Studies On The Synthesis Of Cinacalcet Hydrochloride,Its Tablets And Formulations

Cinacalcet hydrochloride is produced by NPS Pharmaceuticals US for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyroid carcinoma.We made a brief introduction of hyperparathyroidism and the drugs used in the clinic,the physical and chemical properties of the cinacalcet hydrochloride and the related information about the cinacalcet hydrochloride tablet.The pharmacodynamics,pharmacology,toxicology and clinical application of cinacalcet hydrochloride were summarized.According to the latest progresses in the synthesis of cinacalcet hydrochloride at home and abroad,the synthetic routes of cinacalcet hydrochloride were analyzed and a new synthetic method was designed.Cinacalcet hydrochloride was prepared from 3-(3-trifluoromethylphenyl)-1-propanol via three steps,including DMSO/P2O5 mediated oxidation,iron triflate catalyzed reductive amination of aldehydes using sodium borohydride,followed by the formation of hydrochloride salt.This new method is convenient and high efficiency and uses the environmentally benign reagents.By this novel method,cinacalcet hydrochloride was obtained in high purity both chemically and optically,that met the the requirements for chemicals in drug developments.The prescription process of cinacalcet hydrochloride tablets was studied.We investigated the compatibility of cinacalcet hydrochloride and excipients,and the influences of the excipients on the stability of cinacalcet hydrochloride.The results indicated that the excipients have no interaction with the drug,so the excipients are suitable for the use in the prescription.Through screening,the most suitable dosages of pregelatinized starch,microcrystalline cellulose,povidone K30,crospovidone,talc,magnesium stearate,and silica were determined.By comparison of the direct compression,dry granulation and wet granulation methods,the wet granulation was used for the cinacalcet hydrochloride tablet preparation.We also established a preliminary dissolution testing method.Through the dispersive medium selection and the tests on rotation speed,specificity,membrane adsorption,linearity and range,accuracy,and solution stability,we verified that the dissolution test method was suitable for the drug meaurements.This method features with simple operation,good specificity and reliably.In comparison with the reference drug,the in vitro dissolution curve showed that the self-made tablets have the similar dissolution behaviors at the conditions of 0.01 mol/L hydrochloric acid,pH 4.5 acetate buffer,pH 6.8 phosphate buffer and aqueous medium.Based on these results,an amplification test(scale up)was run,the tablet appearance,weight differences,content,dissolution,relevant substances and others of were examined.The results showed that the product met with its quality requirements.In the stability test,the tablets were packaged and put at the high temperature(60℃),high humidity(25℃,92.5%relative humidity),and light 4500Lx conditions,for 10 days.The result showed that the tablet appearance,dissolution,content,and the related substances ware not obviously changed,indicating the high stability of the packaged products under the rash conditions.Three batches were put in the six-month accelerated(40 ℃ and 75%relative humidity)and long-term(25℃ and 60%relative humidity)stability tests,all the product showed no significant changes on the tablet appearance,dissolution,content,and the relevant substances,and met with the drug quality requirements.Therefore,this tablet famulation and preparation process was feasible with good stability.Our data provided a good reference for the cinacalcet hydrochloride tablet production,packaging,storage,validity period,etc.