Novel hydrated form of erlotinib free base and a process for preparation of erlotinib hydrochloride polymorph form a substantially free of polymorph form b

Abstract

The present invention provides a novel and stable hydrated form of erlotinib free base, and a process for its preparation thereof. The present invention also provides a process for preparation of erlotinib hydrochloride crystalline polymorph A substantially free of polymorph B. The present invention further relates to erlotinib hydrochloride crystalline particles having mean particle size (D 50 ) ranging from about 4 μm to 15 μm and 90 volume-% of the particles (D 90 ) ranging from about 14 μm to 30 μm, to the methods for the manufacture of said crystalline particles, and to pharmaceutical compositions comprising said crystalline particles.

1 . A hydrated crystalline form of erlotinib free base having water content in the range of about 1-10% by weight, characterized by peaks in the powder X-ray diffraction pattern having 26 angle positions at about 6.4, 7.4, 11.2, 12.8, 14.5, 16.3, 18.2, 20.0, 20.5, 21.9, 22.3, 23.3, 23.5, 24.6, 27.6 and 30.0-0.2 degrees. 
   
   
       2 . The crystalline erlotinib hydrate as claimed in  claim 1 , wherein the erlotinib hydrate is further characterized by a Differential Scanning Calorimetry (DSC) thermogram having a small endotherm in the range between 100-112° C. followed by a sharp endotherm in the range between 156-159° C. 
   
   
       3 . A process for preparation of crystalline erlotinib hydrate having water content in the range of about 1-10% by weight as claimed in  claim 1 , which comprises:
 a) slurrying erlotinib free base in water; and   b) collecting the crystalline erlotinib hydrate having water content in the range of about 1-10% by weight from the slurry.   
   
   
       4 . The process as claimed in  claim 3 , wherein the slurrying is carried out at a temperature below 60° C. 
   
   
       5 . The process as claimed in  claim 4 , wherein the slurrying is carried out at a temperature between 0° C. and 45° C. 
   
   
       6 . The process as claimed in  claim 5 , wherein the slurrying is carried out at 20-40° C. 
   
   
       7 . The process as claimed in  claim 3 , wherein the slurry obtained in step (a) is stirred at least for about 30 minutes. 
   
   
       8 . The process as claimed in  claim 7 , wherein the slurry is stirred at least for about 1 hour. 
   
   
       9 . The process as claimed in  claim 8 , wherein the slurry is stirred for about 1 hour to 4 hours. 
   
   
       10 . The process as claimed in  claim 3 , wherein the crystalline erlotinib hydrate in step (b) is collected from the slurry by filtration or centrifugation. 
   
   
       11 . The process as claimed in  claim 3 , wherein the water content of crystalline erlotinib hydrate obtained is between 1.5% and 9% by weight. 
   
   
       12 . The process as claimed in  claim 11 , wherein the water content of crystalline erlotinib hydrate is between 1.8% and 8% by weight. 
   
   
       13 . The process as claimed in  claim 12 , wherein the water content of crystalline erlotinib hydrate is between 2% and 5.5% by weight. 
   
   
       14 . A process for preparation of crystalline erlotinib hydrate having water content in the range of about 1-10% by weight as claimed in  claim 1 , which comprises:
 a) dissolving erlotinib free base in an organic solvent or a mixture of organic solvents;   b) adding water as an anti-solvent to the solution obtained in step (a); and   c) collecting the precipitated crystalline erlotinib hydrate having water content in the range of about 1-10% by weight.   
   
   
       15 . The process as claimed in  claim 14 , wherein the organic solvent used in step (a) is selected from the group consisting of acetone, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, acetonitrile, and an alcoholic solvent such as methanol, ethanol, propanol, isopropyl alcohol, butanol, isoamyl alcohol. 
   
   
       16 . The process as claimed in  claim 15 , wherein the organic solvent is selected from methanol, ethanol, isopropyl alcohol and acetone. 
   
   
       17 . The process as claimed in  claim 14 , wherein the erlotinib free base in step (a) is dissolved in the organic solvent at a temperature above about 30° C. 
   
   
       18 . The process as claimed in  claim 17 , wherein the erlotinib free base is dissolved in the organic solvent at a temperature between 40° C. and reflux temperature of the solvent used. 
   
   
       19 . The process as claimed in  claim 18 , wherein the erlotinib free base is dissolved in the organic solvent at a temperature between 45° C. and 80° C. 
   
   
       20 . The process as claimed in  claim 14 , wherein the water in step (b) is added to the solution slowly at a temperature above about 30° C. 
   
   
       21 . The process as claimed in  claim 20 , wherein the water is added to the solution at a temperature between 40° C. and reflux temperature of the solvent used. 
   
   
       22 . The process as claimed in  claim 21 , wherein the water is added to the solution at a temperature between 45° C. and 80° C. 
   
   
       23 . The process as claimed in  claim 14 , wherein the precipitated erlotinib hydrate in step (c) is collected by filtration or centrifugation. 
   
   
       24 . The process as claimed in  claim 14 , wherein the water content of crystalline erlotinib hydrate obtained is between 1.5% and 9% by weight. 
   
   
       25 . The process as claimed in  claim 24 , wherein the water content of crystalline erlotinib hydrate is between 1.8% and 8% by weight. 
   
   
       26 . The process as claimed in  claim 25 , wherein the water content of crystalline erlotinib hydrate is between 2% and 5.5% by weight. 
   
   
       27 . A process for preparation of erlotinib hydrochloride crystalline polymorph form A substantially free of polymorph form B, which comprises adding hydrochloric acid to a solution of erlotinib free base in a solvent or a mixture of solvents selected from isopropyl acetate and methyl isobutyl ketone, and isolating erlotinib hydrochloride crystalline polymorph form A substantially free of polymorph B from the solution. 
   
   
       28 . The process as claimed in  claim 27 , wherein the erlotinib hydrochloride crystalline polymorph form A substantially free of polymorph form B obtained is characterized by peaks in the powder X-ray diffraction pattern having 2θ angle positions at about 5.75, 9.88, 11.40, 18.97, 22.84, 23.65, 24.29, 24.75, 25.56 and 29.37±0.2 degrees. 
   
   
       29 . The process as claimed in  claim 27 , wherein the hydrochloric acid in the form of aqueous hydrochloric acid or in the form of hydrogen chloride gas or hydrogen chloride dissolved in an organic solvent is used. 
   
   
       30 . The process as claimed in  claim 29 , wherein the organic solvent is selected from the group consisting of ethanol, methanol, isopropyl alcohol, ethyl acetate, diethyl ether, dimethyl ether and acetone. 
   
   
       31 . The process as claimed in  claim 30 , wherein the organic solvent is ethyl acetate. 
   
   
       32 . The process as claimed in  claim 27 , wherein the process of the invention is carried out by dissolving erlotinib free base in a solvent or a mixture of solvents selected from isopropyl acetate and methyl isobutyl ketone to form a clear solution; adding hydrochloric acid to the solution; and isolating erlotinib hydrochloride crystalline polymorph form A substantially free of polymorph B from the solution. 
   
   
       33 . The process as claimed in  claim 32 , wherein the erlotinib free base is dissolved in the solvent or a mixture of solvents at a temperature above about 30° C. 
   
   
       34 . The process as claimed in  claim 33 , wherein the erlotinib free base is dissolved in the solvent or a mixture of solvents at a temperature between 40° C. and reflux temperature of the solvent used. 
   
   
       35 . The process as claimed in  claim 34 , wherein the erlotinib free base is dissolved in the solvent or a mixture of solvents at a temperature between 50° C. and 80° C. 
   
   
       36 . The process as claimed in  claim 27 , wherein the hydrochloric acid is added to the solution slowly at a temperature above about 30° C. 
   
   
       37 . The process as claimed in  claim 36 , wherein the hydrochloric acid is added to the solution at a temperature between 40° C. and reflux temperature of the solvent used. 
   
   
       38 . The process as claimed in  claim 37 , wherein the hydrochloric acid is added to the solution at a temperature between 50° C. and 80° C. 
   
   
       39 . The process as claimed in  claim 27 , wherein the isolation of erlotinib hydrochloride crystalline particles is carried out by cooling, partial removal of the solvent from the solution, addition of precipitating solvent or a combination thereof. 
   
   
       40 . Erlotinib hydrochloride crystalline polymorph form A characterized by peaks in the powder X-ray diffraction pattern having 26 angle positions at about 5.75, 9.88, 11.40, 18.97, 22.84, 23.65, 24.29, 24.75, 25.56 and 29.37±0.2 degrees and by the absence of a peak at about 6.26±0.2 degrees. 
   
   
       41 . Crystalline particles of erlotinib hydrochloride having mean particle size (D 90 ) ranging from about 4 μm to 15 μm and 90 volume-% of the particles (D 90 ) ranging from about 14 μm to 30 μm. 
   
   
       42 . A process for preparation of erlotinib hydrochloride crystalline particles as defined in  claim 41 , which comprises adding hydrochloric acid to a solution of erlotinib free base in isopropyl acetate, and isolating erlotinib hydrochloride crystalline particles having mean particle size (D 90 ) ranging from about 4 μm to 15 μm and 90 volume-% of the particles (D 90 ) ranging from about 14 μm to 30 μm. 
   
   
       43 . The process as claimed in  claim 42 , wherein the process of the invention is carried out by dissolving erlotinib free base in isopropyl acetate to form a clear solution; adding hydrochloric acid to the solution; and isolating erlotinib hydrochloride crystalline particles having mean particle size (D 50 ) ranging from about 4 μm to 15 μm and 90 volume-% of the particles (D 90 ) ranging from about 14 μm to 30 μm from the solution. 
   
   
       44 . The process as claimed in  claim 42 , wherein the erlotinib hydrochloride crystalline particles obtained are having mean particle size (D 50 ) ranging from about 4.5 μm to 10 μm and 90 volume-% of the particles (D 90 ) ranging from about 14.5 μm to 26 μm. 
   
   
       45 . The process as claimed in  claim 44 , wherein the erlotinib hydrochloride crystalline particles having mean particle size (D 50 ) ranging from about 4.6 μm to 9.5 μm and 90 volume-% of the particles (D 90 ) ranging from about 14.6 μm to 24.5 μm. 
   
   
       46 . The process as claimed in  claim 45 , wherein the erlotinib hydrochloride crystalline particles having mean particle size (D 50 ) ranging from about 4.8 μm to 10 μm and 90 volume-% of the particles (D 90 ) ranging from about 14.8 μm to 22 μm. 
   
   
       47 . The process as claimed in  claim 43 , wherein the erlotinib free base is dissolved in isopropyl acetate at a temperature above about 30° C. 
   
   
       48 . The process as claimed in  claim 47 , wherein the erlotinib free base is dissolved in isopropyl acetate at a temperature between 40° C. and reflux temperature of the solvent used. 
   
   
       49 . The process as claimed in  claim 48 , wherein the erlotinib free base is dissolved in isopropyl acetate at a temperature between 50° C. and 80° C. 
   
   
       50 . The process as claimed in  claim 42 , wherein the hydrochloric acid is added to the solution slowly at a temperature above about 30° C. 
   
   
       51 . The process as claimed in  claim 50 , wherein the hydrochloric acid is added to the solution at a temperature between 40° C. and reflux temperature of the solvent used. 
   
   
       52 . The process as claimed in  claim 51 , wherein the hydrochloric acid is added to the solution at a temperature between 50° C. and 80° C. 
   
   
       53 . The process as claimed in  claim 42 , wherein the hydrochloric acid in the form of aqueous hydrochloric acid or in the form of hydrogen chloride gas or hydrogen chloride dissolved in an organic solvent is used. 
   
   
       54 . The process as claimed in  claim 53 , wherein the organic solvent is selected from the group consisting of ethanol, methanol, isopropyl alcohol, ethyl acetate, diethyl ether, dimethyl ether and acetone. 
   
   
       55 . The process as claimed in  claim 54 , wherein the organic solvent is ethyl acetate. 
   
   
       56 . The process as claimed in  claim 42 , wherein the isolation of erlotinib hydrochloride crystalline particles is carried out by cooling, partial removal of the solvent from the solution, addition of precipitating solvent or a combination thereof. 
   
   
       57 . A pharmaceutical composition comprising erlotinib hydrochloride crystalline particles having mean particle size (D 50 ) ranging from about 4 μm to 15 μm and 90 volume-% of the particles (D 90 ) ranging from about 14 μm to 30 μm, and one or more pharmaceutically inert excipients. 
   
   
       58 . The pharmaceutical composition as claimed in  claim 57 , wherein the pharmaceutical composition is selected from a solid dosage form and an oral suspension. 
   
   
       59 . The pharmaceutical composition as claimed in  claim 58 , wherein the solid dosage form includes tablet, capsule, granules and sachet. 
   
   
       60 . A pharmaceutical composition comprising erlotinib hydrochloride crystalline polymorph form A characterized by peaks in the powder X-ray diffraction pattern having 29 angle positions at about 5.75, 9.88, 11.40, 18.97, 22.84, 23.65, 24.29, 24.75, 25.56 and 29.37±0.2 degrees and by the absence of a peak at about 6.26±0.2 degrees, and one or more pharmaceutically inert excipients. 
   
   
       61 . The pharmaceutical composition as claimed in  claim 60 , wherein the pharmaceutical composition is selected from a solid dosage form and an oral suspension. 
   
   
       62 . The pharmaceutical composition as claimed in  claim 61 , wherein the solid dosage form includes tablet, capsule, granules and sachet.