Development of dual-drug resinates of dextromethorphan and diphenhydramine

Abstract

The aim of this work was to develop the dual-drug resinate containing equivalent content of dextromethorphan hydrobromide (DTM) and diphenhydramine hydrochloride (DPH). To obtain this specific resinate, a procedure of simultaneous dual-drug loading using loading solutions composed of different proportions of DTM and DPH was performed and a dual-drug loading diagram was constructed to determine the equivalent drug content (EQC) and also the equivalent drug loading solution (ELS). The effects including degree of resin crosskinkage, overall drug concentration of loading solutions, resin quantity, temperature during drug loading and resin size on the values of ELS and EQC were assessed and discussed. It was found that increasing overall drug concentration from 0.25 to 1.0% w/v elevated the EQC values from 18 to 35% w/w for 2 and 4% crosslinked resins, and from 18 to 27 % w/w for 8% crosslinked resin. It also changed the values of ELS from 0.50 to 0.48 for 2 and 4% crosslinked resins, while from 0.50 to 0.55 for 8% crosslinked resin. Increasing resin quantity during drug loading exerted opposite effects on the values of EQC and ELS when compared with and effect of increasing overall drug concentration For 8% crosslinked resin, an increase of loading temperatures from 35 to 65 degrees Celsius caused further increase of EQC values from 27 to 32% w/w but changed the values of ELS in the reverse direction from 0.55 to 0.48. The change of loading temperatures (35 to 55degrees Celsius) did not have significant effect on the values of EQC and ELS for 2 and 4 % crosslinked resins. Different particle size of 4% crosslinked resins had no effect on the values of EQC and ELS. The drug release from the resonates was performed in 0.05 to 0.4 N of KCI solutions and a simulated intestinal fluid. The resonates using 2 and 4% crosslinked resins provided rapid drug release; while, the resinate using 8% crosslinked resin gave considerably extended drug release. An increase in the total cation concentration generally accelerated the release of both drugs, except for 0.4 N KCI solution in which the drug release from the resinate of 8% crosslinked resin was slightly decreased. The release kinetic of both drugs from the resonates could be described by the particle diffusion controlled process. DSC and XRD analysis revealed that DTM and DPH were transformed from the crystalline to amorphous state. It indicated that both drugs mono-molecularly dispersed in the resinate. IR results confimed ionic interaction occurring between the opposite charges of loaded drugs and resin. In conclusion, the above finding demonstrated that the proposed method could be used to produce the equivalent content dual-drug resinate The dual-drug resinate using a suitable crosslinked resin could be applied for the concurrent delivery of two combined drugs which have the same therapeutic dose.