Category: Formulation and Quality
Purpose: Approximately 60–70 % of APIs are estimated to be poorly soluble in aqueous media, hence leading to suboptimal bioavailability once administered. As a result, there is an urgent need to improve the properties of drugs currently on the market, commonly done through the formation of multicomponent complexes (MCCs). By synthesizing MCCs of an API with excipients, the physicochemical properties of the drug may be altered, such as aqueous solubility and bioavailability, without compromising on thermodynamic stability (1). Albendazole was chosen to be investigated in this work, as it is a BCS Class II drug which possesses functional groups able to participate in H-bonding. Albendazole has also recently been shown to have anti-cancer capabilities, however the insolubility of this drug is restricting potential use of its treatment at this time (2). As a result, it is of significant interest to improve the solubility and hence bioavailability of this drug.
Methods: Albendazole was complexed with maleic acid in differing mole fractions of albendazole (χ = 0.1 – 0.9) using mechanochemical techniques, including physical mixing, liquid-assisted grinding (LAG) and hot-melt extrusion (HME). The complexes thus formed were then analysed and characterized using PXRD, thermal analysis (DSC and TGA) and FT-IR spectroscopy. Dissolution testing (pH 1.2 solution over 2 h) was also carried out, to quantify the increased albendazole dissolution rate.
Results: The phase behaviour of albendazole (ABZ) and maleic acid (MA) was investigated, with a eutectic complex seen at a 1:2 ratio with a melt of 105.38±0.98 °C and a 1:1 salt was also observed, with a melting point of 148.16±0.58 °C. FT-IR spectroscopy showed a red-shift of the MA carbonyl peak in the 1:1 ratio from 1704 – 1661 cm-1, indicative of salt formation due to ionisation of the carboxylic acid group. In both ratios, the intramolecular H-bond between ABZ C=O and N-H is broken by the mechanical energy input, resulting in a red-shift of the ABZ C=O from 1712 – 1741 cm-1. In both ratios, the ABZ N-H carbamate band is red-shifted from 3320 – 3188 cm-1, another indication of H-bonding between ABZ and MA. Solubility studies were also carried out on both the 1:1 and 1:2 complexes, with each complex demonstrating a solubility enhancement of the pure drug. The ABZ-MA complex was also shown to increase ABZ solubility after extrusion within Eudragit® EPO, a polymeric carrier, in comparison to a dispersion of ABZ.
Conclusion: MCCs were formed between albendazole and maleic acid; a low-melting eutectic at a ratio of 1:2 and a salt at 1:1. Both of these complexes were shown to increase the solubility of BCS Class II drug albendazole. When dispersed in a polymeric matrix, both ABZ-MA complexes again showed an increased rate of dissolution when compared with a pure ABZ dispersion.