ao7b01454_si_002.cif (4.78 MB)
Role of Biorelevant Dissolution Media in the Selection of Optimal Salt Forms of Oral Drugs: Maximizing the Gastrointestinal Solubility and in Vitro Activity of the Antimicrobial Molecule, Clofazimine
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posted on 2017-12-14, 18:18 authored by Pauric Bannigan, Edel Durack, Conor Madden, Matteo Lusi, Sarah P. HudsonClofazimine is an antimycobacterial agent that
is routinely used for the treatment of leprosy. Clofazimine has also
been shown to have high clinical potential for the treatment of many
Gram-positive pathogens, including those that exhibit high levels
of antibiotic resistance in the medical community. The use of clofazimine
against these pathogens has largely been limited by the inherently
poor water solubility of the drug substance. In this work, the possibility
of repurposing and reformulating clofazimine to maximize its clinical
potential is investigated. To achieve this, the potential of novel
salt forms of clofazimine as supersaturating drug-delivery vehicles
to enhance the aqueous solubility and gastrointestinal solubility
of the drug substance was explored. The solution properties of seven
novel salt forms, identified during an initial screening process,
were examined in water and in a gastrointestinal-like media and were
compared and contrasted with those of the free base, clofazimine,
and the commercial formulation of the drug, Lamprene. The stability
of the most promising solid forms was tested, and their bioactivity
against Staphylococcus aureus was also
compared with that of the clofazimine free base and Lamprene. Salts
forms which showed superior stability as well as solubility and activity
to the commercial drug formulation were fully characterized using
a combination of spectroscopic techniques, including X-ray diffraction,
solid-state NMR, and Fourier transform infrared spectroscopy.