EP2475636A1 - A process for preparing dexketoprofen trometamol form a and form b crystals - Google Patents

Abstract

This invention relates to simple, economic and reliable methods to prepare Dexketoprofen Trometamol polymorphs of Form A and Form B.

Description

Description

Title of Invention: A PROCESS FOR PREPARING DEXKE- TOPROFEN TROMETAMOL FORM A AND FORM B

CRYSTALS

[1] This invention relates to simple, economic and reliable methods to prepare Dexke- toprofen Trometamol polymorphs of Form A and Form B.

[2] There exist numerous biological compounds in a mixture of R and S isomers. The ones with pharmaceutical use are usually based on either R or S form of the related biological compounds. In this area of research, scientists have being paid more attention to isolate and use of pure forms for related applications. It has been known that pharmacological activity level of the enantiomers may be very different, in some cases its activity may be different even in the area used.

[3] Ketoprofen is a well known member of non-steroidal anti-inflammatory drugs

(NSAIDs). Its therapeutic acitivity is based on the ability to block the production of prostaglandins which are produced in response to injury or certain diseases. Ketoprofen has an asymetric carbon in its chemical structure and it is commercially available as a racemic mixture in the drug market.

[4] Dexketoprofen trometamol (hereinafter DKT is used for abbreviation) is the

trometamol salt of S (+) enantiomer of Ketoprofen which has superior properties compared to ketoprofen in point of view of solubility and efficacy. It is used mainly as analgesic and marketed by Menarini under the Keral ® trademark as tablet and other dosage forms.

[5] Polymorphism is a well known phenomen among pharmaceutical active compounds influencing properties such as solubility, stability, melting point among others and thus important .

[6] EP1739072 discloses that dexketoprofen trometamol also shows polymorphism. In

EP1739072 patent application, Form A and Form B are characterized. This designation will be used below. In patents and literature there are no identified polymorphs other than form A and form B .

[7] EP668851 patent points out a way of crystallization of dexketoprofen trometamol.

Repeating of this method led to Form A or mixture of Form A and Form B. This method includes many steps and sometimes leading to polymorphic mixtures, instead of solely form A, thus not feasable and reliable.

[8] To solve targeted DKT polymorph preparation problem, Menarini applied crystallization from Ethanol / Methylethylketon / Xylene solvent mixture in EP1739072 patent. Depending on the cooling rate Form A at slow cooling rate, Form B at faster cooling rate precipitates. Our attemps to repeat this procedure led to precipitation of unattended polymorphs leading to the conclusion that this method is unreliable as well and not feasable due to solvent mixtures and high boiling point Xylene used.

[9] There is a need for easy, simple, economic and reliable processes for the preparation of pure polymorphic forms of Dexketoprofen trometamol Form A and Form B.

[10] To solve the complexity , polymorphic mixture problem and to find a reliable process many attempts were undertaken by many solvent crystallization processes starting from Dexketoprofen (hereinafter abbreviated as DK) and Trometamol. By these processes we tried classical crystallization method. Heating the participants to dissolve them completely in a solvent or solvent mixture and then cooling to precipitate led to DKT Form A and Form B . But depending on cooling rate and crystallization conditions we obtained different polymorphic forms with the same solvent system.

[11] We have invented robust crystallization methods which mean invented methods are reproducible. Among some improvements compared to prior art we have invented a simple and reliable process to prepare pure polymorphic forms of Dexketoprofen trometamol Form A and Form B . Namely we simply stirred dexketoprofen and trometamol in a solvent in which Dexketoprofen is soluble, trometamol is very less or less soluble and Dexketoprofen trometamol is insoluble or very less soluble.

Depending on the solvent choice pure Form A or Form B is precipitated and removed by filtering. There is no need to dissolve whole system and no need for evaporation and recrystallization such as in prior art processes applied. There exist no need for heating to dissolve completely the reactants dexketoprofen and trometamol since DKT remains as precipitate in the system there is less degradation and no polymorphic form changes .

[12] Prior art processes lead to polymorphic form mixtures or to unintended polymorphic forms . They have the potential for leading to high level of degradation and loss of yield as well, due to complete solution of dexketoprofen at high temperature in process. In our method there exist no need to work with solvent mixtures to achieve yield improvement of DKT as described in prior arts.

[13] So, we have invented a reliable, inexpensive , simple and easy way of crystallization of pure crystalline forms of DKT Form A and Form B which is superior to the prior art.

[14] Herein we disclose a simple process for the preparation of crystal forms of DKT

Form A and Form B with economical impact.

[15] According to this invention, the reaction is carried out in a single solvent containing dexketoprofen and trometamol. The reactants don't need to be completely soluble in the solvent . DKT is insoluble in these solvent systems and dexketoprofen and /or trometamol are less soluble in these solvents. This type of reaction leads to less degradation since DKT is insoluble in the solvent system thus less prone to

degradation .The reaction is carried out preferably at ambient temperatures due to the reasons of convenience and degradation issues. Pure crystal forms are obtained by carrying out the reaction in these systems, since DKT is less soluble or insoluble in those systems. This system has advantages over EP668851 patent method of preparing DKT crystals of Form A and Form B. In example 1, dexketoprofen and trometamol are dissolved in Ethanol/ water and after removing solvent DKT is crystallized from Ethanol / Ethylacetate mixture (page 4, lines 10-25). Since this method uses solvent mixture and applies many steps it is time and solvent consuming hence not very feasible. Solvent recovery from used solvent mixtures poses a technical problem sometimes solved with special technical equipment which increases investment costs.

[16] Besides, applying EP668851 patent method leads to Form A or mixtures of Form A and Form B by not applying appropriate crystallization conditions as can be seen in some commercial batches. Our trials to repeat the crystallization process ,mentioned in Example 1 of this patent (page 4, lines 10-25), led to Form A. But depending on crystallization conditions this procedure can lead to mixtures of Form A and Form B . Our method always leads to the desired single polymorphic form which makes it more reliable.

[17] EP1739072 patent claims to have solved above mentioned problems by applying solvent mixtures including Xylene. In this process Dexketoprofen and trometamol are dissolved in Ethanol / Ethylmethylketon mixture , Xylene is added onto it at elevated temperature to obtain a solution. Depending on the cooling rate DKT precipitates at slower cooling rate as Form A and at faster cooling rate as Form B. It is obvious Form A is the thermodynamically stable form. This procedure is not easier than the method of EP668851 patent since this method uses solvent mixtures as well and Xylene is not a prefered solvent of choice by crystallization due to its high boiling point.

[18] Our trials to repeat this procedure led in most attempts to unintended polymorphic forms. There seems to be a problem with cooling rate and other crystallization parameters which appears to make this method not a robust one . However our method is safe to achieve intended type of crystall form of DKT. Additionally it is economical and simple .

[19] By our system pure Form A and Form B crystalls of DKT is obtained such as

explained below:

[20] a) Dexketoprofen is dissolved in an appropriate solvent

[21] b) Powder form trometamol is added .

[22] Whereas solvents which do not dissolve trometamol are the choice of solvent.

[23] c) The mixture is stirred for sufficient period of time.

[24] The reaction can be monitored with an XRD equipment by totally consuming of trometamol and rise of DKT peaks. Solvents in which DKT is not dissolving are the choice of solvent.

[25] d) Filtering DKT precipitate

[26] e) Drying of the precipitate. Optionally applying moderate heat and vacuum.

[27] This procedure leads by applying ,Methyl tertiary butyl ether, Isopropyl acetate, n-

Butyl acetate, Diisopropyl ether, n-Propyl acetate, Isobutyl acetate, Methylene chloride to pure Form A and by applying Acetonitrile, Dibutylether,Toluen, Xylene to pure Form B which are characterized with '072 patent X Ray and IR datas. This list can be expanded with other suitable solvents by holding on the spirit of the invention . The scope of the invention should not be limited to these solvents. Other suitable solvents especially from class of esters, ethers, ketone , halogenated organic solvents, aryl, alkyl hydrocarbons among others. Suitable solvent mixtures which do not dissolve DKT and less dissolve Dexketoprofen and Trometamol and lead to the desired polymorph may also be applied. But single solvents are more preferable.

[28] Attempts applying same method with some solvents led regularly to polymorphic mixtures with defined range of polymorphic ratio. These solvents with observed polymorph ratios are Methyl isobutyl keton Form A : Form B around 90 : 10, Ethyl acetate around 60 : 40 , Methyl acetate around 50:50 and Methyl ethyl keton around 70:30 . This list can be expanded with other suitable solvents by holding on the spirit of the invention. Suitable solvent mixtures which do not dissolve DKT and less dissolve Dexketoprofen and Trometamol and lead to the desired ratios of polymorph mixtures may also be applied. But single solvents are more prefferable.

[29] To determine sufficient stirring times, samples ,which are taken during the crystallization process, are measured preferably with XRD . Typical reaction times sufficient for total consumption of trometamol and precipitating DKT of intended crystallin form lay between 10 to 30 hours at ambient temperature. Depending on solvent choice and reaction conditions like stirring speed and temperature reaction times may vary.

Reaction temperatures from 0⁰C to reflux may be applied . Applying heat may diminish reaction times. But this is not preferred since this may lead to degradation and polymorphic changes.

[30] The X Ray Powder Diffraction analyses are carried out with Rigaku ® Ultima IV diffractometer with conditions below ;

[31] XRay source : Cu/40kV/30mA

[32] Scan Speed : 1 degree/minute

[33] Sampling width : 0,020 degree

[34] Scan range : 3.00-40.0 degree

[35] Goniometer : 185 mm

[36] The FT-IR spectral analyses werw carried out with Perkin Elmer Spectrum 1 STIR ATR equipment between 600cm ¹ and 2000 cm ¹

[37] Applied solvent amounts are typically around 10 times of reagent amounts. Less solvent may lead to increased reaction times .More solvent applied may lead to yield loss and expenditure.

[38] Stirring speed is a factor as well influencing reaction times and particle size.

[39] Considering all of the above mentioned parameter optimal reaction conditions can be tailored.

[40] Compared with '851 patent method our method uses only one solvent, evaporation and heating are not needed and reaction is carried out in only one step which poses a substantially improvement .

[41] Compared with '072 patent our method does not utilize solvent mixture and no

heating and no gradually cooling is applied. Cooling rate is decisive about the polymorphic form obtained, which should be monitored carefully . This is not an issue in our method . Our method applies no solvent mixtures and no control of temperature gradient which minimizes the risk of obtaining polymorphic mixtures and even unintended polymorphic forms. Our repetetive attempts of the '072 procedure led in most cases to unintended polymorph or polymorph mixtures.

[42] Further, additional to the methods explained above there exist in the literature no single solvent crystallization method starting from Dexketoprofen trometamol. In the patent literature applied crystallization method is solvent / antisolvent method, namely DKT is dissolved in a solvent and precipitated with antisolvent. We also additionally found that applying sole solvent crystallization method Form A and Form B can be crystallized in pure form.

[43] Typical crystallization method for this purpose is :

[44] a) Dissolving dexketoprofen trometamol in sufficient amount of a single solvent at elevated temperatures

[45] b) Cooling of the solution while stirring until crystallization starts

[46] c) Stirring the precipitate at this temperature fur further crystallization

[47] d) Optionally cooling to complete crystallization

[48] e) Filtering the crystals

[49] Solvents that lead to form A by applying this method are: Methylisobutyl keton,

Methylethyl keton, Methylene chloride,

[50] Solvents that lead to form B by applying this method are : n-Butyl acetate, Iso- propanol, n-propanol

[51] Following examples disclose the invention but these should not limit the scope of the invention.

[52] Referential Example

[53] Repeating EP668851, Example 1: In a 250 ml three necked round bottomed glass flask equipped with glass rod and teflon paddle 1O g Dexketoprofen is weighed and dissolved in 30 ml Ethanol. 4.8 g Trometamol is dissolved in 16 ml water and added to Dexketoprofen solution. Resulting solution is evaporated to dryness . 20 ml of Ethanol is added to the residue to dissolve and again evaporated to dryness. The solid residue is dissolved in 16 ml Ethanol at 55 ⁰C . 40 ml Ethylacetate is added . The obtained solution is cooled. Around 25°C precipitation occured. After stirring 15 min at 25°C the mixture is cooled to 5°C to complete the precipitation and stirring is continued for an additional hour at this temperature. The precipitation is filtered, washed with cold Ethanol /Ethylacetate mixture and dried at 40⁰C for 16 hours. 13 g of dexketoprofen trometamol Form A crystals are obtained. Polymorphic form is determined with PXRD and IR. X Ray and IR signals are matching well with Form A signals . (see Figure 1 and Figure 2)

[54] Example 1 ; Preparation of Form A

[55] In a 250 ml three necked round bottomed glass flask equipped with glass rod and teflon paddle 5 g Dexketoprofen is weighed and dissolved in 50 ml Methyl tertiary butyl ether . To complete the solution 10 minutes additionally stirring is applied. 2.4 g Trometamol is added as a powder. The thus obtained suspension is stirred for 30 hours . The completion of the reaction is monitored with X Ray by consuming trometamol crystals and arising dexketoprofen trometamol peaks. The precipitation is filtered , washed with cold Methyl tertiary butyl ether and dried at 45°C in vacuum for 16 hours.7 g of dexketoprofen trometamol form A is obtained. Polymorphic form is determined with PXRD (See XRD Figure 1 ) 2 Theta: 5.10, 7.96, 10.02, 10.24, 16.06, 16.24, 17.42, 20.04, 21.40, 22.50 and FT IR (See IR Figure 2) wavenumber ; (cm -1): 1571, 1536, 1020, 771, 641.

[56] Example 2 ; Preparation of Form B

[57] In a 250 ml three necked round bottomed glass flask equipped with glass rod and teflon paddle 5 g Dexketoprofen is weighed and dissolved in 50 ml Acetonitrile.To complete the solution 10 minutes additionally stirred .2.4 g Trometamol is added as a powder. This suspension is stirred for 19 hours . The completion of the reaction is monitored with X Ray by consuming trometamol crystals and arising of dexketoprofen trometamol peaks. The precipitation is filtered , washed with cold Acetonitrile and dried at 45°C in vacuum for 16 hours. 6.8 g of dexketoprofen trometamol form B is obtained. Polymorphic form is determined with PXRD ( See XRD Figure 3) ; 2 Theta : 4.66, 9.00, 12.54, 14.82, 17.12, 18.00, 20.30, 22.64, 27.30 and FT IR (See IR Figure 4) wavenumber (cm- 1) : 1630, 1554, 1426, 1354, 1083, 1043, 833

[58] Example 3 ; Preparation of Form A and Form B Mixture

[59] In a 250 ml three necked round bottomed glass flask equipped with glass rod and teflon paddle 2 g Dexketoprofen is weighed and dissolved in 20 ml Ethyl acetate. To complete the solution 10 minutes additionally stirred . 0.96 g Trometamol is added as a powder. This suspension is stirred for 19 hours . The completion of the reaction is monitored with X Ray by consuming trometamol crystals and arising of dexketoprofen trometamol peaks. The precipitation is filtered , washed with cold Ethylacetate and dried at 45°C in vacuum for 16 hours.6.7 g of dexketoprofen trometamol with polymorph mixture Form A : Form B 60 : 40 is obtained. Polymorphic form is determined with PXRD (See XRD Figure 5)

[60] Example 4 ; Preparation of Form A

[61] In a 100 ml double necked round bottomed glass flask equipped with glass rod and teflon paddle 3 g of dexketoprofen trometamol is dissolved in 20 ml Methylethyl ketone byheating above 50° C to 60° C . The clear solution is stirred for additional 15 minutes to complete the solution. The solution is cooled to room temperature.After 5 minutes stirring precipitation started. The mixture is stirred for additional lhour at room temperature and filtered. Crystalls are dried in a drying chamber at 40⁰C for 5 hours . 2.4 g dexketoprofen trometamol Form A crystals are obtained .

[62] Example 5 ; Preparation of Form B

[63] In a 100 ml double neckedround bottomed glass flask equipped with glass rod and teflon paddle 1 g of dexketoprofen trometamol is dissolved in 10 ml n-Butyl acetate by heating above 80° C to 90° C . The clear solution is stirred for additional 15 minutes to complete the solution. The solution is cooled to room temperature, precipitation started. The mixture is stirred for additional 1 hour at room temperature and filtered.

[64] Crystalls are dried in a drying chamber at 40° C for 5 hours . 0.8 g dexketoprofen trometamol Form B crystals are obtained .

[65] Example 6) Preparation of Form A

[66] In a 250 ml three necked round bottomed glass flask equipped with glass rod and teflonpaddle 5 g Dexketoprofen is weighed and dissolved in 50 ml Isopropyl acetate . To complete the solution 10 minutes additionally stirring is applied. 2.4 g Trometamol is added as a powder. The thus obtained suspension is stirred for 26 hours . The completion of the reaction is monitored with X Ray by consuming trometamol crystals and arising dexketoprofen trometamol peaks. The precipitation is filtered , washed with cold Isopropyl acetate and dried at 45°C in vacuum for 16 hours.7.1 g of dexketoprofen trometamol form A is obtained.

[67] Example 7) Preparation of Form B

[68] In a 250 ml three necked round bottomed glass flask equipped with glass rod and teflonpaddle 5 g Dexketoprofen is weighed and dissolved in 50 ml Xylene.To complete the solution 10 minutes additionally stirred .2.4 g Trometamol is added as a powder. This suspension is stirred for 27 hours . The completion of the reaction is monitored with X Ray by consuming trometamol crystals and arising of dexketoprofen trometamol peaks. The precipitation is filtered , washed with cold Xylene and dried at 45°C in vacuum for 16 hours. 6.9 g of dexketoprofen trometamol form B is obtained.

Claims

Claims

[Claim 1] A process for the preparation of dexketoprofen trometamol crystalline

Form A comprising

a. Dissolving dexketoprofen in an appropriate solvent

b. Adding Trometamol to the solution

c. Stirring the reaction mixture until completion of crystallization d. Collecting dexketoprofen trometamol crystals characterized in that, in dissolving of dexketoprofen step, single appropriate solvent is used and single appropriate solvent is selected from solvents in which;

- dexketoprofen is completely soluble and

- trometamol is less soluble and

- dexketoprofen trometamol is less soluble

[Claim 2] According to claim 1 appropriate solvent is selected from group

consisting of Methyl tertiary butyl ether, Isopropyl acetate, n-Butyl acetate, Diisopropyl ether, Methylene chloride n-Propyl acetate, Isobutyl acetate

[Claim 3] Form A mentioned in claim 1 is characterized with X Ray signals with

2theta values ; 5.10, 7.96, 10.24, 16.24, 17.42, 20.04, 22.50

[Claim 4] Form A mentioned in claim 1 having an XRD pattern substantially in accordance with figure 1

[Claim 5] Form A mentioned in claim 1 is characterized with FT IR peaks :

wavenumber (cm -1): 1571, 1536, 1020, 771, 641

[Claim 6] Form A mentioned in claim 1 has an FT IR pattern substantially in accordance with figure 2

[Claim 7] A process for the preparation of dexketoprofen trometamol Form B comprising

a)Dis solving dexketoprofen in an appropriate solvent

b)Adding Trometamol to the solution

c)Stirring the reaction mixture until completion of crystallization d)Collecting dexketoprofen trometamol crystals characterized in that, in dissolving of dexketoprofen step, single appropriate solvent is used and single appropriate solvent is selected from solvents in which;

-Dexketoprofen is completely soluble and

-Trometamol is less soluble and

-Dexketoprofen trometamol is less soluble

[Claim 8] According to claim 7, appropriate solvent is selected from group

consisting of Acetonitrile,n-Butyl ether, Toluen, Xylene.

[Claim 9] Form B mentioned in claim 7 is characterized with X Ray signals with

2theta values;4.66, 9.00, 12.54, 14.82, 17.12, 20.30, 27.30

[Claim 10] Form B mentioned in claim 7 has an XRD pattern well matching with figure 3

[Claim 11] Form B mentioned in claim 7 is characterized with FT IR peaks :

wavenumber (cm-1) : 1630, 1554, 1426, 1354, 1083, 1043, 833

[Claim 12] Form B mentioned in claim 7 has an FT IR pattern substantially in accordance with figure 4

[Claim 13] A process for the preparation of dexketoprofen trometamol with

defined ratios of polymorphic form mixtures comprising

a)Dis solving dexketoprofen in an appropriate solvent

b)Adding Trometamol to the solution

c)Stirring the reaction mixture until completion of crystallization d)Collecting dexketoprofen trometamol crystals characterized in that, in dissolving of dexketoprofen step, single appropriate solvent is used and single appropriate solvent is selected from solvents in which;

-Dexketoprofen is completely soluble and

-Trometamol is less soluble and

-Dexketoprofen trometamol is less soluble

[Claim 14] According to claim 13, appropriate solvent is selected from group consisting of Methyl isobutyl keton, Ethyl acetate, Methyl acetate and Methyl ethyl keton

[Claim 15] According to claim 13 method with Methyl isobutyl keton prepared dexketoprofen trometamol contains polymorphic mixture of Form A : Form B between 95 : 05 to 50 :50 , prefferably 95: 05 to 80 :20

[Claim 16] According to claim 13 method with Ethyl acetate prepared dexketoprofen trometamol contains polymorphic mixture of Form A : Form B between 20 : 80 to 90 :10 , prefferably 40: 60 to 60 :40

[Claim 17] According to claim 13 method with Methyl acetate prepared dexketoprofen trometamol contains polymorphic mixture of Form A : Form B between 20 : 80 to 90 :10 , prefferably 40: 60 to 50 :50

[Claim 18] According to claim 13 method with Methyl ethyl keton prepared

dexketoprofen trometamol contains polymorphic mixture of Form A : Form B between 20 : 80 to 90 :10 , prefferably 40: 60 to 60 :40

[Claim 19] A process for the preparation of dexketoprofen trometamol crystalline Form A comprising:

a) Dissolving dexketoprofen trometamol in sufficient amount of a single solvent at elevated temperatures

b) Cooling of the solution while stirring until crystallization starts c) Stirring the precipitate at this temperature for further crystallization d) Optionally cooling to complete crystallization

e) Filtering the crystals

characterized in that, in dissolving of dexketoprofen trometamol step, single appropriate solvent is used and single appropriate solvent is selected from solvents Methylisobutyl keton, Methylethyl keton, Methylene chloride

[Claim 20] A process for the preparation of crystalline Form B comprising:

a) Dissolving dexketoprofen trometamol in sufficient amount of a single solvent at elevated temperatures

b) Cooling of the solution while stirring until crystallization starts c) Stirring the precipitate at this temperature for further crystallization d) Optionally cooling to complete crystallization

e) Filtering the crystals

characterized in that, in dissolving of dexketoprofen trometamol step, single appropriate solvent is used and single appropriate solvent is selected from solvents n-Butyl acetate, Isopropanol, n-propanol