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

Abstract

Clofazimine 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.

Overcoming the Common Ion Effect for Weakly Basic Drugs: Inhibiting the Crystallization of Clofazimine Hydrochloride in Simulated Gastrointestinal Media

“…Preparation of clofazimine salts. CFZ salts were prepared by recrystallization of CFZ and coformer in a 1:1 molar ratio from methanol, as previously reported [11], [22].…”

“…In this study, solid forms of CFZ were expected to dissolve in the low pH gastric environment and then precipitate from solution as CFZ hydrochloride, through the common ion effect. CFZ hydrochloride does not dissolve to any detectable extent in the presence of chloride ions, even at pH values where other salt forms of CFZ display solubility [11]. Such solid-state transformations…”

“…Briefly these include; (i) solubilising strategies (such as formulation with cosolvents and/or surfactants as well as inclusion into lipid-based formulations) [4], (ii) partial size reduction strategies (such as top down or bottom up manufacture of nanoparticles) [5], [6] and (iii) supersaturating drug delivery systems (SDDS), such as amorphous solids, crystalline salts, cocrystals, etc. [7]- [11]. Along with concentration in the gastrointestinal system, good permeability is a requirement for adequate intestinal absorption.…”

“…The extent to which CFZ dissolves is pH dependent and can be calculated from experimentally derived solubility-pH studies [22]. Being weakly basic and ionisable, CFZ readily forms pharmaceutical salts with acidic coformers [11]. While CFZB exhibits very poor aqueous solubility, salt forms can increase solution concentration in water, and in biorelevant media [11].…”

“…Being weakly basic and ionisable, CFZ readily forms pharmaceutical salts with acidic coformers [11]. While CFZB exhibits very poor aqueous solubility, salt forms can increase solution concentration in water, and in biorelevant media [11].…”