-butanone, 2-pentanone, 3-pentanone, 4- methyl pentanone, 2-methyl-3-pentanone and the like. The aliphatic ketone is preferably acetone.

The quantity of aliphalic ketone may vary from 10 to 100 volumes per weight of the ilaprazole, preferably 40 to 50 volumes.

The tertiary organic amine is selected from trimethylamine, triethylamine, tripropylamine, triisopropylamine, dimethyl ethylamine, diethyl methylamine and the like. The tertiary organic amine is preferably triethylamine.

The quantity of tertiary organic amine may vary in the range 0.001 to 0.1 w/w, preferably 0.01 to 0.05 w/w.

The heating may be performed at a temperature from 40 °C to the boiling point of the aliphatic ketone used. Mixture may be cooled to -10 °C to 30 °C, preferably to 0 °C to 30 °C, most preferably to 20 °C to 25 °C. Mixture is stirred for about one hour. The separation of the crystals occurs slowly. In case crystals are not separated, mixture is optionally seeded with form L.

The solid may be isolated by the known techniques such as filtration, concentration, evaporation etc.

It is another embodiment of the present invention to provide a novel crystalline form L of ilaprazole.

In a further embodiment of the present invention there is provided a novel crystalline form of ilaprazole, referred as form L formed by the said process.

The said crystalline form L of ilaprazole is characterized by a powder X-ray diffraction pattern having peaks at 6.60, 8.24 and 16.05, ± 0.2 degree 2Θ. The form L is further characterized by the additional peaks at 9.69, 13.15, 17.19 and 19.73 ± 0.2 degree 2Θ in XRPD spectrum. The peaks found in XRPD of form L are given in the following table.

Peaks in the XRPD of form L:

20.54 4.32 3.51 30.73 2.90 1.7

21.21 4.18 2.9 33.53 2.67 0.9

22.14 4.01 3.6 36.47 2.46 0.7

22.49 3.95 4.0 38.84 2.31 1.1

The XRPD of form L is as shown in figure 1.

The crystalline form L of ilaprazole is characterized by an infra-red spectrum having peaks at 1434 and 1417 ± 5 cm ^"1 . The form L is further characterized by the additional peaks at 1577, 1477, 1292, 1269, 1257, 1080, 1037, 806, 732 ± 5 cm ^"1 in IR spectrum. The IR spectrum of crystalline form L is as shown in figure 2.

The crystalline form L of ilaprazole characterized by differential scanning calorimetry (DSC) thermogram having an endotherm at 156 °C. The DSC of crystalline form L is shown in figure 3.

The form L was found to be stable at 25 ± 2 °C (60 ± 5 RH).

The ilaprazole obtained by the present invention has sulfone impurity less than 0.1 %, individual impurity less than 0.15 %, total impurity less than 0.4 %; therefore suitable for pharmaceutical compositions.

The form L of ilaprazole of the present invention can be used in the preparation of pharmaceutical composition for inhibiting gastric acid secretion. Such pharmaceutical composition can be prepared by the methods known in the literature.

Experimental:

The powder X-ray diffraction spectrum is measured using PANalytical X'Pert PRO diffractogram (copper anti cathode) and expressed in terms of inter planar distance d, bragg' s 2 theta, intensity and relative intensity (expressed as a percentage of the most intense peak).

The FTIR spectra were obtained using a Shimadzu 8400S instrument. The differential scanning calorimetry (DSC) was done using Perkin Elmer DSC 4000 instrument.

Example 1

Preparation of crystalline form L of ilaprazole

The mixture of ilaprazole (80 g) in acetone (3200 mL) containing triethylamine (1 mL) was heated at 50-55 °C for 30 min and filtered. Solid washed with acetone (80 mL). To the combined filtrate, activated carbon (8 g) and triethylamine (1 mL) were added and heated at 50-55 °C for 30 min. The mixture was filtered through hyflow, washed with acetone (80 mL X 3). The combined filtrate was distilled under reduced pressure and acetone (1600 mL) was recovered. The concentrated solution was stirred at 20-25 °C for 45-60 min. If crystals are not separated then seeds of form L are added. The concentrated solution was stirred at 0-5 °C for 5-6 hours. Solid was filtered, washed with acetone and dried. Yield: 30.2 g.

HPLC purity: 99.84 %.

Sulfone impirity - 0.06 %

Example 2

Preparation of crystalline form L of ilaprazole

The mixture of ilaprazole (70 g) in acetone (2800 mL) containing triethylamine (0.7 mL) was heated at 50-55 °C for 30 min and filtered. Solid washed with acetone (70 mL). To the combined filtrate, activated carbon (7 g) was added and heated at 50-55 °C for 30 min.

The mixture was filtered through hyflow, washed with acetone (70 mL X 2).

Triethylamine (0.7 mL) was added to the combined filtrate and distilled under reduced pressure till 15 volumes acetone remains in the mixture. The concentrated solution was stirred at 20-25 °C for 45-60 min. Seeds of form L were added to the concentrated solution and stirred at 0-5 °C for 5-6 hours. Solid was filtered, washed with acetone and dried. Yield: 31.0 g.

HPLC purity: 99.63 %.

Sulfone impirity - 0.04 %