Effect of Structurally Related Compounds on Desupersaturation Kinetics of Indomethacin.

Autor: Manchanda A; Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT, 06269, USA., Bookwala M; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, 15282, USA., Wildfong PLD; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, 15282, USA., Bogner RH; Department of Pharmaceutical Sciences, University of Connecticut, 69 North Eagleville Road, Unit 3092, Storrs, CT, 06269, USA. robin.bogner@uconn.edu.; Institute of Material Science, University of Connecticut, Storrs, CT, 06269, USA. robin.bogner@uconn.edu.
Jazyk: angličtina
Zdroj: Pharmaceutical research [Pharm Res] 2023 Dec; Vol. 40 (12), pp. 2769-2778. Date of Electronic Publication: 2023 Sep 05.
DOI: 10.1007/s11095-023-03587-w
Abstrakt: Purpose: The pharmaceutical literature contains examples wherein desupersaturation from high concentrations does not proceed to equilibrium concentration of the thermodynamically most stable form but remains above equilibrium. The purpose of the current research was to investigate the effect of structurally related compounds on desupersaturation kinetics as a possible explanation for a higher than equilibrium solubility after crystal growth of γ-indomethacin (γ-IMC).
Methods: Three structurally related compounds (SRC) - cis-sulindac (c-SUL), trans-sulindac (t-SUL) and indomethacin-related compound-A (IMC-A) -were investigated. Desupersaturation kinetics to the most stable γ-IMC, in the presence of c-SUL, t-SUL or IMC-A, was measured at pH 2.0.
Results: The SRCs c-SUL and t-SUL were effective crystallization inhibitors of IMC, while IMC-A was not a potent crystallization inhibitor of IMC. Among the sulindac isomers, t-SUL was a stronger crystallization inhibitor. The apparent solubility of γ-IMC crystals grown from supersaturated solutions in the presence of SRCs matched the equilibrium solubility of γ-IMC. During crystallization of IMC in the presence of IMC-A, the concentration of IMC-A declined initially but rebounded as supersaturation and crystallization rate of IMC declined, suggesting that IMC-A itself became incorporated in the IMC crystal lattice at higher degrees of IMC supersaturation.
Conclusions: The results suggest that high apparent solubility after crystallization of IMC reported by several authors is not related to the presence of IMC-A impurity. The greater IMC crystal growth rate inhibition by t-SUL than by c-SUL was consistent with the proposed orientation of SUL molecules adsorbed on the IMC crystal, providing a mechanistic understanding of the inhibition.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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