Characterisation and thermodynamic stability of solvated crystal forms of mebendazole / Carel André Swartz
Swartz, Carel André
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Solid-state studies form an integral part in the research and development (R&D) of pharmaceuticals. The main objective of these studies is usually the preparation of a crystal form with improved solubility & thermodynamic stability, which will ultimately result in -enhanced therapeutic efficacy. The inclusion of specific solvent molecules into a crystal lattice may stabilise or destabilise the crystal structure (Byrn et aI., 1999:234). These alterations to the stability of the crystal structure may result in significant changes to the physico-chemical properties of the solid. This study focused on the ability of mebendazole to incorporate solvent molecules into its crystal lattice, and on the thermodynamic stability of these solvated systems. A novel pseudo-polymorphic form of mebendazole (Form D) was prepared by means of accelerated recrystallisation using acetic-acid as solvent. The same method was utilised (using propionic-acid as solvent) to prepare the mebendazole propionic acid complex (referred to as Form E) previously reported by Caira et al. (1998:11-15). The physico-chemical properties of the two solvated forms were investigated using DRIFT-IR, DSC, TGA, XRPD, VT-XRPD, KF, & SEM. The incorporation of the two different solvent molecules (i.e. acetic acid and propionic acid) into the crystal lattices, induced a significant difference in the dissolution profiles of the two forms in 0.1 N HCI at 3T°C (f2 = 16). The powder dissolution profiles of Form D indicated a 51% dissolution whereas Form E revealed a 97% dissolution after 120 minutes. The difference in the dissolution profiles was attributed to the fact that a fraction of Form 0 underwent a solvent mediated phase transition (in the dissolution medium) and was transformed to the poorly soluble Form A. The thermodynamic stability of Form D and Form E was investigated. When exposed to increased temperatures both forms desolvated and were transformed into the thermodynamically stable form, Form A. Non-isothermal studies revealed that more energy was required to initiate the desolvation of Form E, compared to the activation energy required for the desolvation of Form D. Based on this observation (and the VT-XRPD results) it was concluded that Form 0 was thermodynamically less stable compared to Form E. Isothermal studies revealed that the mechanism of desolvation for Form 0 and Form E was temperature dependant, and that the rate of desolvation for both forms were in the order: 100•C > 90°C > 80°C. Stability studies of mebendazole Forms 0 and E at: (1) 25±2 °C & 60±5 % RH, (2) 40±2 °C & 75±5 % RH, (3) 25±2 °C & 0 % RH and (4) 40±2 °C & 0 % RH for 28 days - revealed that the rate and mechanism of desolvation of the two forms were temperature dependant. The mechanism for the desolvation of Form 0, when exposed to 25±2°C & 60±5 % RH was best described by the second-order reaction (F2-mode/) and when exposed to 25±2°C & 0 % RH, by the Avrami-Erofeev reaction (A3/2-model). The rate of desolvation of Form 0 at 25±2°C & 60±5 % RH was 18 times faster compared to the desolvation of Form 0 at 25±2°C & 0 % RH. The shelf-life of Form 0 when stored at 25±2°C & 60±5 % RH was 2.6 times lower compared to when Form 0 was stored at 25±2°C & 0 % RH, suggesting that the presence of moisture facilitated the desolvation process. Oesolvation of Form E was detected when it was stored at 25±2°C & 60±5 % RH, 40±2°C & 0 % RH and 40±2°C & 75±5 % RH. The rate of desolvation was in the order: 40±2°C & 75±5 % RH> 25±2°C & 60±5 % RH > 40±2°C & 0 % RH, which once again suggested that moisture might have acted as a catalyst for the desolvation of Form E. The postulated mechanism for the desolvation of Form E when exposed to 25±2°C & 60±5 % RH was best described by the Avrami-Erofeev reaction (A3/2-model). No suitable desolvation mechanism was identified for the desolvation of Form E, when stored at 40±2°C & 75±5 % RH.
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