WO2005042485A1 - Acid added salts of amlodipine - Google Patents

Acid added salts of amlodipine Download PDF

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Publication number
WO2005042485A1
WO2005042485A1 PCT/KR2004/002756 KR2004002756W WO2005042485A1 WO 2005042485 A1 WO2005042485 A1 WO 2005042485A1 KR 2004002756 W KR2004002756 W KR 2004002756W WO 2005042485 A1 WO2005042485 A1 WO 2005042485A1
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WIPO (PCT)
Prior art keywords
acid
amlodipine
salt
acid salt
solution
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PCT/KR2004/002756
Other languages
French (fr)
Inventor
Jae-Sun Kim
Jin Young Choi
Je Ho Ryu
Nam Ho Kim
Nam Kyu Lee
Yong Ho Oh
Joon-Gyo Oh
Woo Jae Jang
Do Seung Kum
Key An Um
Wie-Jong Kwak
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Sk Chemicals, Co., Ltd.
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Priority claimed from KR1020030076407A external-priority patent/KR20050041287A/en
Priority claimed from KR1020030076405A external-priority patent/KR20050041285A/en
Priority claimed from KR1020030076403A external-priority patent/KR20050041283A/en
Priority claimed from KR1020030076404A external-priority patent/KR20050041284A/en
Priority claimed from KR1020030076399A external-priority patent/KR20050041279A/en
Priority claimed from KR1020030076401A external-priority patent/KR20050041281A/en
Application filed by Sk Chemicals, Co., Ltd. filed Critical Sk Chemicals, Co., Ltd.
Publication of WO2005042485A1 publication Critical patent/WO2005042485A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to acid salts of amlodipine, in which amlodipine base is reacted with one of organic acids selected from glutaric acid, hipuric acid, pyroglutamic acid, m-xylenesulfonic acid, malonic acid, L-malic acid and the fore- mentioned acid derivatives thereof. More particularly, these crystalline acid salts of amlodipine show excellent physicochemical properties such as high aqueous solubility, stability, non-hygroscopicity and anti-stiction property, thereby providing an effective therapeutic agent in the treatment of cardiovascular diseases including hypertension.
  • Amlodipine is 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-cl lorophenyl)- 6-methyl-l,4-dihydro-3,5-pyridine dicarboxylate and has been used in the treatment of ischemic and hypertensive heart diseases as a calcium-channel blocker.
  • amlodipine is an effective and useful agent due to its prolonged activity.
  • Amlodipine was first disclosed as a novel compound of 1,4-dihydropyridines in EP Patent Publication No. 89,167.
  • EP Patent Publication No. 89,167 teaches that pharmaceutically acceptable salts of amlodipine can be produced from non-toxic acids with pharmaceutically acceptable anions such as chloride, bromide, sulfate, phophate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and more preferably maleate.
  • Free form of amlodipine is also pharmaceutically useful, but it has been administered in the salt form of a pharmaceutically acceptable acid due to its low stability.
  • 90,479 discloses four physicochemical properties which are required to form pharmaceutically acceptable salts: (1) excellent aqueous solubility; (2) excellent stability; (3) non-hygroscopicity; and (4) processability for tablet formulation. It is, however, very difficult to meet all the four physicochemical property requirements above, and even the maleate salt, which is currently the most preferable pharmaceutical form, has been reported to decompose in the solution within several weeks.
  • Korean Patent No. 91,020 discloses that amlodipine besylate is superior over conventional salts of amlodipine and has excellent processability for pharmaceutical formulation. However, it has been brought for safety issues since benzenesulfonic acid, which is corrosive and toxic, is used in the process for producing amlodipine besylate.
  • an object of the present invention is to provide pharmaceutically effective acid salts of amlodipine with excellent physicochemical properties including aqueous solubility, stability, non-hygroscopicity, and processability for tablet formulation.
  • another object of the present invention is to provide crystalline acid salts of S-(-)-amlodipine from two isomers as a strong calcium-channel blocker which is more stable in the formulation and therapeutically more effective.
  • a further object of the present invention is to provide a method for preparing acid salts of amlodipine.
  • a still further object of the present invention is to provide a pharmaceutical composition containing pharmaceutically acceptable acid slats of amlodipine satisfying all the physicochemical property requirements as a therapeutically active ingredient and its use in the treatment of cardiovascular diseases including hypertension.
  • the present invention relates to acid salts of amlodipine with one of organic acids chosen from glutaric acid, hipuric acid, pyroglutamic acid, m-xylenesulfonic acid, malonic acid, L-malic acid, and the afore-mentioned acid derivatives thereof.
  • the acid salt of amlodipine of the present invention may be an isomer or a mixture of these isomers.
  • the acid salt of amlodipine of the present invention provides excellent physicochemical properties including aqueous solubility, stability, non- hygroscopicity, and processability of tablet formulation.
  • the acid salt of amlodipine of the present invention is therapeutically effective in the treatment of cardiovascular diseases.
  • the acid salt of amlodipine of the present invention is prepared by reacting amlodipine with an appropriate acid in the presence of organic solvent.
  • a method for preparing acid salt of amlodipine comprises the following steps of: 1) dissolving amlodipine in an organic solvent; 2) dissolving an acid in an organic solvent, a mixture of organic solvent or water, and adding it to the amlodipine solution; 3) stirring the reaction mixture, and then filtering, washing, and drying resulting solids to produce a crystalline acid salt.
  • the crystalline acid salt of amlodipine of the present invention is prepared by adding acid to the solution of amlodipine and the process is described in detail hereinafter.
  • the concentration of amlodipine in the reaction solution is important to effectively accelerate crystallization and preferable to be in the range from 3 wt% to 60 wt%.
  • a solvent for dissolving amlodipine can be any conventional organic solvent, preferably methanol, ethanol, isopropanol and acetonitrile.
  • Amlodipine may be (R)-amlodipine, (S)-amlodipine or a mixture thereof, more preferably (S)-amlodipine for calcium-channel blocker.
  • step 2) of adding an acid in the amlodipine solution 0.1-5.0 equivalents of acid are desired per equivalent of amlodipine.
  • acids include glutaric acid, hipuric acid, pyroglutamic acid, m-xylenesulfonic acid, malonic acid, L-malic acid, and the afore-mentioned acid derivatives thereof, for example, glutaric acid means its derivatives such as 3-methylglutaric acid, 2,2-dimethylglutaric acid, 2- methylglutaric acid and the like.
  • the acid is added as a solution in water, organic solvent or a mixture thereof, and the preferred solvent is chosen from methanol, ethanol, isopropanol, acetonitrile or a mixture of water and one of selected organic solvents.
  • step 3) of producing crystalline acid salt of amlodipine the reaction is performed at a temperature of -10 to 50 ° C .
  • the acid salt of amlodipine prepared by the above method according to the present invention satisfies all physicochemical property requirements to be suitable for pharmaceutically acceptable salts, and the following experimental examples will support these results. Further, the acid salts of amlodipine of the present invention are effective in the treatment of cardiovascular disorders.
  • the present invention also includes a pharmaceutical composition consisting an optically pure compound or a racemic mixture of the acid salt of amlodipine as an active ingredient and its use in the treatment of cardiovascular disorders.
  • the pharmaceutical composition of the present invention may be formulated into oral or parenteral dosage forms or into general pharmaceutically acceptable dosage forms.
  • a pharmaceutically acceptable filler in the formulation into oral or parenteral dosage forms, a pharmaceutically acceptable filler, a diluent, a binder, a wetting agent, a disintegrant, a surfactant or an excipient may be combined.
  • solid dosage forms for the oral administration include tablets, granules, powders, capsules and the like. Such solid dosages may contain at least one excipient such as starch, sucrose, lactose and gelatin. Additionally, lubricating agent such as magnesium stearate and talc may be included.
  • liquid preparation for the oral administration examples include suspensions, solutions, emulsions, syrups and the like, and such liquid forms may contain diluent such as water and aqueous paraffin, and excipient such as wetting agent, sweetening agent, flavoring agent, preserving agent and the like.
  • formulation for the parenteral administration examples include sterile aqueous solution, non-aqueous solution, suspensions, emulsions, lyophillized preparation, and suppositories.
  • Injectable ester such as ethyl olate and vegetable oil such as propylene glycol, polyethylene glycol and olive oil may be used for non-aqueous solution and suspensions.
  • the suppository preparation can be prepared by using a base such as witepsol, macrogol, Tween 61, cacao oil, laurin oil, glycerol-gelatin and the like.
  • a base such as witepsol, macrogol, Tween 61, cacao oil, laurin oil, glycerol-gelatin and the like.
  • the amount of the pharmaceutical composition actually administered will be determined in the light of the relevant circumstances, including the patient's age, weight, and sex, the selected route of administration, the condition to be treated, the severity of the patient's symptoms, and the like.
  • a compound can be administered in a single daily dose or in multiple doses per day.
  • Suitable doses of the acid salt of amlodipine are 1.0-10.0 mg/kg per day, preferably 2.0-8.0 mg/kg per day.
  • Example 1 Preparation of amlodipin hemi-3-methyl glutarate salt 1.0 g(0.0024 mol) of amlodipine was dissolved in 15 mL of f-butanol. After dissolving 3-methyl glutaric acid 0.178 g(0.0012 mol) in 5 mL of i-butanol, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 2 hr. After adding 50 mL of diethyl ether to the reaction mixture, it was cooled to 5 ° C and then further reacted for 2 hr. The solid produced was filtered out and dried to obtain 1.01 g of the desired white crystalline compound (yield 85.7%).
  • Example 2 Preparation of amlodipin 2,2-dimethyl glutarate salt 1.0 g(0.0024 mol) of amlodipine was dissolved in 15 mL of i-butanol. After dissolving 0.412 g(0.0025 mol) of 2,2-dimethyl glutaric acid in 5 mL of i-butanol, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 2 hr. After adding 50 mL of diethyl ether to the reaction mixture, it was cooled to 5 ° C and then further reacted for 2 hr. The solid produced was filtered out and dried to obtain 1.13 g of the desired white crystalline compound (yield 80.5%).
  • Example 3 Preparation of amlodipin hemi-2-methyl glutarate salt 1.0 g(0.0024 mol) of amlodipine was dissolved in 15 mL of i-butanol. After dissolving 0.178 g(0.0012 mol) of 2-methyl glutaric acid in 5 mL of f-butanol, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 2 hr. After adding 50 mL of diethyl ether to the reaction mixture, it was cooled to 5 ° C and then further reacted for 2 hr. The solid produced was filtered out and dried to obtain 1.12 g of the desired white crystalline compound (yield 95.0%).
  • Example 4 Preparation of amlodipin hipurate salt 5.0 g(0.012 mol) of amlodipine was dissolved in 40 mL of ethanol and the solution was cooled to 5 ° C . After dissolving 1.4 g(0.013 mol) of hipuric acid in ethanol 15 mL, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 10 mL of ethanol, and dried to obtain 6.07 g of the desired white crystalline compound (yield 96.8%). m.p. 157-160 ° C; ⁇ -NMR(300MHz, DMSO-d 6 ) ⁇ (ppm) 8.23(brt, IH), 7.85(d,
  • Example 5 Preparation of amlodipin pidolate salt 5.0 g(0.012 mol) of amlodipine was dissolved in 30 mL of ethanol and the solution was cooled to 5 ° C . After dissolving 1.58 g(0.012 mol) of L-pyroglutamic acid in 30 mL of ethanol, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 10 mL of ethanol, and dried to obtain 6.39 g of the desired white crystalline compound (yield 97.1 %). m.p.
  • Example 7 Preparation of amlodipin malonate salt 5.0 g(0.012 mol) of amlodipine was dissolved in 40 mL of ethanol and the solution was cooled to 5 ° C . After dissolving 1.4 g(0.013 mol) of malonic acid in 15 mL of ethanol, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 10 mL of ethanol, and dried to obtain 6.07 g of the desired white crystalline compound (yield 96.8%). m.p.
  • Example 8 Preparation of amlodipin hemi-L-malate salt 5.0 g(0.012 mol) of amlodipine was dissolved in 40 mL of ethanol and the solution was cooled to 5 ° C . After dissolving 0.82 g(0.006 mol) of malaic acid in 20 mL of ethanol , the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 10 mL of ethanol, and dried to obtain 5.59 g of the desired white crystalline compound (yield 96.0%). m.p. 132-135 ° C; ⁇ -NMR(300MHz, DMSO-d 6 ) ⁇ (ppm) 7.35-7.12(m, 4H, ArH),
  • Example 9 Preparation of (S)-(-) ⁇ amlodipin 2,2-dimethylglutarate salt (S)-(-)-Amlodipine 1 g(0.0024 mmol) was suspended in 10 mL of ethanol and the solution was stirred. After dissolving 0.400 g(0.0025 mol) of 2,2-dimethylglutaric acid in 10 mL of water, the solution was slowly added to the (S)-(-)-amlodipine solution. The reaction solution was reacted at room temperature for 1 hr.
  • Example 10 Preparation of (S)-(-)-amlodipin-hemi-2-methylglutarate salt (S)-(-)-Amlodipine 1 g(0.0024 mmol) was suspended in 1 mL of ethanol and the solution was stirred. After dissolving 0.176 g (0.0012 mol) of 2-methylglutaric acid in The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 5 mL of cold water, and dried at 50 °C under the vacuum for overnight to obtain 0.99 g of the desired (S)-(-)-amlodipin 2- methylglutarate salt (yield 84%). m.p. 102-105 ° C; ⁇ -NMR(300MHz, DMSO-d 6 ) ⁇ (ppm) 7.35-7.09(m, 4H,
  • Example 11 Preparation of (S)-(-)-amlodipine pidolate salt (S)-(-)-Amlodipine 1 g(0.0024 mmol) was dissolved in 10 mL of ethanol and the solution was stirred. After dissolving 0.323 g(0.0025 mol) of L-pyroglutamic acid in 5 mL of ethanol, the solution was slowly added to the (S)-(-)-amlodipine solution. The reaction solution was reacted at room temperature for 1 hr.
  • Example 12 Preparation of (S)-(-) ⁇ amlodipine malonate salt (S)-(-)-Amlodipine 1 g(0.0024 mmol) was dissolved in 10 mL of ethanol and the solution was stirred. After dissolving 0.260 g(0.0025 mol) of malonic acid in 5 mL of ethanol, the solution was slowly added to the (S)-(-)-amlodipine solution. The reaction solution was reacted at room temperature for 1 hr.
  • Example 13 Preparation of (S)-(-)-amlodipine L-malate salt (S)-(-)-Amlodipine 1 g(0.0024 mmol) was dissolved in 10 mL of ethanol and the solution was stirred. After dissolving 0.335 g(0.0025 mol) of L-malic acid in 5 mL of ethanol, the solution was slowly added to the (S)-(-)-amlodipine solution. The reaction solution was reacted at room temperature for 1 hr.
  • preparation examples of the present invention are representatives for preparing pharmaceutical compositions containing an acid salt of amlodipine as an active ingredient and appropriate formulations of prepared compositions used for therapeutic agents.
  • the acid salt of amlodipine is generally described as the active ingredient, it can be glutamate salt, hipurate salt, pidolate salt, meta-x lenesulfonate salt, malonate salt, or malate salt of amlodipine.
  • Preparation Example 1 Formulation of tablets containing acid salt of amlodipine Anhydrous calcium hydrogenphosphate (315 g) and microcrystalline cellulose (525 g, 90 ⁇ m) were mixed and transferred into a drum. Acid salt of amlodipine(70 g) and microcrystalline cellulose (187.5 g, 50 ⁇ m) were mixed and passed through a screen into the drum containing the above powder mixture. The screen used in the previous step was rinsed with microcrystalline cellulose(525 g, 90 ⁇ m). Anhydrous calcium hydrogenphosphate(315 g) was added to the mixture and blended for 10 min. Sodium starch glycollate(40 g) was added to the mixture, followed by blending for 6 min. Magnesium stearate(20 g) was added and the resulting mixture was then blended for 3 min. The powder mixture was then pressed into tablets by conventional methods.
  • Preparation Example 2 Formulation of capsules containing acid salt of amlodipine Microcrystalline cellulose(525 g, 90 ⁇ m) and corn starch were first mixed. Acid salt of amlodipine(70 g) was added to a part of the pre-mixed mixture and the mixture was sieved. The rest of pre-mixed mixture was added and mixed for 10 min. The whole mixture was sieved and blended for additional 5 min. The resulting mixture was encapsulated into suitably sized capsules.
  • Preparation Example 3 Formulation of injections containing acid salt of amlodipine Sodium chloride was dissolved in sterile water for injection and propylene glycol was added thereto. An acid salt of amlodipine was added and dissolved and sterile water for injection was additionally added to obtain a desired concentration.
  • the resulting solution was filtered through a filter for sterilization and filled into sterilized ampoules.
  • Experimental Example 1 Test for Oral Toxicity Results of relative oral toxicity tested for benzenesulfonic acid, which is generally used for preparing acid salt of amlopine, and five representative acids such as hipuric acid, L-pyroglutamic acid, meta-zylenesulfonic acid, malonic acid and L-malic acid, which are used for preparing acid salts of amlodipine in the present invention, are sumrriarized and compared to each other in the following Table 1.
  • Test for Aqueous Solubility In the preparation of pharmaceutically acceptable salts, a test solution is required to be about pH 7.4 which is close to physiological pH of blood and have solubility of 1 mg/mL or above in pH range of 1.0 to 7.5. Aqueous solubility and pH of acid salts of amlodipine of the present invention were determined and compared to those of amlodipine besylate salt. Test for aqueous solubility was conducted according to the method in the Korean Pharmacopoeia. Each compound was saturated in distilled water and analyzed by liquid chromatography to determine the dissolved amount based on the weight of amlodipine, which is converted from the salts. The results are summarized in the following Table 2.
  • aqueous solubilities of acid salts of amlodipine of the present invention are far greater than that of amlodipine besylate.
  • Test for Stability Table 3 represents the result of light stability of acid salts of amlodipine of the present invention compared to that of amlodipine besylate and the total amount of UN light was 200 W -h/ m !
  • these crystalline acid salts of amlodipine are suitable for the preparation of pharmaceutical formulations since they show either comparable or improved physicochemical properties compared to those of amlodipine besylate, thus being useful for the treatment of cardiovascular diseases.

Abstract

The present invention relates to crystalline acid salts of amlodipine which exhibit excellent physicochemical properties such as high aqueous solubility, stability, non-hygroscopicity and anti-stiction property, thereby providing an effective therapeutic agent in the treatment of cardiovascular diseases including hypertension.

Description

ACID ADDED SALTS OF AMLODIPINE
Field of the Invention The present invention relates to acid salts of amlodipine, in which amlodipine base is reacted with one of organic acids selected from glutaric acid, hipuric acid, pyroglutamic acid, m-xylenesulfonic acid, malonic acid, L-malic acid and the fore- mentioned acid derivatives thereof. More particularly, these crystalline acid salts of amlodipine show excellent physicochemical properties such as high aqueous solubility, stability, non-hygroscopicity and anti-stiction property, thereby providing an effective therapeutic agent in the treatment of cardiovascular diseases including hypertension.
Background of the Invention Amlodipine is 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-cl lorophenyl)- 6-methyl-l,4-dihydro-3,5-pyridine dicarboxylate and has been used in the treatment of ischemic and hypertensive heart diseases as a calcium-channel blocker.
Furthermore, it has been well known that amlodipine is an effective and useful agent due to its prolonged activity. Amlodipine was first disclosed as a novel compound of 1,4-dihydropyridines in EP Patent Publication No. 89,167. EP Patent Publication No. 89,167 teaches that pharmaceutically acceptable salts of amlodipine can be produced from non-toxic acids with pharmaceutically acceptable anions such as chloride, bromide, sulfate, phophate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, and more preferably maleate. Free form of amlodipine is also pharmaceutically useful, but it has been administered in the salt form of a pharmaceutically acceptable acid due to its low stability. Korean Patent No. 90,479 discloses four physicochemical properties which are required to form pharmaceutically acceptable salts: (1) excellent aqueous solubility; (2) excellent stability; (3) non-hygroscopicity; and (4) processability for tablet formulation. It is, however, very difficult to meet all the four physicochemical property requirements above, and even the maleate salt, which is currently the most preferable pharmaceutical form, has been reported to decompose in the solution within several weeks. Korean Patent No. 91,020 discloses that amlodipine besylate is superior over conventional salts of amlodipine and has excellent processability for pharmaceutical formulation. However, it has been brought for safety issues since benzenesulfonic acid, which is corrosive and toxic, is used in the process for producing amlodipine besylate.
Summary of the Invention The intensive and thorough research into overcoming the problems associated with the prior arts, resulted in providing acid salts of amlodipine by reacting amlodipine with various acids to be pharmaceutically acceptable and satisfy the above four physicochemical properties. Therefore, an object of the present invention is to provide pharmaceutically effective acid salts of amlodipine with excellent physicochemical properties including aqueous solubility, stability, non-hygroscopicity, and processability for tablet formulation. Particularly, another object of the present invention is to provide crystalline acid salts of S-(-)-amlodipine from two isomers as a strong calcium-channel blocker which is more stable in the formulation and therapeutically more effective. A further object of the present invention is to provide a method for preparing acid salts of amlodipine. A still further object of the present invention is to provide a pharmaceutical composition containing pharmaceutically acceptable acid slats of amlodipine satisfying all the physicochemical property requirements as a therapeutically active ingredient and its use in the treatment of cardiovascular diseases including hypertension.
Detailed Description of the Invention The present invention relates to acid salts of amlodipine with one of organic acids chosen from glutaric acid, hipuric acid, pyroglutamic acid, m-xylenesulfonic acid, malonic acid, L-malic acid, and the afore-mentioned acid derivatives thereof. The acid salt of amlodipine of the present invention may be an isomer or a mixture of these isomers. The acid salt of amlodipine of the present invention provides excellent physicochemical properties including aqueous solubility, stability, non- hygroscopicity, and processability of tablet formulation. The acid salt of amlodipine of the present invention is therapeutically effective in the treatment of cardiovascular diseases. The acid salt of amlodipine of the present invention is prepared by reacting amlodipine with an appropriate acid in the presence of organic solvent. A method for preparing acid salt of amlodipine comprises the following steps of: 1) dissolving amlodipine in an organic solvent; 2) dissolving an acid in an organic solvent, a mixture of organic solvent or water, and adding it to the amlodipine solution; 3) stirring the reaction mixture, and then filtering, washing, and drying resulting solids to produce a crystalline acid salt. The crystalline acid salt of amlodipine of the present invention is prepared by adding acid to the solution of amlodipine and the process is described in detail hereinafter. In step 1), the concentration of amlodipine in the reaction solution is important to effectively accelerate crystallization and preferable to be in the range from 3 wt% to 60 wt%. A solvent for dissolving amlodipine can be any conventional organic solvent, preferably methanol, ethanol, isopropanol and acetonitrile. Amlodipine may be (R)-amlodipine, (S)-amlodipine or a mixture thereof, more preferably (S)-amlodipine for calcium-channel blocker. In step 2) of adding an acid in the amlodipine solution, 0.1-5.0 equivalents of acid are desired per equivalent of amlodipine. Examples of acids include glutaric acid, hipuric acid, pyroglutamic acid, m-xylenesulfonic acid, malonic acid, L-malic acid, and the afore-mentioned acid derivatives thereof, for example, glutaric acid means its derivatives such as 3-methylglutaric acid, 2,2-dimethylglutaric acid, 2- methylglutaric acid and the like. The acid is added as a solution in water, organic solvent or a mixture thereof, and the preferred solvent is chosen from methanol, ethanol, isopropanol, acetonitrile or a mixture of water and one of selected organic solvents. In step 3) of producing crystalline acid salt of amlodipine, the reaction is performed at a temperature of -10 to 50 °C . The acid salt of amlodipine prepared by the above method according to the present invention satisfies all physicochemical property requirements to be suitable for pharmaceutically acceptable salts, and the following experimental examples will support these results. Further, the acid salts of amlodipine of the present invention are effective in the treatment of cardiovascular disorders. The present invention also includes a pharmaceutical composition consisting an optically pure compound or a racemic mixture of the acid salt of amlodipine as an active ingredient and its use in the treatment of cardiovascular disorders. The pharmaceutical composition of the present invention may be formulated into oral or parenteral dosage forms or into general pharmaceutically acceptable dosage forms. In the formulation into oral or parenteral dosage forms, a pharmaceutically acceptable filler, a diluent, a binder, a wetting agent, a disintegrant, a surfactant or an excipient may be combined. Examples of solid dosage forms for the oral administration include tablets, granules, powders, capsules and the like. Such solid dosages may contain at least one excipient such as starch, sucrose, lactose and gelatin. Additionally, lubricating agent such as magnesium stearate and talc may be included. Examples of liquid preparation for the oral administration include suspensions, solutions, emulsions, syrups and the like, and such liquid forms may contain diluent such as water and aqueous paraffin, and excipient such as wetting agent, sweetening agent, flavoring agent, preserving agent and the like. Examples of the formulation for the parenteral administration include sterile aqueous solution, non-aqueous solution, suspensions, emulsions, lyophillized preparation, and suppositories. Injectable ester such as ethyl olate and vegetable oil such as propylene glycol, polyethylene glycol and olive oil may be used for non-aqueous solution and suspensions. The suppository preparation can be prepared by using a base such as witepsol, macrogol, Tween 61, cacao oil, laurin oil, glycerol-gelatin and the like. The amount of the pharmaceutical composition actually administered will be determined in the light of the relevant circumstances, including the patient's age, weight, and sex, the selected route of administration, the condition to be treated, the severity of the patient's symptoms, and the like. According to physician or pharmacist, a compound can be administered in a single daily dose or in multiple doses per day. Suitable doses of the acid salt of amlodipine are 1.0-10.0 mg/kg per day, preferably 2.0-8.0 mg/kg per day.
Example A better understanding of the present invention may be obtained in light of the following examples which are set forth to illustrate, but are not to be construed to limit the present invention.
Example 1: Preparation of amlodipin hemi-3-methyl glutarate salt 1.0 g(0.0024 mol) of amlodipine was dissolved in 15 mL of f-butanol. After dissolving 3-methyl glutaric acid 0.178 g(0.0012 mol) in 5 mL of i-butanol, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 2 hr. After adding 50 mL of diethyl ether to the reaction mixture, it was cooled to 5 °C and then further reacted for 2 hr. The solid produced was filtered out and dried to obtain 1.01 g of the desired white crystalline compound (yield 85.7%). m.p. 148-151 °C; Η-NMR(300MHz, DMSO-d6) δ(ppm) 7.36-7.12(m, 4H, ArH), 5.30(s, IH), 4.70-4.52(d.d., 2H), 4.16-3.88(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, 1.5H)
Example 2: Preparation of amlodipin 2,2-dimethyl glutarate salt 1.0 g(0.0024 mol) of amlodipine was dissolved in 15 mL of i-butanol. After dissolving 0.412 g(0.0025 mol) of 2,2-dimethyl glutaric acid in 5 mL of i-butanol, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 2 hr. After adding 50 mL of diethyl ether to the reaction mixture, it was cooled to 5 °C and then further reacted for 2 hr. The solid produced was filtered out and dried to obtain 1.13 g of the desired white crystalline compound (yield 80.5%). m.p. 133-136 °C; Η-NMR(300MHz, DMSO-d6) δ(ppm) 7.36-7.12(m, 4H, ArH), 5.30(s, IH), 4.71-4.51(d.d., 2H), 4.06-3.88(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 amlodipin hemi-2-methyl glutarate salt 1.0 g(0.0024 mol) of amlodipine was dissolved in 15 mL of i-butanol. After dissolving 0.178 g(0.0012 mol) of 2-methyl glutaric acid in 5 mL of f-butanol, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 2 hr. After adding 50 mL of diethyl ether to the reaction mixture, it was cooled to 5 °C and then further reacted for 2 hr. The solid produced was filtered out and dried to obtain 1.12 g of the desired white crystalline compound (yield 95.0%). m.p. 142-145 °C; Η-NMR(300MHz, DMSO-d6) δ(ppm) 7.36-7.12(m, 4H, ArH), 5.30(s, IH), 4.70-4.52(d.d., 2H), 4.06-3.88(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, IH), 1.69-1.49(m, IH), l.ll(t, 3H), 0.98(d, 1.5H)
Example 4: Preparation of amlodipin hipurate salt 5.0 g(0.012 mol) of amlodipine was dissolved in 40 mL of ethanol and the solution was cooled to 5 °C . After dissolving 1.4 g(0.013 mol) of hipuric acid in ethanol 15 mL, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 10 mL of ethanol, and dried to obtain 6.07 g of the desired white crystalline compound (yield 96.8%). m.p. 157-160 °C; Η-NMR(300MHz, DMSO-d6) δ(ppm) 8.23(brt, IH), 7.85(d,
2H), 7.51-7.11(m, 7H), 5.30(s, IH), 4.71-4.53(d.d., 2H), 4.00-3.93(m, 2H), 3.71(d, 2H), 3.62(brt, 2H), 3.50(s, 3H), 2.99(brt, 2H), 2.32(s, 3H), 1.10(t, 3H)
Example 5: Preparation of amlodipin pidolate salt 5.0 g(0.012 mol) of amlodipine was dissolved in 30 mL of ethanol and the solution was cooled to 5 °C . After dissolving 1.58 g(0.012 mol) of L-pyroglutamic acid in 30 mL of ethanol, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 10 mL of ethanol, and dried to obtain 6.39 g of the desired white crystalline compound (yield 97.1 %). m.p. 172-175 °C; Η-NMR(300MHz, DMSO-d6) δ(ppm) 7.53(brs, IH), 7.36- 7.12(m, 4H, ArH), 5.30(s, IH), 4.71-4.51(d.d., 2H), 4.00-3.94(m, 2H), 3.79-3.60(m, IH), 3.59(brt, 2H), 3.50(s, 3H), 2.94(brt, 2H), 2.31(s, 3H), 2.28-2.20(m, IH), 2.19-2.03(m, 2H), 1.98-1.93(m, IH), 1.10(t, 3H) Example 6: Preparation of amlodipin meta-xylenesulf onate salt 5.0 g(0.012 mol) of amlodipine was dissolved in 40 mL of ethanol and the solution was cooled to 5 °C . After dissolving 2.51 g(0.013 mol) of meta-xylenesulfonic acid in 20 mL of ethanol, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 10 mL of ethanol, and dried to obtain 6.63 g of the desired white crystalline compound (yield 91.1%). m.p. 96-99 °C; Η-NMR(300MHZ/ DMSO-d6) δ(ppm) 8.41(brs, IH), 7.58(d, IH), 7.35-7.12(m, 4H), 6.93-6.88(m, 2H), 5.30(s, IH), 4.73-4.55(d.d., 2H), 4.01-3.94 (m, 2H), 3.65(brt, 2H), 3.50(s, 3H), 3.07(brt, 2H), 2.47(s, 3H), 2.30(s, 3H), 2.24(s, 3H), 1.10(t, 3H)
Example 7: Preparation of amlodipin malonate salt 5.0 g(0.012 mol) of amlodipine was dissolved in 40 mL of ethanol and the solution was cooled to 5 °C . After dissolving 1.4 g(0.013 mol) of malonic acid in 15 mL of ethanol, the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 10 mL of ethanol, and dried to obtain 6.07 g of the desired white crystalline compound (yield 96.8%). m.p. 164-167 °C; Η-NMR(300MHz, DMSO-d6) δ(ppm) 8.42(brs, IH), 7.35- 7.10(m, 4H, ArH), 5.31(s, IH), 4.73-4.55(d.d., 2H), 4.02-3.94(m, 2H), 3.65(brt, 2H), 3.51(8, 3H), 3.07(brt, 2H), 2.72(s, 2H), 2.31(s, 3H), l.ll(t, 3H)
Example 8: Preparation of amlodipin hemi-L-malate salt 5.0 g(0.012 mol) of amlodipine was dissolved in 40 mL of ethanol and the solution was cooled to 5 °C . After dissolving 0.82 g(0.006 mol) of malaic acid in 20 mL of ethanol , the solution was slowly added to the amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 10 mL of ethanol, and dried to obtain 5.59 g of the desired white crystalline compound (yield 96.0%). m.p. 132-135 °C; Η-NMR(300MHz, DMSO-d6) δ(ppm) 7.35-7.12(m, 4H, ArH),
5.30(s, IH), 4.71-4.54(d.d., 2H), 4.02-3.92(m, 2H), 3.82(d.d., 0.5H), 3.55(brt, 2H), 3.50(s, 3H), 2.92(brt, 2H), 2.51-2.44(m, 0.5H), 2.33-2.30(m, 0.5H), 2.31(s, 3H), 1.10(t, 3H)
Example 9: Preparation of (S)-(-)~amlodipin 2,2-dimethylglutarate salt (S)-(-)-Amlodipine 1 g(0.0024 mmol) was suspended in 10 mL of ethanol and the solution was stirred. After dissolving 0.400 g(0.0025 mol) of 2,2-dimethylglutaric acid in 10 mL of water, the solution was slowly added to the (S)-(-)-amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 5 mL of cold water, and dried at 50 °C under the vacuum for overnight to obtain 1.34 g of the desired (S)-(-)-amlodipin 2,2- dimethylglutarate salt (yield 96.0%). m.p. 106-109 °C; Η-NMR(300MHz, DMSO-d6) δ(ppm) 7.35-7.09(m, 4H, ArH), 5.29(s, IH), 4.69-4.51(d.d., 2H), 4.00-3.93(m, 2H), 3.52(brs, 2H), 3.50(s, 3H), 2.84(brt, 2H), 2.30(s, 3H), 2.10(brt, 2H), 1.67(brt, 2H), 1.10(t, 3H), 1.05(s, 6H)
Example 10: Preparation of (S)-(-)-amlodipin-hemi-2-methylglutarate salt (S)-(-)-Amlodipine 1 g(0.0024 mmol) was suspended in 1 mL of ethanol and the solution was stirred. After dissolving 0.176 g (0.0012 mol) of 2-methylglutaric acid in The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 5 mL of cold water, and dried at 50 °C under the vacuum for overnight to obtain 0.99 g of the desired (S)-(-)-amlodipin 2- methylglutarate salt (yield 84%). m.p. 102-105 °C; Η-NMR(300MHz, DMSO-d6) δ(ppm) 7.35-7.09(m, 4H,
ArH), 5.29(s, IH), 4.69-4.52(d.d., 2H), 4.01-3.91(m, 2H), 3.53(brt, 2H), 3.51(s, 3H), 2.84(brt, 2H), 2.30(s, 3H), 2.37-2.28(m, 0.5H), 2.23-2.08(m, IH), 1.63-1.55(m, IH), l.ll(t, 3H), 0.98(d, 1.5H)
Example 11: Preparation of (S)-(-)-amlodipine pidolate salt (S)-(-)-Amlodipine 1 g(0.0024 mmol) was dissolved in 10 mL of ethanol and the solution was stirred. After dissolving 0.323 g(0.0025 mol) of L-pyroglutamic acid in 5 mL of ethanol, the solution was slowly added to the (S)-(-)-amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 10 mL of diethyl ether, and dried at 50 °C under the vacuum for overnight to obtain 1.28 g of the desired (S)-(-)-amlodipin pidolate salt (yield 97%). m.p. 177-180 °C; Η-NMR(300MHz, DMSO-d6) δ(ppm) 7.53(brs, IH), 7.35- 7.09(m, 4H, ArH), 5.30(s, IH), 4.71-4.51(d.d., 2H), 4.00~3.93(m, 2H), 3.84-3.79(m, IH), 3.58(brt, 2H), 3.50(s, 3H), 2.93(brt, 2H), 2.31(s, 3H), 2.23-2.14(m, IH), 2.09- 2.03(m, 2H), 1.97-1.9Q(m, IH), 1.10(t, 3H)
Example 12: Preparation of (S)-(-)~amlodipine malonate salt (S)-(-)-Amlodipine 1 g(0.0024 mmol) was dissolved in 10 mL of ethanol and the solution was stirred. After dissolving 0.260 g(0.0025 mol) of malonic acid in 5 mL of ethanol, the solution was slowly added to the (S)-(-)-amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 10 mL of diethyl ether, and dried at 50 °C under the vacuum for overnight to obtain 1.21 g of the desired (S)-(-)-amlodipine malonate salt (yield 96%). m.p. 167-170 °C; Η-NMR(300MHz, DMSO-d6) δ(ppm) 8.42(brs, IH), 7.34- 7.13(m, 4H, ArH), 5.30(s, IH), 4.73-4.55(d.d., 2H), 3.99-3.96(m, 2H), 3.65(brt, 2H), 3.50(s, 3H), 3.07(brt, 2H), 2.71(s, 2H), 2.30(s, 3H), 1.10(t, 3H)
Example 13: Preparation of (S)-(-)-amlodipine L-malate salt (S)-(-)-Amlodipine 1 g(0.0024 mmol) was dissolved in 10 mL of ethanol and the solution was stirred. After dissolving 0.335 g(0.0025 mol) of L-malic acid in 5 mL of ethanol, the solution was slowly added to the (S)-(-)-amlodipine solution. The reaction solution was reacted at room temperature for 1 hr. The solid produced was filtered out, washed with 10 mL of diethyl ether, and dried at 50 °C under the vacuum for overnight to obtain 1.26 g of the desired (S)-(-)-amlodipine L-malate salt (yield 95%). m.p. 153-156 °C; Η-NMR(300MHz, DMSO-d6) δ(ppm) 7.35-7.13(m, 4H, ArH), 5.30(s, IH), 4.72-4.54(d.d„ 2H), 4.01-3.96(m, 2H), 3.83(d.d., IH), 3.64(brt, 2H), 3.50(s, 3H), 3.05(brt, 2H), 2.51-2.44(m, IH), 2.34-2.27(m, IH), 2.30(s, 3H), 1.10(t, 3H)
Preparation Examples The following preparation examples of the present invention are representatives for preparing pharmaceutical compositions containing an acid salt of amlodipine as an active ingredient and appropriate formulations of prepared compositions used for therapeutic agents. Even though the acid salt of amlodipine is generally described as the active ingredient, it can be glutamate salt, hipurate salt, pidolate salt, meta-x lenesulfonate salt, malonate salt, or malate salt of amlodipine.
Preparation Example 1: Formulation of tablets containing acid salt of amlodipine Anhydrous calcium hydrogenphosphate (315 g) and microcrystalline cellulose (525 g, 90 μm) were mixed and transferred into a drum. Acid salt of amlodipine(70 g) and microcrystalline cellulose (187.5 g, 50 μm) were mixed and passed through a screen into the drum containing the above powder mixture. The screen used in the previous step was rinsed with microcrystalline cellulose(525 g, 90 μm). Anhydrous calcium hydrogenphosphate(315 g) was added to the mixture and blended for 10 min. Sodium starch glycollate(40 g) was added to the mixture, followed by blending for 6 min. Magnesium stearate(20 g) was added and the resulting mixture was then blended for 3 min. The powder mixture was then pressed into tablets by conventional methods.
Preparation Example 2: Formulation of capsules containing acid salt of amlodipine Microcrystalline cellulose(525 g, 90 μm) and corn starch were first mixed. Acid salt of amlodipine(70 g) was added to a part of the pre-mixed mixture and the mixture was sieved. The rest of pre-mixed mixture was added and mixed for 10 min. The whole mixture was sieved and blended for additional 5 min. The resulting mixture was encapsulated into suitably sized capsules. Preparation Example 3: Formulation of injections containing acid salt of amlodipine Sodium chloride was dissolved in sterile water for injection and propylene glycol was added thereto. An acid salt of amlodipine was added and dissolved and sterile water for injection was additionally added to obtain a desired concentration.
The resulting solution was filtered through a filter for sterilization and filled into sterilized ampoules.
Experimental Example 1: Test for Oral Toxicity Results of relative oral toxicity tested for benzenesulfonic acid, which is generally used for preparing acid salt of amlopine, and five representative acids such as hipuric acid, L-pyroglutamic acid, meta-zylenesulfonic acid, malonic acid and L-malic acid, which are used for preparing acid salts of amlodipine in the present invention, are sumrriarized and compared to each other in the following Table 1.
Table 1
Figure imgf000015_0001
Figure imgf000016_0001
As shown in Table 1, it is noted that benzenesulfonic acid itself, which has been generally used for preparing crystalline acid salt of amlodipine, shows somewhat higher toxicity, while those acids used for preparing crystalline acid salt of amlodipine in the present invention show relatively lower toxicities compared to that of benzenesulfonic acid.
Experimental Example 2: Test for Aqueous Solubility In the preparation of pharmaceutically acceptable salts, a test solution is required to be about pH 7.4 which is close to physiological pH of blood and have solubility of 1 mg/mL or above in pH range of 1.0 to 7.5. Aqueous solubility and pH of acid salts of amlodipine of the present invention were determined and compared to those of amlodipine besylate salt. Test for aqueous solubility was conducted according to the method in the Korean Pharmacopoeia. Each compound was saturated in distilled water and analyzed by liquid chromatography to determine the dissolved amount based on the weight of amlodipine, which is converted from the salts. The results are summarized in the following Table 2.
Table 2
Figure imgf000017_0001
As seen in Table 2, aqueous solubilities of acid salts of amlodipine of the present invention are far greater than that of amlodipine besylate.
Experimental Example 3: Test for Stability Table 3 represents the result of light stability of acid salts of amlodipine of the present invention compared to that of amlodipine besylate and the total amount of UN light was 200 W -h/ m!
Table 3
Figure imgf000018_0001
As seen in Table 3, it is demonstrated that the acid salts of amlodipine of the present invention show far superior light stability over that of amlodipine besylate.
Industrial Applicability As aforementioned, according to the characteristic arrangements of the present invention, these crystalline acid salts of amlodipine are suitable for the preparation of pharmaceutical formulations since they show either comparable or improved physicochemical properties compared to those of amlodipine besylate, thus being useful for the treatment of cardiovascular diseases.

Claims

CLAIMSWhat is claimed is:
1. An acid salt of amlodipine produced with one of organic acids selected from the group consisting of glutaric acid, hipuric acid, pyroglutamic acid, m-xylenesulfonic acid, malonic acid, L-malic acid, and the acid derivatives thereof.
2. The acid salt of amlodipine according to claim 1, wherein said salt is a pure isomer or a racemic mixture.
3. The acid salt of amlodipine according to claim 1, wherein said glutaric acid or its derivative is one selected from the group consisting of glutaric acid, 3-methylglutaric acid, 2,2-dimethylglutaric acid, and 2-methylglutaric acid.
4. A method for preparing acid salt of amlodipine, in which amlodipine is reacted with one acid selected from the group consisting of glutaric acid, hipuric acid, pyroglutamic acid, m-xylenesulfonic acid, malonic acid, L-malic acid, and the acid derivatives thereof in an organic solvent or a mixture of organic solvent and water.
5. The method for preparing acid salt of amlodipine according to claim 4, wherein said amlodipine is (S)-amlodipine, (R)-amlodipine or a mixture thereof.
6. The method for preparing acid salt of amlodipine according to claim 4, wherein a concentration of amlodipine is 3-60 wt% in said reaction mixture.
7. The method for preparing acid salt of amlodipine according to claim 4, wherein said acid is 0.1-5.0 equivalents per equivalent of amlodipine.
8. The method for preparing acid salt of amlodipine according to claim 4, wherein said reaction is performed at a temperature of from -10 to 50 °C .
9. The method for preparing acid salt of amlodipine according to claim 4, wherein said solvent is an organic solvent selected from the group consisting of methanol, ethanol, and a mixture of said organic solvent and water.
10. A pharmaceutically active composition, comprising an active ingredient of the acid salt of amlodipine, where said acid salt of amlodipine is produced with one of organic acids selected from the group consisting of glutaric acid, hipuric acid, pyroglutamic acid, m-xylenesulfonic acid, malonic acid, L-malic acid, and the acid derivatives thereof .
11. The pharmaceutically active composition according to claim 9, wherein said acid salt of amlodipine is a pure isomer or a racemic mixture.
12. The use of the acid salt of amlodipine as a therapeutic agent in the treatment for cardiovascular diseases, where said acid salt of amlodipine is produced with one of the organic acids selected from the group consisting of glutaric acid, hipuric acid, pyroglutamic acid, m-xylenesulfonic acid, malonic acid, L-malic acid, and the acid derivatives thereof.
13. The use of the acid salt of amlodipine according to claim 12, wherein said acid salt of amlodipine is a pure isomer or a racemic mixture.
14. The use of the acid salt of amlodipine according to claim 12, wherein said therapeutic agent is formulated into tablets, capsules, or injections.
PCT/KR2004/002756 2003-10-30 2004-10-29 Acid added salts of amlodipine WO2005042485A1 (en)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
KR1020030076407A KR20050041287A (en) 2003-10-30 2003-10-30 Amlodipine malate, and process for preparing it
KR1020030076405A KR20050041285A (en) 2003-10-30 2003-10-30 Amlodipine glutarate, and process for preparing it
KR10-2003-0076403 2003-10-30
KR10-2003-0076404 2003-10-30
KR10-2003-0076399 2003-10-30
KR10-2003-0076401 2003-10-30
KR10-2003-0076407 2003-10-30
KR1020030076403A KR20050041283A (en) 2003-10-30 2003-10-30 Amlodipine m-xylene-4-sulfonic acid salt, and process for preparing it
KR1020030076404A KR20050041284A (en) 2003-10-30 2003-10-30 Amlodipine malonate, and process for preparing it
KR1020030076399A KR20050041279A (en) 2003-10-30 2003-10-30 Amlodipine pidolate, and process for preparing it
KR10-2003-0076405 2003-10-30
KR1020030076401A KR20050041281A (en) 2003-10-30 2003-10-30 Amlodipine hippurate, and process for preparing it

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WO2002079158A1 (en) * 2001-03-29 2002-10-10 Hanmi Pharm. Co., Ltd. Novel amlodipine camsylate and method for preparing thereof
WO2004018426A1 (en) * 2002-08-21 2004-03-04 Cj Corp. Organic acid salt of amlodipine

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CN1343663A (en) * 2000-09-15 2002-04-10 付俊昌 Amlodipine-series salts and preparing process and application thereof
WO2002079158A1 (en) * 2001-03-29 2002-10-10 Hanmi Pharm. Co., Ltd. Novel amlodipine camsylate and method for preparing thereof
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Publication number Priority date Publication date Assignee Title
CN102516159A (en) * 2011-12-15 2012-06-27 扬子江药业集团江苏海慈生物药业有限公司 Method for producing S-(-)-amlodipine besylate
US11535610B2 (en) * 2016-09-21 2022-12-27 Hk Inno.N Corporation Acid addition salts of benzimidazole derivative
US11912690B2 (en) 2016-09-21 2024-02-27 Hk Inno.N Corporation Acid addition salts of benzimidazole derivative

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