CHARACTERIZATION, THERMODYNAMIC PARAMETERS, MOLECULAR MODELING AND IN VIVO STUDIES OF INCLUSION COMPLEXES OF PYRIMETHAMINE WITH NATIVE β-CYCLODEXTRIN AND ITS DERIVATIVES
Renu Chadha, Sushma Gupta, Raghuvir R. S. Pissurlenkar, Evans C. Coutinho · 2012
Inclusion complexes of pyrimethamine with β-cyclodextrin (β-CD) and its derivatives (methyl and hydroxypropyl) were prepared with an aim to increase its solubility as well as to boost its antimalarial activity. Phase solubility studies and mass spectrometry indicated a 1:1 stoichiometry for pyrimethamine cyclodextrin (CD) complexes which were confirmed by solution calorimetry. Stability constant (K) and other thermodynamic parameters determined by solution calorimetry indicated that the inclusion of drug is exothermic process accompanied by negtive value of enthalpy (ΔH o) and small positive value of entropy (ΔS o). Molecular modelling calculations performed with Fast Rigid Exhaustive Docking acronym for drug cyclodextrins depicted the existance of two types of complexes differing slightly in energy of binding. The experimentally determined Gibb’s free energy (ΔG o) is found to be closer to complex-2 where chlorobenzene ring snugly fits into the cavity and is supported by 2D NMR. Efficiency of the encapsulated drug was evaluated by in vitro drug release and lyophilized complexes of pyrimethamine with M-β-CD found to be best. The in vivo studies were performed to predict the pharmacological activity and have shown significantly higher survival rate for β-CD (50%), M-β-CD (83.3%) and HP-β-CD (67.3%) complexes respectively as compared to the commercial drug (16.7%).