KR20070022037A - Pharmaceutical composition comprising a salt of mirtazapine - Google Patents

Abstract

The present invention provides pharmaceutically suitable non-sublimable solid salts of the enantiomers of mirtazapine, in particular the mirtazapine salt selected from the list of salts of maleic acid, hydrobromic acid and fumaric acid, and the S- or R-mirtazapine It provides a use for the manufacture of a pharmaceutical composition comprising a salt of.

Description

Pharmaceutical composition containing the salt of mirtazapine {PHARMACEUTICAL COMPOSITION COMPRISING A SALT OF MIRTAZAPINE}

The present invention relates to pharmaceutical formulations comprising pure enantiomers of mirtazapine.

Mirtazapine is a widely used drug with a number of therapeutic uses. The form of drug available as a pharmaceutical composition for prescription to a patient is the base form of a compound, such as a racemic mixture. In view of the novel use of the drug and the different pharmacological properties of the enantiomers, it is necessary to prepare individual single S- and R-enantiomers usable in pharmaceutical compositions. Pharmaceutical compositions for oral use of enantiomers are described in the publications of Fink and Irwin, which describe the administration of S-enantiomers and R-enantiomers of mirtazapine to human volunteers for research purposes [Psychopharmacology, Vol 78, pp. 44-48, 1982]. The compound is provided in the form of the free base of the S- or R-enantiomer of mirtazapine.

Such formulations have been found to have problems due to the sublimation of mirtazapine. Pure bases of S- and R-mirtazapine slowly sublimate the compounds at room temperature, but it has been found that not all salts of S- and R-mirtazapine have this disadvantage. Therefore, the usefulness of such pharmaceutical compositions comprising the enantiomer of mirtazapine in solid form is selected according to the present invention to a pharmaceutically suitable non-sublimable solid salt of mirtazapine enantiomer for use as the mirtazapine form in the composition. This can be improved. The present invention also provides a process for the preparation of a pharmaceutical formulation comprising the pure enantiomer of mirtazapine in solid form, wherein the solid form is a pharmaceutically suitable non-sublimable salt of S- or R-mirtazapine.

Other desirable properties of the pharmaceutical component, such as ease of manufacture or purification or chemical or physical stability in capsules and / or tablets, can also be obtained with the use of salts according to the invention. Improved physical stability can be attributed to reduced migration of the compound from the formulation, and improved chemical stability can be attributed to reduced degradation of mirtazapine. Non-sublimable solid salts of S-Mirzazapine, including R-Mirzazapine, have been found to be, for example, maleic acid salts, hydrochloride salts, hydrobromic acid salts, fumaric acid salts and methanesulfonic acid salts of mirtazapine. Maleic acid salts are particularly advantageous because they have a high melting point, readily form crystals that do not form another polymorph, and are not hygroscopic. In addition, methanesulfonic acid salts are very useful salts for the enantiomer of mirtazapine from the viewpoint of non-sublimation and non-hygroscopicity. Trifluoroacetic acid salts of S- or R-mirtazapine are examples of salts that show sublimation. In addition, the latter salts are not pharmaceutically suitable salts.

The properties of sublimation can be observed and quantified by known methods of measuring sublimation. For example, sublimation can be measured with a device having a chamber in which the test compound is in a solid state and the temperature is controlled and maintained in that state. Optionally under low pressure, the gas phase in the chamber can be analyzed for the content of the test compound. It is also possible to continuously remove the gaseous test compound from the chamber by means of a continuous renewal stream of gas or by generating a precipitate of the test compound from the gas phase, for example as a cold surface. Do. The amount of material collected from sublimation or released from the sample by sublimation can be analyzed. The degree of sublimation is expressed as a fraction of the starting sample size (as a percentage).

The term 'non-sublimable salt' refers to the amount of base when about 10 mg of sample (for example, amount of 8-12 mg) is left for a duration of 72 hours under standard conditions of 150 mBar pressure and 60 ° C. temperature. It is defined that up to 1% of mirtazapine is a salt of S- or R-mirtazapine that sublimes from the sample when calculated by.

Pharmaceutically suitable acids accepted for providing anions to salts of pharmaceutically active compounds include hydrochloric acid, hydrobromic acid, sulfuric acid, maleic acid, fumaric acid, methylsulfonic acid, acetic acid, and Philip L. Gould's [International Journal of Pharmaceutics, Vol. 33, (1986), pp. 201-207 is another acid mentioned. This publication provides a list of limited and limited acids, which can be tested according to the procedures described in the detailed description of the invention for obtaining salts according to the invention.

The term 'solid' in the detailed description of the invention means that the amorphous or crystalline compound remains solid at room temperature.

The term mirtazapine is the compound 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino [2,1-a] pyrido [2,3-c as active ingredient for pharmaceutical formulations. ] [2] benzazepine. The term is used herein to refer to the free base as an individual compound, or to refer to the base component in the mirtazapine salt.

Reference to formulations comprising enantiomers of mirtazapine refers to formulations in which the pure enantiomeric form of mirtazapine is used in preparation, in contrast to formulations in which the racemic form of mirtazapine is used. Tablets in this paragraph are intended to encompass one or more of the steps of preparing mirtazapine, which preparation is intended to obtain some degree of separation of the two enantiomers. Preferably a purity of 95%, 98%, 99%, 99.5% or 99.8% is used for 90% pure enantiomers, or more preferably another enantiomer.

Mirtazapine, 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino [2,1-a] pyrido [2,3-c] [2] benzazepine is known It can be prepared by the method. Synthesis of racemic mirtazapine is described in US 4062848, which discloses, for example, a four step synthetic scheme starting from 2-substituted nicotinitriles. Further modifications to the various steps of this route are described in WO 00/62782, WO 01/23345 and US 6,376,668.

The preparation of the enantiomer pure mirtazapine is described in US 4062848, WO 00/62782 and in Selditz et. al., 1998 (J. Chromatography, 1998, vol 803, pp 169-177). Diastereomers formed by reacting racemate mirtazapine with enantiomeric pure dibenzoyltartaric acid in ethanol and then treating with aqueous ammonium to regenerate the free base by the method disclosed in US 4062848. Obtained by fractional determination of salts. Another method for forming pure mirtazapine by recrystallization of crude mirtazapine is disclosed in WO 00/62782. Selditz et al. Describe a chromatographic method for separating enantiomers.

The pharmaceutical composition is prepared from the active ingredient, which in the context of the present application is a salt of S- or R-mirtazapine, to which a carrier or other excipient is added. The features of the salts according to the invention make them most suitable for the manufacture and use of various pharmaceutical formulations for dose administration to a subject. This form is improved for use in specific routes of administration, such as oral, rectal or subcutaneous.

Formulations such as pills, tablets, suppositories, (micro-) capsules, powders, emulsions, creams, ointments, implants, patches, gels or any other sustained release preparations, injections in the form of sprays, suspensions, suitable adjuvants such as fillers, Binders, lubricants, dispersants, emulsifiers, stabilizers, surfactants, penetration enhancers, antioxidants, colorants, preservatives and the like are described, for example, in standard references [Gennaro et al., Remington; The Science and Practice of Pharmacy; 20th Edition, Publisher: Lippincott Williams &Wilkins;Baltimore; USA, Part 5) and the Handbook of Pharmaceutical Excipients (3rd edition, Arthur H. Kibbe edited by the American Pharmaceutical Association, Washington D.C., The Pharmaceutical Press, London, 2000). In general, any pharmaceutically acceptable adjuvant that does not interfere with the action of the active compound may be suitable and used. The amount of S- or R-mirzazapine salt in the formulation may be improved depending on the particular circumstances. Generally, dosage units are expressed based on the amount of base and will contain from 0.05 mg to 90 mg of the S- or R-mirtazapine salt.

Suitable fillers or carriers that can be administered with the compositions include agar, alcohol, fat, lactose, starch, cellulose derivatives, polysaccharides, polyvinylpyrrolidone, silica, sterile saline, and the like, used in appropriate amounts, or Mixtures thereof.

Binders are agents used to impart cohesive properties to pharmaceutical compositions that induce minimal loss from pharmaceutical compositions during production and handling. Examples of the binder include cellulose, starch, polyvinylpyrrolidone and the like.

Suitable lubricants that can be administered with the activators of the invention are, for example, magnesium stearate.

Surfactants are agents that promote the contact and migration of compounds in different physical environments, such as hydrophilic and hydrophobic environments. Many surfactants are described, for example, in Gennaro et al, Remington; The Science and Practice of Pharmacy; 20th Edition, Publisher: Lippincott Williams &Wilkins;Baltimore; USA, which is known in the art for preparing pharmaceutical compositions as described in Chapter 21 of the USA. Surfactants that can be used in the process of preparing pharmaceutical formulations are, for example, polyethylene glycol (PEG) and the like.

Salts according to the invention can be prepared by methods known in the art. The base is dissolved in a suitable solvent such as methanol, ethanol, ethyl acetate or acetone and the acid is added by itself or dissolved by, for example, ethanol, ethyl acetate or acetone. Salts can be collected from the solvent by precipitation or crystallization, and if necessary, precipitation and crystallization can be caused by cooling the solution or by evaporating the solvent.

Schematic of the sublimation test apparatus. The sample is placed at the bottom of the vessel, which is closed at the top by a stopper in the form of a vessel through which the cooling solution CL circulates internally and has an outlet to which the vacuum pump Vac is connected. The vessel is located in a closed chamber under constant temperature control (TC). Sublimates Subl may accumulate on the closure surface in the container.

In the examples, S-mirtazapine was used. In terms of balance, they can be directly copied and applied to R-mirtazapine, with the exception of Example 8, where (-)-O, O-dibenzoyl-L-tartaric acid should be used for R-mirtazapine. have.

1.S- Mirtazapine Hydrochloric acid  crystallization

To a solution of 3.01 g of S-mirtazapine in 5 ml of methanol was added a solution of 939 μl hydrochloric acid in 20 ml of ethyl acetate at room temperature. A portion of the solvent was evaporated to form an oil in solution. The solution was then cooled to 0 ° C. Seed crystals were added to initiate crystallization. White crystals were collected by filtration and dried in a vacuum oven at 40 ° C. This gave 1.96 g (57%) of white crystals of S-mirtazapine hydrochloride. Endothermic peak (DSC): 275 ° C .; XRPD and ss-NMR: crystalline, no amorphous in one polymorphic form. The compound began to sublimate above 170 ° C. Dynamic vapor sorption measurement confirmed that the salt was very hygroscopic.

2. Crystallization of S-Myrzazapine.Maleic Acid Salt

To a solution of 3.01 g of S-mirtazapine in 10 ml of ethanol was added a solution of 1.32 g of maleic acid in 10 ml of ethanol at room temperature. After stirring for several minutes, crystallization was initiated. After stirring for several hours at room temperature, the white crystals were collected by filtration and dried in a vacuum oven at 40 ° C. This gave 3.98 g (92%) of white crystals of the S-mirtazapine.maleic acid salt. Endothermic peak (DSC): 206 ° C .; XRPD and ss-NMR: crystalline material; Ratio of mirtazapine / maleic acid: 1: 1; One polymorphic formation, no amorphous material. Dynamic vapor sorption measurements confirmed that the salt was not hygroscopic.

3. S- Mirtazapine Crystallization of fumarate

To a solution of 3.01 g S-mirtazapine in 5 ml of methanol was added 1.31 g of fumaric acid at room temperature to induce rapid precipitation. In addition, 5 ml of methanol and 20 ml of ethyl acetate were added to the suspension to redissolve the solids. A portion of the solvent was evaporated to initiate crystallization from the clear solution. After stirring for several hours, the white crystals were collected by filtration and dried in a vacuum oven at 40 ° C. This gave 3.76 g (87%) of white crystals of the S-mirtazapine.fumaric acid salt. Endothermic peak (DSC): 178 ° C .; XRPD and ss-NMR: A mixture of three polymorphic formations with some amorphous material. Fumaric acid salts absorb water from the atmosphere to form hydrates, which can dry out and lose water content.

4. S- Mirtazapine  Crystallization of Hydrobromic Acid Salts

To a solution of 3.01 g of S-mirtazapine in 5 ml of methanol was added a solution of 1290 μl hydrochloric acid in 20 ml of ethyl acetate at room temperature. A portion of the solvent was evaporated and an oil formed. The mixture was cooled to 0 ° C., thereby initiating crystallization. White crystals were collected by filtration and dried in a vacuum oven at 40 ° C. This gave 3.74 g (95%) of white crystals of the S-myrzazapine hydrobromide salt. Endothermic peak (DSC): 253 ° C .; XRPD and ss-NMR: mainly one polymorphic formation and some amorphous materials. The HBr salt had obvious hydrophilicity and formed monohydrate under ambient conditions. Anhydrous drug samples absorb water when in contact with the atmosphere, while losing moisture upon drying.

5. S- Mirtazapine Methanesulfonic acid  Crystallization of salts

To a solution of 3.01 g S-mirtazapine in 5 ml of methanol was added a solution of 743 μl of methanesulfonic acid in 20 ml of ethyl acetate at room temperature. A portion of the solvent was evaporated, thereby initiating crystallization. White crystals were collected by filtration and dried in a vacuum oven at 40 ° C. This gave 2.09 g (51%) of white crystals of the S-mirtazapine methanesulphonic salt. Endothermic peak (DSC): 208 ° C .; XRPD and ss-NMR: crystalline material, mainly one polymorph.

6. S- Mirtazapine Trifluoroacetic acid  Crystallization of salts

To a solution of 0.50 g of S-mirtazapine in ethyl acetate was added a solution of 142 μl of trifluoroacetic acid in ethyl acetate. The crystals did not start spontaneously, so the solvent evaporated slowly. During evaporation of the solvent, the salt began to crystallize. This gave 0.65 g of S-mirtazapine trifluoroacetic acid salt. Endothermic peak (DSC): 185 ° C. In the experiments according to example 10, it was found that this salt is not a non-sublimable salt according to the definition of the non-sublimable salt in this description.

7. S- Mirtazapine  Formate, S- Mirtazapine Acetate , S- Mirtazapine Porric acid  Salt and S- Mirtazapine Phosphate  Solidification was not successful.

Example 8.

This is to confirm the first step of the preparation method of the enantiomer pure mirtazapine. Salts of this example are not acceptable for pharmaceutical use.

S- Mirtazapine  (+)-O, O- Dibenzoyl Crystallization of -D-tartaric Acid Salt

23.33 g of mirtazapine (Org 3770) was dissolved in 94 ml of ethanol at a temperature of 52 ° C. A filtered solution of 33.06 g of (+)-O, O-dibenzoyl-D-tartaric acid hydrate in 132 ml (100%) of ethanol was added to the warm solution. The reaction mixture was then cooled to room temperature. Seed crystals were added to the reaction mixture to initiate the crystals. After stirring for 19 hours, the crystals were collected by filtration. Yield of wet crystals was 25.7 g, e. e. was 88.04%. The crystals were suspended in 880 ml of ethanol and dissolved at reflux temperature. The reaction mixture was cooled down and crystallization started. After 16 hours, the crystals were collected by filtration. The yield of wet crystals was 20.4 g and e. e. was 98.9%. Residual mother liquors can also be used to obtain R-mirtazapine by mixing with (-)-O, O-dibenzoyl-L-tartaric acid.

9. HPLC By S- Mirtazapine  And analysis of degradation products

column Hypersil ODS, 250 x 4.6 mm I.D., 5 μm or equilibrium column Column temperature 40 ℃ Solution A Methanol + Acetonitrile + Tetrahydrofuran, 36.2 + 42.5 + 21.3, V + V + V Mobile phase Solution A + tetramethylammonium hydroxide pentahydrate solution 0.1 M (pH = 7.4), 35 + 65, V + V Flow rate 1.5 mL / min detection S-Myrzazapine: UV 290 nm Decomposition product A: UV 240 nm Decomposition product B: UV 240 nm Decomposition product C: UV 240 nm Decomposition product D: UV 240 nm Injection volume 10 μL operating time 27 mins Approximate Retention Time ^* S-Myrzazapine Decomposition Product A Decomposition Product B Decomposition Product C Decomposition Product D 14.5≤t _R ≤17.5 minutes 23.1 minutes 3.0 minutes 5.6 minutes 3.7 minutes

* If the residence time of the S-Myrzazapine peak does not meet the system suitability standards prior to analysis, the mobile phase should be adjusted by the addition of any solution A or 0.1 M of tetramethylammonium hydroxide pentahydrate solution. The detection limit of S-mirtazapine as free base, or as an active entity in the form of a salt thereof, is below 0.02 mg.

denomination:

Decomposition product A: 2,3,4,4a-tetrahydro-3-methylpyrazino [2,1-a] pyrido [2,3-c] [2] benzazepin-9 (1H) -one

Decomposition product B: 1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3c] [2] benzazepine-2-oxide dihydrate

Decomposition product C: 3,4,10,14b-tetrahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c] [2] benzazepin-1 (2H) -one

Decomposition product D: N- [2- (5,10-Dihydro-10-oxo-11H-pyrido [2,3-c] [2] benzazepin-11-yl) ethyl] -N-methyl- Formamide

10. Sublimation Test

Samples (approximately 10 mg) were placed in the sample chamber of the sublimation test equipment as illustrated in FIG. 1. The temperature of the sample chamber is controllable. The sample holder had a reduced pressure of 150 mBar, the initial setting. The sample chamber also consisted of a portion with reduced temperature (“cold finger”), which temperature was approximately 5 ° C. Most of the material that sublimes in the hot test sample will settle in the finger cooler. The amount of material on the finger cooler after the 72-hour Tets period was quantified using HPLC analysis. The degree of sublimation was expressed as a fraction (as a percentage) on the finger cooler of the initial sample size. In addition, sublimation of the active compounds from tablet "drugs" was tested.

result

Table 1 shows the sublimation results of tablets containing S-mirtazapine, S-mirtazapine.HBr, S-mirtazapine.maleic acid, S-mirtazapine.fumaric acid and some of these compounds under a number of test conditions. Listed.

Sublimation results Sublimation ^a Temperature: 40 ℃ Pressure: 150 mbar Test time: 72 hours Drug S-Myrtazapine Batch E S-Mirtazapine Batch J  0.75% 0.88% Temperature: 60 ℃ Pressure: 150 mbar Test time: 72 hours Drug S-Mirzazapine Batch E S-Mirzazapine Batch J S-Mirzazapine.HBr S-Mirtazapine.Maleic Acid S-Mirtazapine.Fumaric Acid S-Mirtazapine HCl S-Mirtazapine Methanesulfonic Acid  5.32%, 2.22% 4.29% <DL <DL <DL 0.2% 0.2% 0.1%, 0.0% Drugs (Tablets) ¹ S-Myrzazapine Tablets ² S-Myrzazapine.HBr Tablets S-Myrzazapine.Maleic Acid Tablets   7.21% <DL <DL

<DL = below detection level

^{a If} two values are mentioned, they are the result of repeated experiments.

The composition of the tablets used in the ¹ sublimation test is described in Table 3.

² Formulation C as in Table 3.

Stability results drug Formulation ¹ Content (% of initial content) T = 1 month 5 ℃ / A 25 ℃ / 60% RH 30 ℃ / 60% RH 40 ℃ / A 40 ℃ / 75% RH 60 ℃ / A S-Myrzazapine Formulation A 100.7 94.1 S-Myrzazapine Formulation B 100.5 94.8 S-Myrzazapine Formulation C 100.2 96.4 S-Myrzazapine Formulation D 95.8 91.0 S-Myrzazapine.maleic acid ² Formulation F 99.8 98.8 99.0 99.5 100.2 99.3 S-Myrzazapine.maleic acid ² Formulation G 98.9 99.3 99.1 99.9 99.9 100.0 T = 3 months 5 ℃ / A 25 ℃ / 60% RH 30 ℃ / 60% RH 40 ℃ / A 40 ℃ / 75% RH 60 ℃ / A S-Myrzazapine Formulation A 100.6 101.0 96.3 90.5 18.0 S-Myrzazapine Formulation B 100.6 99.6 96.8 91.8 25.5 S-Myrzazapine Formulation C 101.1 98.5 95.3 91.3 43.0 S-Myrzazapine Formulation D 95.4 96.9 93.3 90.9 33.6 S-Myrzazapine.maleic acid ² Formulation F 103.3 102.4 102.9 103.2 104.8 103.4 S-Myrzazapine.maleic acid ² Formulation G 101.2 102.4 100.0 100.3 102.6 101.5

A = atmospheric humidity

RH = relative

¹ Some S-Myrzazapine. All tablets except maleic acid salt tablets contain about 1 mg of S-Myrzazapine, calculated based on the amount of salt. However, due to losses during the manufacturing process, the content may be lower. The formulations are shown in Table 3.

² The first column shows the results of the 1 mg / 65 mg tablet (Formulation F; see Table 3). The second column shows the result of the 10 mg / 160 mg tablet (Formulation G; see Table 3).

Composition of tablets ingredient Dose Per Tablet [mg] Formulation A Formulation B Formulation C Formulation D Formulation E Formulation F Formulation G S-Myrzazapine ¹ 1.0 1.0 1.0 1.0 S-Mirtazapine.HBr ¹ 1.305 ² S-Myrzazapine.Maleic acid ¹ 1.437 ² 14.37 ³ Magnesium stearate 0.325 0.325 0.325 0.325 0.325 0.325-0.49 1.2 Starch sodium glycolate 1.95 1.95 1.95 1.95 4.8 Corn starch 6.5 Potato starch 5.1 Calcium Diphosphate 26.0 Hydroxypropyl cellulose 1.3 Aerosil 0.975 Povidone 15.4 Lactose Monohydrate Filled up to 65 Filled up to 65 43.5 Filled up to 65 Filled up to 65 Filled up to 160 Microcrystalline cellulose 65 or less Total tablet weight 65 65 65 65 65 65 160

Description of Table 3

¹ Due to losses or other problems during the manufacturing process, the content may be lower or higher.

Corresponds to 1 mg S-mirtazapine as a ^two base.

Corresponding to 10 mg S-mirtazapine as ³ bases.

The results of the sublimation test show that the free base S-mirtazapine sublimated at the conditions used. S-mirtazapine hydrobromide, S-mirtazapine.maleic acid salt and S-mirtazapine.fumaric acid salt did not sublime. This difference is also seen in tablets containing S-mirtazapine, S-mirtazapine.HBr or S-mirtazapine.maleic acid. In addition, the stability of the tablets containing S-mirtazapine and S-mirtazapine.maleic acid was measured (Tables 2 and 4). It was evident that the S-mirtazapine content in the tablets containing the free base S-mirtazapine was reduced. The decrease was largely caused by sublimation. In tablets containing S-mirtazapine.maleic acid, no decrease in content was observed.

Chemical stability of the drug was further analyzed by measurement of chemical degradation products. Analytical values after storage are shown in Table 4.

Analysis of stability results and degradation products drug Formulation ¹ T = 3 months 5 ℃ / A 25 ℃ / 60% RH 30 ℃ / 60% RH 40 ℃ / A 40 ℃ / 75% RH 60 ℃ / A S-Myrtazapine Decomposition Product A Decomposition Product B Decomposition Product C Decomposition Product D Formulation A 100.6 <0.1% <0.1% <0.1% <0.1% 101.0 <0.1% <0.1% <0.1% 0.11% 96.3 <0.1% <0.1% <0.1% 0.14% 90.5 <0.1% 0.16% 0.14% 0.35% 18.0 0.53% 3.70% 1.06% 5.57% S-Myrzazapine.Maleic Acid Decomposition Product A Decomposition Product B Decomposition Product C Decomposition Product D Formulation F 103.3 n.d. 102.4 <0.1% <0.1% <0.1% <0.1% 102.9 <0.1% <0.1% <0.1% <0.1% 103.2 <0.1% <0.1% <0.1% <0.1% 104.8 <0.1% 0.18% <0.1% 0.11% 103.4 n.d.

Comments on Table 4

¹ All tablets contained about 1 mg active substance (S-mirtazapine). However, due to losses during the manufacturing process, the active substance content may be lower. The formulations are shown in Table 3.

n.d. = Not detected

A = atmospheric humidity

It is noteworthy that in tablets containing S-Mirtazapine.maleic acid, no decrease in content was observed. The degradation products found in the tablets containing S-mirtazapine or S-mirtazapine. Maleic acid are shown in Table 4. The formulation of the tablet is similar (see Table 3). S-Myrzazapine, stored for 3 months at 40 ° C./75% RH. In tablets containing maleic acid, the concentration of degradation products was lower than tablets containing free base S-Mirtazapine stored for the same period. Loss under 60 ° C. conditions at ambient temperature was not high for maleic acid salts, while degradation products for formulations with free bases had already reached about 11%.

Claims (5)

A pharmaceutical formulation comprising an enantiomer of mirtazapine, wherein the mirtazapine is present as a pharmaceutically suitable non-sublimable solid salt of mirtazapine. The pharmaceutical formulation of claim 1, wherein the salt is selected from the list consisting of salts of maleic acid, hydrobromic acid, fumaric acid and methanesulfonic acid. The pharmaceutical formulation of claim 2, wherein the salt is a salt of maleic acid or a salt of methanesulfonic acid. The pharmaceutical formulation according to any one of claims 1 to 3, wherein the enantiomer of mirtazapine is an S-enantiomer. A process for the preparation of a pharmaceutical formulation comprising an enantiomer of mirtazapine in solid form, wherein the solid form is a pharmaceutically suitable non-sublimable salt of S- or R-mirtazapine.

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