Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin.

Ciprofloxacin (CIP) is a poorly soluble drug that also displays poor permeability. Attempts to improve the solubility of this drug to date have largely focused on the formation of crystalline salts and metal complexes. The aim of this study was to prepare amorphous solid dispersions (ASDs) by ball milling CIP with various polymers. Following examination of their solid state characteristics and physical stability, the solubility advantage of these ASDs was studied, and their permeability was investigated via parallel artificial membrane permeability assay (PAMPA). Finally, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the ASDs were compared to those of CIP. It was discovered that acidic polymers, such as Eudragit L100, Eudragit L100-55, Carbopol, and HPMCAS, were necessary for the amorphization of CIP. In each case, the positively charged secondary amine of CIP was found to interact with carboxylate groups in the polymers, forming amorphous polymeric drug salts. Although the ASDs began to crystallize within days under accelerated stability conditions, they remained fully X-ray amorphous following exposure to 90% RH at 25 °C, and demonstrated higher than predicted glass transition temperatures. The solubility of CIP in water and simulated intestinal fluid was also increased by all of the ASDs studied. Unlike a number of other solubility enhancing formulations, the ASDs did not decrease the permeability of the drug. Similarly, no decrease in antibiotic efficacy was observed, and significant improvements in the MIC and MBC of CIP were obtained with ASDs containing HPMCAS-LG and HPMCAS-MG. Therefore, ASDs may be a viable alternative for formulating CIP with improved solubility, bioavailability, and antimicrobial activity.

Polymer/Amorphous Salt Solid Dispersions of Ciprofloxacin.

PURPOSE: To improve the pharmaceutical properties of amorphous ciprofloxacin (CIP) succinate salts via formulation as polymer/amorphous salt solid dispersions (ASSDs). METHODS: ASSDs consisting of an amorphous CIP/succinic acid 1:1 or 2:1 salt dispersed in PVP or Soluplus were produced by spray drying and ball milling. The solid state characteristics, miscibility, stability, solubility and passive transmembrane permeability of the ASSDs were then examined. RESULTS: The ASSDs had higher glass transition and crystallization temperatures than the corresponding amorphous succinate salts, and were also more stable during long-term stability studies. The results of inverse gas chromatography and thermal analysis indicated that the salts and polymers form a miscible mixture. The solubility of the pure drug in water and biorelevant media was significantly increased by all of the formulations. The permeability of the ASSDs did not differ significantly from that of the amorphous CIP succinate salts, however all samples were less permeable than the pure crystalline drug. CONCLUSIONS: The formulation of amorphous CIP succinate salts as ASSDs with polymer improved their long-term stability, but did not significantly affect their solubility or permeability.