Effect Of Drug-polymer Interactions On The Physical Stability And Supersaturation Of Amorphous Solid Disperisons

Amorphous solid dispersion(ASD)is a promising way to enhance the solubility,dissolution and bioavailability of poorly water soluble drugs.Carrier,the most important ingredient for an ASD plays an important role in the properties of ASDs.The purpose of this work is to investigate the effects of drug-polymer interactions on the physical stability and supersaturation of ASDs.Indomethacin(IDM)was used as a model compound and HPMC,HPMCAS and PVP were used as polymeric carriers.The IDM-polymer thin films were prepared using film casting method and the IDM ASDs were prepared using rotary evaporation method.The IDM-polymer miscibility was determined by DSC,fluorescence microscope,fluorescence and IR spectroscopy.The miscibility of IDM with HPMC,HPMCAS and PVP are 50%,30%and 80%respectively.The IR results showed that IDM interacted with HPMC and PVP by hydrogen bonding and the strength of hydrogen bonding between IDM and PVP was stronger than that between IDM and HPMC,indicating a good correlation between the drug-polymer miscibility and drug-polymer interactions.The spinodal curves of IDM-polymer were predicted by using Flory-Huggins theory,and the predicted results did not match with the experimental results,indicating that the drug-polymer interaction is a key factor for drug-polymer miscibility.To investigate the relationship between drug-polymer miscibility and the physical stability of corresponding ASD,the IDM-polymer films were prepared using film casting method and stored at 40℃ and dry conditions.IR and fluorescence microscope were performed on films at different time and the results showed that the physical stability decreased in the order of IDM-PVP<IDM-HPMC<IDM-HPMCAS,in agreement with the order of drug-polymer miscibility.The IDM ASDs were also prepared using rotary evaporation method and stored at 40℃ and dry conditions.PXRD were performed on samples at different time and the results showed that crystallization occurred rapidly for immiscible systems and miscible systems kept their amorphous state during the experimental time scale.A good correlation was found between drug-polymer miscibility and the physical stability of corresponding ASDs.The bulk crystal growth rate of IDM crystals grown from supercooled liquid were determined in the absence and presence a of polymers to investigate the mechanism of how polymers improving the physical stability of amorphous drug.The amorphous IDM were prepared using hot stage in the absence and presence of polymers,and stored at different temperatures,generating IDM crystals of δ,α and γ polymorphs.The growth rates of IDM crystals were determined using hot stage and polarized microscope.The results showed that the growth rates of IDM crystals were reduced significantly by polymers.PVP showed the best inhibitory effect on the growth rates of IDM crystals in the lower temperature range,followed by HPMC and HPMCAS,which agrees with the order of the IDM-polymer interactions.The possible mechanisms of polymer inhibiting the crystal growth are that polymers can reduce the migration of drug molecules in the supercooled liquid and decrease the thermodynamic driving force for crystal growth.The same polymer showed different inhibitory effects on the crystal growth of different IDM polymorphs.Polymers reduced the crystal growth of δ and a polymorph most in the lower and higher temperature range respectively,and showed the least effectively inhibitory effect on the crystal growth of γ polymorph in the whole temperature range.The effects of water on the drug-polymer miscibility and the physical stability of ASDs were investigated.IDM-polymer films were prepared using film casting method under different RHs and were determined using IR and fluorescence microscope.It was found that water can induce AAPS and weaken the drug-polymer interactions.Water was added to the organic solvent to prepared IDM ASDs using a rotary evaporation method.DSC and PXRD were performed on the samples and the results showed that water in the solvent can induce the AAPS and crystallization,reducing the physical stability of IDM ASDs.IDM films and ASDs were prepared at low RH and using organic solvent without additional water added respectively,and stored at 97%RH.IR,fluorescence microscope,DSC and PXRD were performed on samples and the results showed that water absorbed during storage can induce AAPS and crystallization of IDM ASDs.The ASD with a more hygroscopic polymer is more susceptible to water.The effects of polymer on the supersaturation of IDM were evaluated by determining the drug concentration as a function of time.Solution of IDM in methanol was added to pH 2.0 phosphate buffer using a syringe pump in the absence and presence of polymers.Polymers used were HPMC and PVP.The drug concentration was determined using a fiber UV/V is fiber-optic probes in situ and plotted vs.time.It was found that the nucleation induction time(NIT)and crystal growth rate of IDM in pH 2.0 phosphate buffer was 36 min and 0.0269 min-1 respectively under the conditions used in this experiment.HPMC and PVP had no influences on the NIT of IDM,but inhibit the production of IDM crystals effectively.IDM seed was added to the IDM supersaturation solution and the drug concentration was determined as a function of time.Results showed that nucleation induction process disappeared after the addition of IDM seed,but the production of IDM crystals were still inhibited effectively,indicating that HPMC and PVP inhibited the production of IDM crystals by reducing the crystal growth rate.Additionally,HPMC showed better inhibitory effects on the crystal growth of IDM than PVP.It was suggested that the mechanism of HPMC and PVP inhibiting the crystal growth of IDM is interface absorption.In this work,the effects of drug-polymer interactions on the drug-polymer miscibility,the physical stability and the supersaturation of IDM ASDs were investigated.The mechanisms of how polymers improving the physical stability and supersaturation of ASDs,and how the water destabilizing the ASDs were also discussed for better understanding the role of polymers in ASDs and reasonable formulation design for an ASD.