Salification Controls the In-Vitro Release of Theophylline

Abstract

Sustained released formulation is the most used strategy to control the efficacy and the adverse reactions of an API (active pharmaceutical ingredient) with a narrow therapeutic index. In this work, we used a different way to tailor the solubility and diffusion of a drug. Salification of Theophylline with Squaric Acid was carried out to better control the absorption of Theophylline after administration. Salification proved to be a winning strategy decreasing the dissolution of the APIs up to 54% with respect to Theophylline. Most importantly, this was accomplished in the first 10 min of the dissolution process, which are the most important for the API administration. Two polymorphs were identified and fully characterized. Theophylline squarate was discovered as trihydrate (SC-XRD) and as a metastable anhydrous form. Indeed, during the Variable Temperature-XRPD experiment, the trihydrate form turned back into the two starting components after losing the three molecules of water. On the other hand, the synthesis of the trihydrate form was observed when a simple mixing of the two starting components were exposed to a high humidity relative percentage (90% RH).

Multicomponent Pharmaceutical Solids

“…Drugs with a narrow therapeutic index, such as theophylline, are better administered with sustained-release formulations, which reduce the likelihood of adverse reactions. L. Marchiò et al [8] address the optimization of theophylline pharmacokinetics by using the salification strategy. The authors successfully decreased the dissolution rate of the API, which might allow better control of drug release into the bloodstream, therefore reducing adverse effects without losing drug efficacy.…”