SK492010A3 - Novel addition salts of galantamine 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

The present invention relates to a process for the preparation of novel addition salts of Galantamine, 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.

Field of the invention

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, NF and Yakoleva, AP 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 salt forms of Galantamine 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 hydrobromide salt of galantamine has also been the subject of numerous patents for various pharmaceutical forms and preparations to ensure a constant level of the blood level of the drug while ensuring that the drug / level exhibits its effect as soon as possible. administration is desirable, inter alia for the salts to exhibit better yrophil solubility and stability.

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 λ. used to prepare solid dosage forms with better release from the dosage form as compared to the hitherto 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 invention is solved above. the above problems by preparing new Galantamine addition salts in order to achieve the following objectives:

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 known Galantamine salts so far 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 formulations comprising Galantamine addition salts generally administered in solid form.

The invention also relates to solvate 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 preferably from the group of acids: 1,2-ethanedisulfonic acid, sulfoacetic acid, 2-hydroxyethanesulfonic acid, 1,3-benzenedisulfonic acid, 1,23 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.

A further advantage of the sulfonic acids used to prepare addition salts in the present invention is that when used in the manufacturing processes, from the viewpoint of increasing production safety, environmental impact as well as safety at work, the process offered is preferable to using hydrobromic acid.

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 exhibit low hygroscopicity and good solubility 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 above 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, methyltetrahydrofuran, methyltetrahydrofuran, methyltetrahydrofuran, hexetrahydrofuran, methyltetrahydrofuran, methyltetrahydrofuran, hexetetrahydrofuran, methyltetrahydrofuran are used. , 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 according to the invention.

By 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 can also give a mixed product with the above 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, 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 of the present invention is in particular the uniformity of the product as a result of which their mechanical processing properties (filtration, drying, etc.) are improved.

As a result, the novel addition salts of the present invention are less hygroscopic than those derived from hydrobromic acid as shown in Table 2. First

For better illustration, Table 1 shows the behavior of Galantamine addition salts: Galantamine 1,2-ethanedisulfonate addition salt 2: 1 (salt I), Galantamine salicyl 5-sulfonate hemihydrate addition salt (salt II), Galantamine 3-sulfobenzoate ( salt III) and Galantamine hydrobromide (salt IV) when exposed to a defined humidity. Tests were performed under the conditions below (Table 1). These salts were left in stability 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 the above 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 the present invention may be unsolvated or may form solvates such as hydrates. The number of water molecules is not limited, for example 0.5 molecules, 1 molecule or 2 molecules.

Table no. 1. Results of exposure to addition salts of relative humidity

relative humidity (%) Final water content after absorption somersault Sált Π Sált III Sált IV 25 00:18 1.69 00:42 00:11 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 new sulfone salts of Galantamine exhibit very high water-solubility 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 conditions below ( 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 Solubility in water (%) 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 present invention, the addition salts of Galantamine not only include 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 present invention include the preparation of amorphous forms.

According to another point, compositions comprising novel sulfonic acid addition salts and Galantamine 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 principal active ingredient is used in combination with some of the elements such as binders, fillers, diluents, disintegrants, lubricants and paints, 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. ..

The diluents that may be included according to the present invention are preferably selected from the group of natural or artificial carbohydrates such as lactose, sucrose, glucose, starches, sorbitol and micro crystalline cellulose. Of the binders, similarly, preferably starches, sugars, cellulose and its derivatives, gelatin and polyvinylpyrrolidone are selected. Starch and micro crystalline cellulose are preferred in 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 pictures

Figures 1 to 6 are Fourier transform infrared spectra of FTIR addition salts of Galantamine and sulfonic acids measured on a Spectrometer Nicolet, Impact 410. ATR measurement technique, Omnic version 5.2 program was used.

Figure 7 is an illustrative diffactogram (XRPD-X-ray powder diffraction) for addition salts. The measurement was performed on a Phillips PW3040 / 60 X'Pert PRO diffractometer powder diffractometer, CuKa radiation 1.541874 L.

The following examples describe the process for the preparation of 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 crystalline form of Galantamine and 1,2-ethanedisulfonic acid addition salt (2: 1) • P

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, after which the reaction mixture was 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). For C36H48N2O12S2 (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 moderate 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 2-propanol (ca. 10 ml) while boiling. 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. Ethyl acetate was added to the solution under stirring with stirring. 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 while a white precipitate formed. The resulting product was filtered off, washed with 2-propanol-ethyl acetate (10mi, 1: 1) and dried under vacuum at 25mbar at 40 ° C. 0.11 g of acid addition salt of Galantamine and 1,2-ethanedisulfonic acid (1) were obtained. : 1) hemiisopropanol solvate. 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 over P2O5.

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 Galantamine 2-naphthalenesulfonic acid addition salt

A solution of 2-naphthalenesulfonic acid (0.23 g) in 2-propanol (10 mL) was filtered through a nylon filter (0.22 µm). The filtrate was transferred to a 20 mL flask. While stirring, Galantamine (0.3 g) was added to the solution 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 the 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 (20ml) to the filtrate placed in an ultrasonic bath at 35 ° C resulted in 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. For C36H48N2O12S2 (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. Half of the solvent was then distilled off in vacuo. After addition of cold methyl tert-butyl ether (MTBE, 1 mL), the reaction mixture was ice-cooled with 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 (8ml, 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 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 over P2O5.

Example 7

Preparation of Galantamine-5-sulfosalicylic acid addition salt hydrate

The sample obtained in Example 6 (20mg) 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 product was crystallized 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 4 were used to prepare the galantamine addition salts. 3

Table 3

Example # Sulfo acid [α] (c, MeOH) 8 xylenesulfonic acid -89 ° (l, MeOH) 9 sulfoacetic acid -82 ° (1, MeOH) 10 2-Hydroxyethanesulfonic acid -85 ° (1, MeOH) 11 Hydroquinone sulfonic acid -85.4 (1, MeOH) 12 Benzene-1,3-disulfonic acid (2: 1) -98 ° (0.43, MeOH) 13 Benzene-1,3-disulfonic acid (1: 1) -89.4 (1, MeOH) 14 Benzene-1,2-disulfonic acid -85.5 (l.MeOH) 15 4-Hydroxy-1-naphthalene sulfonic acid -99.5 ° (0.43, MeOH) 16 2-naphthalenesulfonic acid -88.4 (1, MeOH)

(* MeOH methanol)

Example 17

Preparation of crystalline Form I of the Galantamine-3-sulfobenzoic acid addition salt 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. While 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

MTBE. 0.4 g of the Galantamine 3-sulfobenzoate addition salt Form I was obtained. Melting point 219 ° C.

Claims (8)

1. Galantamine and sulfonic acid addition salts 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, xylene sulfonic 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 the group of 1,2-ethanedisulfonic acid, sulfoacetic acid, 2-hydroxyethanesulfonic acid, 1,3-benzenedisulfonic acid, 1,2-benzenedisulfonic acid, 2, 5-dihydroxybenzenesulfonic, 3sulfobenzoic, 4-sulfobenzoic, 2-hydroxy-3-sulfobenzoic, 2-naphthalenesulfonic, 4hydroxy-1-naphthalenesulfonic and xylenesulfonic. Process according to claim 1, 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, characterized in that it is used for the preparation of a medicament for the treatment of memory dysfunction. A composition comprising at least one addition salt according to claim 1. 7. A formulation 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.