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WO2014064076A1 - Procédé de préparation d'un polymorphe de maléate d'asénapine - Google Patents

Procédé de préparation d'un polymorphe de maléate d'asénapine Download PDF

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Publication number
WO2014064076A1
WO2014064076A1 PCT/EP2013/072026 EP2013072026W WO2014064076A1 WO 2014064076 A1 WO2014064076 A1 WO 2014064076A1 EP 2013072026 W EP2013072026 W EP 2013072026W WO 2014064076 A1 WO2014064076 A1 WO 2014064076A1
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WO
WIPO (PCT)
Prior art keywords
asenapine maleate
polymorph
hydrocarbon
comprised
asenapine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2013/072026
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English (en)
Inventor
Giuseppe Barreca
Gianpiero Ventimiglia
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chemo Iberica SA
Original Assignee
Chemo Iberica SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chemo Iberica SA filed Critical Chemo Iberica SA
Publication of WO2014064076A1 publication Critical patent/WO2014064076A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to the process for the preparation of a polymorph of asenapine maleate, in addition to the use of this compound for the preparation of pharmaceutical compositions.
  • Asenapine is marketed as the maleic acid salt under the trade name SAPHRIS ® (a registered trademark of N.V. Organon, a subsidiary of Merck & Co., Inc.).
  • polymorphism The property of some molecules or molecular complexes to take more than one amorphous or crystalline form in the solid state is commonly referred to as polymorphism, and the different forms of a compound are referred to as polymorphs.
  • polymorphism is due to the ability of the molecules in a compound to change their conformation or give rise to different inter- or intramolecular interactions, such as hydrogen bonds, which are reflected in different atomic arrangements in the crystal lattice of the various polymorphs.
  • the various polymorphs of a substance have different crystal lattice energies, thus showing different physical properties such as shape, density, melting point, color, stability, dissolution level, ability to be milled, granulated or compacted. These differences in morphology or polymorphism can also have a significant effect on the flowability of the milled solid (flowability affects the ease of handling a material during its transformation into a pharmaceutical product); on the stability during transport and storage of individual forms of administration; on the ability to produce different forms of administration and their application; on solubility in polar or apolar, protic or aprotic solvents, in aqueous solutions, in gastric juices or serum; and finally, on bioavailability.
  • a salt of a pharmaceutical compound From a physical point of view, once a salt of a pharmaceutical compound has been isolated, it can be characterized by its thermal behavior. Said thermal behavior is normally determined in the laboratory using differential scanning calorimetry (DSC). Melting point, glass transitions, crystallinity, presence of solvates and/or polymorphs can be noticed through their endo- or exothermic peaks or the variations of the baseline in the corresponding DSC diagram.
  • DSC differential scanning calorimetry
  • Polymorphism can also give rise to different physicochemical properties which are detectable by X-ray powder diffraction (XRPD).
  • XRPD X-ray powder diffraction
  • only crystalline samples diffract at well defined angles, whereby different peaks are observed depending on the nature of the crystalline form.
  • each crystalline form gives rise to a unique diffraction profile.
  • Asenapine maleate was obtained for the first time as anhydrous monocline form (also known as form H), as described by Funke et al. in Arzneim.-Forsch/Drug Res., 40:536-539 (1999).
  • this form is characterized by a melting point in the range between 141 and 145 °C.
  • the particle size of a pharmaceutical compound significantly affects its biopharmaceutical properties and thus, as described in this application, obtaining asenapine maleate salt as fine powder is a desirable feature.
  • the fine powders described have size lower than 100 ⁇ or preferably in the range between 10 and 50 ⁇ .
  • the particle size of these powders can be further reduced to below 10 ⁇ through a micronization process which, however, when conducted on form H (monocline), partly converts it into the orthorhombic form (form L).
  • form H monocline
  • form L orthorhombic form
  • fine powders represents a desirable condition not only for preparing solid pharmaceutical forms such as tablets or capsules, but also for preparing pharmaceutical forms that include a step of solubilizing the active ingredient (e.g. freeze drying), since especially in the case of poorly soluble compounds, such as the salt subject of this application, obtaining said dimensions results in a significant increase in the solubilization rate.
  • solubilizing the active ingredient e.g. freeze drying
  • the present invention relates to a process for the preparation of a polymorph of asenapine maleate as a fine powder, comprising the following steps:
  • step b) adding the solution obtained in step a) to a hydrocarbon or a suspension containing a seed of said polymorph of asenapine maleate in a hydrocarbon, kept under conditions of turbulent flow, in a time range between 0.5 and 10 hours, at a temperature between -30 and 30 °C;
  • a further step, a') is carried out between steps a) and b).
  • the solution obtained in step a) is filtered before being added to the hydrocarbon or the suspension containing a seed of said polymorph of asenapine maleate in a hydrocarbon.
  • the inventors have unexpectedly identified a method for preparing a polymorphic form of asenapine maleate as a fine powder.
  • seeding defines a crystalline substance that is added to the solution of the same substance to be crystallized. Such a seeding aims to activate the nucleation process and thus facilitate crystallization.
  • the seeding with a specific crystalline form often has the useful effect of favoring the crystallization of the product in the same crystalline form as the seed used.
  • excipient means any substance contained in the final pharmaceutical form that is not the active ingredient and that generally is not therapeutically effective per se. Excipients are essential for the administration of the active ingredient because they allow the dosage form to be appropriately formulated for conveying the drug to the target site. Excipients are commonly referred to as raw materials that go into the composition of a pharmaceutical preparation with the aim of giving a form, easing administration and preserving the active ingredient. Moreover, they contribute to characterizing the pharmaceutical preparation in terms of appearance, stability, biopharmaceutical profile and acceptability by the patient.
  • DSC tests referred to in the following description are carried out at a scanning rate of 10 °C/min and under an inert atmosphere; besides, in the following description, the values of lower and upper limits of temperature ranges in which DSC features occur are to be intended as given with an approximation of ⁇ 0.5 °C.
  • the invention relates to a new process for the preparation of fine powders of a polymorph of asenapine maleate characterized by an XRPD pattern comprising peaks at 10.1 °, 10.7°, 12.1 °, 17.1 °, 20.0°, 22.4°, and 24.4° 2 ⁇ and by a DSC thermogram showing an intense endothermic feature between 1 12.8 and 144.2 °C. Any values of 2 ⁇ angles reported above, in the following description and in the claims, must be intended as given with an approximation of ⁇ 0.2.
  • the polymorph obtained by the process of the present invention corresponds to the polymorph referred to as form G1 in international patent application WO 2012/080195 A2; for the sake of brevity, the definition "form G1 " will be adopted in the rest of the description and in the examples.
  • the particle size distribution in a powder sample can be determined by using various techniques generally known in the field, such as by using calibrated screens or optical microscopy.
  • the distribution of asenapine maleate particles of the present invention was preferably determined by laser scattering using, in particular, a laser beam diffraction instrument Malvern Mastersizer 2000 (Malvern Instruments Ltd., Worcestershire, UK). Samples of asenapine maleate were suspended in heptane, then sonicated for 180 seconds to completely disperse the particles. The dispersion was circulated in the flow cell of Malvern ® Mastersizer 2000 for 120 seconds before the measurement.
  • D 90 One of the parameters most commonly used to describe the particle size distribution of powders is the value of D 90 , i.e. such that 90% of the particles making up the sample being examined is smaller than said value.
  • the value of D 90 is expressed as diameter; for non-spherical particles, the Malvern ® Mastersizer 2000, using an internal algorithm of the instrument, relates the particle size to that of spheres.
  • This process allows fine powders to be obtained, characterized by a D 90 less than 100 ⁇ , preferably in the range between 10 and 50 ⁇ , particularly in the range between 20 and 40 ⁇ .
  • step a) of the process the asenapine maleate is solubilized in a chlorinated solvent such as dichloromethane, dichloroethane, chloroform or a mixture thereof (preferably dichloromethane) at a temperature preferably in the range between 20 and 60 °C, for example in the range between 30 and 35 °C.
  • a chlorinated solvent such as dichloromethane, dichloroethane, chloroform or a mixture thereof (preferably dichloromethane) at a temperature preferably in the range between 20 and 60 °C, for example in the range between 30 and 35 °C.
  • the amount of asenapine maleate solubilized in these solvents can vary in a very wide range; preferably, the volume of solvent used can vary in the range between 2 mL/g and 4 mL/g with respect to the amount of asenapine maleate used, even more preferably said volume is 2 mL/g; working with more diluted solutions leads to obtaining lower yields and increased economic and environmental impact of the process.
  • step b) of the process the solution thus obtained is added, in a time ranging between 0.5 and 10 hours, preferably in the range between 1 and 3 hours (e.g. 2 hours), to a hydrocarbon or a suspension containing a seed of form G1 of asenapine maleate in a hydrocarbon, at a temperature in the range between -30 and 30 °C, preferably in the range between -20 and 10 °C.
  • Hydrocarbons useful for the purpose are aliphatic (preferably heptane) or aromatic (preferably toluene or xylene) hydrocarbons, used in an amount in the range between 4 mL/g and 8 mL/g, preferably between 5 mL/g and 7 mL/g, with respect to the amount of asenapine maleate used.
  • the solution obtained in step a) is filtered in a step a') before being added to the hydrocarbon or the suspension containing a seed of form G1 of asenapine maleate in a hydrocarbon in order to eliminate any particulate or impurity which could promote undesired crystallization.
  • Turbulence is a flow regime of fluids. At low motion speed, both in case of straight and rotational flow, a fluid moves in an ordered fashion called “laminar flow regime", in which the particles of the fluid move along a constant and foreseeable trajectory. When the motion speed of the fluid is increased, the same is subject to a transition into the turbulent flow regime, in which the movement of fluid particles becomes chaotic. The transition from laminar to turbulent flow is favoured by low a viscosity of the fluid (which, in a given fluid, is inversely proportional to the temperature of the same), and by high values of density.
  • turbulent flow can be established for instance by mechanical stirring, usually in the range between 20 and 500 revolutions per minute (rpm), preferably in the range between 50 and 150 rpm (for example 100 rpm).
  • rpm revolutions per minute
  • Stirrers usually consist of a shaft carrying some radial blades; if the stirrer must also impart axial motion to the liquid, in addition to radial motion, the rotatable member consists of helical blades or turbines.
  • the mixing operation can be affected by the formation of vortexes which make inefficient the stirrer functioning.
  • baffles has the further advantages of favoring the transition from laminar to turbulent flow when rotation rates are comprised between 20 and 50 rpm and to increase turbulence with rotation rates above 50 rpm.
  • step c) of the process form G1 of asenapine maleate is recovered as a solid.
  • This step can be performed using one of the methods known to the man skilled in the art for separating a crystallized solid from the mother liquor, for example through filtration, optionally under pressure or vacuum, or by centrifugation.
  • the solid thus obtained is then washed with at least one solvent, usually the same used in the previous crystallization step, and dried. Drying can be carried out in a range of temperatures between 40 and 80 °C (preferably at 40 °C).
  • the crystalline solid obtained by means of the process comprising steps a), b) and c) is a fine powder, i.e.
  • a particle diameter lower than 100 ⁇ preferably in the range between 10 and 50 ⁇ , particularly in the range between 20 and 40 ⁇ .
  • This operation can be done, for example, through sieves or screens.
  • the form of asenapine maleate object of the present invention is particularly stable at room temperature and its preparation is reproducible and particularly suitable for large-scale production. This process can be used to obtain asenapine maleate having a chemical purity determined by HPLC higher than 99.5%, particularly suitable for the preparation of pharmaceutical dosage forms.
  • Form G1 of asenapine maleate can be used in particular in combination with a pharmaceutically acceptable excipient, in the preparation of pharmaceutical formulations such as tablets, capsules, pills, powder, granules, lozenges, elixirs, syrups, solutions, suspensions, emulsions, drops, lotions, sprays, dyes, creams, ointments, gels, unguents, rectal capsules and transdermal devices for oral, enteral, parenteral or topical administration.
  • pharmaceutical formulations such as tablets, capsules, pills, powder, granules, lozenges, elixirs, syrups, solutions, suspensions, emulsions, drops, lotions, sprays, dyes, creams, ointments, gels, unguents, rectal capsules and transdermal devices for oral, enteral, parenteral or topical administration.
  • the acquisition was carried out in 2 ⁇ step scan mode and in Bragg-Brentano configuration, at a scan speed of 0.04 degrees per second in the range between 3° and 40° in ⁇ /2 ⁇ .
  • the samples were carefully ground into a mortar and placed in the hollow of an aluminum sampler. Before carrying out the measurement (remotely, using the WinAcq32 software), the instrument was calibrated with zinc oxide (purity > 99.5%).
  • DSC analyses were performed with a differential scanning calorimeter Mettler- Toledo Star 8 in open aluminum pans, heating the sample from 30 to 300 °C under nitrogen atmosphere with a gradient of 10 °C per minute.
  • Example 1 -7 are carried out with the use of a seed of form G1
  • Example 8 is carried out without seeding; the procedure of the latter example can be used to produce seeds of form G1 .
  • Asenapine maleate (1500 g, 3.73 mol) is solubilized under mechanical stirring at 30 °C, in dichloromethane (3000 mL). Such a solution is filtered on a carbon and celite pad, then the pad is washed with dichloromethane (100 mL). The filtered solution and the washings are combined and the resulting solution is added dropwise over about 2 hours to a suspension cooled to 0 °C, containing a seed of form G1 of asenapine maleate in toluene (7500 mL), under vigorous stirring (about 100 rpm) and in the presence of baffles.
  • Example 1 The procedure described in Example 1 is repeated with the only difference that the suspension of toluene containing a seed of form G1 of asenapine maleate is cooled to 5 °C instead of 0 °C, leading to 1337 g of form G1 of asenapine maleate having a D 90 value of 29 ⁇ .
  • Example 1 The procedure described in Example 1 is repeated with the only difference that the suspension of toluene containing a seed of form G1 of asenapine maleate is cooled to -5 °C instead of 0 °C, leading to 1420 g of form G1 of asenapine maleate having a D 90 value of 34 ⁇ .
  • Asenapine maleate (1078 g, 2.68 mol) is solubilized under mechanical stirring at 30 °C, in dichloromethane (2160 ml_). Such a solution is filtered on a carbon and celite pad, then the pad is washed with dichloromethane (300 ml_). The filtered solution and the washings are combined and the resulting solution is added dropwise over about 2 hours to a suspension cooled to -15 °C, containing a seed of form G1 of asenapine maleate in toluene (7550 ml_), under vigorous stirring (about 100 rpm) and in the presence of baffles.
  • Example 4 The procedure described in Example 4is repeated with the only difference that the suspension of toluene containing a seed of form G1 of asenapine maleate is cooled to -20 °C instead of -15 °C, leading to 979 g of form G1 of asenapine maleate having a D 90 value of 30 ⁇ .
  • Example 4 The procedure described in Example 4is repeated with the only difference that the suspension of toluene containing a seed of form G1 of asenapine maleate is cooled to -10 °C instead of -15 °C, leading to 969 g of form G1 of asenapine maleate having a D 90 value of 35 ⁇ .
  • Asenapine maleate (101 g, 0.25 mol) is solubilized in dichloromethane (200 ml_) under mechanical stirring at 30 °C.
  • the solution is filtered on a carbon and celite pad and then added dropwise over about 2 hours to a suspension maintained at 15 °C, containing a seed of form G1 of asenapine maleate in toluene (400 ml_), under vigorous stirring (about 100 rpm).
  • the suspension is left under vigorous stirring for 30 minutes, then the solid obtained is filtered, washed with toluene and dried at 40 °C under reduced pressure.
  • 89 g of form G1 of asenapine maleate are obtained, having a D 90 value of 55 ⁇ .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé de production d'un polymorphe connu de maléate d'asénapine, sous la forme de poudres dont la valeur D90 est inférieure à 100 µm.
PCT/EP2013/072026 2012-10-24 2013-10-22 Procédé de préparation d'un polymorphe de maléate d'asénapine Ceased WO2014064076A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2012A001810 2012-10-24
IT001810A ITMI20121810A1 (it) 2012-10-24 2012-10-24 Poliformi di maleato di asenapina e processo per la loro preparazione

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

Citations (5)

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Publication number Priority date Publication date Assignee Title
US4145434A (en) 1976-05-24 1979-03-20 Akzona Incorporated Tetracyclic derivatives and pharmaceutical compositions of matter
WO1995023600A1 (fr) 1994-03-02 1995-09-08 Akzo Nobel N.V. Composition pharmaceutique sublinguale ou buccale
WO2006106135A1 (fr) 2005-04-07 2006-10-12 N.V. Organon Forme cristalline du maléate d'asenapine
WO2008040816A1 (fr) 2006-10-06 2008-04-10 N.V. Organon Asénapine amorphe et ses procédés de préparation
WO2012080195A2 (fr) 2010-12-13 2012-06-21 Chemo Iberica, S.A. Formes polymorphes de maléate d'asénapine et procédés pour leur préparation

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WO2012114325A1 (fr) * 2011-02-23 2012-08-30 Mapi Pharma Limited Polymorphes d'de maléate d'asénapine
WO2012123325A1 (fr) * 2011-03-11 2012-09-20 Medichem S.A. Nouvelles formes cristallines du sel de trans-5-chloro-2-méthyl-2,3,3a,12b-tétrahydro-1h-dibenzo[2,3:6,7] oxépino[4,5-c]pyrrole avec l'acide maléique

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US4145434A (en) 1976-05-24 1979-03-20 Akzona Incorporated Tetracyclic derivatives and pharmaceutical compositions of matter
WO1995023600A1 (fr) 1994-03-02 1995-09-08 Akzo Nobel N.V. Composition pharmaceutique sublinguale ou buccale
WO2006106135A1 (fr) 2005-04-07 2006-10-12 N.V. Organon Forme cristalline du maléate d'asenapine
WO2008040816A1 (fr) 2006-10-06 2008-04-10 N.V. Organon Asénapine amorphe et ses procédés de préparation
WO2012080195A2 (fr) 2010-12-13 2012-06-21 Chemo Iberica, S.A. Formes polymorphes de maléate d'asénapine et procédés pour leur préparation
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US12138353B2 (en) 2016-12-20 2024-11-12 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

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