| Research objectives:Aprepitant is the first brain neurokinin-1（NK-1）receptor antagonist used for nausea and vomiting（CINV）after tumor chemotherapy,belonging to classⅣdrug BCS,which has problems of low solubility and poor permeability,thus leading to low bioavailability of this drug in human,which restricts the clinical use of oral preparation of this product.Drug eutectic is a new crystal obtained by combining active ingredient with another medicinal ligand through a specific method by hydrogen bonding.In recent years,it has attracted more and more attention in the field of drug modification.This technology can increase the apparent solubility and dissolution rate of drugs within a certain time without changing the drug structure or adding a variety of other excipients,which is conducive to improving the oral bioavailability of insoluble drugs.In this paper,aprepitant eutectic was prepared by solvent evaporation method,and its pharmaceutical properties were preliminarily investigated,which provided research ideas for the development of new oral preparations of aprepitant in the later stage.Method:1.Physicochemical properties of aprepitant APIThe observation method was used to investigate the apparent properties and microscopic morphology of aprepitant,and the apparent solubility of aprepitant at different temperatures and in different media was investigated by saturation solubility determination;the stability of the API under high temperature and high humidity light was investigated by the influence factor experiment.The basic physicochemical properties and stability of the API were evaluated to establish the basis for the subsequent preparation of aprepitant eutectic.2.Preparation of aprepitant drug co-crystalsBy COSMO-Logical simulation,the ligands of the eutectic were initially screened by using excess enthalpy as the judging index;the apparent solubility was used as the evaluation index to determine the eutectic ligands by fixing the preparation process,and the preparation method of the eutectic was also investigated;the solvent types and ratios of the ligands were investigated by single-factor experimental method to determine the optimal ligands;the apparent solubility was used as the investigation index,and the preparation process of the eutectic was investigated on the basis of single-factor On the basis of the experimental study,the preparation process of solvent volatilization method was investigated,and the process factors such as sonication time,sonication temperature and saturation time were further optimized by the star point response surface method,and the optimal preparation process was obtained and verified by experiments.3.Characterization of aprepitant eutecticThe physical morphology of aprepitant eutectic was observed by scanning electron microscopy（SEM）;the formation of aprepitant eutectic was initially determined by the change of characteristic peaks in powder X-ray diffraction（PXRD）;the formation of aprepitant eutectic was further confirmed by evaluating the thermal properties of aprepitant eutectic and the change and migration of peak positions using scanning differential calorimetry（DSC）and Fourier transform infrared spectroscopy（FTIR）.4.Preliminary quality evaluation of aprepitant eutecticThe dynamic solubility curves of the API and eutectic samples were compared over a certain period of time,and the increase in apparent solubility of the eutectic samples was determined;the changes in the appearance,microstructure and dynamic solubility of the eutectic samples under high temperature,high humidity and light conditions were investigated by the influence factor experiments;the in vivo intestinal experiments in rats were used to compare the degree and rate of absorption of the eutectic and the API in rats.Results:1.API physical property studyArepitant is white crystals at room temperature,the form is flaky under the microscope;Arepitant in p H 1.0～8.0 buffer solution,are"almost insoluble",in the solvent p H lower than 2.0,solubility with the decrease in p H has increased significantly;when the solvent p H is higher than 2.0,solubility remains basically the same;temperature The solubility increased with the increase of temperature;the appearance,microstructure and dynamic solubility of aprepitant did not change significantly under the conditions of high temperature and high humidity and light.2.Preparation of aprepitant drug eutecticOn the basis of software simulation,tyrosine was identified as the eutectic ligand of aprepitant by experiment;the solvent volatilization method was used,with ethanol as the solvent and the ratio of aprepitant:tyrosine 1:2.5;the preparation process was:sonication time 65.59 min,sonication temperature:40.18℃,saturation time 71.83 h.3.Physical characterization of aprepitant eutecticSEM results showed that the prepared samples had changed microscopic morphology compared to the API;PXRD results showed the appearance of new characteristic peaks at 31.30°,36.93°and 71.35°,and the disappearance of the characteristic peaks at 20.28°and 24.06°in the original aprepitant,indicating the formation of new objects;DSC analysis showed a decrease in the melting temperature of the samples,indicating a change in the thermodynamic properties The FTIR results showed that the peaks of aprepitant at 3435 cm-1 and tyrosine at 2080 cm-1 were shifted to the lower wave numbers of 3423 cm-1 and 2071 cm-1 in the eutectic,indicating that the formation of aprepitant eutectic may be due to the formation of hydrogen bonds by the corresponding groups.4.Preliminary quality evaluation of aprepitant eutecticThe results of dynamic solubility test showed that the apparent solubility of the prepared aprepitant eutectic reached the highest level at 15 min,which was about 35times higher than that of the API;the appearance,microstructure and dynamic solubility of the eutectic did not change significantly under the conditions of high temperature and high humidity and light;the absorption rate constant of the prepared eutectic in rats was about 2.6 times higher than that of the API,and the effective permeation rate was 3.0times higher than that of the API.Conclusion:In this experiment,we obtained the aprepitant drug co-crystals with improved apparent solubility,improved in vivo absorption and good stability by the solvent volatilization method,which is safe and easy to obtain,and the preparation process is simple and reproducible. |
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