Influence of Ionization and the Addition of Cyclodextrins andHydrophilic Excipients on the Solubility of Benzthiazide,Isoxicam, and Piroxicam

Abstract

Background: The bioavailability of a drug depends, among other parameters,on solubility. One of the strategies used to enhance the solubility of sparingly solubledrugs is the use of excipients. Excipients can interact with the drug by increasing its solubilityand/or stabilizing supersaturated solutions. Some of the most common excipientsare cyclodextrins and hydrophilic polymers. Objectives: The effect of two cyclodextrins(captisol and cavasol) and three hydrophilic polymers (klucel, kollidon and plasdoneS630) on the solubility of three ionizable drugs (benzthiazide, isoxicam, and piroxicam) isevaluated at biorelevant pH values, using two complementary techniques. Methods: Thesolubility enhancement was evaluated by the comparison of the solubility with and withoutthe presence of excipients through the shake-flask and CheqSol methodology. Results:Captisol and cavasol slightly increase the concentration of the neutral species of the drugsin the solution before precipitation begins, although they do not enhance the supersaturationduration nor the thermodynamic solubility of the drugs. The increase in solubilityin the presence of cyclodextrins is mainly caused by the ionization state of the drug. Hydrophilicpolymers not only improve thermodynamic solubility but also the extent andthe duration of the supersaturation. Some metastable forms are observed for benzthiazideand isoxicam in the presence of kollidon and plasdone S630. Conclusions: The shake-flaskmethod enabled the evaluation of thermodynamic solubility both in the absence and presenceof excipients. Meanwhile, the CheqSol method provided insights into the presenceof supersaturated solutions. Different behavior is observed depending on the nature ofthe excipient.