Study On Synthetic And Preparation Of Anti-cancer Drug Osimertinib

Osimertinib is a 3rd generation mutant selective epidermal growth factor receptor tyrosine kinase inhibitor researched and produced by Astra Zeneca.It ismainly suitable for patients with special EGFR gene mutations and have received Patients who have advanced to non-small cell cancer after treatment with other EGFR inhibitors.The poor dissolution effect of Osimertinib in water results in extremely low solubility and poor dissolution effect.In order to improve its solubility and dissolution rate,this article attempts to disperse Osimertinib ina hydrophilic polymer carrier to form a solid dispersion.(Solid dispersion,SD),to improve the solubility of Osimertinib,thereby improving is bioavailability.Poloxamer 188(F68),polyvinylpyrrolidone(PVPK30)and copovidone(co PVP)were used as carriers.Osimertinib solid dispersion was prepared by solvent method,melting method,and solvent melting method,and capsules were prepared based on the solid dispersion.The research contents of this article are as follows:1.Synthesis of Osimertinib:In this paper,the starting materials 4-fluoro-2-methoxy-5-nitroaniline and 3-(2-chloropyrimidin-4-yl)-1-methylindole were synthesized by substitution reaction under acid activation.The key intermediate is N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine,then the key intermediate is in palladium The reduction reaction,the subsequent acylation reaction,and the elimination reaction occur under the catalysis of carbon and hydrazine hydrate,and the target compound,Osimertinib,is finally synthesized.The product is a light yellow powder with a single yield of 78.12%.During the reaction,anhydrous ρ-toluenesulfonic acid was used as a catalyst to activate the chlorine at the 4th position of the pyrimidine ring,thereby increasing the cost of the experiment.Therefore,methanesulfonic acid,which is similar in acidity and relatively inexpensive,was used instead.The reduction effect of the reduction system used is not very well,so the reduction system of palladium carbon and hydrazine hydrate is selected,which greatly improves the reduction effect;the one-pot method is used to simplify the experimental operation and reduce the loss during post-treatment when synthesizing Osimertinib.By optimizing the reaction conditions,the reaction yield is improved and the reaction cost is reduced.2.Pre-formulation study of Osimertinib solid dispersions:The main content of this paper is to study the physical and chemical propertie s of Osimertinib and obtain the best preparation process for the preparation of Osi mertinib solid dispersion through experimental research.The ultraviolet-visible spectr ophotometry is established,which includes the determination of the dissolution medi um and the detection wavelength.Determine and draw the standard curve.3.Preparation of Osimertinib solid dispersionSelect the F68,PVPK30 and Co PVP as three carriers with good water solubility and no side effects on the human body as the carrier.Physical dispersion method,solvent method,melting method and solvent melting method are used to prepare solid dispersion body.The carrier type,material loading ratio,preparation method,preparation time and preparation temperature of the solid dispersion were studied,and the cumulative dissolution rate of the solid dispersion in the dissolution medium within 60 min was used as the evaluation criterion to obtain the best preparation of the solid dispersion Preparation process: When the load ratio of osimertinib to Co PVP is 1: 7,the solid dispersion prepared by reacting at 60 ℃ for 45 min has the best dissolution effect in vitro,and reaches the equilibrium of dissolution at 45 min.4.Quality evaluation of Osimertinib solid dispersion:Differential scanning calorimetry(DSC),X-ray diffraction(XRD),and scanning electron microscopy(SEM)were used to identify the phase of the prepared solid dispersion.The results showed that Osimertinib existed in crystalline form in the physical mixture,when Osimertinib existed in the amorphous state in the solid dispersion as a basis for improving the dissolution of the drug substance.This article also studies the stability of the solid dispersion.After completing a series of research experiments,the test results indicate that the stability of the solid dispersion will not be affected under high temperature conditions and strong light conditions.5.Preparation process and quality evaluation of Osimertinib solid dispersion capsules:In this paper,three factors were set through investigation and research,namely the proportion of filler,the ratio of disintegrant and the proportion of lubricant.Each factor needs to be set at three levels.The dissolution of the prepared capsule is used as the evaluation standard.Through the experiment,the influence levels of three factors can be obtained to adjust the prescription of the preparation of osimertinib capsules.The results of orthogonal experiments can be used to obtain the best prescription of osimertinib solid dispersion capsules.The optimized formulation process is as follows: the filler is microcrystalline cellulose,the disintegrant is sodium carboxymethyl starch,the lubricant is sodium lauryl sulfate,and the capsule is filled with powder directly.