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Home » sNDA » The USFDA has accepted for filing Astellas Pharma’s supplemental new drug application (sNDA) for Tarceva (erlotinib) tablets for a genetically distinct form of advanced lung cancer.

The USFDA has accepted for filing Astellas Pharma’s supplemental new drug application (sNDA) for Tarceva (erlotinib) tablets for a genetically distinct form of advanced lung cancer.



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17 jan 2013

The USFDA has accepted for filing Astellas Pharma’s supplemental new drug application (sNDA) for Tarceva (erlotinib) tablets for a genetically distinct form of advanced lung cancer.

Astellas is seeking approval to use Tarceva as the first-line therapy to treat patients with EGFR activating mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC).

The sNDA, which was granted priority review status, included data from EURTAC trial, a randomized, controlled Phase 3 study designed to assess the use of Tarceva compared to platinum-based chemotherapy in NSCLC patients with EGFR activating mutations.

Astellas Pharma Global Development medical oncology head, vice president Stephen Eck said the FDA granted an expedited six-month review of the application.

“We are proud of Tarceva’s already approved indications for the maintenance and relapsed advanced NSCLC settings,” Eck added.

“If approved, people with a genetically distinct form of lung cancer could have a potential new personalized medicine for use as a first-line treatment.”

The cobas EGFR Mutation Test, developed by Roche Molecular Diagnostics, is a companion diagnostic for which a pre-market approval application was also submitted to the regulatory body.

Erlotinib hydrochloride (trade name Tarceva) is a drug used to treat non-small celllung cancerpancreatic cancer and several other types of cancer. It is a reversibletyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR). It is marketed in the United States by Genentech and OSI Pharmaceuticals and elsewhere by Roche

Erlotinib is an EGFR inhibitor. The drug follows Iressa (gefitinib), which was the first drug of this type. Erlotinib specifically targets the epidermal growth factor receptor (EGFR)tyrosine kinase, which is highly expressed and occasionally mutated in various forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor.[1] For the signal to be transmitted, two EGFR molecules need to come together to form a homodimer. These then use the molecule of ATP to trans-phosphorylate each other on tyrosine residues, which generates phosphotyrosine residues, recruiting the phosphotyrosine-binding proteins to EGFR to assemble protein complexes that transduce signal cascades to the nucleus or activate other cellular biochemical processes. By inhibiting the ATP, formation of phosphotyrosine residues in EGFR is not possible and the signal cascades are not initiated.

Erlotinib hydrochloride (1), chemically named as N-(3-ethynylphenyl)-6,7-bis-(2-meth- oxyethoxy)-4-qumazolimmine monohydro chloride, is an inhibitor of oncogenic and proto- oncogenic protein tyrosine kinases, e.g. epidermal growth factor receptor (EGFR). Erlotinib is therefore useful in the treatment of proliferative disorders and is currently marketed for the treatment of lung cancer and pancreatic cancer.

Figure imgf000002_0001

(Erlotinib Hydrochloride)


It has been reported that erlotinib hydrochloride can exist in different polymorphic forms. The manufacturing process for many pharmaceuticals is hindered by the fact that the organic compound which is the active ingredient can exist in more than one polymorphic form. It is essential in pharmaceutical development to ensure that the manufacturing process for the preparation of the active ingredient affords a single polymorph with a consistent level of polymorphic purity. If the manufacturing process produces a product with varying degrees of polymorphic purity and/ or or where the process does not control polymorphic inter-conversion, it could lead to serious problems in dissolution and/ or bioavailability in the finished pharmaceutical composition comprising the active ingredient, Erlotinibhydrochloride is disclosed in patent US 5,747,498 and details of the disclosed method for the preparation of erlotinib hydrochloride are described in Scheme 1.

Figure imgf000003_0001

Scheme 1

4-Chloro-6,7-bis-(2-methoxyed oxy)qiunazoline (2) was reacted with 3-emynylaniline (3) or its hydrochloride salt using various solvents and pyridine as a base to yield erlotinib hydrochloride (1) which was treated widi a biphasic mixture consisting of saturated aqueous NaHC03, chloroform and methanol, to formerlotinib base (4). The base (4) obtained in the organic phase was purified by flash chromatography to afford purified erlotinib base. The purified base was further treated with hydrochloric acid in the presence of diethyl ether and chloroform to yield erlotinib hydrochloride. This isolation of purified erlotinib base required the use of a lengthy workup process including column chromatography and required the chlorinated solvent, chloroform, which is not particularly suitable £01 commercial production of pharmaceuticals. Furthermore, the p irification by column chromatography is neither economical nor feasible at industrial scale. In addition, substantially pure erlotinib could not be obtained. Two crystalline forms of erlotinib hydrochloride (polymorph A and polymorph B), were characterized by XRPD in patent application, WO 01/34574. Erlotinib hydrochloride can be obtained in form A or in a mixture of polymorph A and B, by refluxing 3-ethynylaniline and 4-chloro-6,7-bis-(2-methoxyemoxy)-qitiiiazoline in a mixture of toluene and acetonitrile. This afforded polymorph A or a mixture of polymorph A and B. It was also disclosed that the formation of polymorph A was favoixred by reducing the amounts of acetonitrile with respect to toluene. Furthermore, erlotinibhydrochloride polymorph A can be converted into polymorph B by refluxing the polymorph A with alcohol/water. Consequently, in the disclosed methods, there was always contamination of form A with form B and vice-versa. In addition, the products of the reaction are not chemically pure and difficult to purify thereafter. Consequently, these methods are not suitable for preparation of commercial quantities of pure polymorph A.

A process for the preparation of erlotinib hydrochloride, polymorph E by condensation reaction of 3-emynylaiiiline and 4-chloro-6,7-bis-(2-memoxyethoxy)quii azoline in ( , , )- trifiuorotoluene and HC1 was disclosed in U.S. Patent application 2004/0162300. Polymorph E was characterized by XRPD, IR and melting point. However, (α,α,α)- trifluorotoluene is a highly flammable and dangerous solvent for the environment and is not suitable for commercial production. A process for the preparation of erlotinib hydrochloride, polymorph A by reaction of erlotinib base widi aqueous or gaseous HC1 was disclosed in US 2009/0131665. In this method, toluene, a mixture of toluene and methanol, TBME, ethyl acetate, 1-butanol or MIBK were used as a solvent. However, when DCM, diethyl ether, isopropyl acetate, was used as a solvent, polymorph B was formed. In practice, it has been found that the disclosed methods are inconsistent and afford polymorphic mixtures. In particular, example 1 of US 2009/131665 was repeated and erlotinib hydrochloride was obtained with only 97% purity. In addition, XRPD analysis showed d at the example afforded form B or mixtures of forms A and B. Furthermore, several crystallizations of erlotinib hydrochloride, obtained from repetition of the example, using various solvents and their combinations would not yield a product pure enough to comply with ICH guidelines.

A process for the preparation of a hydrate of erlotinib hydrochloride comprising crystallization of erlotinib hydrochloride using water as solvent, preferably in the absence of organic solvent was disclosed in US 20080167327. This patent also disclosed the process to prepare hemihydrate polymorph form I as well as form II.

A process for the preparation of erlotinib hydrochloride, polymorph M, N and P by reaction of erlotinib base and aqueous or gaseous HC1 dissolved in organic solvents was disclosed in WO 2008/102369.

A process for the preparation of erlotinib hydrochloride by condensation reaction of 4- chloro~6,7-bis-(2-me oxyemoxy)-quinazoline and 3-ethynylaniline in isopropyl alcohol as a solvent and pyridine as a base was disclosed in Molecules Journal (Vol, 11, 286, 2006) but no details on the polymorph were disclosed.

A method for the preparation of erlotinib hydrochloride polymorph A comprising passing hydrochloride gas onto solid erlotinib base containing residual amounts of isopropanol was disclosed in WO 2010/040212. However, in practice it was found that the process did not afford chemically or polymorphically pure product. Repetition of example 1 (page 8) of WO 2010/040212 to prepare erlotinibhydrochloride, by reaction of erlotinib base and gaseous HQ in IPA as a solvent, afforded a mixture of polymorph A and polymorph B (as checked by XRPD).

A process for the preparation of acid salts of erlotinib by reaction of 4-chloro-6,7-bis-(2- memoxyemoxy)-quinazoline and 3-emynykniline or an acid salt of 3-emynylaniline under acidic conditions to form the corresponding erlotinib salt was disclosed in US 2010/0094004. In order to complete the reaction, several hours (6 hours) of reflux was required and hence it is not a cost effective process. In addition, in practice it was found that the process did not afford chemically or polymorplxLcally pure product. A process £oi the preparation of erlotinib base, polymorph Gl, G2 and G3 was disclosed in WO 2009/002538 and WO 2010/05924.

Figure imgf000006_0001

Scheme 2

A method for the preparation of eiiotinib hydrochloride was disclosed in US 2009/0306377. The method, illustrated in Scheme 2, involves treating 6,7-dimethoxy- 4(3H)-quinazolone (5) with hydrobiOmic acid or pyridine-hydrochloric acid to afford 6,7- dihydroxy-4(3H)-quinazolone (6), which was diacetylated with acetic anhydride to afford diester (7), which was treated with oxalyl chloride/DMF to afford 4-chloro-6,7- ctiacetoxyquinazoline (8). Compound (8) was condensed with 3-e ynylaniline to afford JV- (3-ethynylphenyl)-6,7-dihydfoxy-4-quinazolinamine hydrochloride (9), which was converted into the diol N-(3-emynylphenyl)-6,7-dmyckOxy-4-quinazolinamine (10) by treatment with aqueous ammonia/methanol. The diol (10) was treated with 2-iodo-ethylmethyl ether to yield compound (4) which on treatment with HC1 afforded erlotinib hydrochloride (1). However, this preparation of erlotinib hydrochloride is a long synthetic route and gives low yields and requires very toxic reagents like pyridine, HBi and controlled reagents like acetic anhydride. Hence, it is not suitable for large scale production. Object of the invention

The priot art processes described above for the preparation of erlotinib and its salts have major disadvantages with respect to the formation and removal of process related chemical and polymorphic impurities; poor commercial viability due to die use of hazardous reactants; expensive, time consuming separation methods such as column chromatography and/ or low yields and purity of final and intermediate products.

As the commercial production of erlotinib hydrochloride is of great importance, for the treatment of cancer, and in view of the above disadvantages associated with the prior art there is a real need for alternative and improved processes for the preparation of erlotinib hydrochloride which do not involve multiple steps and further eliminates the need for cumbersome purification techniques, particularly for the removal of the chemical and polymorphic impurities. The alternative processes must be economical and high yielding and provide erlotinib and its salts with a high degree of chemical and polymorphic purity.

U.S. Patent No. 5,747,498 disclosed 4-(substituted phenylamino) quinazoline derivatives, processes for their preparation, pharmaceutical compositions in which they are present and method of use thereof. These compounds are Tyrosine Kinase Inhibitors and are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. Among them, erlotinib hydrochloride, chemically N-(3-ethynylphenyl)-6,7-bis(2-methoxy ethoxy)-4-quinazolinamine hydrochloride is a selective inhibitor of the erbB family of oncogenic and protooncogenic protein tyrosine kinases, such as epidermal growth factor receptor (EGFR), and is useful for the treatment of proliferative disorders, such as cancers, particularly non small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, head cancer or neck cancer.

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. 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.

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

The U.S. Patent No. 5,747,498 (herein after referred to as the ‘498 patent) makes no reference to the existence of specific polymorphic forms of erlotinibhydrochloride. 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 with 3-ethynylaniline or its hydrochloride salt in a solvent such as a d-Cβ-alcohol, dimethylformamide, N-methylpyrrolidin-2-one, chloroform, acetonitrile, tetrahydrofuran, 1,4-dioxane, pyridine or other aprotic solvents, preferably isopropanol) is basified with saturated aqueous NaHCO3 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 the presence of diethyl ether and chloroform to give erlotinib hydrochloride (melting point: 228° – 2300C).

PCT Patent Publication No. WO 99/55683 disclosed erlotinib mesylate anhydrate and hydrate polymorphic forms, their method of preparation and pharmaceutical compositions containing thereof.

PCT Patent Publication No. WO 01/34574 A1 (herein after referred to as the ‘574 patent publication) described two crystalline forms of erlotinib hydrochloride (polymorph A and polymorph B), characterized by powder X-ray diffraction (p-XRD) pattern. The publication further taught that the synthetic procedure described and exemplified in the ‘498 patent produces the erlotinib hydrochloride as a mixture of the polymorphs A and B.

TARCEVA (erlotinib), a kinase inhibitor, is a quinazolinamine with the chemical name N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. TARCEVA contains erlotinib as the hydrochloride salt that has the following structural formula:

TARCEVA® (erlotinib) Structural Formula Illustration

Erlotinib hydrochloride has the molecular formula C22H23N3O4•HCl and a molecular weight of 429.90. The molecule has a pKa of 5.42 at 25oC. Erlotinib hydrochloride is very slightly soluble in water, slightly soluble in methanol and practically insoluble in acetonitrile, acetone, ethyl acetate and hexane.

Aqueous solubility of erlotinib hydrochloride is dependent on pH with increased solubility at a pH of less than 5 due to protonation of the secondary amine. Over the pH range of 1.4 to 9.6, maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2.




wo 2012028861




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