Field of the invention

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.

State of the art

Asenapine, the chemical name of which is (3af?,12b/ ^: ?)-5-chloro-2-methyl- 2,3,3a,12b-tetrahydro-1 H-dibenzo[2,3:6,7]oxepin[4,5-c]pyrrole, is a compound of formula (I):

This compound, described for the first time in patent US 4,145,434, is suitable for the treatment of central nervous system disorders, particularly schizophrenia, due to its ability to act as receptor antagonist of dopamine and serotonin.

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.).

It is well known to the man of ordinary skill in the art that the crystalline form and the morphology of the solid form of a pharmaceutical compound can significantly influence its physicochemical properties, for example its stability, dissolution level, bioavailability, and so on.

Some substances exist in a single crystalline form; others, however, may exist in two, three or even more crystalline forms. 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. In general, 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.

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.

Polymorphism can also give rise to different physicochemical properties which are detectable by X-ray powder diffraction (XRPD). In particular, only crystalline samples diffract at well defined angles, whereby different peaks are observed depending on the nature of the crystalline form. In particular, each crystalline form gives rise to a unique diffraction profile.

The discovery of a new polymorph of a known active ingredient provides an opportunity to improve the characteristics of the latter, widening the possibilities which are available to a formulation specialist when designing a new pharmaceutical form, a drug with a particular release profile or a certain dissolution level. Logical consequence of the above is a constant research in the field of the pharmaceutical industry for new polymorphs of known compounds, in order to improve their pharmacological properties which are not satisfactory.

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). In particular, this form is characterized by a melting point in the range between 141 and 145 °C.

International patent application WO 2006/106135 describes a different crystalline form of asenapine maleate, defined orthorhombic (form L), the melting point of which is in the range between 138 and 142 °C.

International patent application WO 2008/040816 describes an amorphous form asenapine maleate, prepared through a spray-drying or freeze-drying process. However, the amorphous form prepared according to these processes is particularly unstable and spontaneously evolves to give form H.

International patent application WO 2012/080195 (to the present applicant) describes the preparation of three new polymorphic forms of asenapine maleate, G, G1 and G2.

International patent application WO 95/23600 describes the preparation of a formulation for oral or sublingual administration of asenapine maleate.

It is known that 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. In particular, the fine powders described have size lower than 100 μιτι or preferably in the range between 10 and 50 μιτι. The particle size of these powders can be further reduced to below 10 μιτι through a micronization process which, however, when conducted on form H (monocline), partly converts it into the orthorhombic form (form L). The drawback of this process comes from the unpredictable ratio between the two forms L and H generated by the micronization process.

Since each crystalline form is characterized by its physico-chemical properties, a mixture of polymorphs in a pharmaceutical form gives rise to unpredictable properties, thus impairing the effectiveness itself of the drug.

The use of 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.

According to these considerations, the preparation of a solid form of asenapine maleate directly in the form of fine powders is of considerable interest in the field of formulation.

These objects are achieved with the present invention, which relates to the preparation of a polymorph of asenapine maleate as a fine powder.

Summary of the invention

The present invention relates to a process for the preparation of a polymorph of asenapine maleate as a fine powder, comprising the following steps:

a) dissolving asenapine maleate in a chlorinated solvent or a mixture of chlorinated solvents;

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;

c) recovering the solid.

In a variant of the process object of the present invention, a further step, a'), is carried out between steps a) and b). In this variant, 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.

Detailed description of the invention

The inventors have unexpectedly identified a method for preparing a polymorphic form of asenapine maleate as a fine powder.

All terms used in the present application, unless otherwise indicated, must be interpreted in their ordinary meaning as known in the technical field. Other more specific definitions for some terms used in the present application are given below and are intended to be applied uniformly to the entire application, unless otherwise indicated.

The term "about" includes the experimental error range that can normally take place when making a measurement.

The term "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.

The term "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.

XRPD analysis and DSC thermal analysis were used to characterize polymorphic forms of asenapine maleate. 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° 2Θ and by a DSC thermogram showing an intense endothermic feature between 1 12.8 and 144.2 °C. Any values of 2Θ 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.

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 μιτι, preferably in the range between 10 and 50 μιτι, particularly in the range between 20 and 40 μιτι.

In 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. 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.

In 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.

In a variant of the process object of the present invention, 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.

The hydrocarbon or the suspension to which the solution of asenapine maleate is added must be kept under conditions of turbulent flow. 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. Although turbulence is an extremely complex parameter to define and measure, it is commonly known that the transition of a fluid motion regime to turbulent flow can be obtained by means of a vigorous stirring; with the organic solvents used in step b) of the present invention, 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). 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. This drawback can be avoided by placing appropriate vortex-breaker baffles within the system to be stirred. The use of 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. Despite the difficulties in describing the conditions of turbulent flow from the theoretical point of view, and hence the difficulty of giving numerical figures that characterize it, with the information given above about typical rpm stirring ranges and the possible use of baffles, the skilled person may easily identify, with a few tests, what mixing conditions allow to obtain the turbulent flow regime needed for the reproduction of the present invention.

In 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. characterized by a particle diameter lower than 100 μιτι, preferably in the range between 10 and 50 μιτι, particularly in the range between 20 and 40 μιτι. In addition to the operation described above, it is also possible to sift said powder to separate the fraction thereof having unsuitable dimensions. 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.

The present invention will be further described by means of the following examples.

XRPD analysis was carried out using a diffractometer APD 2000 Ital Structures operating at room temperature, using a CuKcc tube (40 kV, 30 mA, λ = 1 .5406 A) as the X-rays source.

The acquisition was carried out in 2Θ 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 Θ/2Θ. 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.

The following examples illustrate the preparation of form G1 of asenapine maleate directly in the form of fine powders. Examples 1 -7 are carried out with the use of a seed of form G1 , while Example 8 is carried out without seeding; the procedure of the latter example can be used to produce seeds of form G1 .

Example 1

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. At the end of the addition, 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. 1378 g of form G1 of asenapine maleate are obtained, having a D ₉₀ value of 26 μιτι.

Example 2

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 μιτι.

Example 3

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 μιη.

Example 4

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. At the end of the addition, 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. 1020 g of form G1 of asenapine maleate are obtained, having a D ₉₀ value of 22 μιη.

Example 5

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 μιτι.

Example 6

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 μιτι.

Example 7

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). At the end of the addition, 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 μιη.

Example 8

A solution of asenapine maleate (10.0 g, 24.9mmol) in dichloromethane (70 mL) at 30 °C is filtered (on a paper filter)under reduced pressure and then poured into a flask containing toluene (210 mL) cooled to -15 °C. At the end of the addition, the mixture 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. 8.5 g of form G1 of asenapine maleate are obtained.