PROCESS FOR THE PREPARATION OF ASENAPINE IN THE FORM OF ITS FREE BASE

Abstract

The present invention relates to a process for the preparation of asenapine in the form of its free base, a process for the preparation of an active ingredient-containing layer for use in a transdermal therapeutic system, asenapine in the form of its free base, obtainable by said process for the preparation of asenapine in the form of its free base, an active ingredient-containing layer for use in a transdermal therapeutic system, obtainable by said process for the preparation of an active ingredient-containing layer and a transdermal therapeutic system containing such an active ingredient-containing layer.

Claims

1. A process for the preparation of asenapine in the form of its free base comprising the steps of: 1) providing a reaction mixture comprising asenapine maleate and an alkali metal silicate in a solvent, wherein the reaction mixture contains the alkali metal silicate in dispersed form, and 2) reacting asenapine maleate with the alkali metal silicate in the reaction mixture provided in step 1) in order to obtain a product mixture which contains dissolved asenapine in the form of its free base and alkali metal maleate in dispersed form.

2. The process according to claim 1 further comprising the step of: 3) isolating a solution containing asenapine in the form of its free base from the product mixture obtained in step 2.

3. The process according to claim 1, wherein the solvent used in step 1) contains water.

4. The process according to claim 1, wherein the alkali metal silicate is selected from the group consisting of sodium metasilicate, sodium trisilicate, potassium silicate and mixtures thereof.

5. The process according to claim 1, wherein the d50 particle diameter of the alkali metal silicate used in step 1) is 125 μm or more, or less than 125 μm.

6. The process according to claim 1, wherein the solvent in step 1) contains an alcoholic solvent.

7. A process for the preparation of an active ingredient-containing layer for use in a transdermal therapeutic system, wherein said process comprises the following steps of: i. preparing asenapine in the form of its free base by means of the process according to claim 1, ii. combining at least the asenapine in the form of its free base obtained in step i) and a polymer in a further solvent in order to obtain a coating composition; iii. coating the coating composition on a back layer, a peelable film or an intermediate film, and iv. drying the coated coating composition to form the active ingredient-containing layer.

8. Asenapine in the form of its free base, obtainable by a process according to claim 1, wherein the asenapine in the form of its free base has a purity of 99.0% or more, 99.5% or more, or 99.95% or more, wherein the purity is determined by means of HPLC.

9. An active ingredient-containing layer for use in a transdermal therapeutic system, obtainable by a process according to claim 7, wherein the asenapine in the form of its free base in the active ingredient-containing layer has a purity of 99.0 % or more, 99.5% or more, or more, wherein the purity is determined by means of HPLC.

10. A transdermal therapeutic system containing an active ingredient-containing layer according to claim 9.

11. The process according to claim 3, wherein the solvent used in step 1) contains water and asenapine maleate in a molar ratio of 4 or less parts of water, 3 or less parts of water, from 3 to ¼ parts of water, or from 2 to ⅓ parts of water, each based on 1 part of asenapine maleate.

12. The process according to claim 1, wherein the d80 particle diameter of the alkali metal silicate used in step 1) is less than 200 μm.

13. The process according to claim 6, wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, l-propanol, 2-propanol and mixtures thereof.

14. A process for the preparation of an active ingredient-containing layer for use in a transdermal therapeutic system, wherein said process comprises the following steps of: i) preparing asenapine in the form of its free base by means of the process according to claim 2, ii) combining at least the asenapine in the form of its free base obtained in step i) and a polymer in a further solvent in order to obtain a coating composition, wherein the asenapine in the form of its free base obtained in step i) and used in step ii) is present in a solution isolated according to step 3); iii) coating the coating composition on a back layer, a peelable film or an intermediate film, and iv) drying the coated coating composition to form the active ingredient-containing layer.

15. Asenapine in the form of its free base, obtainable by a process according to claim 2, wherein the asenapine in the form of its free base has a purity of 99.0% or more, 99.5% or more, or 99.95% or more, wherein the purity is determined by means of HPLC, and wherein the asenapine in the form of its free base is present in a solution isolated according to step 3).

16. An active ingredient-containing layer for use in a transdermal therapeutic system, obtainable by a process according to claim 14, wherein the asenapine in the form of its free base in the active ingredient-containing layer has a purity of 99.0 % or more, 99.5% or more, or 99.95% or more, wherein the purity is determined by means of HPLC.

17. A transdermal therapeutic system containing an active ingredient-containing layer according to claim 16.

Description

DETAILED DESCRIPTION

Process for the Preparation of Asenapine in the Form if its Free Base

[0061] According to a first aspect, the present invention relates to a process for the preparation of asenapine in the form of its free base.

[0062] The process comprises first a step 1) of providing a reaction mixture wherein asenapine maleate as well as alkali metal silicate are used in a solvent. This produces a reaction mixture in which asenapine maleate can be present in dispersed form, i.e. partly dissolved and partly as a solid, or completely dissolved in the solvent. The solubility of the asenapine maleate depends in particular on the type and the mass of the solvent used and on the mass of the asenapine maleate used. In any event, the alkali metal silicate is present as part of the reaction mixture in dispersed form in the solvent. Here, the asenapine maleate can be completely or partially present as a solid in the solvent. The asenapine maleate can be present in the reaction mixture as a solid in an amount of 0% by mass, 10% by mass or more, 30% by mass or more, 50% by mass or more, or 70% by mass or more, based on the total mass of the asenapine maleate used. Correspondingly, asenapine maleate can be present in dissolved form in the solvent in an amount of 100% by mass, 90% by mass or less, 70% by mass or less, 50% by mass or less, or 30% by mass or less, based on the total mass of the asenapine maleate used. The alkali metal silicate can essentially be present as a solid in the solvent of the reaction mixture, for example in an amount of 50% by mass or more, 60% by mass or more, 70% by mass or more, 80% by mass or more, 90% by mass or more, or 95% by mass or more; or completely, that is, to about 100% by mass, based on the total mass of the alkali metal silicate used. It was found, surprisingly, that the use of an alkali metal silicate, i.e. using alkali metal cations, in particular potassium cations and/or sodium cations, is important because metal silicates, that only contain higher-valent metal cations, such as, for example, magnesium cations, calcium cations or aluminum cations, do not lead to a significant conversion of asenapine maleate. The fraction of the alkali metal silicate which is not present in the solvent as a solid but in dissolved form is, for example, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, or 5% by mass or less, or 1% by mass or less, based on the total mass of the alkali metal silicate used. In other words, the reaction mixture is a dispersion which contains fractions of a suspension and fractions of a solution.

[0063] After the reaction mixture has been completely provided, i.e. no further substances are added, in a second step 2) reacting at a specific temperature, for example at room temperature and for example with stirring, is carried out. After the reaction, a product mixture is formed which contains dissolved asenapine in the form of its free base and alkali metal maleate in dispersed form (e.g., with a solids fraction of about 100% by mass, based on the total mass of the alkali metal maleate). Both solid alkali metal maleate as well as dissolved asenapine in the form of its base are contained in the solvent. In particular, the alkali metal maleate that is formed, is present in the product mixture surprisingly approximately completely as a solid (e.g., ≥98% by mass). The conversion of the asenapine maleate to asenapine in the form of its free base takes place in that the maleic acid is deprotonated by the alkali metal silicate, wherein solid alkali metal maleate and dissolved asenapine in the form of its free base are formed. Moreover, free silicic acid is formed by protonation of the silicate anion. Without wishing to be bound by theory, it is assumed that the free silicic acid reacts further with elimination of water to form silicon dioxide, which is present in the product mixture as a solid (e.g., a solids fraction of about 100% by mass, based on the total mass of silicon dioxide).

[0064] In this manner, surprisingly, by the reaction of asenapine maleate with an alkali metal silicate, high conversions to asenapine in the form of its free base in high purity can be obtained. Without wishing to be bound by theory, it is believed that the driving force for the high conversions is the formation of solid silicon dioxide as well as solid alkali metal maleate, and that the high purities are achieved because there are no further reactions or side reactions of dissolved asenapine in the form of its free base.

[0065] For example, the reaction can be carried out under a protective gas, in particular comprising argon and/or nitrogen. For this purpose, a protective gas atmosphere, in particular comprising argon and/or nitrogen, can be generated by flushing gas through a reaction vessel while the reaction mixture is being prepared.

[0066] Therefore, the process according to the invention for the preparation of asenapine in the form of its free base comprises the steps of: [0067] 1) providing a reaction mixture comprising asenapine maleate and an alkali metal silicate in a solvent, wherein the reaction mixture contains the alkali metal silicate in dispersed form; and [0068] 2) reacting asenapine maleate with the alkali metal silicate in the reaction mixture provided in step 1) in order to obtain a product mixture which contains dissolved asenapine in the form of its free base and alkali metal maleate in dispersed form.

[0069] In certain embodiments, the process according to the invention comprises a third step of isolating a solution containing asenapine in the form of its free base from the product mixture obtained in step 2). Here, in particular, a solid contained in the product mixture, which solid may contain silicon dioxide and alkali metal maleate, for example, is removed from the product mixture in order to obtain a solution containing asenapine in the form of its free base. In particular, the isolation can be carried out by means of a filtration, a solid phase extraction, a sedimentation, a decanting, or by means of a centrifugation. Said isolation can simplify further processing of the asenapine in the form of its free base. Otherwise, the product mixture contains solids, such as silicon dioxide and alkali metal maleate, which would be present as impurities in particular during the preparation of a matrix layer and thus could affect the quality of the matrix layer to be prepared. In particular, the solution obtained can be used directly for the preparation of a matrix layer.

[0070] According to certain embodiments the solvent used in step 1) contains water. For example, water can be used to increase the solubility of the asenapine maleate and/or the solubility of the alkali metal silicate, as a result of which the conversion takes place faster. In particular, the solvent used in step 1) contains water and asenapine maleate in a molar ratio of 4 or less parts of water, preferably 3 or less parts of water, more preferably from 3 to ¼ parts of water, and most preferably from 2 to ⅓ parts of water, each based on 1 part of asenapine maleate. A molar ratio between water and asenapine maleate in the ranges defined above leads to a high conversion of asenapine maleate to asenapine in the form of its free base and a high purity of asenapine in the form of its free base. This is surprising and unexpected, since in general, without wishing to be bound by theory, it can be assumed that one of the driving forces of the reaction, namely the formation of silicon dioxide, which takes place with elimination of water, should be inhibited due to the presence of additional water in the reaction mixture. Accordingly, on the contrary, a lower conversion would have to be expected due to the addition of water. Surprisingly, it was also found that a molar ratio of more than 4 parts of water based on 1 part of asenapine maleate significantly slowed down the conversion of the asenapine maleate.

[0071] In certain embodiments, the alkali metal silicate is selected from the group consisting of sodium metasilicate, sodium trisilicate, potassium silicate and mixtures thereof. Sodium metasilicate is particularly preferred. Furthermore, the alkali metal silicate can also contain heterogeneous alkali metal metasilicates which, in addition to alkali metal cations, also can contain alkaline earth metal cations, such as, for example, calcium and/or magnesium, or earth metal cations such as aluminum. Examples are potassium aluminum disilicates or sodium aluminosilicates, for example AlNa.sub.12SiO.sub.5

[0072] According to certain embodiments, the d50 particle diameter of the alkali metal silicate used in step 1) is 125 μm or more, or less than 125 μm. Alternatively, the d80 particle diameter can be less than 200 μm. Surprisingly, it has here been found that particularly high conversions in a shortened reaction time, for example within one day, could be achieved by using alkali metal silicates with a d50 particle diameter of less than 125 μm or a d80 particle diameter of less than 200 μm.

[0073] In certain embodiments, the solvent used in step 1) contains alkali metal silicate and asenapine maleate in a molar ratio of 1 or more parts of alkali metal silicate, from 1 to 10 parts alkali metal silicate, from 1 to 5 parts alkali metal silicate, from 1 to 4 parts alkali metal silicate, from 1 to 3 parts of alkali metal silicate, or from 1 to 2 parts of alkali metal silicate, in each case based on 1 part of asenapine maleate. It was found, surprisingly, that its increased molar ratio of the alkali metal silicate based on the asenapine maleate leads to improved conversions in shorter periods of time, for example within one day.

[0074] According to certain embodiments, the solvent in step 1) contains an alcoholic solvent. The alcoholic solvent is preferably selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol and mixtures thereof. Ethanol is particularly preferred as an alcoholic solvent. In particular, a mass fraction of the alcoholic solvent based on the total mass of the reaction mixture provided in step 1) is 40% by mass to 97% by mass, preferably 45% by mass to 70% by mass.

[0075] In certain embodiments, the reaction of the process is carried out at a temperature of 15° C. to 45° C., at a temperature of 15° C. to 25° C., or at a temperature of 35° C. to 45° C. In particular, in a temperature range from 35° C. to 45° C., a high conversion can be achieved in a shortened time.

[0076] In certain embodiments, the mass fraction of asenapine maleate is 1% by mass to 40% by mass, preferably 2% by mass to 35% by mass, more preferably 15% by mass to 30% by mass, based on the total mass of the reaction mixture provided in step 1).

[0077] In certain embodiments, step 2) is carried out for a period of 2 h to 144 h, preferably for a period of 8 h to 60 h, particularly preferably for a period of 12 h to 50 h.

[0078] According to certain embodiments, the conversion in step 2) is 80% or more, preferably 90% or more, particularly preferably 99% or more, wherein the conversion is determined by means of HPLC as indicated above as well as in the examples and below. It is thus clear that very high conversions of asenapine maleate to form asenapine in the form of its free base can be achieved with the process according to the invention.

[0079] According to certain embodiments, asenapine in the form of its free base having a purity of 99.0% or more, preferably 99.5% or more, particularly preferably 99.95% or more is formed in step 2), wherein the purity is determined by means of HPLC as indicated above. This makes it clear that asenapine in the form of its free base can be obtained with a high degree of purity.

[0080] According to certain embodiments, antioxidants are used in step 1) as part of the reaction mixture, wherein the antioxidants are selected in particular from the group consisting of α-tocopherol, sodium metabisulfite, which is preferably used as an aqueous solution, in particular as a 10% to 40% solution, in step 1), ascorbyl palmitate, which is preferably used as an ethanolic solution, in particular as a 5% to 15% ethanolic solution, in step 1), and mixtures thereof. Using antioxidants, the purity of asenapine in the form of its free base can be increased significantly, as the antioxidants can reduce the formation of degradation products. In particular, the mass fraction of α-tocopherol is 0.01% by mass to 0.5% by mass, based on the total mass of the reaction mixture provided in step 1). Additionally or alternatively, the mass fraction of sodium metabisulfite can be 0.01% by mass to 0.5% by mass, based on the total mass of the reaction mixture provided in step 1). Additionally or alternatively, the mass fraction of ascorbyl palmitate can be 0.05% by mass to 1.0% by mass, based on the total mass of the reaction mixture provided in step 1).

Process for the Preparation of an Active Ingredient-Containing Layer for Use in a TTS

[0081] According to a second aspect, the present invention relates to a process for the preparation of an active ingredient-containing layer, in particular an active ingredient-containing matrix layer, for use in a transdermal therapeutic system, wherein the process comprises the following steps of: [0082] i) preparing asenapine in the form of its free base by means of the process according to the first aspect of the invention; [0083] ii) combining at least the asenapine in the form of its free base obtained in step i) and a polymer in a further solvent in order to obtain a coating composition, wherein the asenapine in the form of its free base obtained in step i) and used in step ii) is preferably contained in the solvent used in step ii), and is more preferably present in a solution isolated according to step 3) according certain embodiments from the first aspect of the invention; [0084] iii) coating the coating composition on a back layer, a peelable film or an intermediate film; and [0085] iv) drying the coated coating composition to form the active ingredient-containing layer.

[0086] In particular, an active ingredient-containing layer can be prepared in a simple manner by this process because the asenapine in the form of its free base, which is prepared according to step i), is already present in a sufficient amount by the high conversion as well as in sufficiently high purity and no further purification is required.

[0087] In particular, the active ingredient-containing layer formed on the back layer, on the peelable film, or on the intermediate film after drying iv) is a matrix layer.

[0088] In particular, the asenapine maleate can be used in a solution obtained according to step 2) of the process according to the first aspect of the invention, so that only a few process steps in total are necessary to obtain an active ingredient-containing layer containing asenapine in the form of its free base.

[0089] The second aspect of the present invention, accordingly, has the technical features as well as the effects and advantages as the embodiments of the first aspect of the invention.

[0090] According to certain embodiments, the solvent of step ii) is selected from alcoholic solvents, especially methanol, ethanol, isopropanol and mixtures thereof, and from non-alcoholic solvents, in particular ethyl acetate, hexane, n-heptane, petroleum ether, toluene, and mixtures thereof. The solvent is particularly preferably selected from ethanol and ethyl acetate.

[0091] The polymer used in step ii) ensures a sufficient cohesion of the matrix layer. According to certain embodiments, the polymer can also ensure sufficient adhesion. In such embodiments, the polymer is selected from pressure-sensitive adhesive polymers.

[0092] In certain embodiments, the polymer is an acrylic polymer and preferably a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate, or based on vinyl acetate, 2-ethylhexyl acrylate, and 2-hydroxyethyl acrylate, which is provided as a solution, and is preferably present as a solution in ethyl acetate, n-heptane, methanol, ethanol and mixtures thereof with a solids content of 30% by mass to 60% by mass.

[0093] According to certain embodiments, antioxidants such as α-tocopherol, sodium metabisulfite, which is preferably provided in an aqueous solution which is in particular a 10% to 40% aqueous solution, ascorbyl palmitate, which is preferably provided in an ethanolic solution which is in particular a 5% to 15% ethanolic solution; a triglyceride and/or a polyvinylpyrrolidone are combined with the isolated solution containing asenapine in the form of its free base and the acrylic polymer in the solvent in step ii) to obtain the coating composition.

[0094] In particular, the triglyceride used is a medium chain triglyceride.

[0095] According to certain embodiments, the active ingredient-containing layer formed in step iv) comprises [0096] A) 4% by mass to 12% by mass asenapine in the form of its free base; and [0097] B) 65% by mass to 85% by mass acrylic polymer; [0098] C) 5% by mass to 15% by mass polyvinylpyrrolidone; [0099] D) 5% by mass to 15% by mass triglyceride; [0100] E) 0.1% by mass to 0.5% by mass ascorbyl palmitate; [0101] F) 0.05% by mass to 0.3% by mass sodium metabisulfite; [0102] G) 0.01% by mass to 0.1% by mass α-tocopherol; and [0103] H) optionally 0.1 to 1% by mass aluminum acetylacetonate, based on the total mass of the active ingredient-containing layer obtained in step iv) from the coating composition. Aluminum acetylacetonate can be used in particular when the coating composition contains a crosslinking agent.

[0104] According to certain embodiments, the drying in step iv) is carried out at a temperature of 50° C. to 90° C., particularly preferably at a temperature of 60° C. to 85° C.

[0105] According to certain embodiments, the active ingredient-containing layer formed has a grammage in a range from 50 to 90 g/m.sup.2 or 90 to 230 g/m.sup.2, preferably from 110 to 210 g/m.sup.2, and most preferably from 120 to 170 g/m.sup.2.

[0106] According to the invention, the active ingredient-containing layer, which is in particular a matrix layer, contains asenapine in the form of its free base in a therapeutically effective amount.

[0107] In certain embodiments, the active ingredient-containing layer is a matrix layer.

[0108] The asenapine in the matrix layer may be completely dissolved, or the matrix layer composition may contain asenapine particles consisting of the free base of asenapine.

[0109] Without wishing to be bound by theory, it is believed that the amount of asenapine in the form of its free base is important for a good release of the active ingredient, and can be adjusted, for example, by the asenapine concentration. Thus, in certain embodiments, the amount of asenapine in the matrix layer composition ranges from 2 to 20%, preferably from 3 to 15%, and more preferably from 4 to 12% of the matrix layer composition.

[0110] According to certain embodiments, the asenapine in the form of its free base in the active ingredient-containing layer formed has a purity of 95.0% or more, preferably 99.0% or more, particularly preferably 99.95% or more, wherein the purity is determined by means of quantitative HPLC. Quantitative HPLC can be carried out using reverse phase HPLC with UV detection. In particular, the following conditions can be used if HPLC is carried out isocratically: [0111] Column: Octadecyl phase according to Ph. Eur. 2.2.29 (USP phase L1) Kromasil C18 125 mm×4.0 mm; 5 μm or equivalent [0112] Mobile phase: KH.sub.2PO.sub.4/methanol/TEA (45:55:0.1; v:v:v); pH 2.5±0.05 (TEA=triethylamine) [0113] Gradient: isocratic [0114] Flow: 1.0 ml [0115] Injection volume: 30 μl [0116] Column temperature: 40° C. [0117] Wavelength: 225 nm, 270 nm and 3-D field; evaluation is carried out at 270 nm [0118] Run time: 10 min
Furthermore, the following conditions can be used when HPLC is carried out with a gradient: [0119] Column: Octadecyl phase according to Ph. Eur. 2.2.29 (USP phase L1) Kinetex C18 EVO 100 mm×4.6 mm; 2.1 μm or equivalent [0120] Mobile phase: A: 0.02 mol KH.sub.2PO.sub.4 buffer/methanol/TEA (70:30:0.1; v:v:v) adjusted to pH 2.5 B: 0.02 mol KH.sub.2PO.sub.4 buffer/methanol/TEA (30:70:0.1; v:v:v); adjusted to pH 2.5 (TEA=triethylamine) [0121] Flow: 1.0 ml [0122] Injection volume: 30 μl [0123] Column temperature: 40° C. [0124] Wavelength: 225 nm, 270 nm and 3-D field; evaluation is carried out at 225 nm [0125] Run time: 32 min [0126] Gradient profile: 0.00 min: A: 100% B: 0% 12.00 min: A: 40% B: 60% 18.00 min: A: 0% B: 100% 27.00 min: A: 0% B: 100% 27.01 min: A: 100% B: 0% 32.00 min: A: 100% B: 0%

[0127] According to certain embodiments, drying in step iv) is carried out for a period of 10 min to 60 min.

[0128] In certain embodiments, a mass fraction of asenapine in the form of its free base is 95% by mass or more, preferably 99% by mass or more, particularly preferably 100% by mass, based on the total mass of asenapine in the active ingredient-containing layer formed.

[0129] According to certain embodiments, drying in step iv) is carried out in two stages, wherein drying in the first stage is carried out at 15° C. to 25° C. for a period of 5 min to 15 min, and subsequently drying in the second stage is carried out at 60° C. to 85° C. for a period of 10 min to 40 min.

Asenapine in the Form of its Free Base

[0130] According to a third aspect, the present invention relates to asenapine in the form of its free base, obtainable by a process according to the first aspect of the invention. Asenapine in the form of its free base has in particular a purity of 99.0% or more, preferably 99.5% or more, particularly preferably 99.95% or more, wherein the purity is determined by means of HPLC, as indicated above, wherein the asenapine in the form of its free base is preferably present in a solvent and particularly preferably in a solution isolated according to step 3) according to the first aspect of the invention.

[0131] The third aspect of the invention, accordingly, has the technical features as well as the effects and advantages as the embodiments of the first aspect of the invention.

[0132] Asenapine in the form of its free base in high purity may be obtained directly from the preparation process without the need for further costly and complex purification steps.

Active Ingredient-Containing Layer

[0133] According to a fourth aspect, the present invention relates to an active ingredient-containing layer which, in particular, is a matrix layer, for use in a transdermal therapeutic system, obtainable by a process according to the second aspect of the invention, wherein the asenapine in the form of its free base in the active ingredient-containing layer preferably has a purity of 99.0% or more, preferably 99.5% or more, particularly preferably 99.95% or more, wherein the purity is determined by means of HPLC, as indicated above.

[0134] The fourth aspect of the invention, accordingly, has the technical features as well as the effects and advantages as the embodiments of the second aspect of the invention.

[0135] Thus, an active ingredient-containing layer which, in particular, is a matrix layer, can be provided in high purity without additional purification steps.

[0136] The active ingredient-containing layer comprises a therapeutically effective amount of asenapine in the form of its free base.

TTS Containing an Active Ingredient-Containing Layer

[0137] According to a fifth aspect, the present invention relates to a transdermal therapeutic system containing an active ingredient-containing layer according to the fourth aspect of the invention, which is obtainable by the process according to the second aspect of the invention.

[0138] The fifth aspect of the invention, accordingly, has the technical features as well as the effects and advantages as the embodiments of the second and the fourth aspect of the invention. Thus, within the scope of the present invention, a TTS can be provided which contains asenapine in the form of its free base, as a result of which said TTS has improved skin permeation properties, for example compared to a TTS containing asenapine maleate. Furthermore, solids, in particular, which arise during the preparation of asenapine in the form of its free base, can be easily removed so that they can be excluded as impurities in the TTS prepared.

[0139] In particular, the transdermal therapeutic system has an asenapine-containing (in the form of its free base) self-adhesive layer structure.

[0140] The transdermal therapeutic system according to the present invention is preferably a transdermal therapeutic system for the transdermal administration of asenapine in the form of its free base, wherein the TTS in particular is an asenapine-containing (in the form of its free base) self-adhesive layer structure, comprising: [0141] A) a back layer; [0142] B) an asenapine-containing (in the form of its free base) active ingredient-containing layer, which is in particular a matrix layer, consisting of a composition comprising: [0143] 1. asenapine in the form of its free base; and [0144] 2. a polymer selected from acrylic polymers;
wherein the transdermal therapeutic system has a release area of 5 to 100 cm.sup.2.

[0145] In particular, the back layer is essentially asenapine-impermeable.

[0146] The TTS according to the present invention may be a TTS of the matrix type or a TTS of the reservoir type, and is preferably a TTS of the matrix type.

[0147] The TTS can also contain components known to the person skilled in the art, such as, for example, a skin contact layer and/or a top layer. When the TTS is of the reservoir type, the TTS may contain other components known to the person skilled in the art, such as a rate controlling membrane.

EXAMPLES

[0148] The present invention will now be described more fully with reference to the accompanying examples. It should be understood, however, that the following description is illustrative only and should in no way be taken as a limitation on the invention. The numerical values given in the examples with regard to the amount of the ingredients in the composition/in the reaction mixture or the grammage may vary slightly due to preparation fluctuations.

Examples 1a-c

Reaction Mixtures

[0149] The masses and the fractions of the ingredients of the reaction mixtures, which were used in Examples 1a-c, are summarized in Table 1.1. All percentages in Table 1.1 refer to mass percent (% by mass).

TABLE-US-00001 TABLE 1.1 Ex. 1a Ex. 1b Ex. 1c Mass Fraction Mass Fraction Mass Fraction Ingredient [g] [%] [g] [%] [g] [%] Asenapine maleate 0.6627 19.33 0.6772 24.29 0.6794 24.29 Water (total)* 0.0987 2.88 0.0319 1.14 0.0320 1.14 Sodium metasilicate 0.3966 11.57 0.4104 14.72 0.4118 14.72 Ethanol with 1% 2.2527 65.70 1.6499 59.18 1.6553 59.18 MEK (total)** α-Tocopherol 0.0024 0.07 0.0025 0.09 0.0025 0.09 Ascorbyl palmitate 0.0095 0.28 0.0097 0.35 0.0097 0.35 solution [10% in ethanol with 1% MEK]*** Sodium metabisulfite 0.0060 0.18 0.0061 0.22 0.0062 0.22 solution [30% in water]**** Temperature [C.] 20.0 40.0 20.0 *Sum of the masses/fractions of the water, which is added in the form of a 30% sodium metabisulfite solution, and the remaining water, which is added as part of the solvent of the reaction mixture. **Sum of the masses/fractions of the ethanol, which is present in the form of 10% ascorbyl palmitate solution, and the remaining ethanol, which is added as part of the solvent of the reaction mixture. ***Mass and fraction refer to ascorbyl palmitate. ****Mass and fraction refer to sodium metabisulfite.

Preparation of Asenapine in the Form of its Free Base

[0150] For the preparation of the reaction mixture for Examples 1a-c, an asenapine maleate base mixture was prepared first. For this purpose, a glass vessel was charged with α-tocopherol (0.0536 g). Thereafter, ethanol with 1% MEK (33.6898 g) as the solvent was added and the resulting mixture was stirred at 300 rpm. Then, a 30% aqueous sodium metabisulfite solution (0.4419 g) and a 10% ethanolic ascorbyl palmitate solution (2.0916 g) were added in succession, each with stirring at 300 rpm. Subsequently asenapine maleate was added (14.6009 g) and the asenapine base mixture was stirred at 300 rpm.

[0151] For providing the reaction mixture of Example la, 2.3090 g of this asenapine maleate base mixture were taken out of the glass vessel with stirring and placed in a reaction vessel, whereupon additional ethanol with 1% MEK (0.6381 g) as solvent was added and the resulting mixture was stirred at 900 rpm. In addition, water (see Table 1.1 for the mass) was added as a further solvent with stirring at 900 rpm. Then, ground sodium metasilicate (see Table 1.1 for the mass) was added in order to obtain the reaction mixture according to Example 1a (see Table 1.1). Then, the reaction vessel was flushed with argon and the reaction mixture was stirred for approximately 3 days at 20° C. and at 300 rpm for the conversion of asenapine maleate to asenapine in the form of its free base.

[0152] For providing the reaction mixture of Example 1c, 44.803 g asenapine maleate base mixture were taken out with stirring and placed in a glass vessel, whereupon water (0.3324 g) was added to the asenapine maleate base mixture with stirring in order to obtain a precursor mixture. Then, the resulting precursor mixture (21.4939 g) was taken out with stirring and placed in a further glass vessel. Thereafter, ground sodium metasilicate (3.7108 g) was added. Then, the glass vessel was flushed with argon and stirred at 300 rpm. Thereafter, 2.7877 g of the mixture thus obtained were taken out with stirring at 500 rpm in order to obtain the reaction mixture according to Example 1b (see Table 1.1). This reaction mixture was placed in a reaction vessel and stirred for 3 days at 40° C. and 300 rpm for the conversion of asenapine maleate to asenapine in the form of its free base.

[0153] For providing the reaction mixture of Example 1c, 44.803 g of asenapine maleate base mixture were taken out with stirring and placed in a glass vessel, whereupon water (0,3324 g) was added to the asenapine maleate base mixture with stirring in order to obtain a precursor mixture. Then, the resulting precursor mixture (21.4939 g) was taken out with stirring and placed in another glass vessel. Thereafter, ground sodium metasilicate (3.7108 g) was added. Then, the glass vessel was flushed with argon and stirred at 300 rpm. Thereafter, 2.7968 g of the mixture thus obtained were taken out with stirring at 500 rpm in order to obtain the reaction mixture according to Example 1c (see Table 1.1). This reaction mixture was placed in a reaction vessel and stirred for 3 days at 20° C. and 300 rpm for the conversion of asenapine maleate to asenapine in the form of its free base.

Conversion of Asenapine Maleate and Purity of Asenapine in the Form of its Free Base

[0154] For reaction analysis, a liquid sample of 500 μl were taken out of the product mixtures of Examples 1 a-c in each case after one day, after two days and after three days of reaction by means of an Eppendorf pipette. After the first and second sampling, the reaction vessel in each case was flushed again with argon and stirring was continued.

[0155] For determining the conversion, a total mass of asenapine (which originates from asenapine in the form of its free base as well as asenapine maleate) and a mass of maleic acid of the liquid samples were determined by means of quantitative HPLC (see below in Examples 5a-d). In this way, the mass fraction of asenapine in the form of its free base can be determined by calculation. The conversion of asenapine maleate (see Table 1.2) in this case corresponds to the mass fraction of asenapine in the form of its free base, based on the total mass of asenapine of the sample.

[0156] The liquid samples were also used to determine any degradation products of asenapine by means of quantitative HPLC. The smaller the sum of the degradation products, the higher the purity of asenapine in the form of its free base.

[0157] The values of conversions of asenapine maleate as well as the sums of the degradation products are summarized in Table 1.2.

TABLE-US-00002 TABLE 1.2 Conversion of Sum of the asenapine maleate degradation products Ex. Day 1 Day 2 Day 3 Day 1 Day 2 Day 3 Ex. 1a 79.84% 83.77% 87.68% 0.04% 0.01% 0.01% Ex. 1b 97.85% 99.36% 99.75% 0.00% 0.05% 0.05% Ex. 1c 84.66% 97.53% 99.51% 0.01% 0.01% 0.01%

[0158] From Table 1.2 it can be seen that high conversions and high purities could be obtained with the reaction mixtures of Examples 1a-c. It was also found, surprisingly, that a lower fraction of water (cf. Ex. 1a and Ex. 1c) and a higher reaction temperature of 40° C. (cf. Ex. 1a and Ex. 1b) result in a faster conversion, i.e. a higher conversion is achieved within a shorter time, from asenapine maleate to asenapine in the form of its free base.

Reference Examples 1a-c

Reaction Mixtures

[0159] The masses as well as the fractions of the ingredients of the reaction mixtures, which were used in Reference Examples 1a-c, are summarized in Table 2.1. All percentages in Table 2.1 refer to mass percent (% by mass).

TABLE-US-00003 TABLE 2.1 Ref. Ex. 1a Ref. Ex. 1b Ref. Ex. 1c Mass Fraction Mass Fraction Mass Fraction Ingredient [g] [%] [g] [%] [g] [%] Asenapine maleate 0.7060 24.73 0.6860 24.46  0.6697 24.20 Water (total)* 0.0332 1.16 0.0323 1.15 0.0315 1.14 Aluminum silicate 0.3767 13.19 — — — — Calcium silicate, meta — — 0.3964 14.13  — — Magnesium silicate — — — — 0.4163 15.04 monohydrate Ethanol with 1% 1.7201 60.25 1.6713 59.59  1.6315 58.96 MEK (total)** α-Tocopherol 0.0026 0.09 0.0025 0.09 0.0025 0.09 Ascorbyl palmitate 0.0101 0.35 0.0098 0.35 0.0096 0.35 solution [10% by mass in ethanol with 1% MEK]*** Sodium metabisulfite 0.0064 0.22 0.0062 0.22 0.0061 0.22 solution [30% by mass in water]**** *Sum of the masses/fractions of the water, which is added in the form of a 30% sodium metabisulfite solution, and the remaining water, which is added as part of the solvent of the reaction mixture. **Sum of the masses/fractions of the ethanol, which is present in the form of 10% ascorbyl palmitate solution, and the remaining ethanol, which is added as part of the solvent of the reaction mixture. ***Mass and fraction refer to ascorbyl palmitate. ****Mass and fraction refer to sodium metabisulfite.

Preparation of Asenapine in the Form of its Free Base

[0160] For providing the reaction mixtures of Reference Example 1a-c, the precursor mixture of Example 1c was used first.

[0161] For providing the reaction mixture of Reference Example 1a, the precursor mixture (2.4784/g was taken out with stirring at 650 rpm and placed in a reaction vessel. Aluminum silicate (0.3767 g) was added in order to obtain the reaction mixture according to Reference Example 1a. Then, the reaction vessel was flushed with argon. The reaction mixture was stirred at 300 rpm and 20.0° C. for 3 days for the conversion of asenapine maleate to asenapine in the form of its free base.

[0162] For providing the reaction mixture of Reference Example 1b, the precursor mixture (2.4082 g) was taken out with stirring at 650 rpm and placed in a reaction vessel. Calcium silicate, meta (0.3964 g) was added in order to obtain the reaction mixture according to Reference Example 1b. Then, the reaction vessel was flushed with argon. The reaction mixture was stirred at 300 rpm and 20.0° C. for 3 days for the conversion of asenapine maleate to asenapine in the form of its free base.

[0163] For providing the reaction mixture of Reference Example 1c, the precursor mixture (2.3508 g) was taken out with stirring at 455 rpm and placed in a reaction vessel. Magnesium silicate monohydrate (0.4163 g) was added to this precursor mixture in order to obtain the reaction mixture according to Reference Example 1c. Thereafter, the reaction vessel was flushed with argon and the reaction mixture was stirred at 300 rpm and 20.0° C. for 3 days for the conversion of asenapine maleate to asenapine in the form of its free base.

Conversion of Asenapine Maleate and Purity of Asenapine in the Form of its Free Base

[0164] The conversion of asenapine maleate and the sum of the degradation products were determined analogously to Examples 1a-c. The conversions as well as the sum of the degradation products are summarized in Table 2.2.

TABLE-US-00004 TABLE 2.2 Conversion of Sum of the asenapine maleate degradation products Ex. Day 1 Day 2 Day 3 Day 1 Day 2 Day 3 Ref. Ex. 1a — — — 0.02% 0.02% 0.04% Ref. Ex. 1b — — — 0.03% 0.02% 0.05% Ref. Ex. 1c — — — 0.02% 0.02% 0.02%

[0165] Surprisingly, it was found that silicates with higher-valent cations such as Ca.sup.2+, Mg.sup.2+ and Al.sup.3+ (see Ref. Ex. 1a-c in Table 2.2), in contrast to silicates with sodium cations (cf. Example 1a-c in Table 1.2), do not result in any conversion.

Example 2a and Reference Examples 2a-c

Reaction Mixtures

[0166] The masses as well as the fractions of the ingredients of the reaction mixtures, which were used in Example 2a as well as in Reference Examples 2a-c, are summarized in Table 3.1. All percentages in Table 3.1 refer to mass percent (% by mass).

TABLE-US-00005 TABLE 3.1 Ex. 2a Ref. Ex. 2a Ref. Ex. 2b Ref. Ex. 2c Mass Fraction Mass Fraction Mass Fraction Mass Fraction Ingredient [g] [%] [g] [%] [g] [%] [g] [%] Asenapine maleate 0.5809 21.17 0.6208 21.84  0.5961 21.45  0.58956 21.01 Water (total)* 0.0273 1.00 0.0292 1.03 0.0280 1.01 0.02773 0.99 Sodium metasilicate 0.7042 25.67 — — — — — Aluminum silicate — — 0.6635 23.34  — — — Calcium silicate, meta — — — — 0.6870 24.72  — Magnesium silicate — — — — — — 0.7365 26.25 monohydrate Ethanol with 1% 1.4152 51.59 1.5123 53.20  1.4523 52.25  1.43635 51.19 MEK (total)** α-tocopherol 0.0021 0.08 0.0023 0.08 0.0022 0.08 0.00216 0.08 Ascorbyl palmitate 0.0083 0.30 0.0089 0.31 0.0085 0.31 0.00845 0.30 solution [10% in ethanol with 1% MEK]*** Sodium metabisulfite 0.0053 0.19 0.0056 0.20 0.0054 0.19 0.00536 0.19 solution [30% in water]**** *Sum of the masses/fractions of the water, which is added in the form of a 30% sodium metabisulfite solution, and the remaining water, which is added as part of the solvent of the reaction mixture. **Sum of the masses/fractions of the ethanol, which is present in the form of 10% ascorbyl palmitate solution, and the remaining ethanol, which is added as part of the solvent of the reaction mixture. ***Mass and fraction refer to ascorbyl palmitate. ****Mass and fraction refer to sodium metabisulfite.

Preparation of Asenapine in the Form of its Free Base

[0167] For providing the reaction mixture of Example 2a and Reference Examples 2a-d, the precursor mixture according to Example 1c was used.

[0168] For Example 2a, 2.0391 g of the precursor mixture were taken out with stirring at 650 rpm and placed in a reaction vessel. Thereafter, sodium metasilicate (0.7042 g) was added in order to obtain the reaction mixture according to Example 2a (see Table 3.1). Thereafter, the reaction vessel was flushed with argon, whereupon the reaction mixture was stirred at 300 rpm and 20.0° C. for 3 days for the conversion of asenapine maleate to asenapine in the form of its free base.

[0169] For Reference Example 2a, 2.1791 g of the precursor mixture were taken out with stirring at 650 rpm and placed in a reaction vessel. Thereafter, aluminum silicate (0.6635 g) was added in order to obtain the reaction mixture according to Reference Example 2a (see Table 3.1). Thereafter, the reaction vessel was flushed with argon, whereupon the reaction mixture was stirred at 300 rpm and 20.0° C. for 3 days for the conversion of asenapine maleate to asenapine in the form of its free base.

[0170] For Reference Example 2b, 2.0926 g of the precursor mixture (from Example 1c) were taken out with stirring at 650 rpm and placed in a reaction vessel. Thereafter, calcium silicate, meta (0.6870 g) was added in order to obtain the reaction mixture according to Reference Example 2b (see Table 3.1). Thereafter, the reaction vessel was flushed with argon, whereupon the reaction mixture was stirred at 300 rpm and 20.0° C. for 3 days for the conversion of asenapine maleate to asenapine in the form of its free base.

[0171] For Reference Example 2c, 2.0696 g of the precursor mixture were taken out with stirring at 455 rpm and placed in a reaction vessel. Thereafter, magnesium silicate monohydrate (0.7365 g) was added in order to obtain the reaction mixture according to Reference Example 2c (see Table 3.1). Thereafter, the reaction vessel was flushed with argon, whereupon the reaction mixture was stirred at 300 rpm and 20.0° C. for 3 days for the conversion of asenapine maleate to asenapine in the form of its free base.

Conversion of Asenapine Maleate and Purity of Asenapine in the Form of its Free Base

[0172] The conversion of asenapine maleate and the purity of asenapine in the form of its free base were determined analogously to Examples 1a-c. The conversions as well as the sum of the degradation products are summarized in Table 3.2.

TABLE-US-00006 TABLE 3.2 Conversion of Sum of the asenapine maleate degradation products Ex. Day 1 Day 2 Day 3 Day 1 Day 2 Day 3 Ex. 2a 97.35% 99.67% 99.66 0.01 0.01 0.01% Ref. Ex. 2a — — — 0.02% 0.03% 0.05% Ref. Ex. 2b — — — 0.03% 0.03% 0.05% Ref. Ex. 2c — — — 0.02% 0.02% 0.04%

[0173] From Table 3.2 it can be seen that the use of a higher mass fraction of sodium metasilicate resulted in a higher and faster conversion, e.g., achievement of a conversion in a shorter time, at high purity (see Ex. 2a), wherein no conversion took place when using calcium silicate, magnesium silicate and aluminum silicate in higher parts by mass (see Ref. Ex. 2a-c).

Examples 3a and 3b

Reaction Mixtures

[0174] The masses as well as the fractions of the ingredients of the reaction mixtures, which were used in Examples 3a and 3b, are summarized in Table 4.1. All percentages in Table 4.1 refer to mass percent (% by mass).

TABLE-US-00007 TABLE 4.1 Ex. 3a Ex. 3b Mass Fraction Mass Fraction Ingredient [g] [%] [g] [%] Asenapine maleate 0.6852 24.78 0.6076 21.55 Water (total) * 0.0309 1.12 0.0274 0.97 Sodium metasilicate 0.4150 15.01 0.7355 26.09 Ethanol with 1% MEK (total) ** 1.6248 58.76 1.4407 51.10 α-Tocopherol 0.0015 0.05 0.0013 0.05 Ascorbyl palmitate solution 0.0051 0.18 0.0045 0.16 [10% in ethanol with 1% MEK] *** Sodium metabisulfite solution 0.0026 0.09 0.0023 0.08 [30% in water] **** * Sum of the masses/fractions of the water, which is added in the form of a 30% sodium metabisulfite solution, and the remaining water, which is added as part of the solvent of the reaction mixture. ** Sum of the masses/fractions of the ethanol, which is present in the form of 10% ascorbyl palmitate solution, and the remaining ethanol, which is added as part of the solvent of the reaction mixture. *** Mass and fraction refer to ascorbyl palmitate. **** Mass and fraction refer to sodium metabisulfite.

Preparation of Asenapine in the Form of its Free Base

[0175] For the preparation of the reaction mixture of Examples 3a and 3b first, a base mixture of asenapine maleate prepared first. For this purpose, α-tocopherol (0.0146 g) was weighed out in a glass vessel. Thereafter, ethanol with 1% MEK (15.7001 g) was added as the solvent and the mixture was stirred at 300 rpm. A 30% aqueous sodium metabisulfite solution (0.0856 g) and a 10% ethanolic ascorbyl palmitate solution (0.5047 g) were then added in succession, each with stirring at 300 rpm. Next, asenapine maleate (6.8126 g) was added, whereupon the resulting mixture was further stirred at 300 rpm. Then, water (0.2471 g) as a further solvent was added with stirring in order to obtain the base mixture of asenapine.

[0176] For providing the reaction mixture of Example 3a, 2.3500 g of this base mixture of asenapine maleate were taken out with stirring at 500 rpm and placed in a reaction vessel. Ground sodium metasilicate (0.4150 g) was added in order to obtain the reaction mixture according to Example 3a. Thereafter, the reaction vessel was flushed with argon. Subsequently, the reaction mixture was stirred at 300 rpm and 20.0° C. for 3 days for the conversion of asenapine maleate to asenapine in the form of its free base.

[0177] For providing the reaction mixture of Example 3b, 2.0838 g of the base mixture of asenapine maleate were taken out with stirring at 500 rpm and placed in a reaction vessel. Ground sodium metasilicate (0.7355 g) was added in order to obtain the reaction mixture according to Example 3b. Then, the reaction vessel was flushed with argon. Thereafter, the reaction mixture was stirred at 300 rpm and 20.0° C. for 3 days for the conversion of asenapine maleate to asenapine in the form of its free base.

Conversion of Asenapine Maleate and Purity of Asenapine in the Form of its Free Base

[0178] The conversion of asenapine maleate and the purity of asenapine in the form of its free base were determined analogously to Examples 1a-c. The conversion as well as the sum of the degradation products are summarized in Table 4.2.

TABLE-US-00008 TABLE 4.2 Conversion of Sum of the asenapine maleate degradation products Ex. Day 1 Day 2 Day 3 Day 1 Day 2 Day 3 Ex. 3a 67.02% 81.05% 91.80% 0.01% 0.00% 0.01% Ex. 3b 97.85% 99.36% 99.75% 0.01% 0.01% 0.01%

[0179] From Table 4.2 it can be seen that an antioxidant fraction (in the form of sodium metabisulfite, ascorbyl palmitate as well as α-tocopherol) that is reduced in comparison with the reaction mixtures of Examples 1a-c also leads to high conversions and high purities (see Ex. 3a and 3b). Furthermore, it could be shown, surprisingly, that an increase in the mass fraction of the sodium metasilicate used (see Ex. 3b, Table 4.1) leads to higher conversions and to a faster conversion.

Examples 4a-c

Reaction Mixtures

[0180] The masses as well as the fractions of the ingredients of the reaction mixtures, which were used in Examples 4a-c, are summarized in Table 5.1. All percentages in Table 5.1 refer to mass percent (% by mass).

TABLE-US-00009 TABLE 5.1 Ex. 4a Ex. 4b Ex. 4c Mass Fraction Mass Fraction Mass Fraction Ingredient [g] [%] [g] [%] [g] [%] Asenapine maleate 0.6833 22.95 0.6854 21.41 0.6836 21.12 Water (total)* 0.0470 1.58 0.0471 1.47 0.0375 1.16 Sodium metasilicate 0.4161 13.98 0.4160 12.99 0.4169 12.88 Ethanol with 1% 0.1401 4.71 0.1424 4.45 2.0990 64.84 MEK (total) ** Methanol 1.6608 55.78 — — — — 1-Propanol — — 1.8812 58.76 — — α-Tocopherol 0.0055 0.18 0.0032 0.10 — — Ascorbyl palmitate 0.0156 0.52 0.0158 0.49 — — solution [10% in ethanol with 1% MEK]*** Sodium metabisulfite 0.0088 0.29 0.0106 0.33 — — solution [30% in water]**** *Sum of the masses/fractions of the water, which is added in the form of a 30% sodium metabisulfite solution, and the remaining water, which is added as part of the solvent of the reaction mixture. ** Sum of the masses/fractions of the ethanol, which is present in the form of 10% ascorbyl palmitate solution, and the remaining ethanol, which is added as part of the solvent of the reaction mixture. ***Mass and fraction refer to ascorbyl palmitate. ****Mass and fraction refer to sodium metabisulfite.

Preparation of Asenapine in the Form of its Free Base

[0181] For providing the reaction mixture according to Example 4a, asenapine maleate was placed in a reaction vessel. Then, α-tocopherol and methanol (as solvent) were added. Thereafter, a 30% aqueous sodium metabisulfite solution and a 10% ethanolic ascorbyl palmitate solution were added in succession with stirring at 300 rpm. Water was added as a further solvent. Furthermore, ground sodium metasilicate was added in order to obtain the reaction mixture according to Example 4a. The reaction vessel was flushed with argon and the reaction mixture according to Example 4a was stirred at 300 rpm and 20.0° C. for 3 days for the conversion of asenapine maleate to asenapine in the form of its free base.

[0182] For providing the reaction mixture according to Example 4b, α-tocopherol was placed in a reaction vessel. Then, 1-propanol was added as a solvent and the resulting mixture was stirred at 300 rpm. Thereafter, a 30% aqueous sodium metabisulfite solution and a 10% ethanolic ascorbyl palmitate solution were added in succession with stirring at 300 rpm. Then, asenapine maleate was added and the resulting mixture was stirred at 300 rpm. Furthermore, water (as a further solvent) and then ground sodium metasilicate were added in order to obtain the reaction mixture according to Example 4b. The reaction vessel was flushed with argon and the reaction mixture according to Example 4b was stirred at 300 rpm and 20.0° C. for 3 days for the conversion of asenapine maleate to asenapine in the form of its free base.

[0183] For providing the reaction mixture according to Example 4c, asenapine maleate was placed in a reaction vessel. Then, ethanol (with 1% MEK) and water, as a solvent in each case, were added in succession. Furthermore, ground sodium metasilicate was added in order to obtain the reaction mixture according to Example 4c. The reaction vessel was flushed with argon and the reaction mixture according to Example 4c was stirred at 300 rpm and 20.0° C. for 3 days for the conversion of asenapine maleate to asenapine in the form of its free base.

[0184] The masses of the ingredients used for the reaction mixtures according to Examples 4a-c are summarized in Table 5.1.

Conversion of Asenapine Maleate and Purity of Asenapine in the Form of its Free Base

[0185] The conversion of asenapine maleate and the sum of the degradation products were determined analogously to Examples 1a-c. The conversions and the sum of the degradation products are summarized in Table 5.2.

TABLE-US-00010 TABLE 5.2 Conversion of Sum of the asenapine maleate degradation products Ex. Day 1 Day 2 Day 3 Day 1 Day 2 Day 3 Ex. 4a 32.59% 44.90% 57.04% 0.01% 0.01% 0.01% Ex. 4b 56.28% 63.37% 79.87% 0.01% 0.01% 0.03% Ex. 4c 71.86% 82.58% 94.38% 0.01% 0.05% 0.05%

[0186] From Table 5.2 it can be seen that the use of various alcoholic solvents also results in a high purity of asenapine in the form of its free base (see Ex. 4a and 4b). It was found, surprisingly, that particularly high conversions took place using ethanol (cf. Ex. 4a and 4b in Table 5.2 and Ex. 1c in Table 1.2). Furthermore, it was found, surprisingly, that even without the use of antioxidants, dissolved asenapine in the form of its free base could be obtained in high purity (see Table 5.2, Example 4c).

Examples 5a-f

Reaction Mixtures

[0187] The masses as well as the fractions of the ingredients of the reaction mixtures, which were used in Examples 5a-d are summarized in Table 6.1. All percentages in Table 6.1 refer to mass percent (% by mass).

TABLE-US-00011 TABLE 6.1 Ex. 5a Ex. 5b Ex. 5c Ex. 5d Mass Fraction Mass Fraction Mass Fraction Mass Fraction Ingredient [g] [%] [g] [%] [g] [%] [g] [%] Asenapine maleate 2.5377 24.94 2.5379 24.94 2.3339 22.84 2.2388 21.33 Water (total) * 0.1078 1.06 0.1055 1.04 0.1142 1.12 0.1083 1.03 Sodium metasilicate 1.5478 15.21 1.5476 15.21 2.1350 20.89 2.7314 26.02 Ethanol with 1% 5.9477 58.45 5.9520 58.48 5.5996 54.79 5.3886 51.33 MEK (total)** α-Tocopherol 0.0053 0.05 0.0058 0.06 0.0061 0.06 0.0041 0.04 Ascorbyl palmitate 0.0181 0.18 0.0183 0.18 0.0167 0.16 0.0153 0.15 solution [10% in ethanol with 1% MEK]*** Sodium metabisulfite 0.0115 0.11 0.0109 0.11 0.0140 0.14 0.0107 0.10 solution [30% in water] **** * Sum of the masses/fractions of the water, which is added in the form of a 30% sodium metabisulfite solution, and the remaining water, which is added as part of the solvent of the reaction mixture. **Sum of the masses/fractions of the ethanol, which is present in the form of 10% ascorbyl palmitate solution, and the remaining ethanol, which is added as part of the solvent of the reaction mixture. ***Mass and fraction refer to ascorbyl palmitate. **** Mass and fraction refer to sodium metabisulfite.

Preparation of Asenapine in the Form of its Free Base

[0188] To give the reaction mixture according to Example 5a, a reaction vessel was first charged with α-tocopherol. Then, ethanol (with 1% MEK) was added as a solvent, whereupon the resulting mixture was stirred at 300 rpm. Thereafter, a 30% aqueous sodium metabisulfite solution and a 10% ethanolic ascorbyl palmitate solution were added in succession with stirring. Thereafter, asenapine maleate was added. The resulting mixture was stirred at 300 rpm. Then, water (as a further solvent) and subsequently sodium metasilicate (d50 particle diameter<125 μm) were added with stirring in order to obtain the reaction mixture according to Example 5a. The reaction mixture was stirred at 300 rpm and 21.0° C. for 2 days for the conversion of asenapine maleate to asenapine in the form of its free base.

[0189] Examples 5b-d were carried out in an analogous manner, wherein the reaction of Example 5b was carried out at 40° C.

[0190] The masses of the ingredients of the reaction mixtures according to Examples 5a-5d are listed in Table 6.1.

Reaction Mixture and Filtrate

[0191] The masses as well as the fractions of the ingredients of the reaction mixture and the filtrate obtained following the reaction and used in Example 5e, are summarized in Table 6.2. Table 6.2 also shows the masses as well as the fractions of the ingredients of the product filtrate obtained with the reaction mixture according to Example 5e after the reaction has ended. All percentages in Table 6.2 refer to mass percent (% by mass).

TABLE-US-00012 TABLE 6.2 Ex. Ex. 5e Product filtrate Ex. 5e Mass Fraction Mass Fraction Ingredient [g] [%] [g] [%] Asenapine maleate 2.5256 24.88 0.0251 0.32 Asenapine in the form of its — — 1.7696 22.50  free base Water (total)* 0.1206 1.19 0.1205 1.53 Sodium metasilicate 1.5411 15.18 — — Ethanol with 1% MEK** 5.9258 58.38 5.9258 75.34  α-Tocopherol 0.0059 0.06 0.0059 0.08 Ascorbyl palmitate solution 0.0189 0.19 0.0189 0.24 [10% in ethanol with 1% MEK]*** Sodium metabisulfite solution 0.0119 0.12 n/a***** — [30% in water]**** *Sum of the masses/fractions of the water, which is added in the form of a 30% sodium metabisulfite solution, and the remaining water, which is added as part of the solvent of the reaction mixture. **Sum of the masses/fractions of the ethanol, which is present in the form of 10% ascorbyl palmitate solution, and the remaining ethanol, which is added as part of the solvent of the reaction mixture. ***Mass and fraction refer to ascorbyl palmitate. ****Mass and fraction refer to sodium metabisulfite. *****Not measured due to the small residual amount.

Preparation of Asenapine in the Form of its Free Base

[0192] To give the reaction mixture according to Example 5e, a reaction vessel was first charged with α-tocopherol. Then, ethanol with 1% MEK was added as a solvent, whereupon the resulting mixture was stirred at 300 rpm. Thereafter, a 30% aqueous sodium metabisulfite solution and a 10% ethanolic ascorbyl palmitate solution were added in succession with stirring. Then, asenapine maleate was added. The resulting mixture was stirred at 300 rpm. Then, water and subsequently sodium metasilicate (d50 particle diameter<125 μm) were added with stirring in order to obtain the reaction mixture according to Example 5e. The reaction vessel was flushed with argon. The reaction mixture was stirred at 300 rpm and 20.2° C. for 2 days for the conversion of asenapine maleate to asenapine in the form of its free base. The masses of the ingredients of the reaction mixture according to Example 5e are listed in Table 6.2. Following the reaction, the solid that was present in the reaction mixture, was filtered off through a suction filter on a porcelain frit with blue band filter paper in order to obtain the filtrate of Example 5e.

Coating Composition

[0193] The formulation of the asenapine-containing (in the form of its free base) coating compositions of Example 5f is summarized in Table 6.3 below. All percentages in Table 6.3 below refer to mass percent (% by mass).

TABLE-US-00013 TABLE 6.3 Ex. 5f Ingredient Mass [g] Solid fraction [%] Asenapine in the form of its free 0.8315 7.76 base as a component of the filtrate of Ex. 5e* DURO-TAK 87-4287 7.6500 71.36 Povidone K30 red. 1.1005 10.27 peroxide content α-Tocopherol 0.0061 0.06 Ascorbyl palmitate solution [10% 0.0222 0.21 in ethanol with 1% MEK] Sodium metabisulfite solution [30% 0.0117 0.11 in water] Miglyol 812 N 1.0987 10.25 Ethanol with 1% MEK** 6.0631 — *Solution was obtained by filtration. **Mass of the ethanol used as a solvent for the coating composition minus the mass of the ethanol used for the 10% ascorbyl palmitate solution.

Preparation of the Coating Composition

[0194] In example 5f, a glass vessel was charged with α-tocopherol. In the second step, the solvent (ethanol with 1% MEK) was added. The mixture was stirred at 200 rpm. Thereafter, a 30% aqueous sodium metabisulfite solution and a 10% ethanolic ascorbyl palmitate solution were added in succession with stirring. Furthermore, Miglyol 812 N and Povidone K30 (reduced peroxide content) were added in succession with stirring. The pressure sensitive acrylic adhesive (DURO-TAK 87-4287) was added and the mixture was stirred at approximately 800 rpm for approximately 3.75 hours. Then, the resulting mixture was left overnight without stirring. Then, the product filtrate (3.5950 g) obtained by virtue of Example 5e and containing asenapine in the form of its free base, was added to the mixture and stirring was continued for 3 hours at 800 rpm.

Coating the Coating Composition

[0195] A polyethylene terephthalate film (75 μm thickness), which can function as a peelable film, was coated with the resulting asenapine-containing (in the form of its free base) coating composition and dried for approximately 10 minutes at room temperature and for 20 minutes at 80° C. The coating thickness gave a grammage of the matrix layer of 160.0 g/m.sup.2. The resulting matrix layer has very good adhesive properties. The dried film was laminated with a polyethylene terephthalate back layer (23 μm thickness). The laminate was sealed in a packaging material (AR Neutral P/PET/AL/COC-Coex 628 mm) under nitrogen and stored at room temperature.

Conversion of Asenapine Maleate and Purity of Asenapine in the Form of its Free Base

[0196] The conversion of asenapine maleate and the sum of the degradation products in Examples 5a-d were determined by means of quantitative HPLC. For this purpose, a liquid sample of 500 μl was taken by means of an Eppendorf pipette from the product mixtures of Examples 5a-d in each case after one day and after two days of reaction.

[0197] The following sample preparation steps and the following sample measurement methods were applied to all liquid samples of Examples 5a-d. For technical reasons, the sample preparations of the liquid samples differed slightly from one another; however without affecting the comparability of the results. A liquid sample was placed in a centrifuge and centrifuged therein for 15 minutes at room temperature and 15000 rpm. A 25 ml volumetric flask was charged with 2.0 ml of methanol (as extraction agent) for the centrifuged liquid sample. 25 μl of the centrifuged liquid sample was added using an Eppendorf pipette. This mixture was made up to volume using a phosphate buffer/methanol mixture (60:40 v/v, as diluent).

[0198] For the preparation of an HPLC standard, maleic acid was weighed out in a 20 ml volumetric flask and made up to volume with methanol and dissolved in order to obtain a stock solution with a concentration of 1031 μg/ml. 1.0 ml of this stock solution was pipetted into a 20 ml volumetric flask and made up to volume with a buffer solution in order to obtain a standard solution with a concentration of 51.55 μg/ml. The centrifuged and diluted liquid samples, which were taken out after one day, were measured with a dilution of 1:1000, whereas the centrifuged and diluted liquid samples, which were taken out after two days, were measured with a dilution of 1:2000 by means of quantitative HPLC. The quantitative HPLC measurement was carried out under the conditions detailed in the detailed description. The total mass of asenapine (containing asenapine in the form of its free base as well as asenapine maleate) and the mass of maleic acid were determined using the maleic acid standard solution.

[0199] For the determination of the conversion, in each case a total mass of asenapine (which originates from asenapine in the form of its free base as well as asenapine maleate) and a mass of the maleic acid of the liquid sample were determined by means of quantitative HPLC (see above). The mass fraction of asenapine in the form of its free base can thus be determined by calculation. In this case, the conversion of asenapine maleate (see Table 6.4) corresponds to the mass fraction of asenapine in the form of its free base based on the total mass of asenapine of the centrifuged and diluted liquid sample.

[0200] The liquid samples were also used to determine any degradation products of asenapine by means of quantitative HPLC. The smaller the sum of the degradation products, the higher the purity of asenapine in the form of its free base.

[0201] The conversions and the sum of the degradation products are summarized in Table 6.4.

TABLE-US-00014 TABLE 6.4 Conversion of asenapine Sum of the degradation maleate products Ex. Day 1 Day 2 Day 1 Day 2 Ex. 5a 99.90% 99.69% <0.05% <0.05% Ex. 5b 99.92% 99.83% <0.05% <0.05% Ex. 5c 99.90% 99.76% <0.05% 0.12% Ex. 5d 99.90% 99.77% <0.05% <0.05%

[0202] Furthermore, it was surprisingly found that a d50 particle diameter of sodium metasilicate of <125 μm resulted in a faster and higher conversion of asenapine maleate while high purities were achieved (see Table 6.4).

TABLE-US-00015 TABLE 6.5 Conversion of asenapine Sum of the degradation Ex. maleate products Filtrate Ex. 5e 99.9% <0.05%

[0203] The conversion of asenapine maleate as well as the sum of degradation products in Table 6.5 were determined using the quantitative HPLC analysis described above in detail.

Analysis of the Matrix Layer

[0204] For the analysis of the mass fraction of asenapine in the form of its free base as well as the sum of the degradation products, asenapine was extracted from the matrix layer by means of methanol. The mass fraction of asenapine in the form of its free base as well as its purity are determined by means of quantitative HPLC.

TABLE-US-00016 TABLE 6.6 Ingredient Fraction [%] Asenapine in the form of its free base 7.9 DURO-TAK 4287 71.1 Povidone K30 10.2 Miglyol 812 10.2 α-Tocopherol 0.06 Ascorbyl palmitate 0.2 Sodium metabisulfite 0.109 Grammage 160 g/cm.sup.2 Mass fraction of asenapine in the form of its free base 99.9% Sum of the degradation products <0.05% Content of asenapine in the form of its free base 1262.7 μg/cm.sup.2

[0205] From Table 6.5 it can be seen that a matrix layer of a TTS which contains asenapine in the form of its free base in high purity, could be obtained in a simple manner and without complex purification steps.

Examples 6a-e

Reaction Mixtures

[0206] The masses as well as the fractions of the ingredients of the reaction mixtures, which were used in Examples 6a-6e, are summarized in Tables 7.1 and 7.2. All percentages in Tables 7.1 and 7.2 refer to mass percent (% by mass).

TABLE-US-00017 TABLE 7.1 Ex. 6a Ex. 6b Ex. 6c Mass Fraction Mass Fraction Mass Fraction Ingredient [g] [%] [g] [%] [g] [%] Asenapine maleate 0.5001 2.98 0.5001 2.92 0.4997 2.96 Water (total)* 0.0511 0.30 0.0449 0.26 0.0272 0.16 Sodium metasilicate 0.1533 0.91 0.3030 1.77 0.153 0.90 Ethanol, absolute, 16.0449 95.60 16.2425 94.93 16.2272 95.98 ultrapure (total)** α-Tocopherol 0.0018 0.01 0.0032 0.02 — — Ascorbyl palmitate 0.0101 0.06 0.0108 0.06 — — solution [10% in ethanol absolute, ultrapure]*** Sodium metabisulfite 0.0219 0.13 0.0055 0.03 — — solution [30% in water]**** *Sum of the masses/fractions of the water, which is added in the form of a 30% sodium metabisulfite solution, and the remaining water, which is added as part of the solvent of the reaction mixture. **Sum of the masses/fractions of the ethanol, which is present in the form of 10% ascorbyl palmitate solution, and the remaining ethanol, which is added as part of the solvent of the reaction mixture. ***Mass and fraction refer to ascorbyl palmitate. ****Mass and fraction refer to sodium metabisulfite.

TABLE-US-00018 TABLE 7.2 Ex. 6d Ex. 6e Mass Fraction Mass Fraction Ingredient [g] [%] [g] [%] Asenapine maleate 0.4998 2.93 3.5004 23.44 Water (total)* 0.0280 0.16 0.3456 2.31 Sodium metasilicate 0.3052 1.79 2.1337 14.29 Ethanol, absolute, ultrapure 16.2360 95.12 8.8120 59.01 (total)** α-Tocopherol — — 0.0148 0.10 Ascorbyl palmitate solution — — 0.0804 0.54 [10% in ethanol, absolute, ultrapure]*** Sodium metabisulfite solution — — 0.0455 0.30 [30% in water]**** *Sum of the masses/fractions of the water, which is added in the form of a 30% sodium metabisulfite solution, and the remaining water, which is added as part of the solvent of the reaction mixture. **Sum of the masses/fractions of the ethanol, which is present in the form of 10% ascorbyl palmitate solution, and the remaining ethanol, which is added as part of the solvent of the reaction mixture. ***Mass and fraction refer to ascorbyl palmitate. ****Mass and fraction refer to sodium metabisulfite.

Preparation of Asenapine in the Form of its Free Base

[0207] For providing the reaction mixtures according to Examples 6a-e, a reaction vessel was charged with α-tocopherol (apart from Examples 6c and 6d, in which no antioxidants were used). Thereafter, asenapine maleate was added. Ethanol (absolute, ultrapure) was added as a solvent, and the mixture was stirred at 300 rpm. Thereafter, a 30% aqueous sodium metabisulfite solution and a 10% ethanolic ascorbyl palmitate solution were added in succession with stirring (apart from Examples 6c and 6d, in which no antioxidants were used). Then, ground sodium metasilicate was added. Then, the mixture was flushed with argon. Thereafter, water as a further solvent is added to the mixture (apart from Example 6a, in which the water originates only from the 30% aqueous sodium metabisulfite solution), in order to obtain the reaction mixture, whereupon the reaction mixture was flushed again with argon. Then, the reaction mixture was stirred at 300 rpm for the conversion of asenapine maleate to asenapine in the form of its free base at approximately 20° C. The masses of the reaction mixtures according to Examples 6a-e are summarized in Tables 7.1 and 7.2.

Working up the Reaction Mixture

[0208] After several days summarized in Tables 7.3 and 7.4, samples were taken from the reaction mixtures of Ex. 6a-e. A portion of the samples was filtered, followed by rinsing with ethanol (absolute, ultrapure) in order to obtain a filtrate. The remaining portion of the samples remained in the form of a suspension. The solvent of the samples (both in the form of filtrate as well as in the form of a suspension) was removed by means of a rotary evaporator (Rotavapor Büchi R-100, water bath temperature 50° C., pressure: 150 mbar). Then, the product was dried at 80° C. for 10 minutes and cooled in a desiccator. The product obtained in this way is called “solution” in Tables 7.3 and 7.4. Then, the total mass of the solution is determined using a scale. The solution is taken up in methanol and examined by means of quantitative HPLC with regard to the mass fraction of asenapine and the sum of the degradation products. The mass fraction of asenapine maleate with regard to the total mass of the solution is determined using the quantitative HPLC method. The sum of the degradation products was also determined by means of quantitative HPLC. Tables 7. 3 and 7.4 show the mass fractions of asenapine and the sum of the degradation products in the corresponding samples (solution, suspension, filtrate or centrifugate). Here, “suspension” is understood to mean the reaction mixture (without a filtration step). The sample preparation was done analogously to the liquid sample preparations mentioned above.

TABLE-US-00019 TABLE 7.3 Mass fraction of Sum of the degradation Example asenapine products Ex. 6a 73.1% <0.05% Solution after 2 days Ex. 6b 86.3% <0.05% Solution after 2 days Ex. 6b 92.3% <0.05% Solution after 5 days Ex. 6c 71.8% 2.84% Solution after 2 days Ex. 6d 77.3% 0.78% Solution after 1 day Ex. 6d 78.2% 13.90% Solution after 2 days Ex. 6a 103.6% <0.05% Suspension after 7 days Ex. 6c 105.1% <0.05% Suspension after 7 days Ex. 6d 106.8% <0.05% Suspension after 7 days

[0209] From Table 7.3 it can be seen that in the solution with antioxidants (see solutions in Ex. 6a and 6b) less degradation products form, as compared to the solution without antioxidants (see solutions in Ex. 6c and 6d).

TABLE-US-00020 TABLE 7.4 Mass fraction of Sum of the degradation Example asenapine products Ex. 6e 80.4% 0.29% Solution after 2 days Ex. 6e 91.1% 0.23% Solution after 5 days Ex. 6e 91.0% 0.34% Solution after 8 days Ex. 6e 86.8% 0.39% Solution after 12 days Ex. 6e — 0.27% Centrifugate after 12 days Ex. 6e — 0.27% Filtrate after 12 days

THE INVENTION RELATES IN PARTICULAR TO THE FOLLOWING EMBODIMENTS

[0210] 1. A process for the preparation of asenapine in the form of its free base comprising the steps of: [0211] 1) providing a reaction mixture comprising asenapine maleate and an alkali metal silicate in a solvent, wherein the reaction mixture contains the alkali metal silicate in dispersed form; and [0212] 2) reacting asenapine maleate with the alkali metal silicate in the reaction mixture provided in step 1) in order to obtain a product mixture which contains dissolved asenapine in the form of its free base and alkali metal maleate in dispersed form.

[0213] 2. The process according to embodiment 1 further comprising the step of: [0214] 3) isolating a solution containing asenapine in the form of its free base from the product mixture obtained in step 2), wherein the isolation is preferably carried out by means of filtration.

[0215] 3. The process according to embodiment 1 or 2, wherein the solvent used in step 1) contains water.

[0216] 4. The process according to embodiment 3, wherein the solvent used in step 1) contains water and asenapine maleate in a molar ratio of 4 or less parts of water, preferably 3 or less parts of water, more preferably from 3 to ¼ parts of water, and most preferably from 2 to ⅓ parts of water, each based on 1 part of asenapine maleate.

[0217] 5. The process according to any one of embodiments 1 to 4, wherein the alkali metal silicate is selected from the group consisting of sodium metasilicate, sodium trisilicate, potassium silicate and mixtures thereof.

[0218] 6. The process according to any one of embodiments 1 to 5, wherein the d50 particle diameter of the alkali metal silicate used in step 1) is 125 μm or more, or less than 125 μm, or wherein the d80 particle diameter of the alkali metal silicate used in step 1) is less than 200 μm.

[0219] 7. The process according to any one of embodiments 1 to 6, wherein the solvent used in step 1) contains alkali metal silicate and asenapine maleate in a molar ratio of 1 or more parts of alkali metal silicate, from 1 to 10 parts of alkali metal silicate, from 1 to 5 parts of alkali metal silicate, from 1 to 4 parts of alkali metal silicate, from 1 to 3 parts of alkali metal silicate, or from 1 to 2 parts of alkali metal silicate, each based on 1 part of asenapine maleate.

[0220] 8. The process according to any one of embodiments 1 to 7, wherein the solvent in step 1) contains an alcoholic solvent which is preferably selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol and mixtures thereof.

[0221] 9. The process according to embodiment 8, wherein the mass fraction of the alcoholic solvent is 40% by mass to 97% by mass, preferably 45% by mass to 70% by mass, based on the total mass of the reaction mixture provided in step 1).

[0222] 10. The process according to any one of embodiments 1 to 9, wherein step 2) is carried out at a temperature of 15° C. to 45° C., at a temperature of 15° C. to 25° C., or at a temperature of 35° C. to 45° C.

[0223] 11. The process according to any one of embodiments 1 to 10, wherein the mass fraction of the asenapine maleate is 1% by mass to 40% by mass, preferably 2% by mass to 35% by mass, particularly preferably 15% by mass to 30% by mass, based on the total mass of the reaction mixture provided in step 1).

[0224] 12. The process according to any one of embodiments 1 to 11, wherein step 2) is carried out for a period of 2 h to 144 h, preferably for a period of 8 h to 60 h, particularly preferably for a period of 12 h to 50 h.

[0225] 13. The process according to any one of embodiments 1 to 12, wherein the conversion in step 2) is 80% or more, preferably 90% or more, particularly preferably 99% or more, wherein the conversion is determined by means of HPLC.

[0226] 14. The process according to any one of embodiments 1 to 13, wherein the asenapine in the form of its free base is formed in step 2) with a purity of 99.0% or more, preferably 99.5% or more, particularly preferably 99.95% or more, wherein the purity is determined by means of HPLC.

[0227] 15. The process according to any one of embodiments 1 to 14, wherein antioxidants are used in step 1) as part of the reaction mixture, wherein the antioxidants are selected in particular from the group consisting of α-tocopherol, sodium metabisulfite, which is preferably used as an aqueous solution in step 1), ascorbyl palmitate, which is preferably used as an ethanolic solution in step 1), and mixtures thereof.

[0228] 16. The process according to embodiment 15, wherein the mass fraction of α-tocopherol is 0.01% by mass to 0.5% by mass, based on the total mass of the reaction mixture provided in step 1); and/or

wherein the mass fraction of sodium metabisulfite is 0.01% by mass to 0.5% by mass, based on the total mass of the reaction mixture provided in step 1); and/or
wherein the mass fraction of ascorbyl palmitate is 0.05% by mass to 1.0% by mass, based on the total mass of the reaction mixture provided in step 1).

[0229] 17. A process for the preparation of an active ingredient-containing layer for use in a transdermal therapeutic system, wherein the process comprises the following steps of: [0230] i) preparing asenapine in the form of its free base by means of the process according to any one of embodiments 1 to 16; [0231] ii) combining at least the asenapine in the form of its free base obtained in step i) and a polymer in a further solvent in order to obtain a coating composition, wherein the asenapine in the form of its free base obtained in step i) and used in step ii) is preferably contained in the solvent used in step ii), and is more preferably present in a solution isolated according to step 3) according to embodiment 2; [0232] iii) coating the coating composition on a back layer, a peelable film or an intermediate film; and [0233] iv) drying the coated coating composition to form the active ingredient-containing layer.

[0234] 18. The process according to embodiment 17, wherein the solvent from step ii) is selected from alcoholic solvents, in particular methanol, ethanol, isopropanol and mixtures thereof, and from non-alcoholic solvents, in particular ethyl acetate, hexane, n-heptane, petroleum ether, toluene, and mixtures thereof, and wherein the solvent is particularly preferably selected from ethanol and ethyl acetate.

[0235] 19. The process according to embodiment 17 or 18, wherein the polymer is an acrylic polymer and preferably a copolymer based on vinyl acetate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate and glycidyl methacrylate, or based on vinyl acetate, 2-ethylhexyl acrylate, and 2-hydroxyethyl acrylate, which is provided as a solution, and is preferably present as a solution in ethyl acetate, n-heptane, methanol, ethanol and mixtures thereof with a solids content of 30% by mass to 60% by mass.

[0236] 20. The process according to embodiment 19, wherein α-tocopherol, sodium metabisulfite, which is preferably provided in an aqueous solution, ascorbyl palmitate, which is preferably provided in an ethanolic solution, a triglyceride and/or a polyvinylpyrrolidone are combined with the isolated solution containing asenapine in the form of its free base and the acrylic polymer in the solvent in step ii) to obtain the coating composition.

[0237] 21. The process according to embodiment 20, wherein the active ingredient-containing layer formed in step iv) comprises [0238] A) 4% by mass to 12% by mass asenapine in the form of its free base; and [0239] B) 65% by mass to 85% by mass acrylic polymer; [0240] C) 5% by mass to 15% by mass polyvinylpyrrolidone; [0241] D) 5% by mass to 15% by mass triglyceride; [0242] E) 0.1% by mass to 0.5% by mass ascorbyl palmitate; [0243] F) 0.05% by mass to 0.3% by mass sodium metabisulfite; [0244] G) 0.01% by mass to 0.1% by mass α-tocopherol; and based on the total mass of the active ingredient-containing layer obtained in step iv) from the coating composition.

[0245] 22. The process according to any one of embodiments 17 to 21, wherein the drying in step iv) is carried out at a temperature of 50° C. to 90° C., particularly preferably at a temperature of 60° C. to 85° C.

[0246] 23. The process according to any one of embodiments 17 to 22, wherein the active ingredient-containing layer formed has a grammage in a range from 50 to 90 g/m.sup.2 or 90 to 230 g/m.sup.2.

[0247] 24. The process according to any one of embodiments 17 to 23, wherein the asenapine in the form of its free base in the active ingredient-containing layer formed has a purity of 95.0% or more, preferably 99.0% or more, particularly preferably 99.95% or more, wherein the purity is determined by means of HPLC.

[0248] 25. The process according to any one of embodiments 17 to 24, wherein the drying in step iv) is carried out for a period of 10 min to 60 min.

[0249] 26. The process according to any one of embodiments 17 to 25, wherein a mass fraction of asenapine in the form of its free base is 95% by mass or more, preferably 99% by mass or more, particularly preferably 100% by mass, based on the asenapine total mass in the active ingredient-containing layer formed.

[0250] 27. The process according to any one of embodiments 17 to 26, wherein the drying in step iv) is carried out in two stages, wherein the drying is carried out in the first stage at 15° C. to 25° C. for a period of 5 min to 15 min, followed by drying in the second stage at 60° C. to 85° C. for a period of 10 min to 40 min.

[0251] 28. Asenapine in the form of its free base, obtainable by a process according to any one of embodiments 1 to 16, wherein the asenapine in the form of its free base has a purity of 99.0% or more, preferably 99.5% or more, particularly preferably 99.95% or more, wherein the purity is determined by means of HPLC, wherein the asenapine in the form of its free base is preferably present in a solvent and particularly preferably in a solution isolated according to step 3) according to embodiment 2.

[0252] 29. An active ingredient-containing layer for use in a transdermal therapeutic system, obtainable by a process according to any one of embodiments 17 to 27, wherein the asenapine in the form of its free base in the active ingredient-containing layer has a purity of 99.0% or more, preferably 99.5% or more, particularly preferably 99.95% or more, wherein the purity is determined by means of HPLC.

[0253] 30. A transdermal therapeutic system containing an active ingredient-containing layer according to embodiment 29.