SI8710580A8 - Process for the preparation of benzenesulphonate salt of 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydr o-6-methyl-pyridine-3,5-dicarboxylate - Google Patents

Description

PROCEDURE FOR THE PREPARATION OF THE BENZOLSULPHONATE SALT OF 3-ETHYL-5METHYL-2- (2-AMINOETOXYMETHYL) -4- (2-CHLOROPHENYL) -1,4DIHYDRO-6-METHYLPYRIDINE-3,5-DICARBOXYLATE

Technical field

The invention relates to the field of synthesis of organic compounds. The designation of the invention according to the International Classification is C 07 D 211/10;

A 61 K 31/445.

Technical problem

The present invention solves a technical problem of the process for the preparation of the benzolsulfonate (besylate) salt of 3-ethyl-5-methyl-2- (2aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methylpyridine 3,5,5-dicarboxylate. known as amlodipine. This compound is a potent calcium channel blocker and is useful as an anti-ischemic and anti-hypertensive agent.

The state of the art

Yugoslav patent application P-586/83 describes a process for the preparation of 1,4-dihydro-6-methylpyridine-3,5-dicarboxylate derivatives, including amlodipine.

European patent application no. 89167 describes several different pharmaceutically acceptable salts of amlodipine. The pharmaceutically acceptable acid addition salts of amlodipine are particularly mentioned, which represent salts with non-toxic acids which yield pharmaceutically acceptable anions, such as chlorhydrate, bromhydrate, sulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate . Of these salts, maleate has been described as particularly suitable.

Description of a solution to a technical problem with examples of execution

It has now been unexpectedly discovered that the benzolsulfonate salt (hereinafter referred to as the bezilate salt) has a number of advantages over the known salts of amlodipine and that it also unexpectedly has a unique combination of good properties which make it particularly suitable for the preparation of pharmaceutical preparations of amlodipine .

The invention provides a process for the preparation of amlodipine besylate, which consists of reacting amlodipine with a solution of benzolsulfonic acid or its ammonium salt in an inert solvent, after which the resulting besylate is isolated from the solution.

A preferred inert solvent is industrial methylated spirit.

In the description of the invention there is also provided a pharmaceutical composition of the amylodipine saltless salt with a pharmaceutically acceptable diluent or carrier.

Also provided is a tablet formulation, which consists of the besylate salt of amlodipine in a mixture with suitable excipients. Preferred formulations include besylate salt, a compressing agent such as microcrystalline cellulose, a tablet smoothness additive, such as anhydrous dibasic calcium phosphate, a disintegrating agent such as sodium glycolate, and a lubricant such as magnesium .

A capsule formulation is also provided, which consists of the besylate salt of amlodipine in admixture with excipients. Preferred formulations include besylate salt, inert diluent, dried disintegrating agent and lubricant as described above.

The following is described the besylate salt of amlodipine in sterile aqueous solution for parenteral administration. Preferably such solution contains from 10 to 40% by weight of propylene glycol and also preferably sufficient NaCl to prevent hemolysis, e.g. about 1% w / v%.

The use of the bezilate salt of amlodipine in the treatment of ischemic heart disease, especially angina, or hypertension, has also been described.

Although amlodipine is effective in the form of its free base, in practice it is preferable to administer it in the form of a salt or a pharmaceutically acceptable salt. In order for a pharmaceutically acceptable salt to be suitable for these purposes, it must meet the following physiochemical criteria: (1) good solubility; (2) good stability; (3) not to be hygroscopic; (4) to be suitable for formulated in .tablets, etc.

Although many of the salts listed in the prior art satisfy some of these criteria, none of them satisfies all of them. Even desirable maleate, although exhibiting excellent solubility, tends to decompose after several weeks in solution. Therefore, a selection of pharmaceutically acceptable salts of amlodipine was made, which was evaluated according to the following criteria:

1. It is generally known in science that good solubility in water is essential for good bioavailability. A solubility of more than 1 mg / ml at pH 1-7.5 is usually required, although higher injectability is required. In addition, salts that give solutions with a pH close to the pH of the blood (7.4) are desirable, since they are readily bioavailable and readily buffered to the desired value without altering the solubility.

As can be seen from the following comparative data, the besylate salt of amlodipine, in comparison with other salts, shows good solubility characteristics.

TABLE 1

They are Solubility in mg / ml pH at saturation Benzolsulfonate (besylate) 4.6 6.6 Toluenesulfonate (tosylate) 0.9 5.9 Methanesulfonate (mesylate) > 25 3.1 Succinate 4.4 4.9 Salicylate 1.0 7.0 Maleat 4.5 4.8 Acetate 50 ² 6.6 Chlorhydrate 50 3.5

2. Good stability in the solid state is very important for tablets and capsules, while for aqueous solutions for injection, stability in the solution is important.

To evaluate the chemical stability, each salt was mixed with a powder carrier and formulated into tablets or capsules. In the case of tablets, the carrier consisted of microcrystalline cellulose in 50:50 combined with anhydrous two-base calcium phosphate. In the case of capsules, the carrier consisted of mannitol in 4: 1 combination with dried corn starch. These preparations were then kept in sealed vials at 50 and 75 ° C for * up to three weeks.

The drug and eventual degradation products were extracted with methanol / chloroform (50:50) and separated on thin-layer silica gel plates using a variety of solvent systems.

The results were compared and the salts ranked according to the number and amount of decomposition products obtained.

Comparison of the results gave the following order, in which the leadless salt is the most stable salt, while the chlorhydrate is the least stable.

They are Stability Bezilat Mesylate Tozilat Succinate Salicylate Maleat Nest ibilni Acetate r Chlorhydrate unstable

3. In order to provide stable preparations, it is desirable that the salt is not hygroscopic. In the solid state, where the drug content is high, the absorbed film or moisture can act as a vector for hydrolysis or chemical decomposition. The hygroscopic nature of the drug or its salt is responsible for the free moisture, which causes instability.

When exposed to a relative humidity of 75% for 24 hours at 37 ° C, only maleate, tosylate and besylate do not receive any amount of moisture.

Even when exposed to a relative humidity of 95% for 3 days at 30 ° C, besylate and maleate remain anhydrous while tosylate builds up the dihydrate salt. Bezilate, according to Towers, can be considered non-hygroscopic and build stable formulations that minimize the risk of internal chemical degradation.

4. The last characteristic of the acceptable salt that will be discussed here is its suitability for processing, that is, the compression properties and the non-sticking or adhesive properties of the tablet manufacturing equipment.

In order to prepare elegant, high-dose tablets, good compressibility is very important. With tablets containing a lower dose of the drug, the need for good compressibility can be avoided to some extent by the use of suitable diluents, known as compression agents. A common compression agent is microcrystalline cellulose. Whatever the dose, however, it is necessary to avoid sticking the drug to the impact surface in the tablet machine. When the drug accumulates on the impact surface, an uneven surface of the tablet will form, which is unacceptable. Bonding will also condition the reinforced needle required to remove the tablet from the machine. In practice, it is possible to reduce bonding by the addition of moisture, careful selection of excipients and the use of higher levels of adhesion reducing agents, e.g. magnesium stearate. Choosing a salt that has good anti-adhesive properties in itself, however, minimizes these problems.

In order to compare the stickiness of different salts of amlodipine, the following procedure was performed using conventional tableting devices: 50 tablets containing were made. calcium sulphate dihydrate, microcrystalline cellulose and amlodipine besylate (47.5: 47.5: 5), the material adhered to the impact surface of the tablet was extracted with methanol and the amount was measured by spectrometry. This procedure was then repeated for the 100, 150, 200, 250 and 300 tablets produced. After each operation, after methanol extraction, the amount of material adhering to the impact surface for tabletting was measured. The values are plotted and the average value calculated from the slope of the curve.

This procedure was then repeated for each amlodipine salt. The amount of amlodipine glued to the impact surface is shown in Table 2 for each salt and relative to the maleate salt.

TABLE 2

So__Glue

p tg Amlodipine / cm per tablet in the relationship Mesylate 1.16 Bezilat 1.17 59 Tozilat 1.95 98 Maleat 1.98 100 Free base 2.02 102 Succinate 2.39 121 Chlorhydrate 2.51 127 Salicylate 2.85 144

Clearly, the anti-adhesion properties of besylate are superior to that of maleate. While mesylate also has good processing properties, it tends to be isolated as an anhydride but is balanced to monohydrates, which in finished preparations, after manufacture, leads to variations in composition. This makes the use of mesylate in tablet formulation unacceptable.

The amylodipine bezilate salt, according to friction, exhibits a unique combination of good solubility, good stability, non-hygroscopicity and good processing properties, making it extremely suitable for the production of pharmaceutical formulations of amlodipine.

In order to make the present invention more understandable to them, the following Examples are given.

EXAMPLE 1

Preparation of the bezilate salt of amlodipine

The base of amlodipine (65.6 g, 0.161 mol) was suspended in industrial methylated spirit (326.4 ml) and cooled to 5 ° C. Benzolsulfonic acid (26.2 g 0.168 mol) dissolved in industrial methylated spirit (65.6 ml) was added to the suspension of the base at 5 ° C. The resulting suspension was granulated, filtered and washed with two volumes of industrial methylated spirit (65.6 ml). The wet solid was suspended at 5 ° C for 1 hour, suspended in industrial methylated spirit (32 ^ .6 ml), filtered, washed with two volumes of industrial methylated spirit (65.6 ml) and dried under vacuum at 55 ° C during 24 hours. A yield of 76.5 g (83.8%) was obtained with the following analysis;

T.t. 201.0 ° C.

% C analysis

Calculated 55.07 Found 54.91

H

5.51

5.46

N

4.94

4.93

EXAMPLE 2

Formulation of tablets containing the besylate salt of amlodipl

Amlodipine besylate was mixed with sodium starch glycolate and anhydrous dibasic calcium phosphate for 5 minutes. The mixture was then sieved, re-mixed and re-sifted, followed by mixing with microcrystalline cellulose. The resulting mixture was averaged and stirred for another 10 minutes. Finally magnesium stearate was added and the whole mixture was stirred for another 5 minutes. The mixture was then compressed into tablets in a conventional tablet device.

This process was used to make tablets containing different concentrations of amlodipine besylate salt, as shown in Table 3.

TABLE 3 Composition of tablets

Bezilate salt (mg) Microcrystalline cellulose (mg) Anhydrous double-base calcium phosphate (mg) Sodium starch glycolate (mg) Magnesium stearate (mg) 1.736 63.514 31.750 2.00 1.00 3,472 62.028 31,500 2.00, 1.00 6.944 124.056 63,000 4.00 2.00 13.889 248.111 126,000 8.00 4.00

EXAMPLE 3

Formulation of capsules containing the besylate salt of amlodipine

Microcrystalline cellulose and corn starch were previously mixed, so a part of this mixture was mixed with the unilated salt of amlodipine and the mixture was sieved. Then the rest of the original mixture was added and stirring continued for 10 minutes. The mixture was re-sieved and stirred for a further 5 minutes.

The procedure was used to obtain mixtures containing different concentrations of amlodipine besylate salt, as shown in Table 4, and the mixtures were then filled into capsules of suitable size.

TABLE 4 Capsule composition

Bezilate salt (mg) Microcrystalline cellulose (mg) Dried corn starch (mg) Magnesium stearate (mg) Total capsule weight (mg) 1.736 38.014 10.00 0.250 50 3,472 76.028 8 pm 0.500 100 6.944 72.556 8 pm 0.500 100 13.889 145.111 40.00 1.00 200

EXAMPLE 4

Formulation of a sterile aqueous solution of the amlodipine besylate salt

Sodium chloride was dissolved in water for injection and propylene glycol was mixed with the solution. The amylodipine bezilate salt was added and, when dissolved, more water for injections was added to obtain the desired concentration of amlodipine (1 mg / ml). The solution is then filtered, through a sterilization filter, into suitable sterile vessels, e.g. ampoules, for use in parenteral administration (eg intravenous).

This method was used to obtain the formulations shown in Table 5.

TABLE 5

Sterile aqueous solutions

(D (2) Amylodipine besylate salt 1,389 g 1,389 g Sodium chloride 9,000 g 9,000 g Propylene glycol 200,000 g 400,000 g Water for injections up to 1 liter up to 1 liter

EXAMPLE 5

Alternative preparation of the amylodipine besylate salt

To a suspension of amlodipine base (2 g) in industrial methylated spirit (10 ml) was added ammonium benzenesulfonate (0.943 g) and the resulting solution was refluxed for 10 minutes. The reaction mixture was cooled and granulated at 5 ° C for 1 hour. Amlodipine benzolsulfonate was filtered, washed with industrial

methylated spirit (2x2 ml) and dried under vacuum. Yield 1.9 g (70%) than theoretical values) T.t. 201.0 ° C. % Analysis C H N Calculated 55.07 5.51 4.95 Found 54.98 5.46 4.90

Dos: 3150/45

P-580/87

Apr 5, 1990

Claims (2)

PATENT REQUIREMENTS A process for the preparation of 3-ethyl-5-methyl-2 (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methylpiperidine-3,5-dicarboxylate benzenesulfonate salt, comprising the reaction of a free base of 3-ethyl-5-methyl-2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -1,4-dihydro-6-methylpyridine-3,5-dicarboxylate with a solution of benzenesulfonic acid or its ammonium salt in an inert solvent , and then isolating the benzolsulfonate salt. i The process according to claim 1, wherein the inert solvent is industrially methylated spirit.