WO2013075732A1 - Process for making crystalline form i of etoricoxib - Google Patents

Abstract

The present invention relates to an improved process for making the pharmaceutically advantageous crystalline Form I of etoricoxib, which comprises making a solution of etoricoxib in an organic solvent miscible with aliphatic/alicyclic hydrocarbons, followed by mixing the solution with an aliphatic/alicyclic hydrocarbon antisolvent at a preselected temperature, at which the Form I precipitates.

Description

PROCESS FOR MAKING CRYSTALLINE FORM I OF ETORICOXIB The present invention relates to an improved process for making the pharmaceutically advantageous crystalline Form I of etoricoxib.

BACKGROUND OF THE INVENTION

Etoricoxib, chemically 5-Chloro-3-[4-(methylsulfonyl)phenyl] -2-(6-methylpyridin-3- yl)pyridine of formula (I)

is a pharmaceutically active compound which acts in human body as a cyclooxygenase-

2 (COX-2) inhibitor. It has been launched in a form of oral tablets for treatment of various

COX-2 mediated diseases (e.g., gouty arthritis, dysmenorrhea, osteoarthritis and rheumatoid arthritis) and is sold, e.g., under brand name Arcoxia by Merck. While the compound (I) may form acid addition salts, it has been marketed as a free base.

The compound of formula (I) was first disclosed in WO 98/03484 (EP 912518, US

5,861,419). In Example 23, the compound was obtained by a flash chromatography and evaporation of ethyl acetate solution.

Alternate method of isolation of etoricoxib was provided in US 5861419 (column 54).

The method comprises a precipitation process using isopropyl acetate as a solvent and hexanes as an anti-solvent. WO 01/37833 disclosed several polymorphic forms of etoricoxib: four anhydrous crystalline forms (Forms I to IV), two crystalline hydrates (a hemihydrate and a

sesquihydrate) and the amorphous form. The respective forms can be identified primarily by corresponding X-ray powder diffraction (XRPD) patterns, which have been published therein.

The following has been reported in WO 01/37833 in respect to Forms I - IV:

= The crystalline Form I was obtained by recrystallising Form II from a solvent mixture isopropanol-hexane.

= The crystalline Form II was obtained by a crystallization of raw etoricoxib as prepared in Ex 23 of WO 98/03484 from ethyl acetate.

= The crystalline Form III was prepared by stirring the Form IV in water and

dehydration of the obtained product in vacuo at 90°C.

= The crystalline form IV has been found in batches of raw etoricoxib as prepared in Ex 23 of WO 98/03484. Alternatively it may be prepared by a recrystallisation of Form I or Form II from an organic solvent such as toluene or heptane at temperatures of less than 45 °C. It is enantio tropic with the Form I as it converts to the Form I at temperatures greater than 45 °C.

The subsequent document WO 01/092230 disclosed crystalline Form V of etoricoxib. It is obtainable by combining any of the preceded Forms I -IV with isopropyl acetate, heating to a temperature less than about 75°C and cooling to a low temperature.

As reported in WO 01/37833, the crystalline Form I is thermally stable at the whole range of temperatures prior to melting without conversion to other polymorphic forms.

Therefore it appears that the Form I may be a suitable and advantageous form for

pharmaceutical applications.

In searching possible production processes leading to the Form I, the present inventor performed a careful repetition of the prior art data. It was found out that reworking example 5,861,419 comprising a precipitation process using mixing isopropyl acetate as a solvent and hexanes as an anti-solvent at 60°C provided for the Form IV. A third known process of making raw etoricoxib comprising dissolving etoricoxib tosylate in water-toluene mixture, alkalinizing it by ammonia and recovering the free base from the toluene phase by adding hexane at ambient temperature according to Preparative Example H of WO 01/92230, provided a mixture of polymorphs. Other prior art data are essentially correct.

Thus, an existence of two known processes for making the crystalline form I was confirmed. The first process according to Example 23 of WO 98/03484 requires a step of evaporation of ethyl acetate solution and crystallization from oily phase, which is

technologically disadvantageous. The second process is the process of WO 01/37833 comprising recrystallising Form II from a solvent mixture isopropanol-hexane. As no data about actual performance of the process (concentrations, temperatures, cooling regimen) have been reported, a standard crystallization arrangement ( i.e. providing a solution at an enhanced temperature and cooling said solution under stirring upon the precipitation of the solid ) at various etoricoxib concentrations, mutual ratios of the both solvents in the mixture and crystallization temperatures revealed that Form I is obtainable in most cases but the process is characterized by serious stirring problems (the formation of a thick cake is almost a rule), lower yields (about 60% ) and occasional impurification of the isolated precipitate with the Form IV.

Thus it appears that the known procedures exhibit serious disadvantages. Accordingly, there exists an objective need of finding an improved crystallization process which would lead to reliable formation of the crystalline form I of etoricoxib. BRIEF DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a novel process of making the Form I of crystalline etoricoxib, which is simple, rapid and reliable. The product of the process is typically essentially free from other crystalline forms of etoricoxib.

In a main aspect, the invention provides for a process for making the crystalline Form I of etoricoxib, which comprises making a solution of etoricoxib in an organic solvent miscible with aliphatic/alicyclic hydrocarbons, followed by mixing the solution with an aliphatic/ alicyclic hydrocarbon antisolvent at a preselected temperature, at which the Form I precipitates.

In the specific aspect, the invention provides a process for making the crystalline Form I of etoricoxib comprising the steps of

a) dissolving etoricoxib in an organic solvent miscible with aliphatic/cyclic

hydrocarbons of 5 - 8 carbon atoms, preferably at a temperature of 50°C and higher;

b) adding the obtained solution to an aliphatic/alicyclic hydrocarbon of 5 - 8 carbon atoms at a temperature of 45 °C and lower, to form a precipitate; and

c) optionally, isolating the precipitate from the reaction mixture.

In the preferred aspect, the organic solvent is an aliphatic ester, preferably ethyl acetate or isopropyl acetate or an aromatic C6-C10 hydrocarbon, preferably benzene or toluene and/or mixtures thereof; the aliphatic/alicyclic hydrocarbon is preferably a hydrocarbon of 6-7 carbon atoms, e.g. n-hexane, cyclohexane or n-heptane and/or mixtures thereof. DETAILED DESCRIPTION OF THE PRESENT INVENTION

As discussed above, many polymorphic forms of crystalline etoricoxib are known in the art. The crystalline Form I is relatively stable at ambient conditions of storage and has good handling properties and thus it was considered by the present inventor as an advantageous crystalline form for pharmaceutical applications of etoricoxib. The present invention is a result of a thorough study of properties of this crystalline form and methods for making it.

For clarity, the "Form I" of crystalline etoricoxib exhibits, according to WO 01/37833, the following characteristics:

a) DSC pattern (10°C/min) exhibits the onset of melting at about 134-136°C, peak m.p. at 138°C; and

b) X-ray powder diffraction pattern detected by Cu K alpha source at 45kV and 40mA with divergent beam (2mm and 4 mm) and receiving beam slits (0.5mm and 2 mm) comprises typical reflections at 7.1, 9.7, 11.8, 15.5, 20.1, 22.7 and 24.1 degrees 2 theta; peak positions were calibrated using a standard silicon disk (97.5% pure).

In accordance with the above teaching, the Form I of etoricoxib of this invention is a polymorph having an X-ray powder diffraction pattern of typical reflections at about 7.1, 9.7, 11.8, 15.5, 20.1, 22.7 and 24.1 + 0.2 degrees 2 theta.

It was now found out with surprise that the desired Form I of etoricoxib may be formed by a crystallization of etoricoxib from a suitable solvent system, wherein such crystallization exhibits the advantage in that the form I is formed without contamination with other crystalline forms, in a good yield and of good handling properties.

The crystallization process of the present invention comprises precipitation of the Form I of etoricoxib from a solution of etoricoxib in an organic solvent miscible with aliphatic/ alicyclic hydrocarbons, whereby the precipitation is induced by contacting the solution with an aliphatic/alicyclic hydrocarbon antisolvent at a preselected temperature. The "organic solvent" in the process of the invention is accordingly such solvent, which is miscible with the aliphatic/alicyclic hydrocarbon antisolvent. It may be, e.g., an ester of C1-C4 carboxylic acid with C1-C4 aliphatic alcohol, e.g. ethyl acetate or isopropyl acetate, or an aromatic hydrocarbon of 6 to 10 carbon atoms, e.g. benzene or toluene, incl. mixtures of at least two such components. The "aliphatic/alicyclic hydrocarbon" antisolvent may be a single aliphatic/ alicyclic hydrocarbon, preferably having 5-8 carbon atoms and most preferably 6-7 carbon atoms, for instance n-hexane, n-heptane or cyclohexane, but it may be also a mixture of at least two such hydrocarbons.

In respect to "contacting" of both liquids of the above, it is possible to add the aliphatic hydrocarbon to the solution of the etoricoxib in the organic solvent maintained at a preselected temperature, which is advantageously a temperature lower than 60°C, preferably between 35 and 55°C. While such technique allows for forming the Form I, this technique is less preferred as the crystals so formed are sometimes difficult to stir. Thus, the preferred process of the present invention is based on the reversed order of contact and advantageously comprises the following steps:

a) dissolving etoricoxib in an organic solvent miscible with aliphatic/alicyclic hydrocarbons of 5 - 8 carbon atoms, preferably at a temperature of 50°C and higher;

b) adding the obtained solution to an aliphatic/alicyclic hydrocarbon of 5 - 8 carbon atoms at a temperature of 45 °C and lower, to form a precipitate; and

c) optionally, isolating the precipitate from the reaction mixture.

Sub a)

Typically, etoricoxib is combined with the sufficient amount of the organic solvent as specified above and heated to the preselected temperature until essentially complete dissolution. The preselected temperature is advantageously a temperature of at least 50°C and includes the reflux temperature. The obtained solution is maintained stirred for certain time to ensure that no seeds of another form of etoricoxib are present. Alternately, a flash filtration of the hot solution may be performed to remove traces of foreign solid material.

The starting etoricoxib may be any form of solid state of etoricoxib, both crystalline and amorphous. Alternately, etoricoxib may be directly formed in the organic solvent by a chemical reaction.

Advantageously, the organic solvent is ethyl acetate or toluene. The preferred concentration is 1 g of etoricoxib in 2-10 ml of the organic solvent, most preferably in 3 -5 ml of the organic solvent, but the invention is not limited thereto .

Sub b)

The obtained solution is advantageously added dropwise or portionwise to the stirred aliphatic/alicyclic hydrocarbon of 5 - 8 carbon atoms to assure proper homogenization throughout the dilution.

Before the addition to the hydrocarbon, heating of the solution is advantageously stopped and the system is allowed to cool spontaneously. However, spontaneous nucleation of etoricoxib in the solution prior to addition must be avoided.

During or after mixing the etoricoxib solution in the organic solvent with the hydrocarbon, initiation of the crystallization by seeding with minute amounts of crystals of the Form I may be performed.

The mixture is generally stirred for a time of at least 30 minutes, for to facilitate the crystallization as much complete as possible. Advantageously, the suspension may be additionally stirred at a temperature lower than ambient, for instance at a temperature from - 15 to +15°C, typically at a temperature of about 0°C.

Advantageously, the hydrocarbon is n- heptane, n-hexane or cyclohexane and/or mixtures thereof. The preferred amount of the hydrocarbon is 1.5 - 5 ml per 1 ml of the solvent, more preferably 2-4 ml per 1 ml of the solvent. Sub c)

The solid may be filtered by any filtration / centrifugation process at ambient or diminished pressure; advantageously, the solid product is washed with the hydrocarbon after the filtration. Care is to be taken that drying is performed at relatively low temperature, advantageously in vacuo.

It was proven by XRPD analysis that the product obtained after isolation is the desired Form I of etoricoxib without being contaminated by other known forms or by a solvate comprising molecules of solvent. In addition, no solvent mediated transition occurs within 15- 20 hours stirring in the solvent/antisolvent mixture at R.T.

In general, yields of 90% and higher are easily obtainable.

The etoricoxib product obtained by the process of the present invention may be formulated into pharmaceutical compositions, for instance to tablet compositions for oral administration, and may be used in medicine, for instance in a treatment of various COX-2 mediated diseases (e.g., gouty arthritis, dysmenorrhea, osteoarthritis and rheumatoid arthritis).

The invention will be further described with reference to the following non-limiting examples.

EXAMPLES

Example 1

750 grams of etoricoxib is dissolved in 3.75 liter of toluene at reflux under stirring and maintained stirred at this temperature for 20 minutes. Then the solution is allowed to cool under stirring to 85°C. The hot solution is slowly added to 11.25 liter of n-heptane, mechanically stirred and cooled at 20°C. After addition, the formed suspension is stirred at ambient temperature for 30 minutes. The suspension is filtered over a P3 -glass filter at reduced pressure. The solid is washed with n-heptane and dried. XRPD: Form I

Example 2

100 g of etoricoxib was dissolved in 500 ml toluene at reflux, while stirring

mechanically (150-200 rpm). Reflux was maintained for about 30 minutes. The solution was allowed to cool to ~50°C (stirred at 200 rpm). Around 50°C, 1500 ml n-heptane was added slowly. During addition, a thick solid was formed, the stirrer was set to 350-400 rpm.

After cooling to RT (350 rpm stirrer speed), the suspension was stirred at RT for about 1,25 hr. The suspension was filtered over a P3-glass filter (reduced pressure). The solid was washed with n-heptane and vacuum-dried overnight at 40°C. An off-white to yellowish, fluffy solid with soft lumps was obtained. XRPD showed only Form I. The yield was 97 grams (97%).

Example 3

100 g of etoricoxib was dissolved in 300 ml ethyl acetate at reflux, while stirring mechanically (150 rpm). Reflux was maintained for about 20 minutes. The solution was allowed to cool down. After approximately 5 minutes of cooling time, about 600 ml n-heptane was added dropwise at about 50°C. After cooling to RT (400 rpm stirrer speed, 20 minutes), a part of the suspension was filtered over a P3 -glass filter (reduced pressure). The solid was washed with n-heptane and vacuum-dried overnight at 40°C. A yellowish, fluffy solid with lumps was obtained. XRPD showed Form I.

The remaining part was stirred at RT in a closed flask for an additional 1.5 hour (200 rpm). A part of the suspension was filtered over a P3 -glass filter (reduced pressure). The solid was washed with n-heptane and vacuum-dried overnight at 40°C. A yellowish, fluffy solid with lumps was obtained. XRPD showed Form I. The remaining part was stirred overnight stirred at RT. The suspension was filtered over a P3-glass filter (reduced pressure). The solid was washed with n-heptane and vacuum-dried at 40°C for about 6 hours. A yellowish, fluffy solid with lumps was obtained. XRPD showed Form I.

The total yield of the three portions together was 92 grams (92%).

Example 4

10 g of etoricoxib was dissolved in 30 ml ethyl acetate at reflux. The hot solution was dropwise added to 60 ml n-heptane, magnetically stirred at R.T. A solid was formed. After cooling to R.T. and additional stirring at RT for about 15 minutes, the suspension was filtered over a P3-glass filter (reduced pressure). The solid was washed with n-heptane and vacuum- dried overnight at RT. An off-white to yellowish, fluffy solid with lumps was obtained. The yield was 8.9 grams (89%). XRPD showed only form I. Reference Example

(alternative example 23 of US 5,861,419, column 54)

5.0 g of etoricoxib was suspended in 27.3 ml of isopropyl acetate at R.T. The suspension was heated to 60°C, while stirring. No clear solution was obtained during 10 minutes stirring at 60°C.

The suspension was heated slowly to 68 °C in a 30 min period, while stirring. A clear solution was obtained. The warm solution was filtered over a warm P3-glass filter (reduced pressure) into a warm 3 necked flask of 250 ml. At about 60°C solution temperature, 27.3 ml of n-hexane was added dropwise, resulting in precipitation. The mixture was stirred for about 40 minutes, during which the temperature dropped to about 43 °C. Then, an additional 27.3 ml n-hexane was added dropwise and the suspension was stirred at 43-44°C for an additional 20 minutes. Then, the suspension was slowly cooled to about 15°C in a 2.5 hour period and further cooled to about 3°C in an additional 15 minute period. The suspension was stirred at about 3°C for an additional 30 minutes. The suspension was filtered over a P3-glass filter (reduced pressure). The solid was washed with 15 ml isopropyl acetate /hexane (1:3 V/V) and vacuum-dried overweekend at RT. A yellowish/pale yellow, fine powder was obtained. The yield was 4.15 g.

XRPD: Form IV.

The invention having been described, it will be readily apparent to those skilled in the art that further changes and modifications in actual implementation of the concepts and embodiments described herein can easily be made or may be learned by practice of the invention, without departing from the spirit and scope of the invention as defined by the following claims.

Claims

A process for making the crystalline Form I of etoricoxib, having an X-ray powder diffraction pattern of typical reflections at about 7.1, 9.7, 11.8, 15.5, 20.1, 22.7 and 24.1 + 0.2 degrees 2 theta, which process comprises making a solution of etoricoxib in an organic solvent miscible with aliphatic/alicyclic hydrocarbons, followed by mixing the solution with an aliphatic/alicyclic hydrocarbon antisolvent at a preselected

temperature, at which the Form I precipitates.

The process according to claim 1, comprising the steps of:

a) dissolving etoricoxib in an organic solvent miscible with aliphatic/cyclic

hydrocarbons of 5 - 8 carbon atoms, preferably at a temperature of 50°C and higher; b) adding the obtained solution to an aliphatic/alicyclic hydrocarbon of 5 - 8 carbon atoms at a temperature of 45 °C and lower, to form a precipitate; and

c) optionally, isolating the precipitate from the reaction mixture.

The process according to claims 1-2, wherein the organic solvent is an aliphatic ester, preferably in ethyl acetate or isopropyl acetate or an aromatic C6-C10 hydrocarbon, preferably benzene or toluene and/or mixtures thereof.

The process according to claims 1-3, wherein the aliphatic/alicyclic hydrocarbon is a hydrocarbon of 6-7 carbon atoms, preferably, n-hexane, cyclohexane or n-heptane and/or mixtures thereof.

The process according to claims 1-4, wherein the crystallization is initiated by seeding with minute amounts of crystals of the Form I.