Establishment,Characterization And Stability Investigation Of Voriconazole Complex System Based On Micellization Thermodynics

Purpose:Voriconazole,as a clinical first-line drug for the treatment of deep fungal infections,has a broad antibacterial spectrum and strong antibacterial activity,but its solubility is poor.Most of the currently marketed voriconazole injections useβ-cyclodextrin derivatives as solubilizers to improve the water solubility of voriconazole.However,due to the nephrotoxicity and hemolysis caused by a large dosage of cyclodextrin,its clinical application is limited.Therefore,it is necessary to introduce new technology to reduce side effects and improve drug safety.The research group has reduced the content of cyclodextrin in voriconazole formulation through relevant researches,but it also brings the problem of poor stability of the formulation.This study hopes to adopt a micelle/cyclodextrin complex solubilization method to solve the problem of high cyclodextrin content and poor formulation stability in voriconazole.The micellization thermodynamics method can quickly evaluate the solubilization effect of micellar solution and the thermodynamic stability of the system.Therefore,based on the theory of micellization thermodynamics,this thesis explores the interaction and stability differences between nonionic surfactants andβ-cyclodextrin derivatives,and constructs a voriconazole complex system.Through the establishment of the system,degradation kinetics of voriconazole,process optimization and stability investigation,it is expected to obtain a voriconazole complex system with good water solubility,favorable stability and low nephrotoxicity,and provide an effective reference for further clinical research and industrialization development.Methods:1.Establishment of voriconazole complex system and preparation of freeze-dried agentAt first,this research determined the micellization thermodynamic method for evaluating the stability of the system.Based on this method,the system was screened and the formulation of freeze-dried agent was determined.The micelle/cyclodextrin system can reduce the dosage of cyclodextrin and improve the drug solubility.Therefore,in this thesis,the interaction between surfactant and cyclodextrin was studied and analyzed in detail by micellization thermodynamics method,and the best combination of surfactant and cyclodextrin was determined.The ratio of surfactant/cyclodextrin and the ratio of voriconazole/(surfactant+cyclodextrin)were selected in turn.First,the surface tension of different systems was measured to obtain the critical micelle concentration(CMC),and then the interfacial parameters and thermodynamic parameters of the solution were calculated to judge the stability difference of different systems,and the voriconazole-micelle-cyclodextrin complex system was established.In order to further studying the factors that affect the thermodynamic stability of the solution,the effects of different additives on the thermodynamic stability of voriconazole micellar solution were investigated,in expectation of hoping to find the additives that can improve the stability of the solution.Because the freeze-drying technology can quickly remove the water in the solution and improve the stability of the preparation,the eutectic point temperature and the amount of excipients were screened to obtain a voriconazole complexs freeze-dried system.2.Study on the degradation kinetics and impurity control of voriconazole complex systemThe degradation of the drug and the formation of impurities are the main reason that affects the stability of the drug preparation.The factors that affect the degradation of the drug include temperature and pH.This thesis designd different temperature and pH conditions,investigated the degradation of voriconazole and the formation of impurity I(defluorofvoriconazole).This research analyzed the degradation law of voriconazole and the formation law of impurity I in this sample from the perspective of degradation kinetics,and used Arrhenius equation to predict the shelf life of this sample.According to the characteristics of the preparation,the pH regulator and stabilizer were screened to achieve the purpose of controlling impurities and improving the stability of the complex system.3.Process optimization and characterization of voriconazole complex systemThis research determined the main process conditions that affect the quality of the preparation,and preliminarily judged the main influence range through single factor experiments.This research used the central composite design response surface to design the three-factor experiment of stirring time,stirring temperature and stirring speed.This research optimized the preparation process of voriconazole complex system with encapsulation efficiency,drug loading and Gibbs free energy(ΔG_m)as judgment indicators.Differential scanning calorimetry(DSC),fourier transform infrared spectroscopy(FTIR)and dynamic light scattering(DLS)were used to determine the voriconazole complex system.4.Study on the stability of voriconazole complex systemBased on the fact that the system is a freeze-dried agent,in order to achieve clinically safe medication,its compatibility stability was investigated.This research used particle size,CMC,pH,light transmittance and insoluble particles as indicators to evaluates the compatible stability of voriconazole complex system with several commonly used clinical solvents.In order to evaluate the stability of the optimized preparation,the sensitivity of voriconazole complex system to environmental factors was assessed by high temperature,high humidity and strong light irradiation tests with appearance,solution clarity,pH and impurity as the main detection indexes.The storage stability of voriconazole complex system was evaluated through accelerated and long-term tests,and provide a basis for determining the storage conditions of the preparations.Results:1.This paper determined that the micelle/cyclodextrin drug delivery system was composed of HS15 and SBE-β-CD,and the optimal ratio of the two components was 3:2.The optimal ration of voriconazole to solubilizer was 1:20.The experimental results of additives showed that glucose and sodium chloride can effectively improve the thermodynamic stability of the system.This paper determined the dosage of mannitol in voriconazole freee-dried system to be 60 mg/mL.The freeze-drying process route was that the pre-freezing temperature was-40℃,the vacuum degree during sublimation drying was less than 10 Pa,the sublimation temperature was-20℃,the analytical drying temperature was 25℃and the drying time was 3 h.2.The degradation kinetics of voriconazole in complex system showed that the degradation rate of voriconazole gradually increased with temperature.When the temperature increased from 30℃to 40℃,the degradation rate of the drug increased by25.2 times,and the formation rate of impurity I increased by 16.1 times,which showed that the preparation was extremely sensitive to temperature,and high temperature was not conducive to storage of the preparation.With the increase of pH,the degradation rate of voriconazole increased.When the pH of the solution increased from pH 3 to pH 7,the drug degradation rate increased by 3.1 times,and the rate of impurity I generation increased by 1.8 times.It can be seen that the preparation is also sensitive to pH environment and it is more stable at lower pH.In addition,the screening results of pH regulators showed that phosphoric acid had a better effect on controlling impurities,and the effect wad best when pH is four.When the glucose wad added at a dosage of 20mg/mL,it can best inhibit the formation of impurities.3.The results of DSC and FTIR analysis showed that voriconazole molecules were amorphous and encapsulated in the complex system consisting of HS15 and SBE-β-CD.The particle size of the sample was(15.88±0.700)nm and the polydispersity coefficient was(0.207±0.008)by DLS determination,indicating that the preparation had a small particle size,uniform distribution and narrow distribution range.4.The best compatible solution of voriconazole complex system was 0.45%NaCl injection.It was found that temperature,humidity and light all have effects on voriconazole complex system,among which temperature had the greatest effect.Through long-term and accelerated tests,it was found that voriconazole complex system can be stored stably for six months at room temperature.Conclusion:In view of the low solubility and poor stability of voriconazole,the solubilization ability and the thermodynamic behavior of surfactant/cyclodextrin micellar solution are studied by making full use of the unique advantages of the micellization thermodynamics method.The changes of thermodynamics properties in the process of stability change are revealed.While skillfully combining freeze-drying technology,the degradation kinetics study,formulation and preparation process optimization of voriconazole are carried out to obtain voriconazole complex system.The stability of the system is investigated,and the results show that the system has a good water solubility and stability.Finally,a new voriconazole complex system with good physical and chemical properties,a good market application prospect is successfully established by thermodynamics theory.