WO2014118737A1

WO2014118737A1 - Erlotinib salts

Info

Publication number: WO2014118737A1
Application number: PCT/IB2014/058683
Authority: WO
Inventors: Poonam KAUSHIK; Ram Thaimattam; Mohan Prasad; Sudershan Kumar Arora
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2013-01-31
Filing date: 2014-01-30
Publication date: 2014-08-07

Abstract

The present invention provides erlotinib saccharinate and erlotinib maleate or hydrates thereof, their crystalline forms, processes for their preparation, and pharmaceutical compositions thereof.

Description

ERLOTINIB SALTS

Field of the Invention

The present invention provides erlotinib saccharinate and erlotinib maleate or hydrates thereof, their crystalline forms, processes for their preparation, and

pharmaceutical compositions thereof.

Background of the Invention

Erlotinib hydrochloride of Formula A is known chemically as N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine hydrochloride.

U.S. Patent No. RE41,065, a reissue of U.S. Patent No. 5,747,498, provides a process for the preparation of erlotinib hydrochloride.

U.S. Patent No. 6,706,721 provides a process for the preparation of erlotinib mesylate.

PCT Publication No. WO 2008/122776 provides processes for the preparation of erlotinib hydrochloride, sulphate, tosylate, and oxalate.

PCT Publication No. WO 2011/068403 provides processes for the preparation of erlotinib ethanesulfonate, isethionate, bromide, malonate, L-lactate, and succinate.

PCT Publication No. WO 2012/008711 provides a process for the preparation of erlotinib dichloroacetate.

Korean Patent Registration No. KR 10-1132937 provides a process for the preparation of erlotinib napsylate.

Several processes have been reported for the preparation of erlotinib or pharmaceutically acceptable salts thereof, for example, U.S. Patent Nos. 6,476,040 and US 8,318,932; U.S. Publication No. 2013/0137867; PCT Publication Nos. WO 01/34574, WO 2004/072049, WO 2007/060691, WO 2007/138612, WO 2007/138613, WO 2008/000418, WO 2008/012105, WO 2008/049645, WO 2008/102369, WO 2008/122776, WO

2009/002538, WO 2009/007984, WO 2009/024989, WO 2009/025873, WO 2009/025876, WO 2010/040212, WO 2010/057430, WO 2010/005924, WO 2010/109443, WO

2011/058525, WO 2011/076813, WO 2011/147102, WO 2012/028861, and WO

2012/150606.

In the pharmaceutical industry there is a constant need to identify the critical physicochemical parameters such as novel salts and novel polymorphic forms that affect the drug's performance, stability, etc., which may play a key role in determining a drug's market acceptance and success.

Since erlotinib and its salts constitute an important therapeutic agent, additional salts of erlotinib are of value to pharmaceutical science. Thus, there is a need to develop novel salts of erlotinib having improved solubility, stability, excellent storage and handling stabilities, bioavailability, and that are less susceptible to degradation at lower temperatures.

Accordingly, the present inventors have prepared the erlotinib saccharinate and erlotinib maleate and hydrates thereof. The salts of the present invention are easy to prepare and isolate in solid form, particularly in crystalline forms. Further, they can be prepared by an efficient, economical, and reproducible process, which is particularly suited to large scale preparation.

Summary of the Invention

A first aspect of the present invention provides erlotinib saccharinate of Formula I.

Formula I

A second aspect of the present invention provides a crystalline form of erlotinib saccharinate.

A third aspect of the present invention provides erlotinib maleate or hydrates thereof. A fourth aspect of the present invention provides a crystalline form of erlotinib maleate monohydrate.

A fifth aspect of the present invention provides a process for the preparation of erlotinib saccharinate or erlotinib maleate or hydrates thereof, comprising;

a) treating erlotinib free base with saccharin or maleic acid, optionally in the presence of a solvent; and

b) isolating erlotinib saccharinate, or erlotinib maleate or hydrates thereof.

A sixth aspect of the present invention provides the use of erlotinib saccharinate or erlotinib maleate or hydrates thereof for the preparation of erlotinib or other salts, solvates, or polymorphs thereof.

A seventh aspect of the present invention provides a pharmaceutical composition comprising erlotinib saccharinate or erlotinib maleate or hydrates thereof, and a pharmaceutically acceptable carrier.

An eighth aspect of the present invention provides a method of treating non-small cell lung cancer in combination with gemcitabine for first-line treatment of patients with locally advanced, unresectable, or metastatic pancreatic cancer, comprising administering to a patient in need thereof a therapeutically effective amount of erlotinib saccharinate, or erlotinib maleate or hydrates thereof, and a pharmaceutically acceptable carrier.

Detailed Description of the Invention

Formula I

A second aspect of the present invention provides a crystalline form of erlotinib saccharinate. The crystalline form of erlotinib saccharinate of the present invention may be characterized by an X-Ray Powder Diffractogram (XRPD) pattern substantially the same as depicted in Figure 1, exhibiting interplanar spacing (d) values at about 18.98, 16.39, 3.56, 3.52, and 3.46 (A), and further exhibiting interplanar spacing (d) values at about 11.62, 5.70, 5.45, 5.07, 4.03, 3.35, and 3.32 (A). The crystalline form of erlotinib saccharinate has an XRPD pattern with characteristic peak values (2Θ) at about 4.65, 5.38, 24.93, 25.27, and 25.72 ± 0.2°, and additional characteristic peak values (2Θ) at about 7.60, 15.52, 16.24, 17.47, 22.00, 26.55, and 26.81 ± 0.2°. The crystalline form of erlotinib saccharinate of the present invention may be characterized by Differential Scanning

Calorimetry (DSC) as depicted in Figure 2, with a characteristic endothermic peak value at about 174.90°C in the DSC thermogram. The crystalline form of erlotinib saccharinate of the present invention may be characterized by Thermogravimetric Analysis (TGA) as depicted in Figure 3 and Fourier-Transform Infra-red (FTIR) as depicted in Figure 4.

A third aspect of the present invention provides erlotinib maleate or hydrates thereof.

In one embodiment of this aspect, the present invention provides erlotinib maleate monohydrate of Formula II.

Formula II

A fourth aspect of the present invention provides a crystalline form of erlotinib maleate monohydrate. The crystalline form of erlotinib maleate monohydrate of the present invention may be characterized by an XRPD pattern substantially the same as depicted in Figure 5, exhibiting interplanar spacing (d) values at about 12.62, 6.40, 4.79, 4.57, and 4.21 (A), and further exhibiting interplanar spacing (d) values at about 10.65, 4.99, 4.65, 4.29, 4.10, 3.61, and 2.84 (A). The crystalline form of erlotinib maleate monohydrate has an XRPD pattern with characteristic peak values (2Θ) at about 7.00, 13.82, 18.48, 19.38, and 21.08 ± 0.2°, and additional characteristic peak values (2Θ) at about 8.30, 17.75, 19.04, 20.67, 21.66, 24.60, and 31.41 ± 0.2°. The crystalline form of erlotinib maleate monohydrate of the present invention may be characterized by DSC as depicted in Figure 6, with characteristic endothermic peak values at about 98.04°C and 171.69°C in the DSC thermogram. The crystalline form of erlotinib maleate monohydrate of the present invention may be characterized by TGA as depicted in Figure 7 and FTIR as depicted in Figure 8. A fifth aspect of the present invention provides a process for the preparation of erlotinib saccharinate, or erlotinib maleate or hydrates thereof, comprising:

b) isolating erlotinib saccharinate, or erlotinib maleate or hydrates thereof.

The erlotinib free base may be prepared by any of the methods known in the art, including that described in U.S. Patent No. RE41,065.

Step a) of treating erlotinib free base with saccharin or maleic acid may include adding, dissolving, slurrying, stirring, or combinations thereof.

Erlotinib is treated with saccharin or maleic acid at a temperature of about 25 °C to about 80°C for a time period sufficient to complete the reaction, preferably for about 5 minutes to about 24 hours, optionally followed by stirring the reaction mass at about 0°C to about 8°C, preferably at about 0°C to about 5°C for a period of about 2 minutes to about 2 hours, preferably for about 5 minutes to about 10 minutes.

Erlotinib prepared by any of the methods known in the art, before treatment with saccharin or maleic acid, is optionally purified to remove foreign particulate matter.

Alternatively, it may be treated with activated charcoal to remove coloring and other related impurities in a suitable solvent.

The term "solvent" includes any solvent or solvent mixture, including water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.

Examples of esters include ethyl acetate, ^-propyl acetate, isopropyl acetate, and n- butyl acetate. Examples of alkanols include those primary, secondary and tertiary alcohols having from one to six carbon atoms. Suitable alkanol solvents include methanol, ethanol, «-propanol, isopropanol and «-butanol, sec-butanol, isobutanol, and fert-butanol, preferably methanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, methyl ethyl ketone, and the like. Examples of ethers include diethyl ether, tetrahydrofuran, and the like. Examples of polar aprotic solvent include N,N-dimethylformamide, NN- dimethylacetamide, dimethylsulphoxide, acetonitrile and N-methylpyrrolidone. Step b) of isolating erlotinib saccharinate, or erlotinib maleate or hydrates thereof may be accomplished by filtration, decantation, solvent precipitation, trituration, evaporation, concentration, centrifugation, distillation, or combinations thereof, optionally followed by drying with appropriate methods, such as suck drying, drying under reduced pressure, vacuum tray drying, air drying, or combinations thereof.

Erlotinib saccharinate or erlotinib maleate or hydrates thereof may be used for the preparation of erlotinib by contacting the erlotinib saccharinate or erlotinib maleate or hydrates thereof with a base. The base is selected from the group comprising of hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals, ammonia, alkyl amines, hydrazine, and the like. Examples of hydroxides, carbonates, and bicarbonates of alkali and alkaline earth metals may include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. Examples of alkyl amines may include diethyl amine, triethyl amine or methyl diethylamine. Erlotinib thus obtained may be converted to other salts, solvates, or polymorphs thereof.

A seventh aspect of the present invention provides a pharmaceutical composition comprising erlotinib saccharinate, or erlotinib maleate or hydrates thereof, and a pharmaceutically acceptable carrier.

Brief Description of the Drawings

Figure 1 and Figure la depict the XRPD of erlotinib saccharinate and the associated values, respectively, prepared as per Example IB.

Figure 2 depicts the DSC thermogram of erlotinib saccharinate prepared as per

Example IB. Figure 3 depicts the TGA thermogram of erlotinib saccharinate prepared as per Example IB.

Figure 4 depicts the FTIR spectrum of erlotinib saccharinate prepared as per Example IB.

Figure 5 and Figure 5a depict the XRPD of erlotinib maleate monohydrate and the associated values, respectively, prepared as per Example 2B.

Figure 6 depicts the DSC thermogram of erlotinib maleate monohydrate prepared as per Example 2B.

Figure 7 depicts the TGA thermogram of erlotinib maleate monohydrate prepared as per Example 2B.

Figure 8 depicts the FTIR spectrum of erlotinib maleate monohydrate prepared as per Example 2B.

The XRPD of the samples were determined by using Instrument: PANalytical^®; Model: X'Pert PRO; Detector: X'celerator^®; Scan Range: 3-40; Step size: 0.02; Range: 3- 40 degree 2 theta; CuKa radiation at 45kV.

The DSC of the samples were determined by using Perkin Elmer^®, Diamond DSC. Data collection parameters: Scanning rate: 10°C/min; Temperature: 30°C to 300°C.

The TGA of the samples were determined by using TA instrument, TGA Q500. Data collection parameters: Scanning rate: 10°C/min; Temperature: 30°C to 300°C.

The FTIR of the samples were determined by using Instrument: Perkin Elmer^®;

Model: Spectrum one; SCAN: 16scans; Resolution: 4.0 cm^"1; potassium bromide pellet method.

While the present invention has been described in terms of its specific

embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. EXAMPLES

Example 1 A: Process for the preparation of erlotinib saccharinate

Methanol (1 mL) was added to a mixture of erlotinib free base (0.4 g) and saccharin (0.366 g) and slurried for 18 hours at 50°C. The solvent was evaporated at 25°C to 30°C and the solid obtained was dried at 55°C in a vacuum tray drier for 6 hours to obtain the title compound.

Yield: 0.706 g

Example IB: Process for the preparation of erlotinib saccharinate

A mixture of erlotinib free base (0.8 g) and saccharin (0.366 g) was dissolved in methanol (40 mL) at 60°C to obtain a clear solution. The solution was kept aside at 25°C to 30°C. After four hours, the reaction mixture was filtered and the solid was dried under vacuum at 60°C for 6 hours to obtain the title compound.

Yield: 0.923 g

Example 1C: Process for the preparation of erlotinib saccharinate

Erlotinib free base (3.0 g) was dissolved in methanol (60 mL) at 60°C to obtain a solution, followed by the addition of saccharin solution (saccharin (1.398 g) dissolved in methanol (75 mL) at 60°C). To the reaction mixture, methanol (165 mL) was added and the clear solution obtained was kept aside at 25°C to 30°C. After four hours, the reaction mixture was filtered and the solid was dried under vacuum at 60°C for 6 hours to obtain the title compound.

Yield: 3.261 g

Example ID: Process for the preparation of erlotinib saccharinate

Erlotinib free base (2.0 g) was dissolved in methanol (35 mL) at 65°C to obtain a solution, followed by the addition of saccharin solution (saccharin (0.932 g) dissolved in methanol (25 mL) at 65°C). The reaction mixture was stirred at 65°C for 5 minutes and cooled to 25 °C to 30°C. The reaction mixture was further cooled to 0°C to 5°C and stirred for 10 minutes. The reaction mixture was filtered and the solid was dried under vacuum at 60°C for 6 hours to obtain the title compound.

Yield: 2.578 g Example 2A: Process for the preparation of erlotinib maleate monohydrate

Methanol (1 mL) was added to a mixture of erlotinib free base (0.4 g) and maleic acid (0.232 g) and then slurried for 18 hours at 50°C. The solvent was evaporated at 25°C to 30°C and the solid obtained was dried at 55°C in a vacuum tray drier for 6 hours to obtain the title compound.

Yield: 0.602 g

Example 2B: Process for the preparation of erlotinib maleate monohydrate

A mixture of erlotinib free base (0.8 g) and maleic acid (0.232 g) was dissolved in methanol (50 mL) at 60°C to obtain a clear solution. The solution was kept aside at 25°C to 30°C. After four hours, the reaction mixture was filtered and the solid was dried under vacuum at 60°C for 6 hours to obtain the title compound.

Yield: 1.023 g

Example 2C: Process for the preparation of erlotinib maleate monohydrate

Erlotinib free base (3.0 g) was dissolved in methanol (60 mL) at 60°C to obtain a solution, followed by the addition of maleic acid solution (maleic acid (0.886 g) dissolved in methanol (75 mL) at 60°C). To the reaction mixture, methanol (30 mL) was added and the clear solution obtained was kept aside at 25°C to 30°C. After four hours, the reaction mixture was filtered and the solid was dried under vacuum at 60°C for 6 hours to obtain the title compound.

Yield: 3.15 g

Example 2D: Process for the preparation of erlotinib maleate monohydrate

Erlotinib free base (2.0 g) was dissolved in methanol (35 mL) at 65°C to obtain a solution, followed by the addition of maleic acid solution (maleic acid (0.590 g) dissolved in methanol (20 mL) at 65 °C). The reaction mixture was stirred at 65 °C for 5 minutes and cooled to room temperature. The reaction mixture was further cooled to 0°C to 5°C and stirred for 5 minutes. The reaction mixture was filtered and the solid was dried under vacuum at 60°C for 6 hours to obtain the title compound.

Yield: 2.333 g

Claims

CLAIMS:

1. Erlotinib saccharinate of Formula I.

Formula I

2. The erlotinib saccharinate of claim 1 , in a crystalline form.

3. The erlotinib saccharinate of claim 2, wherein the crystalline form is characterized by an XRPD pattern substantially the same as depicted in Figure 1.

4. The erlotinib saccharinate of claim 2, characterized by an XRPD pattern having interplanar spacing (d) values at 18.98, 16.39, 3.56, 3.52, and 3.46 (A).

5. The erlotinib saccharinate of claim 4, further characterized by interplanar spacing (d) values at 1 1.62, 5.70, 5.45, 5.07, 4.03, 3.35, and 3.32 (A).

6. The erlotinib saccharinate of claim 2, characterized by an XRPD pattern having characteristic peak values (2Θ) at 4.65, 5.38, 24.93, 25.27, and 25.72 ± 0.2°.

7. The erlotinib saccharinate of claim 6, further characterized by characteristic peak values (2Θ) at 7.60, 15.52, 16.24, 17.47, 22.00, 26.55, and 26.81 ± 0.2°.

8. The erlotinib saccharinate of claim 2, characterized by a DSC thermogram substantially as depicted in Figure 2.

9. The erlotinib saccharinate of claim 2, characterized by an endothermic peak value at about 174.90°C in the DSC thermogram.

10. The erlotinib saccharinate of claim 2, characterized by a TGA spectrum substantially as depicted in Figure 3.

11. The erlotinib saccharinate of claim 2, characterized by an FTIR spectrum substantially as depicted in Figure 4.

12. Erlotinib maleate or hydrates thereof.

13. Erlotinib maleate monohydrate of Formula II.

Formula II

14. The erlotinib maleate monohydrate of claim 13 in a crystalline form.

15. The erlotinib maleate monohydrate of claim 14 characterized by an XRPD pattern substantially the same as depicted in Figure 5.

16. The erlotinib maleate monohydrate of claim 14 characterized by an XRPD pattern having interplanar spacing (d) values at 12.62, 6.40, 4.79, 4.57, and 4.21 (A).

17. The erlotinib maleate monohydrate of claim 16 further characterized by interplanar spacing (d) values at 10.65, 4.99, 4.65, 4.29, 4.10, 3.61, and 2.84 (A).

18. The erlotinib maleate monohydrate of claim 14 characterized by an XRPD pattern having characteristic peak values (2Θ) at 7.00, 13.82, 18.48, 19.38, and 21.08 ± 0.2°. 19. The erlotinib maleate monohydrate of claim 18 further characterized by characteristic peak values (2Θ) at 8.30, 17.75,

19.04, 20.67, 21.66, 24.60, and 31.41 ± 0.2°.

20. The erlotinib maleate monohydrate of claim 14 characterized by a DSC thermogram substantially as depicted in Figure 6.

21. The erlotinib maleate monohydrate of claim 14 characterized by endothermic peak values at about 98.04°C and 171.69°C in the DSC thermogram.

22. The erlotinib maleate monohydrate of claim 14 characterized by a TGA spectrum substantially as depicted in Figure 7.

23. The erlotinib maleate monohydrate of claim 14 characterized by an FTIR spectru substantially as depicted in Figure 8.

24. A process for the preparation of erlotinib saccharinate, or erlotinib maleate or hydrates thereof, comprising:

b) isolating erlotinib saccharinate, or erlotinib maleate or hydrate thereof.

25. The process according to claim 24, wherein the solvent is selected from water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or mixtures thereof.

26. The process according to claim 25, wherein the ester is selected from ethyl acetate, ^-propyl acetate, isopropyl acetate, and «-butyl acetate.

27. The process according to claim 25, wherein the alkanol is selected from methanol, ethanol, «-propanol, isopropanol and «-butanol, sec-butanol, isobutanol, and fert-butanol.

28. The process according to claim 25, wherein the halogenated hydrocarbon is selected from dichloromethane, chloroform, and 1,2-dichloroethane.

29. The process according to claim 25, wherein the ketone is selected from acetone and methyl ethyl ketone.

30. The process according to claim 25, wherein the ether is selected from diethyl ether and tetrahydrofuran.

31. The process according to claim 25, wherein the polar aprotic solvent is selected from NN-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.

32. The process according to claim 24, wherein treating erlotinib free base with saccharin or maleic acid is carried out at a temperature of 25°C to 80°C.

33. Erlotinib saccharinate, or erlotinib maleate or hydrates thereof for use in the preparation of erlotinib or other salts, solvates or polymorphs thereof.

34. A pharmaceutical composition comprising erlotinib saccharinate, or erlotinib maleate or hydrates thereof and a pharmaceutically acceptable carrier.

35. A method of treating non-small cell lung cancer in combination with gemcitabine for first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of erlotinib saccharinate, or erlotinib maleate or hydrates thereof, and a pharmaceutically acceptable carrier.