Study On Preparation And Physicochemical Properties Of Co-amorphous Clofazimine-organic Acids Systems

Clofaczimine(CFZ),a red crystal,has been used as a first-line drug against anti-leprosy in clinical practice for several decades,but its lipid solubility is large,resulting in significant side effects of skin pigmentation,and patients'compliance is poor.Obviously,it is of great clinical significance to increase the solubility of CFZ,reduce the lipid solubility,and thereby reduce the side effects of skin pigmentation.This study aims at the clinical deficiency of CFZ,and is to overcome the side effects of skin pigmentation,through the preparation of co-amorphous CFZ-organic acid systems,while retaining the efficacy of CFZ,which is also an effective and fast way of new drug development.CFZ is a Biopharmaceutics Classification System(BCS)class II drug and virtually insoluble in water.In this study,the solution and dissolution rate of CFZ are improved by co-amorphous technology.Choose 2,3-dihydroxybenzoic acid(2,3-HDBA)2,4-dihydroxybenzoic acid(2,4-HDBA),2,5-dihydroxybenzoic acid(2,5-HDBA),2,6-dihydroxybenzoic acid(2,6-HDBA),3-dihydroxybenzoic acid(3-HDBA)and4-aminobenzoic acid(4-AMBA)as conformer,repectively and six co-amorphous CFZ-organic acid systems were prepared by solvent assisted grinding method.The X-ray powder diffraction(XRPD)proved that six co-amorphous CFZ-organic acid systems are amorphous and homogeneous.The differential scanning calorimetry(DSC)was used to observe the glass transition temperature(T_g)of six different co-amorphous CFZ-organic acid systems,and compared with the amorphous CFZ respectively.The fourier transform infrared spectrometer(FTIR)was used to analyze intermolecular interactions between CFZ and each organic acid in every co-amorphous CFZ-organic acid system.The solubility of the six co-amorphous CFZ-organic acid systems in water,60%ethanol solution and 1%sodium dodecyl sulfate solution increased significantly by 3-60 times.In addition,the six co-amorphous CFZ-organic acid systems has significantly improved the dissolution rate in60%ethanol solution and 1%sodium dodecyl sulfate solution.The co-amorphous CFZ-organic acid samples(except co-amorphous CFZ-2,6-HDBA)remain in the amorphous state for over 90 days at 25°C and 60%RH,while the amorphous CFZ has poor stability.Therefore,the co-amorphous CFZ-organic acid systems with good stability can effectively improve the solubility and dissolution rate of CFZ.Among them,the solubility of co-amorphous CFZ-4-AMBA increased nearly 60 times,showing a potential application prospect,which is worth further study.