HK1066545B - Novel amlodipine camsylate and method for preparing thereof - Google Patents

Description

Novel amlodipine camsylate and method for preparing same

Technical Field

The present invention relates to amlodipine camsylate of formula 1 and a method for preparing the same.

Background

Amlodipine is a generic term for the compound of formula 2, 3-ethyl-5-methyl-2- (2-aminoethoxy-methyl) -4- (2-chlorophenyl) -6-methyl-1, 4-dihydro-3, 5-pyridinedicarboxylate, a long-term calcium channel blocker used for the treatment of cardiovascular (cardiovascular) diseases such as angina pectoris, hypertension and congestive heart failure

European patent publication No. 89167 discloses various different types of pharmaceutically acceptable salts of amlodipine. Pharmaceutically acceptable salts are prepared by adding a pharmaceutically acceptable acid to form a non-toxic salt of amlodipine acid type, examples of which include hydrochloride, hydrobromide, sulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate and gluconate. Of these salts, the maleate salt is most preferred.

Amlodipine in free base form for pharmaceutical use. However, since the amorphous phase amlodipine shows low stability, it is preferable to administer it in the form of a salt of a pharmaceutically acceptable acid.

Korean patent publication No. 95-6710 suggests that pharmaceutically acceptable salts must satisfy four physicochemical requirements: high solubility, good stability, non-hygroscopic properties and processability for tablet formulation.

Most amlodipine salts are amorphous and it is difficult to simply prepare them. In addition, acid-added amlodipine salts satisfying all the above requirements have yet to be developed. For example, it has been found that even though amlodipine maleate, which is suggested to be the most preferred pharmaceutical form of amlodipine, has a relatively high solubility in water, it degrades in solution within a few weeks.

Korean patent laid-open publication No. 95-7228 discloses that a besylate salt of amlodipine (hereinafter, referred to as "amlodipine besylate salt") shows high solubility and good stability, and has properties suitable for the preparation of pharmaceutical formulations. However, amlodipine besylate is derived from toxic benzenesulfonic acid, and thus has a safety problem.

The present invention has been made in an effort to develop a novel crystalline amlodipine that satisfies all the required properties.

Disclosure of Invention

Accordingly, it is a primary object of the present invention to provide a novel crystalline salt of amlodipine that is low in toxicity and has pharmaceutically acceptable properties.

According to an aspect of the present invention, there is provided a method for preparing a crystalline salt of amlodipine using camphorsulfonic acid, which is relatively less toxic than benzenesulfonic acid.

According to still another aspect of the present invention, there is provided amlodipine camsylate having a structure of formula (1) prepared by the method of the present invention.

According to still another aspect of the present invention, there is provided a pharmaceutical composition for treating cardiovascular diseases, comprising amlodipine camsylate as an effective ingredient.

Drawings

The above and other objects of the present invention will become apparent from the following description of the present invention when taken in conjunction with the accompanying drawings, in which:

FIG. 1: an X-ray diffraction scan of amlodipine camsylate of the present invention;

FIG. 2: an X-ray diffraction scan of amlodipine besylate;

FIG. 3: the adhesiveness of amlodipine camsylate and amlodipine besylate of the present invention.

Detailed Description

The present invention provides a method for preparing a crystalline salt of amlodipine using a low-toxic camphorsulfonic acid.

Specifically, the method comprises the following steps:

1) dissolving amlodipine of formula (2) in an organic solvent;

2) adding a solution of camphorsulfonic acid in an organic solvent to the amlodipine solution and stirring the mixture for a sufficient time to form a solid;

3) the solid was filtered, washed and dried.

The amlodipine crystalline salt of the present invention can be prepared by adding an acid to an amlodipine solution or adding an acid to a reaction mixture for preparing amlodipine.

It is preferable to use amlodipine of step 1) at a concentration of 3 to 60 wt% to effectively promote crystallization, more preferably 10 to 30 wt%.

Camphorsulfonic acids that may be used in step 2) include, but are not limited to, (1S) - (+) -10-camphorsulfonic acid of formula (3), (1R) - (-) -10-camphorsulfonic acid of formula (4), and racemic 10-camphorsulfonic acid. The camphorsulfonic acid is preferably used in an amount of 0.1 to 5.0 equivalents, more preferably 1.0 to 1.3 equivalents, based on the amount of amlodipine.

The organic solvent used in step 1) or 2) includes methanol, ethanol, isopropanol and acetonitrile.

The solid in step 2 is preferably formed at-10-50 deg.C, more preferably 0-25 deg.C.

In addition, the present invention provides amlodipine camsylate prepared by the method of the present invention, which is low toxic and has pharmaceutically acceptable properties.

It has been confirmed by X-ray diffraction scan (see fig. 1 and 2) that the amlodipine crystalline salt of the present invention, amlodipine camsylate, has a crystal form different from that of the amorphous compound or amlodipine besylate, and confirmed by NMR analysis to have the structure of formula (1).

It is well known that amlodipine besylate is most suitable for pharmaceutical formulations, but it has stability problems due to the use of toxic benzenesulfonic acid. To solve this problem, the present invention uses camphorsulfonic acid, which has relatively low toxicity than benzenesulfonic acid.

Toxicity of camphorsulfonic acid was compared with toxicity of benzenesulfonic acid according to the Registration of Toxic Effects of Chemical Substations (RTECS) data, and the results are shown in Table 1.

TABLE 1

Substance(s)	Route of administration	Test animal	Dosage form	Literature reference
					Benzene sulfonic acid	Is administered orally	Rabbit	LD50890μl/kg	AIHAAP23，95，1962
Skin(s)	Cat (cat)	LDLO10g/kg	JPETAB84，358，1945
				Is administered orally		Wild bird	LD5075mg/kg	TXAPA921，315，1972
(1S) - (+) -10-Camphorsulfonic acid	Under the skin	Mouse	LD502502mg/kg						PHARAT1，150，1946
				(±) -10-camphorsulfonic acid	Is administered orally	Quail	LD50＞316mgl/kg	EESADV6，149，1982
#LD50: 50% lethal dose, LDLO: minimal lethal dose

As shown in Table 1, since it is impossible to compare LDs of the same species between the two₅₀It is difficult to directly compare the toxicity between camphorsulfonic acid and benzenesulfonic acid, however, it is confirmed that camphorsulfonic acid used in the present invention shows lower toxicity than benzenesulfonic acid.

Further, the present invention provides a pharmaceutical composition for treating cardiovascular diseases, comprising amlodipine camsylate of the present invention as an active ingredient, and a pharmaceutically acceptable excipient, carrier or diluent.

The pharmaceutical compositions may be prepared according to any conventional procedure. In preparing the compositions, the active ingredient is preferably mixed with a carrier or diluted, or enclosed within a carrier in the form of a capsule, sachet or other container. When the carrier is used as a diluent, it may be a solid, semi-solid or liquid material, which acts as a vehicle, excipient or medium. Thus, the formulations may be in the form of tablets, pills, powders, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile packaged powders, and the like.

Examples of suitable carriers, excipients and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. The composition may additionally include fillers, anti-caking agents, lubricants, flavorants, emulsifiers, preservatives and the like. The compositions of the present invention may be formulated so as to provide rapid, sustained or sustained release of the active ingredient after administration to the mammal by employing any of the procedures well known in the art.

The pharmaceutical compositions of the present invention may be administered via a variety of routes including oral, dermal, subcutaneous, intravenous, and intramuscular introduction. In the case of humans, a typical daily dose of amlodipine camsylate may be about 1.0 to 10.0mg/kg body weight, preferably 5.0 to 8.0mg/kg body weight, and may be administered in a single dose or divided doses.

However, it will be understood that the amount of active ingredient actually administered will depend upon a variety of relevant factors including the condition to be treated, the chosen route of administration, the age, sex and weight of the individual patient, and the severity of the patient's condition; and therefore the above dosages are not intended to limit the scope of the present invention in any way.

The following examples and test examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1: preparation of amlodipine camsylate 1

12.25g (0.03mol) of amlodipine (Hanmi pharm. Co. Ltd.) was dissolved in 50ml of methanol, cooled to 10 ℃ and then 7.8g (0.336mol) of a solution of (1S) - (+) -10-camphorsulfonic acid (Aldrich) dissolved in 19.5ml of methanol was gradually added thereto. After the reaction mixture was stirred at room temperature for 2 hours, the solid form compound was filtered, washed with 25ml of methanol, and then dried to obtain 16.7g (yield: 86.8%) of the title compound in the form of white crystals.

m.p.：198℃～202℃

1H-NMR(300MHz，DMSO-d₆)δ(ppm)：8.42(s，1H)，7.82(br，3H)，7.35～7.13(m，4H，ArH)，5.30(s，1H)，4.73～4.55(d.d.，2H)，3.96(q，2H)，3.65(m，2H)，3.50(s，3H)，3.34(s，2H)，3.08(m，2H)，2.90～2.35(d.d.，2H)，2.70(m，1H)，2.31(s，3H)，2.28～2.21(m，1H)，1.95～1.77(m，3H)，1.27(m，2H)，1.26(t，3H)，1.05(s，3H)，0.74(s，3H)

Example 2: preparation of amlodipine camsylate 2

12.25g (0.03mol) of amlodipine is dissolved in 50ml of methanol, cooled to 10 ℃ and then a solution of 7.8g (0.336mol) of (1R) - (-) -10-camphorsulfonic acid (Aldrich) dissolved in 19.5ml of methanol is gradually added thereto. The same procedures as in example 1 were used to give 15.4g (yield: 80.0%) of the title compound as white crystals.

m.p.：198℃～204℃

1H-NMR(300MHz，DMSO-d₆)δ(ppm)：8.42(s，1H)，7.82(br，3H)，7.35～7.13(m，4H，ArH)，5.30(s，1H)，4.73～4.55(d.d.，2H)，3.96(q，2H)，3.65(m，2H)，3.50(s，3H)，3.34(s，2H)，3.08(m，2H)，2.90～2.35(d.d.，2H)，2.70(m，1H)，2.31(s，3H)，2.28～2.21(m，1H)，1.95～1.77(m，3H)，1.27(m，2H)，1.26(t，3H)，1.05(s，3H)，0.74(s，3H)

Example 3: preparation of amlodipine camsylate 3

12.25g (0.03mol) of amlodipine are dissolved in 50ml of methanol, cooled to 10 ℃ and then a solution of 7.8g (0.336mol) of (. + -.) -10-camphorsulfonic acid (Aldrich) dissolved in 19.5ml of methanol is gradually added thereto. The same procedures used in example 1 were used to give 16.0g (yield: 83.2%) of the title compound as white crystals.

m.p.：198℃～202℃

1H-NMR(300MHz，DMSO-d₆)δ(ppm)：8.42(s，1H)，7.82(br，3H)，7.35～7.13(m，4H，ArH)，5.30(s，1H)，4.73～4.55(d.d.，2H)，3.96(q，2H)，3.65(m，2H)，3.50(s，3H)，3.34(s，2H)，3.08(m，2H)，2.90～2.35(d.d.，2H)，2.70(m，1H)，2.31(s，3H)，2.28～2.21(m，1H)，1.95～1.77(m，3H)，1.27(m，2H)，1.26(t，3H)，1.05(s，3H)，0.74(s，3H)

Experimental example 1: solubility test

Amlodipine salts preferably have a solubility in water of more than 1mg/ml at pH 1-7.5, especially at blood pH 7.4. Thus, the solubility and saturation pH of each amlodipine camsylate of examples 1 and 2 were tested and compared with amlodipine besylate (Korean patent laid-open No. 95-7228). According to the Korean pharmacopoeia (Korea minimum of health and Welfare, Gereral principal of medical supports, Vol.1, Clause29, the 7^threview) that includes the following steps: each compound was dissolved in distilled water to saturation, the saturated solution was analyzed by liquid chromatography, and then the dissolved amount of each compound based on amlodipine was measured.

TABLE 2

Salt (salt)	Solubility (mg/ml)	Saturated pH
			Amlodipine benzenesulphonate	1.398	6.2
Amlodipine camsylate (S) of example 1	1.225	6.0
			Fruit of Chinese wolfberryAmlodipine camsylate of EXAMPLE 2 (R)	1.250	6.2

As shown in table 2, the saturation pH of amlodipine camsylate of the present invention is similar to that of amlodipine besylate, but its solubility is slightly lower than that of amlodipine besylate, probably due to the difference between amlodipine camsylate molecular weight (M.W ═ 641.18) and amlodipine besylate molecular weight (M.W ═ 559.06).

Experimental example: stability test

The time-dependent stability of amlodipine camsylate of the present invention prepared in examples 1 and 2 was measured and compared with amlodipine besylate. Specifically, each compound was stored at 55 ℃ at a relative humidity of about 50%, and the residual amount of active amlodipine was measured by liquid chromatography after 1, 2, 3 and 4 weeks.

TABLE 3

Salt (salt)	Initial	1 week	2 weeks	3 weeks	4 weeks
						Amlodipine benzenesulphonate	1	0.992	0.996	0.993	0.993
Amlodipine camsylate (S) of example 1	1	1	0.998	1	1
						Amlodipine camsylate (R) of example 2	1	1	1	1.002	1

As shown in table 3, amlodipine besylate has a slight but significant degradation after 1 week, whereas amlodipine camsylate of the present invention is stable over a 4 week period. Therefore, the amlodipine camsylate of the present invention is more stable than amlodipine besylate.

Experimental example 3: no moisture absorption test

When formulating solid form pharmaceuticals, it is important that the pharmaceutical is not hygroscopic. Therefore, the hygroscopicity of the amlodipine camsylate of the present invention was measured and compared with that of amlodipine besylate.

Each compound was exposed to two conditions: 37 ℃, 75% relative humidity, 24 hours (condition 1), and 30 ℃, 95% relative humidity, 3 days (condition 2), and then the moisture content of each compound was measured according to the method described in korean patent laid-open No. 1995-.

TABLE 4

Salt (salt)	Original humidity	Condition 1 (%)	Condition 2 (%)
				Amlodipine benzenesulphonate	0.05	0.05	0.15
Amlodipine camsylate (S) of example 1	0.05	0.05	0.15
				Amlodipine camsylate (R) of example 2	0.05	0.05	0.15

The results in table 4 indicate that neither amlodipine camsylate of the present invention nor amlodipine besylate is hygroscopic.

Experimental example 4: comparative adhesion test

The adhesiveness of amlodipine camsylate of the present invention was measured and compared with that of amlodipine besylate as follows.

Each compound was tableted according to korean patent laid-open publication No. 95-7228, and the residual compound bound to the tablet press was extracted with methanol in various tablet amounts and the amount thereof was measured by a spectrometer.

The average of the multiple measurements is determined by the slope of the line of fig. 3.

FIG. 5

	Adsorption capacity of tablet (. mu.g)
								Amlodipine benzenesulphonate		Amlodipine camsylate		Camphorsulfonate/benzenesulfonate
Tablet dosage	AVG.	S.D	AVG.	S.D	AVG.	S.D
							50	32.9	5.6	33.0	8.2	1.00	0.08
100	60.6	2.5	60.6	9.1	0.99	0.11
							150	102.7	15.7	101.1	14.6	0.99	0.01
220	183.8	1.1	177.1	2.1	0.96	0.01
							250	235.1	5.3	234.8	13.3	1.00	0.03
300	242.7	2.6	235.4	1.4	0.97	0.02

As can be seen from table 5, the amlodipine camsylate and the amlodipine besylate of the present invention are the same in viscosity inhibitory properties (fig. 3).

While the invention has been described with respect to the above specific embodiments, it will be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims (8)

1. Amlodipine camsylate having the structure of formula 1.

2. A method for preparing amlodipine camsylate of claim 1, comprising the steps of:

1) dissolving amlodipine of formula 2 in an organic solvent;

2) adding a solution of camphorsulfonic acid dissolved in an organic solvent to the amlodipine solution and agitating the mixture for a sufficient time to form a solid;

3) the solid was filtered, washed and dried.

3. The process of claim 2 wherein said camphorsulfonic acid is selected from the group consisting of: (1S) - (+) -10-camphorsulfonic acid of formula (3), (1R) - (-) -10-camphorsulfonic acid of formula (4), and racemic 10-camphorsulfonic acid.

4. The method according to claim 2, wherein the amlodipine concentration of the mixture used in step 2) is 3 to 60% by weight.

5. The method of claim 2, wherein the camphorsulfonic acid is used in an amount of 0.1 to 5.0 equivalents based on the amount of amlodipine.

6. The method according to claim 2, wherein the organic solvent used in step 1) or 2) is selected from the group consisting of: methanol, ethanol, isopropanol and acetonitrile.

7. The process of claim 2, wherein the solid is formed at-10-50 ℃.

8. A pharmaceutical composition for treating cardiovascular diseases, comprising the amlodipine camsylate of claim 1 as an active ingredient.