Comparative kinetic study and tracking of some drug-excipient incompatibility reactions at liquid and solid state model systems using physicochemical methods

Abstract

Background: In a pharmaceutical dosage form several other components may accompany the active pharmaceutical ingredient (API). These components are named excipients and are defined as inert additives which may have different roles such as optimizing the manufacturing process, increasing the efficiency, facilitating the administration, controlling the drug release and finally increasing the product stability or protecting it from environmental conditions. Sometimes unwanted drug-excipients interactions may alter the stability, bioavailability, therapeutic effect, efficacy and safety of a dosage form. Thus selecting suitable excipients is a challenging issue in the preformulation studies.

Aim: In this research, comparative kinetic study and tracking of some drug-excipient incompatibility reactions at liquid and solid state model systems have been performed using simple and sophisticated physicochemical methods.

Materials and Methods: Different amine containing drugs (Type 1, 2 and 3) were selected and subjected to the study (doxepin, sertraline and flovoxamine). FTIR, DSC, HPLC and Mass spectrometery were used to track the potential incompatibility of the selected drugs with reducing carbohydrates (lactose monohydrate, anhydrous lactose, sucrose and dextrose). The Maillard reaction products in the mixtures were successfully identified using mass spectroscopy method. Kinetic evaluations of Hydrochlorothiazide were based on isothermal and non-isothermal methods. Isothermally stressed samples were subsequently analyzed with HPLC and the obtained data were fitted to Arrhenius equation. Non-isothermally derived data were fitted to isoconversional equations named Flynn–Wall–Ozawa (FWO), Freidman and Kissinger–Akahira–Sunose(KAS).Kinetic parameters of alprazolam-lactose mixture calculated using American Standard Test Method (ASTM) and Starink methods.

Results: The average activation energies obtained for fluvoxamin (FLM)-lactose, SER-lactose and doxepin(DOX)-lactose, were equal to 351.50, 265.45and 288.88kJmol-1 respectively. Calculated activation energies for Hydrochlorothiazide-lactose solid state mixture using non-isothermal and isothermal methods showed a good agreement (P value>0.05). Findings revealed that a basic condition favors the Maillard reaction progress in the studied samples. Thermal evaluation of alprazolam (ALP)-lactose mixture showed that mentioned mixture possesses a high thermal stability. Conclusion: According to our results the incompatibility of doxepin-lactose, doxepin-dextrose, doxepine-sucrose, sertraline-lactose, sertraline-dextrose and flovoxamine-lactose were successfully detected. The highest and lowest activation energies derived from non-isothermal DSC studies were assigned to sertraline-dextrose and flovoxamine-lactose, respectively. The observed difference can be attributed to the nucleophilic potency of the amine functional group inside the drug molecules which can be explained using the pKa values.