Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

• 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.
• Ilaprazole is a proton pump inhibitor (PPI) used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease and duodenal ulcer.
• PPI proton pump inhibitor
• Ilaprazole is chemically known as 2-[[(4-methoxy-3-methyl-2-pyridinyl)methyl]sulfinyl]- 6-(lH-pyrrol-l-yl)-lH-benzimidazole havin following structure
• 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 2 ⁇ in X-ray powder differactogram.
• 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.
• 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.
• the present invention relates to the process for preparation of crystalline form L of ilaprazole comprising steps of:
• Figure 1 X-ray powder differactogram of form L.
• 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.
• form L 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 2 ⁇ .
• the form L is further characterized by the additional peaks at 9.69, 13.15, 17.19 and 19.73 ⁇ 0.2 degree 2 ⁇ in XRPD spectrum.
• the peaks found in XRPD of form L are given in the following table.
• 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.
• 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.
• 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.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Citations (5)

• 2013
  • 2013-01-14 WO PCT/IB2013/050327 patent/WO2013114232A1/fr not_active Ceased

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