EP2155698A1

EP2155698A1 - Novel thermodynamically stable polymorphic form-l of letrozole

Info

Publication number: EP2155698A1
Application number: EP07736572A
Authority: EP
Inventors: Amala Kishan Kompella; Sreenivas Rachakonda; A. K. S. Rao; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Ltd
Current assignee: Natco Pharma Ltd
Priority date: 2007-01-22
Filing date: 2007-03-20
Publication date: 2010-02-24
Also published as: WO2008090565A1; WO2008090565B1

Abstract

The present invention relates to a novel crystalline Form L of letrozole and a process for preparing the same. Letrozole is useful for the first-line treatment in post-menopausal women with hormone receptor positive (or) locally advanced (or) metastatic breast cancer.

Description

NOVELTHERMODYNAMICALLYSTABLE POLYMORPHICFORM-L OFLETROZOLE

FIELD OF THE INVENTION

The present invention relates to a novel crystalline form L of letrozole and a process for preparing the same. Letrozole is approved by the USFDA for the first-line treatment in post-menopausal women with hormone receptor positive (or) locally advanced (or) metastatic breast cancer.

A novel polymorph L of Letrozole is prepared by employing the following specific procedures.

i) Solvent crystallization methods wherein the drug substance is crystallized from select solvents. ii) Lyophilization/Freeze drying techniques. iii) Precipitation methods wherein the drug substances is dissolved in a solvent and the pure product is precipitated by addition of an anti-solvent. iv) Regeneration methods wherein the drug substance is dissolved in an acid solution and the pure product is regenerated by addition of a base.

BACKGROUND OF THE INVENTION

Letrozole, 4- [alpha-(4-cyanophenyi)-l-(l,2,4-triazolyl) methyl]-benzonitrile of the formula (I) is a non-toxic non-steroidal aromatase inhibitor

The polymorphic behavior of drugs can be of crucial importance in pharmacy and pharmacology. Polymorphs are, by definition, crystals of the same molecule having different physical properties as a result of the order of changes in the molecules in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Differences in stability can result from changes in chemical reactivity or mechanical changes or both. For example, a dosage form originating from one polymorph might discolor more rapidly when compound to another from a different polymorph. Or tablets might crumble on storage as a kinetically favoured polymorph spontaneously converts into a thermodynamically more stable polymorphic form. As a result of solubility/dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing: for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities

The most important solid state property of a pharmaceutical substance is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patients gastric fluid may have therapeutic consequences as it imposes an upper limit on the rate at which an orally-administered active ingredient reaches the blood stream. The solid state polymorphic form of a compound may also affect its behavior on compaction and its storage stability.

These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different form that of the amorphous material (or) another polymorphic form.

The discovery of new polymorphic forms of a pharmaceutically useful compounds provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

Objectives of the present invention

Although several syntheses of letrozole are described in the literature, polymorphism of the solid product is not disclosed. Nor the solid state properties of the drug substance are characterized.

The applicants have now discovered that the drug substance Letrozole exists in a stable polymorphic form under certain experimental conditions of isolation or purification.

It is known that polymorphic forms of the same drug may have substantial differences in certain pharmaceutically important properties. Therefore, there is a continuing need for stable polymorphic forms of Letrozole and new methods of their preparation.

Therefore , the main objective of the present invention is to provide a novel crystalline polymorphic form L of Letrozole

Another objective of the present invention is to provide processes for the preparation of novel crystalline polymorphic form L of Letrozole.

Yet another objective of the present invention is to provide processes for producing thermodynamically stable polymorphic form L of Letrozole. Description of the invention :

The present invention relates to a novel crystalline thermodynamically stable form L of Letrozole and processes for the preparation of the said form. Form L is stable, and retains its crystalline structure and polymorphic identity after heating to 80⁰C for 10- 12 hrs. The term "stable" as used herein refers to a polymorphic change of less than about 5% by weight, more preferably less than about 2%.

Accordingly the present invention provides novel crystalline form L of Letrozole which is stable at room temperature and even at higher temperatures like 80⁰C having the XRD characteristics given in Table-I

TABLE-I

FORM L-XRD characteristics

PXRD patterns were recorded using a X-ray powder diffractometer (Bruker AXS D5000) in transmission mode (Cu K alpha I₅ PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm^"1 on a Bruker IFS48. Spectral resolution was 2 cm^'1 . Sample preparation was performed generally as KBr disk.

Accordingly the present invention provides a novel stable crystalline form L of letrozole and process for preparing the same. Polymorph L of Letrozole of the present invention is prepared by

i) Solvent recrystallization methods where in the drug substance in its less pure form is crystallized from a select solvent. The solvents for this purpose are selected from methanol, isopropanol, chloroform, Ethyl acetate, Dioxane and the like. ii) Lyophilization / freeze drying techniques where in the drug substance letrozole is dissolved in an alcoholic solvents like methanol and the clarified solution is subjected to lyophilization. iii) Precipitation methods where in the drug substance letrozole in its less pure form is dissolved in solvents like Methano, DMF, acetic acid and the pure product is precipitated by addition of anti-solvents like water, isopropanol, isopropyl ether and the like, iv) Regeneration methods wherein the drug substance Letrozole in its less pure form is dissolved in an acid solution and the pure product is regenerated by addition of a base. The acids used for this purpose are dil.hydrochloric acid, dilute sulfuric acid, dilute acetic acid and the like. The bases employed for regeneration of the product are aqueous ammonia, dil. sodium hydroxide and the like.

The characterization of the crystal form L of Letrozole is based on its XPRD spectra, differential scanning calorimetry diagrams and IR spectra. The said diagrams and spectra are illustrated in the drawings.

Fig. IA) of the drawings accompanying these specifications shows the X-Ray Powder Diffraction (XRPD) pattern which substantially depicts a typically pure sample of Letrozole of form L prepared by the process disclosed in the Example- 1 given below. The 2Θ values and intensities are tabulated in Table- 1.

The infrared spectrum of form L as a KBr pellet has the characteristic absorptions at the following wavelengths (in cm^"1, f for weak, m for average, s for strong):

3407 (f), 3117(F), 3053 (m), 2993 (f), 2230 (s), 1741 (m), 1606 (s), 1503 (s), 1443(s), 1408 (m), 1369 (m), 1334(s), 1315 (s), 1268 (s), 1220(s), 1198(m), 1139 (s), 1003 (s), 954 (m), 880 (s), 868 (s), 820 (s), 789 (s), 715 (f), 695 (f), 675(m), 655 (s), 568 (m), 553(s), 483(m) The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of Form L of letrozole.

The dosage form of the formulation containing the novel, stable L form prepared by the process of the present invention, preferably oral dosage form, may be a tablet containing the composition described in Example -17

Methods known in the art, may be used to prepare the pharmaceutical composition containing letrozole form L in the form of tablets. The excipients which may be employed include micro crystalline cellulose, lactose, Sodium Starch Glycolate IP, colloidal silicondioxide magnesium stearate and talc

This invention also relates to a method for treating patients suffering from breast cancer by administering a therapeutically effective amount of the pharmaceutical composition of Form L of letrozole.

The novel crystal form of the compound (I) according to the present invention is suitable in the same way as the compound (I) itself and thus making available for medicaments useful in the treatment of breast cancer.

EXAMPLES The following examples of preparation of Letrozole crystalline Form L is now disclosed for illustrative non-limiting purposes, together with the results of DSC analysis

Example-l ; The drug substance Letrozole was prepared by an adaptation of the procedure given in EP236940 (1987) as described below.

4- [l-(l,2,4-triazolyl) methylj-benzonitrile (30 g) is treated with potassium tertiary butoxide ( 39 g) at 0-5°C in DMF ( 700ml ).

The resulting mass is stirred at 0-5°C for 1.5 h and a solution of 4-Fluorobenzonitrile (22 gms in 180 ml DMF) is added keeping the temperature of the reaction mixture at 0-5°C. After an additional 1.5 h, the reaction mixture is diluted with water ( 2L ) and neutralized to pH 6.0 by addition of solid ammonium chloride (750 gms ). The reaction mass is extracted with methylene chloride (2x250ml ), and the organic layer is washed with ice-cold water (2x250ml ). The methylene chloride layer is dried over anhydrous sodium sulphite and the solvent is distilled off completely under reduced pressure. The residual solid cake is dried at 50-55⁰C under vacuum. Weight of brown solid : 30 g The product is used in the subsequent experiments described below. Preparation of Letrozole Form L ;

Letrozole crude (10 gms) obtained directly from the synthesis was dissolved in Methanol(200 ml) and heated to reflux during 30 minutes. The reaction mass was stirred at reflux temperature for 20 minutes and cooled to 0-5⁰C slowly during 1 hour. The reaction mass was filtered and washed with methanol. The wet product was dried under vacuum for 6 hours at 45-50⁰C. The yield was 8.9 gms of Letrozole form L. DSC Thermogram 186.3°C (Peak)

Fig l XPRD

Fig 2 IR

Fig 3 DSC

Example-2 :

Preparation of Letrozole Form L ;

Letrozole crude (10 gms) obtained directly from the synthesis was dissolved in Ethyl formate(100 ml) and heated to reflux during 30 minutes .The reaction mass was stirred at reflux temperature for 20 minutes and cooled to room temperature during 30 minutes. The reaction mass was filtered and washed with Ethyl formate. The wet product was dried under vacuum for 6 hours. The yield was 7.8 gms of Letrozole form Z. DSC Thermogram 182.8.2⁰C (Peak)

ExampIe-3 : Preparation of Letrozole Form L:

Letrozole crude (10 gms) obtained directly from the synthesis was dissolved in DMF (50 ml), demineralized water (500 ml) was added slowly during 15 minutes at the same temperature The reaction mass was stirred for 1 hour, filtered and washed with demineralized water. The wet product was dried under vacuum for 6 hours. The yield was 7 gms of Letrozole form L.

DSC Thermogram 183.5⁰C (Peak)

ExampIe-4 : Preparation of Letrozole form L:

Letrozole crude (10 gms) obtained directly from the synthesis was dissolved in methanol

(200 ml) at reflux temperature and cooled to room temperature during 20 minutes. demineralized water (800 ml) was added slowly during 15 minutes at the same temperature and the reaction mass was stirred for 45 minutes. Filtered and washed with demineralized water. The wet product was dried under vacuum for 6 hours. The yield was 9 gms of Letrozole form L. DSC Thermogram 187.9°C (Peak)

Fig 4 XPRD

Fig 5 IR Fig 6 DSC

ExampIe-5 :

Preparation of Letrozble form L: Letrozole crude (5 gms) obtained directly from the synthesis was dissolved in chloroform (100 ml) and THF (25 ml). The reaction mass was distilled under vacuum to a residual volume of 25 ml. The residual reaction mass was brought to 25-30⁰C and maintained at the same temperature for 20-30 minutes. Filtered ..washed with Acetone and dried to yield 2.9 gms of letrozole form L DSC Thermogram 184.7⁰C (Peak)

ExampIe-6 :

Preparation of Letrozole form L; Letrozole crude (5 gms) obtained directly from the synthesis was dissolved in chloroform (100 ml) and acetone (25 ml). The reaction mass was distilled under vacuum to a residual volume of 25 ml. The residual reaction mass was brought to 25-30⁰C and maintained at the same temperature for 20-30 minutes. Filtered , washed with acetone and dried to yield 1.6 gms of letrozole form L DSC Thermogram 185.3⁰C (Peak)

Example-7 :

Preparation of Letrozole form L:

Letrozole crude (5 gms) obtained directly from the synthesis was dissolved in chloroform (100 ml) and dematerialized water (100 ml). The Chloroform was distilled completely under vacuum and the residual reaction mass was brought to 25-3O⁰C and maintained at the same temperature for 20-30 minutes. Filtered .washed with dematerialized water and dried to yield 3.2 gms of letrozole form L DSC Thermogram 186.8°C (Peak)

ExampIe-8 :

Preparation of Letrozole form L: Letrozole crude (5 gms) obtained directly from the synthesis was dissolved in chloroform (100 ml) and isopropanol (25 ml). The reaction mass was distilled under vacuum to a residual volume of 50 ml. The residual reaction mass was brought to 25- 30⁰C and 85ml isopropanol was charged . The reaction mass was maintained at the same temperature for 20-30 minutes filtered and washed with isopropanol. The yield was 3.1 gms of letrozole form L DSC Thermogram 186.1°C (Peak)

Example-9 : Preparation of Letrozole form L:

Letrozole crude (5 gms) obtained directly from the synthesis was dissolved in chloroform (100 ml) and ethyl acetate(25 ml). The reaction mass was distilled under vacuum to a residual volume of 25 ml. The residual reaction mass was brought to 25- 30°C and maintained at the same temperature for 20-30 minutes. Filtered and washed with ethyl acetate to yield 3.3 gms of letrozole form L DSC Thermogram 186.3°C (Peak)

Example-10 : Preparation of Letrozole form L;

Letrozole crude (5 gms) obtained directly from the synthesis was dissolved in chloroform (100 ml) and methanol(25 ml). The reaction mass was distilled under vacuum to a residual volume of 25 ml. The residual reaction mass was brought to 25- 30⁰C and maintained at the same temperature for 20-30 minutes. Filtered and washed with methanol to yield 3.3 gms of letrozole form L DSC Thermogram 184°C (Peak)

Example-11 : Preparation of Letrozole form L:

Letrozole crude (5 gms) obtained directly from the synthesis was dissolved in chloroform (100 ml) and acetonitrile (25 ml). The reaction mass was distilled under vacuum to a residual volume of 25 ml. The residual reaction mass was brought to 25- 3O⁰C and maintained at the same temperature for 20-30 minutes. Filtered and washed with acetonitrile to yield 1.5 gms of letrozole form L DSC Thermogram 184.°C (Peak)

Example-12 :

Preparation of Letrozole form L:

Letrozole crude (5 gms) obtained directly from the synthesis was dissolved in chloroform (100 ml) and isopropyl ether (25 ml). The reaction mass was distilled under vacuum to a residual volume of 25 ml. The residual reaction mass was brought to 25- 30°C and maintained at the same temperature for 20-30 minutes. Filtered and washed with isopropyl ether to yield 3.3 gms of letrozole form L DSC Thermogram 183.5°C (Peak) Exampϊe-13 :

Preparation of Letrozole form L:

Letrozole crude (5 gms) obtained directly from the synthesis was dissolved in chloroform (100 ml) and hexane(25 ml). The reaction mass was distilled under vacuum to a residual volume of 25 ml. The residual reaction mass was brought to 25-30°C and maintained at the same temperature for 20-30 minutes. Filtered and washed with hexane to yield 2.0 gms of letrozole form L DSC Thermogram 183.8°C (Peak) Example-14 :

Preparation of Letrozole form L:

Letrozole crude (5 gms) obtained directly from the synthesis was dissolved in Concd.HCl(7 ml). Aqueous ammonia solution (26 ml) was added slowly during 15 minutes at the same temperature The reaction mass was stirred for 30 minutes, filtered and washed with D.M.water.The wet product was dried at 50⁰C under vacuum for 6 hours. The yield was 4.3 gms of Letrozole form L. DSC Thermogram 187.7°C (Peak)

Fig 7 XPRD

Fig 8 IR

Fig 9 DSC Example-15 :

Preparation of Letrozole Form L:

Letrozole crude (1 gms) obtained directly from the synthesis was dissolved in DMF (10 ml). Isopropyl ether (40 ml) was added slowly during 15 minutes at the same temperature The reaction mass was stirred for 1 hour, filtered and washed with IPE.The wet product was dried at 50°C under vacuum for 6 hours. The yield was 0.3gms of Letrozole form L.

DSC Thermogram 182.0°C (Peak)

Example-16 :

Preparation of Letrozole Form L:

Letrozole crude (5 gms) obtained directly from the synthesis was dissolved in Acetic acid (35 ml). Isopropanol (85 ml) was added slowly during 15 minutes at the same temperature The reaction mass was stirred for 1 hour, filtered and washed with D.M.water.The wet product was dried under vacuum for 6 hours. The yield was 3 gms of Letrozole form L. DSC Thermogram 182.7°C (Peak) Example - 17 :

Pharmaceutical com ositions containin Letrozole L-form

Advantages of the invention

1. The polymorphic form L of Letrozole is novel and not known hitherto.

2. The processes produce novel polymorphic form L of Letrozole consistently.

3. The novel polymorphic form of Letrozole produced is thermodynamically stable.

4. The novel polymorphic form L prepared is suitable for pharmaceutical applications

Claims

We claim

1) A novel crystalline thermodynamically stable polymorphic form of Letrozole designated as Form L having the XPRD characteristics given in Table-I and Fig -1

2) A novel thermodynamically stable polymorphic form of letrozole designated as form L having IR and DSC characteristics as in figs. 2 and 3.

3) A process for the preparation of a novel crystalline polymorphic form of Letrozole designated as Form L₅ comprising crystallization from solvents methanol, chloroform, acetone, ethyl acetate, dioxane and the like. 4) A process for the preparation of novel crystalline polymorphic form L of letrozole comprising lyophilization of a solution of the drug substance in an alcoholic solvent like methanol. 5) A process for the preparation of novel crystalline polymorphic form L of letrozole comprising precipitation from solutions in solvents like methanol, DMF, acetic acid by anti-solvents like water, isopropanol and isopropyl ether.

6) A process for the preparation of novel crystalline polymorphic form L of letrozole comprising regeneration from solution in acids like diluted HCl. sulfuric acid and acetic acid by bases like ammonia and sodium hydroxide.

7) A process for the preparation of novel crystalline polymorphic form L of letrozole substantially as herein described with reference to the examples 1-16

8) A pharmaceutical composition containing the novel crystalline polymorphic form L of Letrozole substantially as herein described with reference to example 17