Solubilization of Nicardipine Hydrochloride via Complexation and Salt Formation

The solubility behavior of nicardipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-[methyl(phenylmethyl)amino]ethyl diester), a calcium channel blocker, used in the treatment of chronic stable angina and mild essential hypertension was investigated. Two techniq...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 1994-10, Vol.83 (10), p.1418-1420
Main Authors: Maurin, Michael B., Rowe, Susan M., Koval, Christopher A., Hussain, Munir A.
Format: Article
Language:English
Subjects:
Antihypertensive agents
Biological and medical sciences
Buffers
Cardiovascular system
Chemical Phenomena
Chemistry, Pharmaceutical
Chemistry, Physical
Evaluation Studies as Topic
Hydrogen-Ion Concentration
Medical sciences
Nicardipine - chemistry
Pharmacology. Drug treatments
Solubility
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Summary:The solubility behavior of nicardipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-[methyl(phenylmethyl)amino]ethyl diester), a calcium channel blocker, used in the treatment of chronic stable angina and mild essential hypertension was investigated. Two techniques that are known to improve solubility, complexation and salt formation, were examined. Concentrations were determined with a specific reversed-phase HPLC assay. The solubility of nicardipine hydrochloride was enhanced exponentially via complexation with aliphatic carboxylic acid buffer systems in a pH dependent fashion. The solubility increased from 5 to 68.6 and 270 mg/mL as the acetate or propionate buffer concentrations, respectively, increased from 0.001 to 5 M, showing a positive deviation from linearity. The conversion of nicardipine hydrochloride to the phosphate salt resulted in a ∼10-fold solubility improvement. The surface tension of the nicardipine phosphate in water as a function of concentration indicated a critical micelle concentration of 5–6 mg/mL. The critical micelle concentration was greater than the equilibrium solubility of the hydrochloride salt in water, suggesting that a self-association phenomena is responsible for the enhanced solubility of the phosphate salt. Both routes provided potential alternatives for the solubilization of nicardipine.
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.2600831011