Physicochemical Characterization of NPC 1161C, A Novel Antimalarial 8-Aminoquinoline, in Solution and Solid State

• Published in: AAPS PharmSciTech 2011-03, Vol.12 (1), p.177-191
• Main Authors: Dutta, Asish Kumar, Stodghill, Steven P., Wyandt, Christy M.
• Format: Article
• Language: English
• Subjects: Aminoquinolines - chemistry; Aminoquinolines - pharmacokinetics; Aminoquinolines - pharmacology; Antimalarials - chemistry; Antimalarials - pharmacokinetics; Antimalarials - pharmacology; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Dosage Forms; Drug Stability; Hot Temperature; Humans; Hydrogen-Ion Concentration; Pharmacology/Toxicology; Pharmacy; Pneumocystis carinii; Research Article; Solubility; Solutions; Succinates - chemistry; Succinates - pharmacokinetics; Succinates - pharmacology
• ISSN: 1530-9932; 1530-9932
• DOI: 10.1208/s12249-010-9578-6

NPC 1161C is a novel antimalarial drug of interest because of its superior curative and prophylactic activity, and favorable toxicity profile against in vivo and in vitro models of malaria, pneumocystis carinii pneumonia, and leishmaniasis. The preformulation studies performed included determination of pK a s, aqueous and pH solubility, cosolvent solubility, log P , pH stability, thermal analysis, and preliminary hygroscopicity studies. The mean pK a1 , pK a2 , and pK a3 were determined to be 10.12, 4.07, and 1.88, respectively. The aqueous solubility was found to be 2.4 × 10 −4  M having a saturated solution pH of 4.3–5.0 and a low intrinsic solubility of 1.6 × 10 −6  M. A mathematical model of the pH-solubility profile was derived from pH 2.2 to 8.0. An exponential decrease in solubility was observed with increasing pH. The excess solid phase in equilibrium with the solution in aqueous buffers was determined to be the free-base form of the drug. A significant increase in solubility was observed with all the cosolvents studied, in both unbuffered and buffered systems. Mean log P of the salt and the free base were estimated to be 2.18 and 3.70, respectively. The compound had poor stability at pH 7.0 at 37°C, with a t 90 of 3.58 days. Thermal analysis of the drug using DSC and TGA revealed that the drug is present as a semi-crystalline powder, which transformed into the amorphous state after melting. The drug was also found to sublime at higher temperatures. Determination of physicochemical properties of NPC 1161C provided useful information for the development of a dosage form and preclinical evaluation.