WO2014136126A2

WO2014136126A2 - A process for preparing erlotinib hydrochloride form a

Info

Publication number: WO2014136126A2
Application number: PCT/IN2014/000145
Authority: WO
Inventors: Srinivas Simhadri; Dattatraya Nivrutti Chavan; Venkata Sunil Kumar Indukuri; Seeta Ramanjaneyulu Gorantla
Original assignee: Laurus Labs Private Limited
Priority date: 2013-03-08
Filing date: 2014-03-04
Publication date: 2014-09-12
Also published as: WO2014136126A3

Abstract

The present invention relates to a process for preparing erlotinib hydrochloride Form A from a solvent mixture comprising dichloromethane, methyl tertiary butyl ether and isopropyl ether. HCl.

Description

A PROCESS FOR PREPARING ERLOTINIB HYDROCHLORIDE FORM A"

PRIORITY

This application claims the benefit under Indian Provisional Application No. 1004/CHE/2013, filed on March 08, 2013 entitled "A process for preparing Erlotinib hydrochloride form A", the contents of which is incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Erlotinib hydrochloride polymorphic form A and its pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

Erlotinib hydrochloride chemically, N-(3-ethynylphenyl)-6, 7-bis-(2-methoxyethoxy) quinazolin-4-amine hydrochloride of Formula I is a compound that inhibits the human epidermal growth factor receptor. tyrosine kinase. It is marketed under the brand name Tarceva® in United States and is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen and in combination with gemcitabine is indicated for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.

Formula I

U.S. Pat. No. 5,747,498 ("the '498 patent") discloses Erlotinib and its preparation. This patent makes no reference to the existence of specific polymorphic forms of erlotinib hydrochloride. In this patent, it is disclosed that the compound is isolated according to conventional techniques; more precisely, according to the embodiments exemplified, crude erlotinib hydrochloride residue (obtained by reaction of 4-chloro-6,7-bis-(2- methoxyethoxy)-quinazoline of Formula II with 3-ethynylaniline or its hydrochloride salt of Formula III in a solvent such as a d-ds-alcohol, dimethylformamide, N- methylpyrrolidin-2-one, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, pyridine or other aprotic solvents, preferably isopropanol) is basified with saturated aqueous NaHC0₃ in the presence of methanol and chloroform followed by flash chromatography on silica using 30% acetone in hexane to afford erlotinib free base, which is further treated with hydrochloric acid in presence of diethyl ether and chloroform to give erlotinib hydrochloride (71%) (Melting point: 228-230° C).

Erlotinib HC1

Erlotinib obtained by the process described in the '498 patent is not satisfactory from purity point of view. The yield of the erlotinib hydrochloride obtained is very poor and the process involves column chromatographic purifications, which is not viable in large scale operation. U.S. Patent No. 6,476,040 ("the Ό40 patent") discloses a process for the preparation of erlotinib hydrochloride by treating erlotinib free base in 2-propanol, butan- l-ol, butan-2- ol or 2-methoxyethanol with concentrated hydrochloric acid. However, the '040 patent makes no reference to the existence of specific polymorphic form of erlotinib hydrochloride except a melting point of 226°C to 229°C. U.S. patent No. 6,900,221 ("the '221 patent") discloses two crystalline forms of erlotinib hydrochloride (polymorph A and polymorph B), characterized by powder X-ray diffraction (p-XRD) pattern. The '221 patent described that the hydrochloride compound obtained from the '498 patent actually comprised of a mixture of polymorph A and polymorph B.

The '221 patent further discloses a process for preparation of erlotinib hydrochloride polymorphic Form A or a mixture of polymorph A and B, by treating the filtrate containing 3-ethylaniline in toluene with 4-chloro-6,7-bis-(2-methoxyethoxy)- quinazoline and acetonitrile to reflux temperature, cooling the reaction mass to between 19°C to 25°C and isolating erlotinib hydrochloride polymorph Form A or a mixture of polymorph A and B. Further, the '221 patent described that the production of polymorph A is favored by the reduction of the amount of acetonitrile relative to toluene, and particularly favored, if isopropanol is used in place of acetonitrile.

Further, the '221 patent also discloses a process for preparation of erlotinib hydrochloride Form B by refluxing (~80°C) erlotinib hydrochloride (polymorph A or mixture of Form A and Form B), 2B-ethanol and water so as to form a solution, cooling the solution to between 65°C and 70°C, clarifying the solution by filtration, cooling the solution to between 50°C and 60°C with low speed agitation followed by granulation of the precipitate, further cooling the mixture to between 0°C and 5°C followed by granulation of the precipitate and isolating erlotinib hydrochloride in polymorph Form B by filtration.

U.S. Patent No. 7,148,231 ("the '231 patent") discloses a process for the preparation of erlotinib hydrochloride Form E by refluxing 4-chloro-6,7-bis(2- methoxyethoxy)quinazoline suspended in (a, ,a)-trifluorotoluene, 3-ethynylaniline dissolved in (a,a, )-trifluorotoluene and hydrochloric acid (37%), after completion of the reaction, cooling the resulting suspension to room temperature, filtering and washing the isolated crystals of erlotinib hydrochloride with ethanol and drying at 60° C/10 mbar overnight to give erlotinib hydrochloride Form E. The '231 patent described that, of the two polymorphs described in the '221 patent, polymorph Form B is thermodynamically more stable than Form A, while Form A exhibits a better solubility and dissolution rate than polymorph B.

U.S. Patent No. 7,625,911 ("the '911 patent") discloses a process for preparing amorphous form of erlotinib hydrochloride by dissolving crystalline erlotinib hydrochloride in methanol, ethanol or a mixture of ethanol and water to complete dissolution followed by removal of the solvent from the reaction mixture using distillation or spray drying.

U.S. Patent No. 7,928,114 ("the '114 patent") discloses a process for preparation of erlotinib hydrochloride by adding erlotinib monohydrate Form I dissolved in acetone and 2-propanol with 5-6 N hydrochloric acid (>1 equivalent of hydrochloric acid) with continuous stirring, isolating the solid by filtration, and air drying overnight at room temperature to give erlotinib hydrochloride in a mixture of Form A and Form B.

U.S. Publication No. 2008/0167327 ("the '327 publication) discloses a process for the preparation of erlotinib hydrochloride hemihydrate Form I by dissolving anhydrous erlotinib hydrochloride in demi-water at reflux, leaving the hot solution unagitated at 4° for 28 days during which slow crystallization occurred, isolating the solid and air drying overnight at ambient temperature to give off-white to pale beige bunches of fibre-like crystals of erlotinib hydrochloride hemihydrate Form I. The '327 publication further discloses a process for the preparation of erlotinib hydrochloride hemihydrate Form II by dissolving anhydrous erlotinib hydrochloride in water at reflux, followed by adding seeds of erlotinib hydrochloride hemihydrate Form I, leaving the solution unagitated at 4° C for 28 days unagitated at 4°C for 4 days, during which slow crystallization occurs, isolating the solid and air drying overnight at ambient temperature to give pale yellow lumps of sticky powder of erlotinib hydrochloride hemihydrate Form II.

PCT Publication No. WO 2007/060691 ("the '691 publication") discloses a process for the preparation of erlotinib hydrochloride by treating erlotinib base dissolved in acetone or acetonitrile with isopropanolic hydrochloride at reflux temperatures, maintained for one hour, followed by cooling to 25°C to 30°C and isolating erlotinib monohydrochloride as a white solid.

PCT Publication No. WO 2008/102369 ("the '369 publication") discloses a process for the preparation of Form M, Form N and Form P of erlotinib hydrochloride. Form M was prepared by treating erlotinib base in methanol with a solution of hydrogen chloride in dry methanol or isopropanol; Form N was prepared by treating erlotinib base in isopropanol with isopropanolic hydrogen chloride and Form P was prepared by treating erlotinib base in methylene chloride with isopropanolic hydrogen chloride.

PCT Publication No. WO 2009/024989 ("the '989 publication") discloses a process for the preparation of erlotinib hydrochloride polymorph Form A substantially free of polymorph B which involves dissolving erlotinib free base in methyl isobutyl ketone or isopropyl acetate treating the solution with 7% ethyl acetate hydrogen chloride.

PCT Publication No. WO 2009/025876 ("the '876 publication") discloses a process for the preparation of erlotinib hydrochloride Form F and Form G by treating erlotinib base dissolved in a solvent selected from 1,3-dioxalane, butanol with hydrogen chloride selected from concentrated hydrochloric acid, aqueous hydrogen chloride in butanol or hydrogen chloride in ether.

WO 2009/025873 ("the '873 publication") discloses a process for the preparation of erlotinib hydrochloride Form A which involves crystallizing erlotinib hydrochloride from a solvent selected from the group consisting of: toluene, a mixture of toluene and methanol, methylal, methyl tert butyl ether (MTBE), ethyl acetate , n-butanol, mixture of n-butanol and water, methylisobutyl ketone ("MIBK"), s-butanol, a mixture of s-butanol and water, n-propanol, 2-propanol, methoxyethanol, a mixture of methoxyethanol and water, ethanol, a mixture of 1,3-dioxolane and methanol, a mixture of 1,3-dioxolane and water and a mixture of butanone and water; wherein the mixture of 1,3-dioxolane and water has about 2% to about 3% v/v of water, the mixture of 1,3-dioxolane and methanol has about 10% v/v of methanol, the mixture of n-butanol and water has about 1% to about 2% v/v of water, the mixture of s-butanol and water has about 1% to about 2% v/v of water, the mixture of methoxy ethanol and water has about 1% to about 2% v/v of water, and the mixture of toluene and methanol has about 2% v/v of methanol.

IP.Com document ID180601D discloses a process for preparation of erlotinib hydrochloride by treating erlotinib base dissolved in 1,3-dioxolane/water (98:2) with 37% hydrogen chloride at 62° C to 65°C.

CN101602734 ("the '734 publication") discloses a process for the preparation of erlotinib hydrochloride Form A which involves dissolving erlotinib free base in organic solvent [organic solvent is selected from the group consisting of 1. polyacene: anisole, toluene or xylene; 2. ethers: tetrahydrofuran, diethyl ether, diisopropyl ether, or methyl tert-butyl ether; 3. ketones: acetone, methyl isobutyl ketone, methyl ethyl ketone or methyl butyl ketone; 4. alkanes: n-heptane, n-pentane, hexane, dioxane, cyclohexane or methyl cyclohexane; 5. chlorinated hydrocarbons: dichloromethane, chloroform, or 1,2 - dichloroethylene; 6. esters: ethyl acetate, isobutyl acetate, butyl acetate, or acetic acid isopropyl; 7. mixed solvent: a mixed solvent of methylene chloride and methyl tert-butyl ether, or chloroform and diethyl ether mixed solvent] and further treating with hydrogen chloride of the ethers include diethyl ether, anisole, isopropyl ether, methyl t-butyl ether.

WO2011058525 ("the '525 publication") discloses a process for the preparation of erlotinib hydrochloride Form A which involves providing a mixture comprising erlotinib and a solvent (solvent include acetone, dichloromethane, or a mixture thereof; (or) dichloromethane, ether or mixture thereof; (or) ethyl acetate) and treating the mixture with HC1 gas or 4% HC1 in ether followed by isolating pure erlotinib hydrochloride Form A.

PCT Publication No's. WO031066602, WO2009/007984, WO2008/122776, WO2007/138612, WO2007/138613, WO2008/000418 discloses various processes for the preparation of erlotinib and its salts.

Our co-pending Patent application 1503/CHE/2012 discloses a process for preparation of erlotinib hydrochloride Form A, which involves providing a mixture comprising erlotinib hydrochloride in one or more solvent selected from methanol, isopropanol or dichloromethane and isolating the pure erlotinib hydrochloride Form A. Solvent medium and way of isolation play an important role in obtaining one polymorphic form over another, for example erlotinib hydrochloride Form A crystals obtained from anhydrous solvent medium favors pure Form A whereas the hydrated medium favors Form B along with Form A. Isolation with different solvents according to the processes described in the literatures of erlotinib hydrochloride Form A produces a product, which is difficult and slow (i.e. inefficient) to filter, and retains a substantial quantity of organic solvents due to formation of fine particles during the course of precipitation/crystallization. This necessitates extensive drying in order to obtain a final product suitable for use as a pharmaceutical. Although manageable on a small (laboratory) or medium scale, on a manufacturing scale, handling a product requiring such treatment is highly problematic and is undesirable in terms of manufacturing output and, potentially, product quality. Further extensive drying at high temperatures leads to interconversion of Form A in to thermodynamically stable Form B. It would be desirable to provide alternate useful methods for making erlotinib hydrochloride Form A, especially a method that can provide for improved results.

The present inventors have discovered a surprising improvement to the process of manufacturing the erlotinib hydrochloride pure Form A, which results in improved efficiency of filtration of the product during the isolation process. Accordingly, the present invention provides a process for preparation of erlotinib hydrochloride Form A, which process involves a suitable solvent such as dichloromethane, methyl tertiary butyl ether, isopropyl ether or mixture thereof that are away from the aforementioned filtration difficulties and provides consistently pure Form A. SUMMARY OF THE INVENTION

In accordance with the principle aspect of the present invention there is provided an improved process for preparing pure erlotinib hydrochloride polymorphic Form A. In accordance with one embodiment, the present invention provides a process for the preparation of erlotinib hydrochloride Form A, comprising: a) providing a solution of erlotinib in an organic solvent, wherein the organic solvent selected from dichloromethane, methyl tertiary butyl ether or mixture thereof, b) optionally, adding seed crystals of erlotinib hydrochloride Form A,

c) treating the resultant solution with hydrogen chloride in isopropyl ether, and d) isolating the erlotinib hydrochloride Form A.

In accordance with a second embodiment, the present invention provides a process for the preparation of erlotinib hydrochloride Form A, comprising: a) providing a solution/mixture of erlotinib acid addition salt in an organic solvent, wherein the organic solvent selected from dichloromethane, methyl tertiary butyl ether or mixture thereof,

b) neutralizing the step a) with a base,

c) separating the erlotinib containing layer,

d) adding an additional organic solvent selected from dichloromethane, methyl - tertiary butyl ether or mixture thereof,

e) optionally, adding seed crystals of erlotinib hydrochloride Form A,

f) treating the resultant solution with hydrogen chloride in isopropyl ether, and g) isolating the erlotinib hydrochloride Form A.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of erlotinib hydrochloride Form A, obtained by the process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a convenient, industrially feasible and efficient process of preparing pure erlotinib hydrochloride polymorphic Form A.

As used herein the term "pure erlotinib hydrochloride Form A" refer to crystalline Form A of erlotinib hydrochloride exhibits an X-ray powder diffraction pattern having characteristic peaks at approximately 5.6, 9.7, 10, 11.3, 17, 17.4, 18.9, 19.5, 20.5, 21.3, 22, 22.7, 23.5, 24.2, 24.6, 25.4, 26.2, 26.6, 28 and 29.2±0.2 degrees 20 and substantially absence peak at about 6.2 degrees 2Θ.

In another embodiment, the present invention provides a process for the preparation of erlotinib hydrochloride Form A, comprising: a) providing a solution of erlotinib in an organic solvent, wherein the organic solvent selected from dichloromethane, methyl tertiary butyl ether or mixture thereof, b) optionally, adding seed crystals of erlotinib hydrochloride Form A,

The erlotinib in the step a) may be any crystalline or other form of erlotinib, including various solvates, hydrates, as long as erlotinib Form A is produced during the process of the invention or erlotinib obtaining as existing solution from a previous processing step. In one embodiment, starting erlotinib can be prepared either from the corresponding erlotinib acid addition salts by neutralization or from the reaction by 4-chloro-6,7-bis-(2- methoxyethoxy)-quinazoline of Formula II and 3-ethynylaniline or its hydrochloride salt of Formula III in presence of a base.

Preferably erlotinib can be prepared by neutralization of the corresponding erlotinib acid addition salts with a base.

In another embodiment, the present invention provides a process for the preparation of erlotinib hydrochloride Form A, comprising: a) providing a solution/mixture of erlotinib acid addition salt in an organic solvent, wherein the organic solvent selected from dichloromethane, methyl tertiary butyl ether or mixture thereof,

b) neutralizing the step a) with a base,

c) separating the erlotinib containing layer,

d) adding an additional organic solvent selected from dichloromethane, methyl tertiary butyl ether or mixture thereof,

e) optionally, adding seed crystals of erlotinib hydrochloride Form A,

The starting material erlotinib acid addition salt may be any acid known in the art, preferably hydrochloric acid. The erlotinib acid addition salt can be prepared by any known method, for example erlotinib acid addition salt may be synthesized as disclosed in U.S. Patent No. 5,747,498.

Step a) of providing a solution of erlotinib acid addition salt, preferably hydrochloride salt in an organic solvent, wherein the organic solvent selected from dichloromethane, methyl tertiary butyl ether or mixture thereof; preferably dichloromethane at a temperature of about 25°C to 35°C. Then adding water to the solution and neutralizing the reaction mixture with a base.

The base include, but are not limited to hydroxide base, carbonate base, bicarbonate base and the like; preferably sodium hydroxide, sodium carbonate, sodium bicarbonate; more preferably sodium bicarbonate. Then, the organic layer and the aqueous layers can be separated and washed with water. The resultant organic layer containing erlotinib base can be further processed directly in the same reaction vessel to form erlotinib hydrochloride Form A of the invention without isolating the solid erlotinib free base. In another embodiment, the present invention provides a process for preparation of erlotinib hydrochloride Form A, wherein the process involves a single step without isolation of solid erlotinib free base.

In another embodiment, an additional organic solvent can be added to the resultant solution. The additional organic solvent may be selected from dichloromethane, methyl tertiary butyl ether or mixture thereof; preferably methyl tertiary butyl ether.

In another embodiment, an optional step of adding seed crystals of erlotinib hydrochloride Form A to the resultant solution to initiate erlotinib hydrochloride Form A precipitation upon addition of hydrogen chloride. In another embodiment, the seed crystals of erlotinib hydrochloride Form A can be added at a temperature of about 25°C to 35°C.

In another embodiment, the seed crystals can be added about 1% to about 5% wt/wt of the starting erlotinib.

The resultant solution obtained from the above is treated with hydrogen chloride in isopropyl ether at a temperature of about 10°C to about 35°C, preferably at about 20°C to 30°C, more preferably at about 25°C to 30°C.

The hydrogen chloride in isopropyl ether is about 5% to about 25% wt/wt, preferably about 10% to about 20% wt/wt, more preferably about 16-18% wt/wt. In another embodiment, the reaction mixture may be stirred for about 1 hour to about 24 hours, preferably, for about 1 hour to about 3 hours, more preferably for about 2 hours.

The stirring can be carried out at a temperature of about 10°C to about 35°C, preferably at about 25°C to 30°C. The isolation of erlotinib hydrochloride Form A crystals obtained may be carried out by filtration, solvent removal under spray drying, freeze drying, evaporation on rotary evaporator under vacuum and the like or combinations thereof; preferably by filtration. The erlotinib hydrochloride Form A crystals obtained may be washed with an organic solvent selected from dichloromethane, methyl tertiary butyl ether or mixture thereof.

The resultant product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 60° C. The drying can be carried out for any desired time until the required product purity is achieved, e.g., a time period ranging from about 1 hour to about 12 hours.

The erlotinib hydrochloride recovered using the process of the present invention is substantially in crystalline Form A. The crystalline erlotinib hydrochloride can be characterized by one or more techniques such as an X-Ray diffraction (XRD) pattern substantially in accordance with Figure.1.

In another embodiment, erlotinib hydrochloride recovered using the process of the present invention is having a chemical purity greater than or equal to about 97%, as measured by HPLC, preferably about 98% as measured by HPLC, and more preferably about 99.9%, as measured by HPLC; and substantially free of other crystalline Forms, for example less than 5% of erlotinib hydrochloride Form B crystals, more preferably less than 1%.

The '734 publication discloses preparation of erlotinib hydrochloride Form A, which was prepared from a mixture of dichloromethane and methyl tertiary butyl ether. The erlotinib hydrochloride Form A obtained by this solvent mixture traps large excess of residual solvents in erlotinib hydrochloride Form A crystals, which are difficult to remove under normal drying techniques and requires drying under high temperatures, this leads to formation of undesired Form B contamination in Form A. In contrast, the process herein described arrives at erlotinib hydrochloride Form A, which may be prepared from a mixture of dichloromethane, methyl tertiary butyl ether and isopropyl ether. The use of isopropyl ether avoids the trapping of residual solvents in erlotinib hydrochloride Form A crystals. Further content of hydrogen chloride in methyl tertiary butyl ether is not well consistent even store under chilled temperatures whereas the isopropyl ether holds consistently about 15% wt/wt of hydrogen chloride at room temperature.

A comparative preparation of erlotinib hydrochloride using the '734 publication process, yielded erlotinib hydrochloride Form A, that had large excess of residual solvent and filtration time than the present process.

The present invention provides erlotinib hydrochloride Form A obtained using the process of the described herein, may have a residual solvent content that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The guideline solvent level depends on the type of solvent but is not more than about 5000 ppm, or about 4000 ppm, or about 3000 ppm.

The present invention provides erlotinib hydrochloride Form A, obtained by the process disclosed herein, having less than about 1000 parts per million (ppm) C_1-4 alcohols such as methanol, ethanol, isopropanol, preferably less than about 500 ppm; less than about 500 ppm ethyl acetate, preferably less than about 100 ppm; less than about 500 ppm diethyl ether, isopropyl ether, methyl tertiary butyl ether, preferably less than about 400 ppm; less than about 500 ppm dichloromethane, preferably less than about 300 ppm; less than about 500 ppm dimethyl formamide, preferably less than about 100 ppm; less than about 500 ppm pyridine, preferably less than 100 ppm. In one embodiment, erlotinib hydrochloride Form A disclosed herein for use in the pharmaceutical compositions of the present invention can independently have a D50 and D90 particle size less than about 100 microns, preferably less than about 50 microns, more preferably less than about 30 microns, still more preferably less than about 15 microns. It is noted the notation Dx means that X% of the particles have a diameter less than a specified diameter D. Thus, a D50 of about 100 microns means that 50% of the micronized particles in a composition have a diameter less than about 100 microns. Any milling, grinding, micronizing or other particle size reduction method known in the art can be used to bring the erlotinib hydrochloride Form A into any desired particle size range set forth above. The erlotinib hydrochloride Form A of the present invention is useful as it is stable under conditions of high relative humidity and elevated temperatures.

In another embodiment, the present invention provides a pharmaceutical composition comprising the erlotinib hydrochloride Form A described above and at least one pharmaceutically acceptable excipient.

The pharmaceutical composition of the present invention can be in a solid or a non-solid form. If the pharmaceutical composition is in a non-solid form, the erlotinib hydrochloride Form A in the composition can present as a solid in the non-solid pharmaceutical composition, e.g., as a suspension. EXAMPLES

The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way. EXAMPLE 1:

Preparation of erlotinib hydrochloride Form A (dichloromethane + methyl tertiary butyl ether + Isopropyl ether. HC1)

Erlotinib hydrochloride (100 g) was dissolved in dichloromethane (5 L) and to this added water (500 ml) at 25-35°C. Stirred for 10 min and 600 ml of sodium bicarbonate solution (48 g of sodium bicarbonate dissolved in 552 ml water) was added over a period of 30 min and stirred for 2 hr at 25-35 °C until clear solution observed. The organic and aqueous layers were separated and washed organic phase twice with water and treated with charcoal at 25-35°C. The charcoal was filtered over hyflo bed and washed with dichloromethane (500 ml). To the filtrate, methyl tertiary butyl ether (2.5 L) was charged at 25-30°C and seed crystals of erlotinib hydrochloride Form A (1 g) was added. 16%wt/wt HC1 in IPE (58.5 g) was added over a period of 30 -60 min at 25-30°C. The solution was stirred for 2 hours at same temperature and precipitated solids was filtered off and washed with dichloromethane (200 ml). The wet product was dried at 40-45°C for 12 hours under vacuum to provide the title compound.

Yield: 90 gms

The XRPD is set forth in Figure 1

Residual solvents:

EXAMPLE 2:

Preparation of erlotinib hydrochloride Form A (dichloromethane + methyl tertiary butyl ether. HC1) Erlotinib hydrochloride (100 g) was dissolved in dichloromethane (5 L) and to this added water (500 ml) at 25-35°C. Stirred for 10 min and 600 ml sodium bicarbonate solution (48 g of sodium bicarbonate dissolved in 552 ml water) was added over a period of 30 min and stirred for 1 hr at 25-35°C until clear solution observed. The organic and aqueous layers were separated and washed organic phase twice with water and treated with charcoal at 35°C to 40°C. The charcoal was filtered over hyflo bed and washed with dichloromethane (500 ml). To the filtrate, seed crystals of erlotinib hydrochloride Form A (1 g) was added and then about 15% wt/wt HC1 in methyl tertiary butyl ether (75 g) was added over a period of 30-60 min at 25-30°C. To this solution methyl tertiary butyl ether (2.5 L) was added and stirred for 2 hours at same temperature and precipitated solids was filtered off and washed with dichloromethane and methyl tertiary butyl ether (50 ml : 50 ml). The wet product was dried at 50-55°C for 6 hours under vacuum to provide the title compound.

Yield: 86 gms

Claims

WE CLAIM

Claim 1 : A process for the preparation of erlotinib hydrochloride Form A,

comprising:

a) providing a solution of erlotinib in an organic solvent selected from dichloromethane, methyl tertiary butyl ether or mixture thereof,

b) optionally, adding seed crystals of erlotinib hydrochloride Form A, c) treating the resultant solution with hydrogen chloride in isopropyl ether, and

d) isolating crystalline erlotinib hydrochloride Form A.

Claim 2: The process of claim 1, wherein the organic solvent is a mixture of dichloromethane and methyl tertiary butyl ether. Claim 3: The process of claim 1, wherein the solution of erlotinib in an organic solvent is prepared by neutralizing the corresponding erlotinib acid addition salt with a base.

The process of claim 3, wherein the organic solvent is dichloromethane.

The process of claim 3, wherein the base is selected from sodium hydroxide, sodium carbonate or sodium bicarbonate.

The process of claim 3, wherein the process further comprises adding additional solvent prior to adding seed crystals of erlotinib hydrochloride Form A.

Claim 7: The process of claim 6, wherein the additional solvent is methyl tertiary butyl ether.

Claim 8: The process of claim 1, wherein the seed crystals are added at a temperature of about 25°C to 35°C. Claim 9: The process of claim 1, wherein the seed crystals are about 1% to about 5% wt/wt of the starting erlotinib.

Claim 10: The process of claim 1, wherein the solution of step a) or step b) is treated with hydrogen chloride in isopropyl ether at a temperature of about 10°C to about 35°C.

Claim 11: The process of claim 10, wherein the temperature is about 25° to about

30°C.

Claim 12: The process of claim 1, wherein the hydrogen chloride in isopropyl ether is about 5% to about 25% wt/wt. Claim 13: The process of claim 12, wherein the hydrogenxhloride in isopropyl ether is about 16 to about 18% wt/wt.

Claim 14: The process of claim 1, wherein the step c) is further comprises stirring the reaction mass at about 25° to about 30°C for a period of about 2 hours.

Claim 15: The process of claim 1, wherein the isolation of erlotinb hydrochloride

Form A is carried out by filtration, solvent removal or a combination thereof.

Claim 16: The process of claim 15, wherein the isolation is carried out by filtration.