SK288146B6 - Addition salts of galantamine, method for their preparation and preparations containing them - Google Patents

Abstract

The invention relates to addition salts of sulfonic acids and galantamine as well as hydrates or solvates thereof in a crystalline or an amorphous form. The invention also relates to a method for the preparation of said salts as well as to their use for therapeutic purposes.

Description

Technical field

The present invention relates to a process for the preparation of novel galantamine addition salts whose chemical name is (4aS, 6R, 8aS) -4a, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro- [3a, 3,2-ef] [2] benzazepin-6-ol.

Galantamine of formula (I), also known in the literature as lycoramine, is a tertiary alkaloid which, by virtue of its pharmacological properties, belongs to the group of reversibly acting acetylcholinesterase inhibitors. Therefore, galantamine is used in pharmacology for the symptoms of paralysis resulting from both and for various diseases of the nervous system. Galantamine hydrobromide is marketed as a pharmaceutical composition for the treatment, e.g. Alzheimer's disease.

BACKGROUND OF THE INVENTION

Galantamine is a tertiary alkaloid that was originally isolated from the cauliflower bulbs of Galanthus woroni (Proskumina, N.F and Yakoleva, A. P 1952, Alkaloids of Galanthus woroni II. Isolation of new alkaloids (in Russian) Zh. Obschchei Khim. (J. Gen. Chem., 22, 1899-1902) It was also isolated from the common snowdrop Galanthus nivalis (Boit, 1954).

Furthermore, galantamine was also isolated from plants of the Amaryllidaceae family. Galantamine can also be prepared by a synthetic route, for example, Kametani et al., Chem. Soc. C. 6, 1043-1047 (1971) or Shimidzu et al. Heterocycles 8, 277-282, (1977).

Various galantamine salts have been published in many publications. Published International Patent Application WO 2006013546 describes the preparation of galantamine addition salts with hydrohalic acids in hydrated or anhydrous form.

Other inorganic acid addition salts of galantamine have been described in WO 2006072818.

US patent 6233195 discloses the preparation of pharmaceutically acceptable forms of galantamine salts such as: tartrate, hydrochloride, citrate, maleate, fumarate, succinate, acetate, malonate and sulfate.

International patent application WO 2004002402 discloses a series of acetylcholinesterase inhibitors, including but not limited to, galantamine and parabromophenylsulfonic acid addition salts and galantamine and donepezil analogues.

Among all known salts, the preferred salt of galantamine in the form of the hydrobromide has also been the subject of numerous patents for various dosage forms and preparations.

In order to ensure a constant level of the drug in the blood while at the same time ensuring that the drug exhibits an effect as soon as possible after its administration, it is desirable to:. i. for the salts to show a better solubility profile while maintaining stability.

Therefore, there is still a need for the development of new stable forms of galantamine addition salts, which are substantially less toxic, have reduced hygroscopic properties, better solubility, and can be used to prepare solid dosage forms with better release from the dosage form compared to the known salts.

The present invention solves the problems with reference to previous publications in that the novel sulfonic acid and galantamine addition salts are disclosed in claim 1.

SUMMARY OF THE INVENTION

The present invention solves these problems by preparing novel galantamine addition salts for the purpose of achieving these objectives, wherein:

SK 288146 Β6

A first object of the present invention are novel sulfonic acid addition salts of galantamine and solvates thereof which are substantially more soluble than the known salts described in the patents cited in the prior art.

A second object of the present invention is a process for the preparation of addition salts of the active galantamine compound having a significantly lower hygroscopic character, better solubility and good processing flow.

It is a further object of the invention to provide alternative galantamine addition salts suitable for use in solid release formulations, in particular for use in the form of tablets.

A disadvantage of the previously known galantamine salts is, inter alia, that they are hygroscopic, which affects their stability and disadvantages the route for preparation and their use for aqueous and non-aqueous forms of suspension.

It is another object of the invention to provide compositions comprising galantamine addition salts generally administered in solid form.

The invention also relates to solvates of addition salts and polymorphic modifications thereof. The discovery of new salts as pharmaceutically useful compounds provides new opportunities for improving the properties and effects of pharmaceutical products. This expands the range of forms whose formulations are available for formulation design.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the preparation of novel addition salts of galantamine and sulfonic acids selected from the group of acids: 1,2-ethanedisulfonic acid, sulfoacetic acid, 2-hydroxyethanesulfonic acid, 1,3-benzenedisulfonic acid, 1,2-benzenedisulfonic acid, 1, 2-dimethylbenzenesulfonic acid, 2,5-dihydroxybenzenesulfonic acid, 3-sulfobenzoic acid, 4-sulfobenzoic acid, 2-hydroxy-3-sulfobenzoic acid, 4-hydroxy-1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, and solvates thereof. These salts are substantially better soluble and have a lower hygroscopicity as compared to known salts.

Another advantage of the sulfonic acids used in the preparation of addition salts in the present invention is that when said acids are used in the manufacturing processes, in terms of increasing production safety, environmental impact as well as safety at work, the process offered is preferable to using bromo acid. hydrogen.

The present inventors have found that in particular the novel addition salts of galantamine and 1,2-ethanedisufonic acid, 3-sulfobenzoic acid and 5-sulfosalicylic acid selected from the list of acids used in the present invention provide considerable advantages. They have low hygroscopicity and good solubility which are suitable for use in solid dosage forms, especially in the form of capsules or tablets.

According to the present invention, one substantially non-toxic and non-hygroscopic addition salt as mentioned is, for example, galantamine 3-sulfobenzoate, prepared by reacting galantamine free base (I) with 3-sulfobenzoic acid in the presence of an organic or inorganic solvent. Preferably, solvents selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, ethylene glycol dimethyl ether, tetrahydrofuran, methyltetrahydrofuran, methyltetrahydrofuran, methyltetrahydrofuran, methyltetrahydrofuran, methyltetra tetrahydrofuran, methyltetra tetrahydrofuran, methyltetrahydrofuran, methyltetrahydrofuran, methyltetrahydrofuran, methyltetrahydrofuran, methyltetrahydrofuran, methyltetrahydrofuran, cyclohexane, acetonitrile, dichloromethane, chloroform, water and mixtures thereof.

Preferably, inert solvents such as ethyl acetate, ethylene glycol dimethyl ether, tetrahydrofuran, methyltetrahydrofuran, hexane, heptane, acetonitrile, dichloromethane, chloroform, water or mixtures thereof are used under the reaction conditions.

According to the process of the present invention, galantamine is capable of forming salts with sulfonic acids without undesirable by-products.

It will be appreciated that the molar ratio of galantamine to disulfonic acid may be 2: 1 or 1: 1. In general, disulfonic acid and galantamine may also provide a blend product with said molar ratio of disulfonic acid to galantamine. According to the invention, defined addition salts of galantamine and sulfonic acids are preferred in which the molar ratio of galantamine to disulfonic acid is 1: 1 and 2: 1. For simplicity, the combination of two galantamine molecules and one disulfonic acid molecule is hereinafter referred to as a 2: 1 addition salt.

Alternatively, the galantamine and sulfonic acid addition salts can be prepared by reacting galantamine hydrohalogen such as hydrochloride or hydrobromide with an alkali salt such as sodium or potassium salt of the respective sulfo acid in the presence of an organic or inorganic solvent or mixtures thereof.

Another advantage of the novel addition salts according to the invention is, in particular, the uniformity of the product, as a result of which their mechanical processing properties (filtration, drying, etc.) are improved.

Ultimately, the novel addition salts of the present invention are less hygroscopic than those derived from hydrobromic acid, as shown in Table 1. First

For better illustration in Table no. 1 shows the behavior of galantamine addition salts: galantamine 1,2-ethanedisulfonate addition salt 2: 1 (salt I), galantamine salicyl 5-sulfonate addition salt (salt II), galantamine 3-sulfobenzoate (salt III), and galantamine hydrobromide ( salt IV) when exposed to a defined humidity. Tests were

EN 288146 Β6 carried out under the above conditions (Table 1). These salts were left in the stability chamber to the point where equilibrium was reached (Table 1). The water content was measured for each salt by the Karl Fischer method (% water content is calculated on the dried substance).

The crystalline form of the addition salt (I) is less hygroscopic at room temperature than its amorphous form. It has also been observed that the salt III is hygroscopic in an area with a relative humidity of up to 75% than the salt IV, whereas the salt III and resp. the resulting hydrate is more stable at higher relative humidity values.

Water absorption experiments showed that said salts (I, II, III) were gradually transformed into defined hydrates. However, as the relative humidity increases, the hydrates of salts I, II or salt III formed are more stable than salt IV, which tends to liquefy. This therefore represents the possibility of preparing hydrates.

As a result, when testing the hydrates of the addition salts prepared by the process of the invention, they have been found to be more stable than the hydrobromic acid salt. It should be noted that the galantamine addition salts of this invention may be unsolvated or may form solvates, for example, hydrates. The number of water molecules is not limited, for example 0.5 molecules, 1 molecule or 2 molecules.

Table no. 1 Results ex positions of relative salt addition salts Relative humidity (%) Final water content after absorption Sol' Salt II Salt III Salt IV 25 0.18 1.69 0.42 0.11 75 2.44 1.75 1.56 0.89 93 > 4.5 3.48 1.82 reflow

The lower hygroscopicity of the hydrates of the novel salts is advantageous for their processing and storage in crystalline form. The crystalline addition salts of galantamine and sulfonic acids also have good mechanical properties due to their low hygroscopicity.

The novel sulfone salts of galantamine have a very high water solubility as compared to other known salts. To illustrate the solubility of the salts of galantamine 1,2-ethanedisulfonate (1: 1) desolvated form (salt V), galantamine 3-sulfobenzooate crystalline form I (salt III) and galantamine hydrobromide crystalline form (salt IV), were tested under the indicated conditions (Table) 2). Solubility tests were carried out in a standard manner by the banking method with stirring at 22 ± 0.5 ° C, in deionized water, respectively. at pH 4.5 (Britton-Robinson buffer). The solubility of galantamine hydrobromide was chosen as a reference value.

Table no. 2 Relative solubility test results

compound Water solubility (%) Solubility pH 4.5 (%) Salt V 1.33 1.45 Salt III 1.25 1.32 Salt IV 1.00 1.00

After exposure of the sample at 93% relative humidity, the new amorphous form of the galantamine-4-sulfobenzoic acid addition salt showed a DSC peak above 195 ° C, which occurred due to the partial conversion of the amorphous salt form to the crystalline form. However, the prepared crystalline salt of galantamine and 4-sulfobenzoic acid showed higher stability of the form in the stress tests.

According to the invention, the galantamine addition salts include not only crystalline forms but can also be in the form of amorphous salts. It is well known that one of the most important physical properties of drugs (amorphous form versus crystalline form) is their solubility (Konno T., Chem. Pharm. Bull., 1990, 38, 2003). In some therapeutic terms, the term bioavailability is one of the key parameters that determines the form of the substance for use in a pharmaceutical composition. There are many advantages where amorphous forms of drug are used in a drug. Better solubility and bioavailability are essential. The crystalline form has been found to be less soluble than its amorphous forms, hence the processes of the invention include the preparation of amorphous forms.

According to another aspect, compositions comprising novel sulfonic acid and galantamine addition salts are disclosed. The method of preparation according to the invention depends on the skill of the person skilled in the art. The addition salts of the present invention can advantageously be formulated into pharmaceutical compositions. In this case, the main active ingredient is used in combination with some of the elements such as binders, fillers, diluents, disintegrants, lubricants and coatings as desired. Solid oral dosage forms, such as hard gelatin capsules and tablets, are preferred. In the compositions of the present invention, the amount of salt ranges from 5% to 85%, most preferably 5% to 35% by weight.

Diluents that may be included in the present invention are preferably selected from the group of natural or artificial carbohydrates such as lactose, sucrose, glucose, starches, sorbitol and microcrystalline cellulose. Similarly, preferably, selected starches, sugars, cellulose and its derivatives are similar,

Gelatine and polyvinylpyrrolidone. Starch and microcrystalline cellulose are preferred for use as good disintegrants. Particularly preferred is Avicel (TM), a type of commercial microcrystalline cellulose.

Lubricants used for solid dosage forms are selected from the group consisting of talc, silica, magnesium stearate, glidant, aerosol, stearic acid and stearin. Magnesium stearate is particularly preferred.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures no. 1 to 6 are the Fourier transform infrared spectra of the FTIR Galantamine and sulfonic acid addition salts measured on a Spectrometer Nicolet, Impact 410. ATR measurement technique, the Omnic program version 5.2, was used.

Picture no. Desolvated form of the addition salt of galantamine and 1,2-ethanedisulfonic acid (1: 1).

Picture no. 2. Crystalline Form I of the galantamine-1,2-ethanedisulfonic acid addition salt (2: 1).

Picture no. 3. Anhydrous form of the galantamine-4-sulfobenzoic acid addition salt.

Picture no. 4. A crystalline form of the galantamine-3-sulfobenzoic acid addition salt.

Picture no. 5. Galantamine-5-Sulfosalicylic Acid Hemihydrate Addition Crystalline Form I.

Picture no. 6. The amorphous form of the galantamine-sulfoacetic acid addition salt.

Picture no. 7 is an illustrative X-ray powder diffraction (XRPD) pattern for addition salts. The measurement was performed on a Phillips PW3040 / 60 X'Pert PRO diffractometer powder diffractometer, CuKa radiation of 1.541874 L.

Addition salt of crystalline form I of galantamine and 1,2-ethanedisulfonic acid (2: 1), top record.

Addition salt of crystalline form I of galantamine and 3-sulfobenzoic acid, medium record.

Addition salt of crystalline form I of galantamine and 5-sulfosalicylic acid, crystalline hemihydrate, bottom entry.

The following examples describe the process for preparing the sulfonic acid and galantamine addition salts of the present invention. The following examples serve to further illustrate the present invention without limiting its scope to the examples described herein.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of the crystalline form of the galantamine-1,2-ethanedisulfonic acid addition salt (2: 1)

To a solution of galantamine (0.3 g) in ethylene glycol dimethyl ether (5 mL) at 85 ° C was added 1,2-ethanedisulfonic acid (0.11 g) in a water / ethylene glycol dimethyl ether solution (v / v 1: 3.2) ml). The reaction mixture was stirred at 20 ° C for 12 hours and then cooled, the resulting crystalline product was filtered off and dried. Galantamine 1,2-ethanedisulfonate 2: 1 addition salt was obtained, melting point: 228-231 ° C, [α] -100 ° (c 1, methanol). Elemental analysis for C ₃₆ H ₄₈ N ₂ O ₁₂ S ₂ (764.9). Theoretical: C, 56.53; H, 6.33; N, 3.66, S, 8.38. Found: C, 56.38; H, 6.17; N, 3.51, S, 7.89. XRPD Form I.

Example 2

Preparation of the desolvated form of the galantamine-1,2-ethanedisulfonic acid addition salt (1: 1)

To a solution of galantamine (0.3 g) in tetrahydrofuran (12 mL) at room temperature was added 1,2-ethanedisulfonic acid (0.21 g). The reaction mixture was stirred at gentle reflux for 4 hours, then the reaction mixture was cooled and the resulting white product was filtered off and dried. Since the product obtained was contaminated with an alternative salt of galantamine, it was subsequently purified by crystallization. The product was dissolved in boiling 2-propanol (ca. 10 ml). The solution was filtered through a nylon filter (0.22 µm). The resulting filtrate was transferred to a 25-mL flask and heated to 75 ° C with stirring. While stirring, ethyl acetate was added to the solution until light turbidity. The reaction mixture was stirred at reflux until clear. The reaction mixture was further stirred at reflux for 2 hours and then at room temperature for 8 hours, whereupon a white precipitate formed. The resulting product was filtered off, washed with 2-propanol-ethyl acetate (10 mL, 1: 1) and dried under vacuum at 25 mbar at 40 ° C. 0.11 g of the acid addition salt of galantamine and 1,2-ethanedisulfonic acid (1: 1) hemiisopropanol solvate was obtained. The desolvated form of the galantamine 1,2-ethanedisulfonate (1: 1) addition salt was obtained by drying the hemiisopropanol solvate at 95 ° C for 6 hours under an inert nitrogen atmosphere. Drying loss determined by thermogravimetric analysis (TGA) - 0.031%. The dried substance was stored in a desiccator above P ₂ O ₅ .

IR (cm ^-1 ) 1621, 1511, 1439, 1282, 1251, 1219, 1195, 1123, 1039, 1019, 1011,987, 763.

Example 3

Preparation of the amorphous form of the 2-naphthalenesulfonic acid galantamine addition salt

A solution of 2-naphthalenesulfonic acid (0.23 g) in 2-propanol (10 mL) was filtered through a nylon filter

SK 288146 Β6 (0.22 pm). The filtrate was transferred to a 20 mL flask. Galantamine (0.3 g) was added to the solution with stirring and the reaction mixture was refluxed for two hours with stirring. Cooling in an ice bath precipitated the product, which was filtered off and washed with diethyl ether. 0.4 g of white galantamine-2-naphthalenesulfonate addition salt was obtained in amorphous form.

IR (cm ^-1 ): 1624, 1593, 1511, 1438, 1280, 1215, 1168, 1088, 1071, 1026, 982,944,753,673.

Example 4

Preparation of the amorphous form of 1,2-ethanedisulfonic acid galantamine addition salt (2: 1)

A mixture of galantamine (0.3 g) and 1,2-ethanedisulfonic acid (0.11 g) in tetrahydrofuran (10 mL) was stirred for 12 hours at room temperature. The solvent was distilled off under vacuum at 40 ° C. The residue was dissolved in 18 mL of dichloromethane and a few drops of methanol and then filtered through a nylon filter (0.22 µm). Addition of cyclohexane (20 mL) to the filtrate placed in an ultrasonic bath at 35 ° C gave a white solid.

The product was filtered off and dried. Galantamine 1,2-ethanedisulfonic acid addition salt (2: 1) amorphous form, [α] -100 ° (c 1, methanol) was obtained. Elemental analysis for C ₃₆ H ₄₈ N ₂ O ₁₂ S ₂ (764.9). Theoretical: C, 56.53; H, 6.33; N, 3.66, S, 8.38. Found: C, 55.59; H, 6.19; N, 3.59, S, 8.11.

Example 5

Preparation of galantamine-5-sulfosalicylic acid addition salt hemihydrate

Galantamine (0.3 g) was added to a solution of 5-sulfosalicylic acid dihydrate (0.28 g) in ethanol (96%, 10 mL). The reaction mixture was stirred at 40-45 ° C for 12 hours. Subsequently, half of the solvent was distilled off in vacuo. After addition of cold methyl tert-butyl ether (MTBE, 1 mL), the reaction mixture was cooled with ice under stirring and the product was filtered off. 0.55 g of a white solid was obtained. Melting point 194 ° C. XRPD Form I.

Example 6

Preparation of the anhydrous form of the galantamine-5-sulfosalicylic acid addition salt

To the product obtained from Example 5 was added a solution of anhydrous ethanol with ethyl acetate (8 mL, 1: 7). The reaction mixture was stirred at 80 ° C for 2 hours. Then the reaction mixture was concentrated to half volume. After stirring at room temperature for 3 hours, the reaction mixture was filtered. 0.3 g of the white product galantamine 5-sulfosalicylate anhydrous form was obtained, which was dried under vacuum at room temperature. Drying loss determined by TGA - 0.019%. The dried substance was stored in a desiccator above P ₂ O ₅ .

Example 7

Preparation of galantamine-5-sulfosalicylic acid addition salt hydrate

The sample obtained in Example 6 (20 mg) was exposed to a relative humidity of 63% in a dynamic vapor sorption (DVS) apparatus at 20 ° C. The product was then subjected to a constant weight gain of 20% at 20 ° C for the next cycle. The obtained material was allowed to crystallize under a dry nitrogen atmosphere at 20 ° C. The galantamine-5-sulfosalicylic acid addition salt hydrate was obtained as a white crystalline solid. Melting point 228 ° C. Drying loss determined by TGA - 3.51%.

Examples 8-15

In analogy to Example 4, the sulfoacids listed in Table 2 were used to prepare the galantamine addition salts. Third

Table no. 3

Example # Sulfo acid [α] (c, MeOH) 8 xylene sulfonic acid -88 ° (1, MeOH) 9 sulfoacetic acid -82 ° (1, MeOH) 10 2-hydroxyethanesulfonic acid -85 ° (1, MeOH) 11 hydroquinone sulfonic acid -85.5 (1, MeOH). 12 Benzene-1,3-disulfonic acid (2: 1) -98 (0.42, MeOH) 13 Benzene-1,3-disulfonic acid (1: 1) -89.5 (1, MeOH). 14 benzene-1,2-disulfonic acid -85.5 (1, MeOH). 15 4-Hydroxy-1-naphthalenesulfonic acid -99.5 ° (0.42, MeOH) 16 2-Naphthalenesulfonic acid -88.5 (1, MeOH).

(* MeOH- methanol)

SK 288146 Β6

Example 17

Preparation of crystalline Form I of the addition salt of galantamine and 3-sulfobenzoic acid

A solution of 3-sulfobenzoic acid (0.22 g) in 2-propanol (5 mL) was filtered through a nylon filter (0.22 µm). The resulting filtrate was transferred to a 20 mL flask. With stirring, galantamine (0.3 g) dissolved in 2-propanol (5 ml) was added to the solution, and the reaction mixture was stirred under gentle reflux for 2 hours. The precipitated product was crystallized from ethanol, filtered and washed with MTBE. 0.4 g of the galantamine 3-sulfobenzoate addition salt Form I was obtained. Melting point 219 ° C.

Claims (8)

PATENT CLAIMS 1. Addition salts of galanthamine and sulfonic acid selected from 1,2-ethanedisulfonic acid, sulfoacetic acid, 2-hydroxyethanesulfonic acid, 1,3-benzenedisulfonic acid, 1,2-benzenedisulfonic acid, 2,5-dihydroxybenzenesulfonic acid, 3- sulfobenzoic acid, 4-sulfobenzoic acid, 2-hydroxy-3-sulfobenzoic acid, 2-naphthalenesulfonic acid, 4-hydroxy-1-naphthalenesulfonic acid, xylenesulfonic acid and their respective solvates. Process for the preparation of galantamine addition salts according to claim 1, characterized in that it consists of reacting galantamine with an acid selected from 1,2-ethanedisulfonic acid, sulfoacetic acid, 2-hydroxyethanesulfonic acid, 1,3-benzenedisulfonic acid, 2-benzenedisulfonic, 2,5-dihydroxybenzenesulfonic, 3-sulfobenzoic, 4-sulfobenzoic, 2-hydroxy-3-sulfobenzoic, 2-naphthalenesulfonic, 4-hydroxy-1-naphthalenesulfonic and xylenesulfonic. Process according to claim 2, characterized in that the reaction is carried out in the presence of an organic or inorganic solvent or mixtures thereof. A process according to claim 3, wherein the solvent is selected from the group of selected solvents methanol, ethanol, 2-propanol, ethyl acetate, ethylene glycol dimethyl ether, tetrahydrofuran, methyltetrahydrofuran, hexane, cyclohexane, acetonitrile, dichloromethane, chloroform and water. Use of galantamine and sulfoacid addition salts according to claim 1 for the preparation of a medicament for the treatment of memory dysfunction. A composition comprising at least one addition salt according to claim 1. A composition comprising at least one addition salt according to claim 6, wherein said formulation is a solid oral dosage form. Crystalline or amorphous sulfo acid-galantamine addition salts according to claim 1. 4 drawings