| Summary: | 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. === Thesis (PhD (Pharmaceutics))--North-West University, Potchefstroom Campus, 2013
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