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Crystal Form Of Besipirdine Chlorhydrate, Process Preparation And Use Thereof

Abstract: ABSTRACT "CRYSTAL FORM OF BESIPIRDINE CHLORHYDRATE, PROCESS PREPARATION AND USE THEREOF" Crystal form of besipirdine chlorhydrate {Form I) corresponding to the Formula below: the aforementioned form being characterized at least by one of the following lysico-chemical properties: a) In FTIR, it displays at least the following absorption ends of the infrared spectrum: 778, 1198, 1121 , but not the following absorption bands the infrared spectrum: 3395, 1583. 732, the aforementioned bands being expressed in n"' at ± 5 cm''; b) In PXRD, it shows at least the following reflections, which are the ost intense ones but whose intensity hereafter is given for information only:Formula (II) In DSC, it displays at least an endothermic peak at 187.3 ± 2.0 °C using 5 °C/min :anning conditions, and a fusion enthalpy &Dgr;H of 130,4 ± 2.0 J/g. The invention also lales to the processes used for the preparation of form I as well as its applications in gology.

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Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
13 August 2008
Publication Number
11/2009
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

UROGENE
1 AVENUE CLAUDE VELLEFAUX, 75010 PARIS ,

Inventors

1. BIENAYAME, HUGUES
6 BIS ALLEE DES TOURNESOLS, 69360 ST. SYMBPORIEN D OZON,
2. FERTE, JACQUES,
5 RUE VOISEMBERT, 92130 ISSY-LES-MOULINIAUX,

Specification

CRYSTAL FORM OF BESIPIRDINE CHLORHYDRATE. PROCESS PREPARATION AND USE THEREOF The present invention relates to a stable crystal fomn, called form I, of N'propyl-N-{4-pyridinyl)-1H-indol-1-amine chlorhydrate (or besipirdine HCI), to its characterisation, to the processes used for obtaining it and to its applications, more particularly in the pharmaceutical field. N-propyl-N-{4-pyridinyl)-1H-indol-1-amine or besipirdine, repre¬sented in its chlorhydrate form by the formula A below, belongs to the N-(4-pyridinyl)-1H-indol-1-amine family. In the description hereafter, the term "besipirdine" is equally used to refer to besipirdine and its salts; the expression "besipirdine.HCI" strictly refers to besipirdine chiorydrate. US4970218. WO02/064126 and WO2005/035496 documents describe the obtention of N-(4-pyridinyl)-1H-indol-1-amines, these processes make it possible to prepare besipirdine and its salts. According to WO02/064126 document, it is known that some N-(4-pyridinyl)-1H-indol-1-amines can have pharmaceutical applications; for example, N-{3-fluoro-4-pyridinyI)-N-propyt-3-methyl-1H-indol-1-amine (or HP184) was shown to slightly iecrease the frequency of bladder contractions induced by bladder irritation in wo, in rats. The applicant recently found that besipirdine can be used in the reatment of symptoms associated with bladder irritation or related to effort ncontinence and mixed incontinence. In view of the prevalence of these disorders, besipirdine appears of great interest in pharmacy. The present invention is based on the discovery that besipirdine.HCl exists as several different crystal fonns differing from each other in stability, in particular. The besipirdine synthesis processes described at present lead to a compound whose polymorphic profile is not reproducible from one batch to another. Hence different batches can contain different polymorphs in variable proportions. Moreover, the polymorphic profile of certain batches synthesised using these methods has been shown to change with time, over a several months period. This lack of reproducibility and stability of the polymorphic profile over time makes it impossible to precisely control the pharmaceutical quality of the active compound. It can also influence the properties of final products containing this compound. Therefore identifying the stable form of besipirdine.HCI and detemnining the process(es) allowing its reproducible obtention appears highly desirable. Three polymorphic forms, called I, It, HI, and two solvates called IV (methanol solvate) and V (ethanol solvate) of besipirdine.HCl were identified that are obtained as a mixture after the synthesis processes described above. Form II is the most predominant fonn obtained following on from the process described in WO 2005/035496, in which it is isolated from conventional techniques ; more precisely, according to the exemplified method of synthesis, the product is obtained by precipitation of besipirdine solution in its base form using methanolic chlortiydric acid in n-butyl acetate solution. These five fomis were characterized and the form I, i.e. the stable form of besipirdine.HCl which, once obtained, does not evolve with time in storage conditions at room temperature, was characterized and compared with the other crystal and solvate fomns 11, 111, IV and V. Hence the present invention relates to a crystal form of besipirdine.HCl, called form I, corresponding to the formula A above and characterized by at least one of the following physico-chemical properties: a) In FTIR, form 1 displays at least the following absorption bands of the infrared spectrum: 778, 1198, 1121, but not the following absorption bands of the infrared spectrum: 3395, 1583, 732, the aforementioned bands being expressed in cm-1 at ± 5 cm-1; b) in PXRD, diffractogram of form 1 shows at least the following reflections, which are the most intense ones but whose intensity hereafter is given for information only: c) In DSC, fomn I displays at least an endothermic peak at 187.3 ± 2.0 "C using 5 "C/min scanning conditions, and a fusion enthalpy AH of 130.3 +2.0 J/g. Thanks to at least one of the characteristics mentioned above, form I can be distinguished from each one of the other forms 11, III, IV and V. it is preferentially characterized by at least two of the characteristics a), b) and c) above, if not all of them. The experimental conditions in which these physicochemical characteristics were measured are precisely decribed hereafter in dedicated subsections. By RMN 1H, besipirdine.HCl is characterized by a spectrum recorded in deutered chloroform {CDCI3) using a Brul 99.97 %. Transformation into form I is confirmed by DSC and PXRD analyses. EXAMPLE 18; preparation of an immediate release fomi from polymorphic form 1 of besipirdine.HCI From polymorphic fomi I of besipirdine.HCI, immediate release geiules are prepared by granulation in humid phase using the composition indicated in the table below: Ingredient Amount (mg) Besipirdine HCl, form I 20.00 Amidon (com) 95.75 Pregelatinised amidon (starch 1500) 35.00 Sodic croscarmellose 12.00 Microcristallin cellulose 80.00 Magnesium stearate 1.50 Colloidal silicon dioxide 0.75 Purified water qsf Total 245.00 Corn amidon and besipirdine.HCI are introduced in the granulator ) and mixed for about 5 minutes. Microcristallin cellulose, pregelatinised amidon and a proportion (50%) of sodic croscamiellose are added. The whole ingredients are mixed for about 5 minutes. Granulation of the powder is performed by adding demineralised water (39% w/w) with a 15 ml/min flow, until obtention of a 5 density of between 0.45 and 0.5 g/cm3 Granules are dried on a fluidised bed at 60°C for 30 minutes until obtention of a residual humidity ratio below 5%. Dried granules are calibrated on a 630 μm sieve, introduced in a container with the remainder of sodium croscarmellose and mixed for 5 minutes. Magnesium stearate and colloidal silicon dioxide are then added 0 and mixed for 15 minutes. Size 1 gelatin geiules are manually filled with the final mixture. EXAMPLE 19: preparation of an immediate release form from polymorphic form I of besipirdine.HCI ,5 From polymorphic form I of besipirdine.HCI, immediate release tablets are prepared that have the composition indicated in the table below; All ingredients, except magnesium stearate, are mixed in a Turbula mixer for 10 minutes. Magnesium stearate is then added and mixed for 5 minutes. Tablets are obtained by direct compression using a rotative press. CLAIMS 1. Crystal form of besipirdine.HCl (Form I) corresponding to the formula A below; Forrnnula A The aforementioned fornn being characterized by at least one of the following physico-chemical properties: a) in FTIR, it displays at least the following absorption bands of the infrared spectrum: 778, 1198, 1121, but not the following absorption bands of the infrared spectrum: 3395, 1583, 732, the aforementioned bands being expressed in cm'' at ± 5 cm'^; b) In PXRD, it shows at least the following reflections, which are the most intense ones but whose intensity hereafter is given for infomiation only; c) In DSC, it displays at least an endothennic peak at 187.3 ± 2.0 "C using 5 °C/min scanning conditions, and a fusion enthalpy AH of 130.4 ± 2.0 J/g. 2) Crystal form according to claim 1, characterized by at least two of the characteristics a), b) and c). 3) Crystal form according to claim 1 or 2, characterized by the three of the characteristics a), b) and c). 4) Process for obtaining crystal form I of besiplrdine.HCI, as defined in any one of claims 1 to 3, characterized in that it includes the following steps: Preparation of besipirdine.HCI, for example according to a known process such as the ones described in US4970218 and WO2005/035496, Solubilisation of besipirdine.HCI in a solvent, a mixture of solvents or a mixture solvent{s)/water, the aforementioned solvent(s) being chosen among those in which besipiniine.HCI is soluble, Evaporation, at least partial, of solvent or mixture, Retrieval and drying of obtained crystals. 5) Process according to claim 4, characterized in that besipirdine.HCI is solubilised in a solvent chosen among polar solvents, alcohols, cetones and esters. 6) Process according to claim 5, characterized in that the solvent is chosen among acetonitrile, acetone, ethanol, butanol. 7} Process according to claim 4, characterized in that the mixture of so!vent(s) with water is chosen among acetonitrileAvater and acetone/water mixtures. 8) Process according to claim 7, characterized in that the mixture of solvent(s) with water is chosen among acetonitrile/water, 90/10 (v/v) and acetone/water, 90/10 (v/v) mixtures. 9) Process according any of claims 4 to 6, characterized in that the solvent or the mixture Is evaporated at a temperature between 0C and room temperature. 10) Process acconding to claim 9, characterized in that evaporation is performed between 0°C and lO'C. 11) Process according to claim 10, characterized in that evaporation is performed at a temperature of about 4''C. 12) Process according to any of claims 4 to 11, characterized in that, before or during evaporation, suspension is seeded with a low amount of crystal form I of besipirdine.HCI. 13) Process according to any of claims 4 to 12, characterized in that besipirdine.HCI is solubilised in the said solvent or mixture until saturation, and, during evaporation of the solvent or mixture, a non solvent more volatile than the said solvent or mixture and in which besjpirdine.HCI is less soluble than in the said solvent or mixture, is diffused during evaporation of the solvent or mixture. 14) Process according to claim 13, characterized in that the non-solvent is diffused at room temperature. 15) Process according to claim 13 or 14, characterized in that the solvent or mixture and the non-solvent are chosen among one of the follow/ing couples: acetonitrile and acetone, acetonitrile and hexane, acetonitrileAvater and cyclohexene, acetonitrile/water and acetone, acetone/water and cyclohexene, butanol and cyclohexene. 16) Process according to any of claims 4 to 15, characterized in that crystals are retrieved by filtration. 17) Process for obtaining crystal fonn 1 of besipirdine.HCI, characterized in that it includes the following steps: Preparation of besipirdine.HCI, for example according to a known process such as the ones described in US4970213 and W02 005/035496, Besipirdine.HCI obtained in that way is maintained, possibly under agitation, in a humid environment in which relative humidity is at least 75%, Retrieval and drying of obtained crystals. 18) Process according to claim 17, characterized in that relative humidity is at least 85%. 19) Process according to claim 17 or 18, characterized in that the humid atmosphere is generated by an aqueous solution saturated in potassium nitrate. 20) Process for obtaining crystal fomi I of besipirdine.HCI, characterized in that it includes the follovi/ing steps: Preparation of besipirdine.HCI, for example according to a known process such as the ones described in US4970218 and WO2005/035496, Preparation of a suspension of besipirdine.HCI in a solvent in which it is not completely soluble, and agitation of this suspension. Washing, retrieval and drying of obtained crystals. 21) Process according to claim 20, characterized in that, before or during evaporation, the suspension is seeded with a low amount of crystal form 1 of besipirdine.HCI. 22) Process according to claim 21, characterized in that the solvent contains water traces, at least. 23) Process according to any of claims 20 to 23, characterized in that the said solvent is chosen among esters, cetones, ethers and alcohols including at least two carbon atoms. 24) Process according to claim 20, characterized in that the said solvent is chosen among n-butyie acetate, methyl-ethyl-cetone and methyl-isobutyl-cetone. 25) Process according to claim 17 or 20, characterized in that the suspension is agitated for at least one day. 26) Crystal forni of besipirdine.HCI corresponding to formula A below: FomnulaA Which is likely to be obtained by a process according to any of claims 4 to 25. 27) Use of crystal fomi I of besipirdine.HCI according to any of claims 1, 2, 3 or 26, for obtaining a stable fonm of a pharmaceutical composition. 28) Use according to claim 27, characterized in that the pharmaceutical composition is a therapeutic composition. 29) Use according to claim 28, characterized in that the pharmaceutic composition Is under a form with immediate or delayed liberation. 30) Use according to claim 28 or 29, characterized In that the therapeutic composition is intended to the trealment of symptoms of bladder irritation associated with indications such as overactive bladder (OAB) or interstitial cystitis, or to the treatnent of stress urinary incontinence or mixed incontinence. 31) Therapeutic composition containing as the active compound, at least 90% of crystal form I of besipinJine.HCI as defined in any of claims 1,2, 3 or 26.

Documents

Application Documents

# Name Date
1 4289-CHENP-2008 FORM-18 02-02-2010.pdf 2010-02-02
1 4289-CHENP-2008_EXAMREPORT.pdf 2016-07-02
2 4289-CHENP-2008 ABSTRACT.pdf 2012-04-25
2 4289-CHENP-2008 PCT.pdf 2012-04-25
3 4289-CHENP-2008 FORM-5.pdf 2012-04-25
3 4289-CHENP-2008 CLAIMS.pdf 2012-04-25
4 4289-CHENP-2008 FORM-3.pdf 2012-04-25
4 4289-CHENP-2008 CORRESPONDENCE OTHERS.pdf 2012-04-25
5 4289-CHENP-2008 DESCRIPTION (COMPLETE).pdf 2012-04-25
5 4289-CHENP-2008 FORM-1.pdf 2012-04-25
6 4289-CHENP-2008 DRAWINGS.pdf 2012-04-25
7 4289-CHENP-2008 DESCRIPTION (COMPLETE).pdf 2012-04-25
7 4289-CHENP-2008 FORM-1.pdf 2012-04-25
8 4289-CHENP-2008 CORRESPONDENCE OTHERS.pdf 2012-04-25
8 4289-CHENP-2008 FORM-3.pdf 2012-04-25
9 4289-CHENP-2008 CLAIMS.pdf 2012-04-25
9 4289-CHENP-2008 FORM-5.pdf 2012-04-25
10 4289-CHENP-2008 PCT.pdf 2012-04-25
10 4289-CHENP-2008 ABSTRACT.pdf 2012-04-25
11 4289-CHENP-2008_EXAMREPORT.pdf 2016-07-02
11 4289-CHENP-2008 FORM-18 02-02-2010.pdf 2010-02-02