Sustained dissolution and pharmacokinetics of risperidone microsuspensions via cocrystallization with kaempferol

The present study aimed to prepare and evaluate a sustained-release microsuspension (MSP) of the antischizophrenic drug risperidone (RIS) via cocrystallization with kaempferol (KAE) (RIS-KAE-MSP). Cocrystal solvates of RIS and KAE in solvent systems of ethanol (EtOH), methanol (MeOH) and ethyl acetate (EA) were successfully prepared by solvent evaporation method. Cocrystal solvates prepared from 3 different solvent systems were characterized in detail using single-crystal X-ray diffraction (SCXRD), Hirshfeld surface analysis (HSA), Gas chromatography (GC), Karl Fischer titration (KFT), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Fourier transform infrared (FT-IR) spectroscopy. SCXRD successfully confirmed that RIS-KAE·0.4EtOH·2.6H₂O and RIS-KAE·MeOH are solvates. The dissolution rates of RIS from cocrystal solvates at pH 6.8 in 12 hours were 9.4-fold (RIS-KAE·0.4EtOH·2.6H₂O), 11.8-fold (RIS-KAE·MeOH) and 7.4-fold (RIS-KAE·EA·H₂O) lower than that of free RIS, showing significant sustained release behaviors. Furthermore, RIS-KAE·0.4EtOH·2.6H 2 O was prepared into microsuspensions (MSP), denoted as RIS-KAE-MSP, for I.M. injection. Pharmacokinetic (PK) results indicated that plasma RIS of RIS-KAE-MSP were still detectable by liquid chromatography-mass spectrometry (LC-MS) for as long as 45 days. In conclusion, cocrystallization with insoluble coformers is a promising strategy for long-term sustained release of RIS.