Synthesis And Quality Inspection Of A New Type Of Pharmaceutical Excipient-anion Exchange Resin And Its Application Of Pantoprazole Sodium Liquid Delayed Release Suspension

With the increasing application of ion exchange technology in the field of medicine,the demand of pharmaceutical grade ion exchange resin is increasing gradually.The purpose of this paper is to synthesize a new type of pharmaceutical excipient-anion exchange resin（cholestyramine）.Although the product has been marketed abroad,it is expensive to import.In order to narrow the gap between China and foreign countries and reduce the cost,the anion exchange resin was synthesized by suspension polymerization,chloromethylation and quaternization and refer to foreign pharmacopoeia for quality inspection.On this basis,with pantoprazole sodium（PAZ-Na）as model drug and self-made exchange resin as the drug carrier,the delayed release suspension of PAZ-Na drug resin was prepared by ion exchange and fluidized bed coating technology to improve the applicability of the model drug.The main conclusions are as follows:1.PS-DVB microspheres were synthesized by suspension polymerization,and the reaction conditions were optimized.The morphology and functional group structure of the products were characterized by SEM and FTIR.Under suitable reaction conditions,the products were uniform spherical with an average particle size of about 190μm;The PS-DVB microspheres were chloromethylated with methanol,formaldehyde and chlorosulfonic acid.The microspheres were analyzed by FTIR,Moir method and SEM,and the chlorine content of microspheres was determined by Mohr method.The results showed that PS-DVB microspheres could be successfully chloromethylated under appropriate reaction conditions,and the chlorine content reached 14.67%and the morphology of microspheres did not change significantly after the reaction;Trimethylamine was selected as quaternization reagent to modify chloromethylated microspheres with functional groups,and the products were characterized by FTIR and SEM.The results showed that the anion exchange resin microspheres were successfully prepared under appropriate reaction conditions.The quality of dialysable quaternary ammonium and exchange capacity,etc were studied according to the USP,the results were basically consistent with the imported resin.2.PAZ-Na drug resin was prepared by bath method,the optimal preparation method was determined as follows:Under 37.0℃±0.5℃temperature conditions,400mg PAZ-Na was accurately weighed and added into 100 m L Na OH solution with p H=9,and 400mg resin was added and stirred at constant temperature for 2 hours.The drug loading（Q_∞）of PAZ-Na resin was 0.93mg/mg and the drug utilization（E）rate was 93.57%.In this paper,SEM was used to observe the morphology of resin before and after drug loading.The results showed that the morphology of resin before and after drug loading was basically the same,and there was no drug particle adhesion on the surface of resin.Subsequently,the physical mixture of PAZ-Na and resin,drug-loaded resin,drug,resin was tested by XRD.The results showed that PAZ-Na was not simple physical adsorption but was bound to the resin by ion exchange reaction.In this paper,the determination method of drug release in vitro was determined as follows:at 37.0℃±0.5℃,drug resin was added into 900 m L 0.15 mol/L Na Cl solution and stirred at 100 r/min.3.In this paper,fluidized bed coating method was used,and enteric-soluble film coating premix was selected as the coating material.The fluidized bed coating process and coating prescription were applied as follows:the air inlet volume is 40 m³/h,the air inlet temperature is 35℃,the spray rate is 2 m L/min;the solid content of the coating liquid is controlled to 15%and continue coating until the weight of microcapsule coating film increased by 30%.Based on the previous research of the group,the suspending agents was selected with sedimentation volume ratio and redispersibility as indicators,and the optimal preparation process was determined with related patents.The drug content,in vitro release and drug leakage of the self-made suspension were investigated and results showed that the self-made suspension had uniform content,low drug leakage and the release of self-made suspension was good in vitro.4.In this part,the HPLC analysis method of PAZ-Na in SD rats was established,and the methodological results were verified to meet the requirements of pharmacokinetic study in vivo.Rats were given ordinary PAZ-Na enteric-coated micro-pill capsules and PAZ-Na delayed release suspension by intragastric administration respectively.Compared with PAZ-Na enteric-coated micro-pill capsules,the C_maxand T_maxof PAZ-Na delayed release suspension were lower and longer,the concentration curve was smoother and had certain delayed release effect;there were significant differences in pharmacokinetic parameters between the two formulations.The results showed that compared with PAZ-Na enteric-coated micro-pill capsules,the T_maxof the PAZ-Na delayed release suspension was extended from 2 hours to 4 hours,and the C_maxwas decreased from 6.162μg/m L to 3.244μg/m L.It indicated that the PAZ-Na delayed release suspension could effectively reduce the blood drug concentration.The AUC_0-24of self-made PAZ-Na delayed release suspension was 19.578μg·h·m L^-1and The AUC_0-24of commercial PAZ-Na enteric-coated micro-pill capsules was 17.388μg·h·m L^-1.The relative bioavailability of the two formulations was 112.67%,which meant the results met the principle of formulation design.Therefore,the two formulations were bioequivalent.