Study On The Synthesis And Quality Of Paliperidone Palmitate

Paliperidone palmitate long-acting suspension is a treatment drug for schizophrenia that is injected once a month.In this paper,the preparation technology of paliperidone palmitate was studied,and a method for quality analysis of paliperidone palmitate was established,The stability of PP ester was investigated.The chemical dosing ratio was paliperidone:palmitic acid=1:1.36(mole ratio,the same below);paliperidone:EDCI=1:2.05,and 1:0.128 for DMAP.The purity of PP ester is about 99.6%and the yield is about 80%.The structure of paliperidone palmitate was confirmed by IR,NMR,HPLC and MS spectrometry respectively.The crystal form of the PP ester were analyzed by differential scanning calorimetry(DSC)and X-ray diffraction(XRD).Impurities were determined by LC-MS.The key processes of extraction,beating and recrystallization were optimized and the optimum conditions were selected.The main impurity nitrogen oxide content in PP ester was reduced.The melting point of PP ester was 114℃～117℃,water content was 0.1%～0.15%.and optical rotation was-0.003°～0.003°.Three batches of small-scale repeated tests were conducted to determine the reliability of the process.The purity of PP ester was about 99.80%,which met the standard requirements of PP ester.The amplification tests of PP ester were carried out at 8,15 and30 times.The purity of the three batches of esters is 99.82%,which shows that the process is stable and the product quality is reliable.HPLC determination of PP ester impurities was verified.The separation degree of 3impurities were greater than 2.5;the linear range of 3 impurities were 18.4～824μg/ml(R~2≥0.995);RSD of precision,stability and reproducibility tests were0.42%～5.81%;recoveries were 91.26%～103.10%,RSD value is 1.56%～3.56%,(n=9).A GC method for determination of residual solvent was established.The results of stability test show that PP ester has good storage stability.