Excipients selection in multidrugformulations development : Solution behavior of structurally relatedcalcium channel blockers combined with indapamide
Abstract: The increased demand of formulations containing more than one drugrequire improved understanding of the solution evolving from suchsystems and the effect of included excipients on their solubilityand dissolution behaviors. In this study, the solution behavior of structurally related drugs(dihydropyridines) combined with indapamide was explored. Inaddition, the origin of solubility differences between the drugswas investigated by determining their solubility and thermalproperties. The concentration of the drugs from supersaturatedsolutions generated by antisolvent addition was measured in bufferand excipients. There were distinct differences between the physiochemicalproperties and solubility values of the dihydropyridines, explainedby the additive effect of their hydrophobicity and strength ofcrystal lattice. Indapamide’s solubility was decreased by the sameextent when combined with either of the dihydropyridines. Thedihydropyridines varied in their behavior. Nifedipine maintainedsame supersaturation level until the amount of indapamide addedexceeded 400 mikrogram/ml and then its solubility increased by 2-folds and was maintained. There was no change in the concentrationof felodipine until the amount of added indapamide exceeded itsamorphous solubility, where a decrease was seen in felodipine’ssolubility. There was a clear differential solubilization effect of felodipineand indapamide by the excipients. The cyclodextrins was used inindapamide and felodipine combination because the relativesolubility improvement of indapamide. The study demonstrates the complexity of the solution behavior ofmultidrug combinations. This doesn’t only involve drugs formulatedtogether in one formulation but could involve medicine formulatedwith various excipients and administrated at the same time.
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