Understanding the influence of stabiliser selection and concentration on the physical stability of dual-drug...

In the treatment of e.g. infectious diseases, administration of multiple drugs over extended periods is common. Long-acting injectables improve patient compliance, and combining multiple drug compounds into a single suspension may provide additional benefits. This study investigated the physical stability of dual-drug co-suspensions prepared by wet bead milling, with particular focus on stabiliser selection and concentration. In total, nine stabilisers were screened in combination with itraconazole and carbamazepine as individual suspensions and in co-suspensions, followed by evaluation of selected stabilisers using the cinnarizine-itraconazole system and concentration optimisation for the carbamazepine-itraconazole system. Physical stability was assessed by laser diffraction over 28 days of storage at 40°C. Poloxamer 338 generally provided the best performance for itraconazole-containing suspensions, whereas PVP K30 was most effective for carbamazepine, despite foaming challenges. The particle size of carbamazepine-itraconazole co-suspensions generally followed the trends observed for itraconazole suspensions, whereas the change in particle size during storage did not directly reflect either individual suspension. Interestingly, several co-suspensions produced smaller particles than the corresponding single-drug suspensions. Increasing stabiliser concentration either enhanced or reduced milling efficiency depending on the formulation, and the concentration providing the greatest particle size reduction did not consistently provide the optimal physical stability. These findings demonstrate that although particle size characteristics of co-suspensions may follow the trends observed for one corresponding single-drug suspension, their physical stability cannot be predicted solely from the individual suspensions.