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

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Abstract

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 pKas, aqueous and pH solubility, cosolvent solubility, log P, pH stability, thermal analysis, and preliminary hygroscopicity studies. The mean pKa1, pKa2, and pKa3 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.

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Acknowledgments

The authors wish to acknowledge National Center for Natural Products Research and Dr. Dhammika N. Nanayakkara for providing NPC 1161C samples. The authors also wish to thank Mr. Frank Wiggers of NCNPR for his technical assistance with NMR spectroscopy.

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Author notes

  1. Asish Kumar Dutta

    Present address: College of Notre Dame of Maryland, School of Pharmacy, 4701 North Charles Street, Baltimore, Maryland, 21210, USA

  2. Steven P. Stodghill

    Present address: School of Pharmacy, Belmont University, Nashville, Tennessee, 37212, USA

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, The University of Mississippi, Oxford, Mississippi, 38677, USA

    Asish Kumar Dutta, Steven P. Stodghill & Christy M. Wyandt

  2. National Center for Natural Products Research, The University of Mississippi, Oxford, Mississippi, 38677, USA

    Steven P. Stodghill & Christy M. Wyandt

Authors
  1. Asish Kumar Dutta
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  2. Steven P. Stodghill
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  3. Christy M. Wyandt
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Correspondence to Asish Kumar Dutta.

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Dutta, A.K., Stodghill, S.P. & Wyandt, C.M. Physicochemical Characterization of NPC 1161C, A Novel Antimalarial 8-Aminoquinoline, in Solution and Solid State. AAPS PharmSciTech 12, 177–191 (2011). https://doi.org/10.1208/s12249-010-9578-6

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