KR20050041285A - Amlodipine glutarate, and process for preparing it - Google Patents

Abstract

The present invention relates to amlodipine glutarate salts and a method for preparing the same, and more particularly, to crystalline acid addition salts prepared by reacting amlodipine and glutaric acid derivatives, such as solubility, stability, non-hygroscopicity, and anti-adhesion properties It relates to amlodipine glutarate salt represented by the following formula (1), which is effective as a therapeutic agent for cardiovascular diseases including hypertension because of its excellent properties, and a method for preparing the same.

Description

Amlodipine glutarate salt and preparation method thereof {Amlodipine glutarate, and process for preparing it}

The present invention relates to amlodipine glutarate salts and a method for preparing the same, and more particularly, to crystalline acid addition salts prepared by reacting amlodipine and glutaric acid derivatives, such as solubility, stability, non-hygroscopicity, and anti-adhesion properties It relates to amlodipine glutarate salt represented by the following formula (1), which is effective as a therapeutic agent for cardiovascular diseases including hypertension because of its excellent properties, and a method for preparing the same.

[Formula 1]

Amlodipine is 3-ethyl-5-methyl-2- (2-aminoethoxy-methyl) -4- (2-chlorophenyl) -6-methyl-1,4-dihydro-3,5-pyridine It has the chemical name of dicarboxylate, is used as a calcium-channel blocker for the treatment of ischemic heart disease and hypertension, and is known as a useful and efficient substance that exhibits activity over a long period of time.

Amlodipine was first reported as one of the novel 1,4-dihydropyridines in EP 89,167. In the above-mentioned European Patent Publication No. 89,167, acid addition salts are exemplified as pharmaceutically acceptable salts of 1,4-dihydropyridine, and pharmaceutically acceptable acid addition salts are non-toxic containing pharmaceutically acceptable anions. Hydrochloride, hydrobromide, sulfate, phosphate or acid phosphate, acetate, malate, fumarate, lactate, tartrate, citrate and gluconate salts are described as formed from acids forming acid addition salts, among which The rate is described as the most preferred.

Pharmaceutically, amlodipine is useful in free form, but due to its low stability, it is administered in the form of acid addition salts with pharmaceutically acceptable acids.

Korean Patent Registration No. 90,479 discloses (1) excellent solubility in preparing in the form of a pharmaceutically acceptable salt; (2) good stability; (3) nonhygroscopic; (4) states that four physicochemical criteria such as processability as tablet formulations should be met. It is very difficult to meet all four of the above conditions as a pharmaceutically acceptable acid addition salt, and in fact even the malate salt, which has been presented in the most preferred pharmaceutical form, is degraded after several weeks in solution and found to have stability problems. lost.

In Korean Patent No. 91,020, a benzene sulfonate salt (hereinafter abbreviated as besylate salt) is presented as an acid addition salt showing excellent stability. Amlodipine besylate salts have a number of advantages over known salts of amlodipine and have been found to have excellent formulation properties that make the preparation of pharmaceutical formulations of amlodipine suitable. However, since the amlodipine besylate salt uses benzene sulfonic acid, which is a toxic compound, the safety problem has been raised.

Accordingly, the present inventors completed the present invention by preparing amlodipine glutarate salt, a novel crystalline acid addition salt of amlodipine, which satisfies all the physicochemical conditions of pharmaceutically acceptable salts using glutaric acid derivatives.

Accordingly, an object of the present invention is to provide an amlodipine glutarate salt that satisfies all physicochemical conditions of pharmaceutically acceptable salts.

Another object of the present invention is to provide a method for preparing amlodipine glutarate salt using glutaric acid derivatives.

The present invention also provides a pharmaceutical composition for treating cardiovascular disease containing amlodipine glutarate salt as an active ingredient that satisfies all of the physicochemical conditions of the pharmaceutically acceptable salt prepared by the above method. There is this.

The present invention is characterized by an amlodipine glutarate salt represented by the following formula (1) effective in treating cardiovascular diseases due to its excellent solubility, stability, non-hygroscopicity and processability as a tablet formulation.

[Formula 1]

In addition, the amlodipine glutarate salt represented by Formula 1 includes all of the salts of each isomer of amlodipine or a mixture of these isomers.

On the other hand, the present invention includes a method for preparing the amlodipine glutarate salt represented by the formula (1), consisting of reacting amlodipine and glutaric acid derivatives in an organic solvent.

When subdividing the manufacturing method of the present invention by each process,

1) dissolving amlodipine in an organic solvent;

2) preparing a mixture by dissolving a glutaric acid derivative in an organic solvent and then adding it to the amlodipine reaction solution; And

3) filtering, washing and drying the solid obtained by stirring the mixture to form a crystalline acid addition salt.

Crystalline acid addition salts of amlodipine according to the present invention are prepared by adding glutaric acid derivatives in amlodipine-containing solutions, which will be described in detail for each preparation step as follows.

In the first step of the preparation process, it is important to control the concentration of amlodipine in the reaction solution. In order to efficiently promote crystallization, it is preferable to adjust the concentration of amlodipine in the range of 3 to 60 wt%. At this time, amlodipine may be added as an isomer of R-amlodipine or S-amlodipine, or may be added as a mixture of these isomers. Considering the pharmaceutical activity, it is more preferable to use S-amlodipine.

In the second step, an acid is added to the amlodipine-containing reaction solution, and the glutaric acid derivative is preferably used in an amount of 0.1 to 5.0 equivalents based on amlodipine. Glutaric acid derivatives that can be used in the present invention may include, for example, 3-methylglutaric acid, 2,2-dimethylglutaric acid, 2-methylglutaric acid, and the like.

In the first and second steps described above, a conventional organic solvent is used as the reaction solvent, and particularly preferably, an organic solvent selected from methanol, ethanol, isopropanol and acetonitrile is used.

The third step is the formation of the crystalline acid addition salt, the reaction is carried out in the temperature range of -10 to 50 ℃.

On the other hand, the amlodipine glutarate salt represented by the formula (1) according to the present invention satisfies all the physicochemical conditions to be provided as a pharmaceutically acceptable salt (see Experimental Examples 1 and 2). Accordingly, the present invention includes a pharmaceutical composition for treating cardiovascular diseases comprising an isomer compound or an isomer mixture of the amlodipine glutarate salt represented by Formula 1 as an active ingredient.

The pharmaceutical composition according to the present invention can be administered orally or parenterally during clinical administration and can be used in the form of general pharmaceutical preparations. That is, it can be formulated into various formulations for oral and parenteral administration, which are prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like. Such solid preparations are prepared by mixing the active compound with at least one excipient such as starch, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspending agents, solvents, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Dosage to the human body of the pharmaceutical composition according to the present invention may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, 1 day at a predetermined time interval depending on the doctor or pharmacist It may be administered in divided doses or several times. The effective dose of the amlodipine glutarate salt represented by Formula 1 is 1.0 to 10.0 mg / kg, preferably 5.0 to 8.0 mg / kg.

The present invention as described above will be described in more detail based on the following Examples and Experimental Examples, but the present invention is not limited thereto.

Example 1 Preparation of Amlodipine 3-methylglutarate Salt

1.0 g (0.0024 mol) of amlodipine was dissolved in 15 mL of t-butanol. 0.376 g (0.0025 mol) of 3-methylglutaric acid was dissolved in 5 ml of t-butanol, and then slowly added to the amlodipine reaction solution. After the mixture was stirred at room temperature for 2 hours, 50 ml of diethyl ether was added thereto, cooled to 5 ° C, and stirred for 2 hours. The resulting solid was filtered and dried to give 1.01 g (yield: 85.7%) of the title compound as white crystals.

mp 148-151 ° C; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.36 to 7.12 (m, 4H, ArH), 5.30 (s, 1H), 4.70 to 4.52 (dd, 2H), 4.16 to 3.88 (m, 2H), 3.54 (brt, 2H), 3.50 (s, 3H), 2.88 (brt, 2H), 2.31 (s, 3H), 2.19-2.02 (m, 0.5H), 2.11 (brs, 2H), 1.10 (t, 3H ), 0.91 (d, 1.5 H)

Example 2: Preparation of amlodipine 2,2-dimethylglutarate salt

1.0 g (0.0024 mol) of amlodipine was dissolved in 15 mL of t-butanol. 0.412 g (0.0025 mol) of 2,2-dimethylglutaric acid was dissolved in 5 ml of t-butanol, and then slowly added to the amlodipine reaction solution. After the mixture was stirred at room temperature for 2 hours, 50 ml of diethyl ether was added thereto, cooled to 5 ° C, and stirred for 2 hours. The resulting solid was filtered and dried to yield 1.13 g (yield: 80.5%) of the title compound as white crystals.

mp 133-136 ° C; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.36 to 7.12 (m, 4H, ArH), 5.30 (s, 1H), 4.71 to 4.51 (dd, 2H), 4.06 to 3.88 (m, 2H), 3.57 (brs, 2H), 3.50 (s, 3H), 2.91 (brt, 2H), 2.32 (s, 3H), 2.08 (brt, 2H), 1.66 (brt, 2H), 1.10 (t, 3H), 1.04 (s, 6H)

Example 3: Preparation of Amlodipine 2-methylglutarate Salt

1.0 g (0.0024 mol) of amlodipine was dissolved in 15 mL of t-butanol. 0.376 g (0.0025 mol) of 2-methylglutaric acid was dissolved in 5 ml of t-butanol, and then slowly added to the amlodipine reaction solution. After the mixture was stirred at room temperature for 2 hours, 50 ml of diethyl ether was added thereto, cooled to 5 ° C, and stirred for 2 hours. The resulting solid was filtered and dried to give 1.12 g (yield: 95.0%) of the title compound as white crystals.

mp 142-145 ° C .; ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.36 to 7.12 (m, 4H, ArH), 5.30 (s, 1H), 4.70 to 4.52 (dd, 2H), 4.06 to 3.88 (m, 2H), 3.53 (brt, 2H), 3.50 (s, 3H), 2.86 (brt, 2H), 2.31 (s, 3H), 2.41-2.22 (m, 0.5H), 2.22-2.04 (m, 1H), 1.69-1.49 (m, 1H), 1.11 (t, 3H), 0.98 (d, 1.5H)

Formulation Example 1 Formulation of Amlodipine Glutarate Salt-Containing Tablet

Anhydrous calcium hydrogen phosphate (315 g) and microcrystalline cellulose (525 g, 90 μm) were combined and transferred to a drum. Amlodipine 3-methylglutarate salt (70 g) and microcrystalline cellulose (187.5 g, 50 μm) were then combined and passed through the screen into a drum containing the powder mixture. The screen used in the previous step was washed with microcrystalline cellulose (525 g, 90 μm). Anhydrous calcium hydrogen phosphate (315 g) was added to the mixture and the entire mixture was blended for 10 minutes. Sodium starch glycolate (40 g) was then added to the mixture and blended for 6 minutes. Finally, magnesium stearate (20 g) was added and the resulting mixture was blended for 3 minutes. The powder mixture was then compressed into tablets by conventional methods.

Formulation Example 2 Formulation of Amlodipine Glutarate Salt-Containing Capsule

Microcrystalline cellulose (525 g, 90 μm) and dry corn starch were premixed and then amlodipine 3-methylglutarate salt (70 g) was mixed with a portion of the premix and sieved. The remaining premix was added and mixed for 10 minutes, then sieved and further mixed for 5 minutes. And the capsule of appropriate size was made to manufacture the capsule.

Formulation Example 3 Formulation of Amlodipine Glutarate Salt-Containing Injection

Sodium chloride was dissolved in sterile water for injection and propylene glycol was mixed with this solution. Amlodipine 3-methylglutarate salt was added and, when dissolved, additional sterile water for injection was added to prepare a solution of the desired concentration. This solution was filtered through a sterile filter and filled into sterile ampoules used as injection containers.

Experimental Example 1: Solubility Test

In general, in preparing a pharmaceutically acceptable salt, it should be possible to prepare a solution that is close to the pH of blood (pH 7.4) and has a solubility in the pH range of 1 to 7.5 or greater than 1 mg / ml. Thus, in this experiment, the solubility and pH at saturation of the amlodipine glutarate salt of the present invention was measured and compared with the conventional amlodipine besylate salt.

Solubility experiment was performed by dissolving each compound in distilled water according to the method introduced in the Korean Pharmacopoeia, and then analyzing the solution by liquid chromatography to measure the amount dissolved based on amlodipine base (free base), The results are shown in Table 1 below.

Amlodipine salt Solubility (mg / ml) PH at saturation Amlodipine Besylate 1.47 6.2 Amlodipine 3-methylglutarate 6.67 6.4 Amlodipine 2,2-dimethylglutarate 10.84 4.9 Amlodipine 2-methylglutarate 5.09 6.3

As shown in Table 1, the amlodipine glutarate salt of the present invention can be confirmed that the solubility is significantly improved compared to the conventional amlodipine besylate salt.

Experimental Example 2: Stability Test

Table 2 shows the results of the light stability comparison experiment, the total amount of light is 200 W · h / ㎡ for ultraviolet (UV) and visible light (VIS) is 1,200,000 lux.h.

Amlodipine salt % Of active substance Early UV-rays Visible light Amlodipine Besylate 100 86.29 92.70 Amlodipine 3-methylglutarate 100 95.76 96.55 Amlodipine 2,2-dimethylglutarate 100 96.14 96.85 Amlodipine 2-methylglutarate 100 93.61 93.54

As shown in Table 2, compared to the conventional amlodipine besylate salt, the amlodipine glutarate salt of the present invention was confirmed that the light stability to the ultraviolet or visible light much better.

As described above, the amlodipine glutarate salt according to the present invention is a crystalline acid addition salt suitable for the preparation of a pharmaceutical formulation, and as a pharmaceutical composition for treating cardiovascular diseases because it meets the same physicochemical criteria as the amlodipine besylate salt. It can be usefully used.

Claims (10)

Amlodipine glutarate salts characterized by the following formula (1): [Formula 1] In Formula 1, glutaric acid derivatives represent 3-methylglutaric acid, 2,2-dimethylglutaric acid, or 2-methylglutaric acid. The amlodipine glutarate salt of claim 1, wherein the compound is an isomer or an isomer mixture. Among the organic solvents, amlodipine represented by the following Chemical Formula 2 is reacted with a glutaric acid derivative selected from 3-methylglutaric acid, 2,2-dimethylglutaric acid, 2-methylglutaric acid, and 2-ketoglutaric acid. Method for preparing amlodipine glutarate salt represented by the following formula (1), characterized in that: [Formula 1] In Formula 1, glutaric acid derivatives represent 3-methylglutaric acid, 2,2-dimethylglutaric acid, or 2-methylglutaric acid. The method of claim 3, wherein the concentration of amlodipine in the reaction solution is characterized in that 3 to 60% by weight. The method of claim 3, wherein the glutaric acid derivative is used in the range of 0.1 to 5.0 equivalents based on amlodipine. The method of claim 3, wherein the reaction is carried out at a temperature range of -10 to 50 ℃. The method of claim 3, wherein the reaction solvent is an organic solvent selected from the group consisting of methanol, ethanol, isopropanol and acetonitrile. The method of claim 3, wherein the amlodipine glutarate salt represented by Formula 1 is an isomer compound or an isomer mixture. A pharmaceutical composition for treating cardiovascular diseases, wherein the isomeric compound or isomer mixture of the amlodipine glutarate salt represented by Formula 1 is an active ingredient: [Formula 1] In Formula 1, glutaric acid derivatives represent 3-methylglutaric acid, 2,2-dimethylglutaric acid, or 2-methylglutaric acid. The pharmaceutical composition for treating cardiovascular diseases according to claim 9, wherein the composition is formulated as a tablet, capsule, or injection.