Investigation of amorphous solid-state forms of spiramycin and clarithromycin

Abstract

Recent studies have shown OIs remain a significant cause of approximately 90% of the morbidity and mortality in PLHIV even in the era of HAART. MAC and cryptosporidiosis are amongst the most prevalent and life threatening OIs among PLHIV. Treatment of these OIs has shown poor outcomes across the globe together with recurring infections. There is dire need to reduce the burden of OIs by optimising treatments. In order to accomplish this, solid-state properties of clarithromycin and spiramycin were investigated. The drugs are indispensable in treatment of MAC and cryptosporidiosis especially in PLHIV. However, they have shown to be poorly water soluble and the culprit could be their poor physico-chemical properties, making investigation of these properties paramount. No other solid state forms of both drugs that might improve the poor aqueous solubility have been reported. Thorough investigation and alteration of physico-chemical properties of clarithromycin and spiramycin were therefore considered a solution for improving aqueous solubility and subsequently bioavailability to achieve optimum treatment outcomes. Of late the use of ASDs has been employed to improve aqueous solubility and stability of poorly soluble drugs. The aim of the study was to prepare neat amorphous forms and ASDs of spiramycin and clarithromycin. HPLC method was developed and validated for identification and quantification of these drugs. Miscibility of clarithromycin and spiramycin in all available polymers was investigated for preparation of optimised ASDs. The quench cooling of the melt method was employed for preparation of CLAM and ASDs. Physical and chemical properties of spiramycin and clarithromycin raw materials, the prepared amorphous form of clarithromycin (CLAM), physical mixtures of the API with polymers (PMs) and prepared amorphous solid dispersions (ASDs) were investigated and reported on. The following characterisation techniques were used: DSC, FTIR, XRPD, SEM, HSM, vapour sorption analysis, equilibrium solubility and dissolution profiles of the macrolide antibiotics. CLAM was physically stable at room temperature and high moisture content. Overall, the dissolution rate of clarithromycin was improved by approximately 6.5 times by ASDs. This will have a positive impact on its aqueous solubility. It was concluded that ASDs successfully enabled better control over the solid-state chemistry of clarithromycin by maintaining the API in a stable amorphous state and enhancing dissolution / solubility which will ultimately lead to improved treatment outcomes. Results proved that spiramycin has a high dissolution rate (90%) due to its amorphous nature. ASDs improved dissolution rate of spiramycin to 100%. Although the 10% increase in dissolution might imply ASDs enhanced aqueous solubility of spiramycin to some extent, it was concluded that the poor treatment outcomes of spiramycin cannot be attributed to a slow dissolution rate. Future studies on spiramycin will be necessary to clarify the discrepancies between current literature sources and data on the successful treatment of cryptosporidiosis.