Thermal kinetics and crystal structure of dapsone polymorphs and solvates
Dapsone (DDS) is currently used in the treatment of leprosy and prophylaxis of opportunistic bacterial infections in immune-compromised patients. Despite the age of this drug; not much is known about the interrelationships between its polymorphs. Also, no previous polymorphic screening studies have been done to determine the probability of solvate formation when exposed to various solvents. Re-evaluation of DDS using modern techniques and equipment such as a variable temperature x-ray diffractometer (VTXRD) and modulated temperature differential scanning calorimeter (MTDSC) were crucial to clarify some aspects of DDS’s polymorphs that were published in the past. Recrystallisation of DDS from various neat solvents was done; the products that formed from recrystallisation included some habit modifications, a hydrate and three solvates. The solid-solid phase transition of DDS form III to form II was observed at ~82°C for most recrystallised products. Most of the recrystallised products melted at ~177.6°C which is the melting point of DDS form II. Some of the recrystallised products melted at ~179.5°C (DDS form I). DDS•(0.33)H2O has been described before by several research groups. A hydrate would be even less water soluble than the anhydrated DDS and was therefore not pursued further. DDS solvates have not been reported before in any literature. Solvates recrystallised from dichloromethane (DCM), 1,4-dioxane (DXN) and tetrahydrofuran (THF) in stoichiometric relationships of DDS•0.5(DCM), DDS•DXN and DDS•THF. The crystal structures of the solvates were elucidated using single-crystal X-ray diffraction. The results were deposited into the Cambridge structural database (CSD) for future reference regarding DDS. The desolvation of these solvates was extensively studied. The activation energy (Ea) and kinetic model that each solvate followed during desolvation was calculated by isothermal thermogravimetric analysis (TGA) and verified by micrographs obtained by using a thermal microscope (TM). The nucleation and growth model (A2) was statistically chosen to explain the desolvation process for DDS•0.5(DCM) although the involvement of the geometric contracting area (R2) model cannot be neglected. Model-fitting results for the desolvation of DDS•DXN and DDS•THF concluded that they respectively followed the A2 and R2-model; the micrographs confirmed these model-fitting results. The order of thermal stability between the solvates is as follows: DDS•0.5(DCM) >> DDS•THF > DDS•DXN. The calculated Ea values followed the opposite trend but unfortunately accurate assumptions about Ea may not be reliable since these three solvates are not isostructural. After desolvation of the solvates they completely converted back to the crystal structure of DDS form III at room temperature. A full polymorphic study was done. This knowledge is absolutely important for manufacturing, storage and use of DDS.
- Health Sciences