A Preliminary Study On The Solid-liquid Phase Equilibrium Of Flunarizine Hydrochloride And Its Intermediates And The Preparation Process Of Orally Disintegrating Tablets

1 Objective of this thesisFlunarizine hydrochloride is the only piperazine calcium antagonist that can penetrate the blood-brain barrier and has a good effect on the treatment of cardiovascular and cerebrovascular diseases.4,4'-Difluorobenzophenone is the key intermediate in its optimal synthesis route,and it is also an important raw material for the synthesis of medicines and special materials.It needs to be purified and increased after crystallization to remove impurities.Solubility is the basic basis of the crystallization process.Relevant researchers have not done comprehensive research reports on the solubility of the two solutes.In addition,it is necessary to obtain the solubility data before the formulation study.The value will affect the dissolution of the drug.Orally disintegrating tablets have a significant effect on the dissolution rate of poorly soluble drugs.It can accelerate the dissolution of poorly soluble drugs,flunarizine hydrochloride,improve bioavailability,enhance curative effect and improve patient compliance with medication.Therefore,the study of solid-liquid equilibrium provides guidance for the purification of Chinese patent medicines and intermediates in the synthesis chain,the selection of solvents and temperature and other conditions.It is of great significance to improve the purity and yield in the crystallization process,and also provides reference for the research and improvement of pharmaceutical dosage forms.This subject has carried out a preliminary study on the solid-liquid equilibrium of flunarizine hydrochloride and its intermediates and the preparation process of flunarizine hydrochloride orally disintegrating tablets.2 Experimental methods(1)The caffeic acid-ethanol system was selected as the reference material,measuring the solubility of caffeic acid in ethanol at different temperatures by the gravimetric method,and the experimental device for the determination was verified according to the relative deviation(RD)between the measured solubility value and the literature value and the reliability of the experimental method.(2)Taking flunarizine hydrochloride and 4,4'-difluorobenzophenone as the research objects,differential scanning calorimetry(DSC)characterization test read melting point(T_m)and melting enthalpy(?_fusH)data;adopting X-ray diffraction(XRD)to characterize the molecular structure of the two target solutes before and after dissolution.(3)In the range of 293.15K?333.15K,the gravimetric method was used to determine the molar solubility of flunarizine hydrochloride and 4,4'-difluorobenzophenone in ten pure solvents and ethanol+ n-propanol(w=0.1?0.9)mixed solvent and drew the solubility curve to analyze the solubility;discussed the influence of Hansen solubility parameter(HSP)and solvent properties on solubility.(4)Analyzing the dissolution thermodynamics of two target solutes,and using the Van't Hoff equation to calculate the enthalpy of dissolution(?H_d),dissolution entropy(?S_d)and dissolution Gibbs free energy(?G_d),relative enthalpy contribution(%?_H)and relative entropy contribution(%?_TS)equal dissolution thermodynamic data to judge the driving force of the dissolution process.(5)Six thermodynamic models,including Apelblat,Van't Hoff,?h,NRTL,Wilson,and UNIQUAC were used to correlate the solubility of flunarizine hydrochloride and 4,4'-difluorobenzophenone in pure solvents.Apelblat,Van't Hoff,?h,NRTL,Wilson,Jouyban-Acree model,the modified Jouyban-Acree model were used to correlate their solubility in mixed solvents;calculating experimental values the average relative deviation(RAD)of the associated value with the model were used to evaluate the best correlation fitting and solubility prediction model of the two solutes.(6)Based on the solid-liquid equilibrium data,flunarizine hydrochloride orally disintegrating tablets were developed by direct compression.Determining the various powder properties of the excipients and screening the disintegrants to select the best excipients for direct compression,establishing the method to determine the disintegration time limit;Single factor and orthogonal experiment were used to select the best prescription for mixed excipients.The suitability and tolerance of crystals were investigated;and the dissolution evaluation of self-made flunarizine hydrochloride orally disintegrating tablets and commercial capsules from three manufacturers was carried out.3 Experimental results(1)The relative deviation between the experimental value of caffeic acid solubility in ethanol and the literature value was less than 2%,indicating that the experimental device and method were reliable and the data measured by gravimetric analysis was accurate and reliable.(2)DSC analysis showed that the melting points were 209.17? and 108.83?,respectively,and the melting enthalpies were 34.15kJ·mol^-1 and 18.08kJ·mol^-1,respectively.The XRD patterns of the two solutes showed that the peak positions were corresponding and it can be judged that the solute was the same substance before and after dissolution.(3)The solubility of flunarizine hydrochloride in pure solvent and mixed solvent both increased with the increase of temperature.The order of solubility was:methanol>ethanol>n-propanol>acetone>isopropanol>acetonitrile>n-butanol>isobutanol>ethyl acetate>methyl acetate.The solubility in mixed solvents increased with the increase of ethanol mass fraction.The influence of HSP on solubility:for pure solvents(except acetone and acetonitrile),the solubility increased with the ?_P and ?_H;for mixed solvents,? increased with the ethanol content.The influence of solvent properties:the solubility in solvents was determined by the tendency of hydrogen bond donors and the cohesive energy density,in non-alcoholic solvents,it may be the combined effect of the hydrogen bonding effect between the solute and solvent molecules,the polarity of the solvent,and the cohesive energy density.For mixed solvents,the hydrogen bonding between solvent molecules weakened with the increase of the ethanol mass fraction,resulting in an enhanced interaction between the solute and the solvent,thus promoting the dissolution of it.The solubility of 4,4'-difluorobenzophenone in pure solvent and mixed solvent increased with the increase of temperature.The order was:methyl acetate>ethylacetate>acetone>acetonitrile>n-butanol>isobutanol>n-propanol>isopropanol>ethanol>methanol.The solubility in the mixed solvent decreased with the increase of ethanol content.The influence of HSP:in pure solvents(except acetone and acetonitrile),the solubility decreased with the ?_P and ?_H;? increased with the increase of ethanol mass fraction in mixed solvents,but the solubility decreased.The influence of solvent properties:the solubility in alcoholic solvents was the competition between solvent-solute and solvent-solvent interactions,and in non-alcoholic solvents,the reason was the hydrogen bond acceptor tendency of the solvent.For mixed solvents,the hydrogen bonds between ethanol molecules increased with mass fraction increasing,resulting in weaker interaction between the solute and the solvent,which hindered the dissolution of it.(4)Whether flunarizine hydrochloride and 4,4'-difluorobenzophenone were dissolved in ten pure solvents or in mixed solvents,the ?H_d,?S_d and ?G_d were all positive values,indicating that the process was a non-spontaneous endothermic entropy increase process.And %?_H was greater than %?_TS,indicating that the dissolution processes of both were enthalpy-driven processes.(5)In flunarizine hydrochloride-pure solvent system,the average values of Apelblat,Van't Hoff,?h,NRTL,Wilson model RAD were 0.60%,0.51%,0.58%,0.48% and 0.62%,respectively,Better correlation fitting effect.Among them,the NRTL model was the best predictive model of solubility in pure solvents.In the flunarizine hydrochloride-mixed solvent system,the average values of RAD for Apelblat,Van't Hoff,?h,NRTL,Wilson,Jouyban-Acree model,and the modified Jouyban-Acree model were 0.74%,0.47%,0.54%,0.67%,0.75%,0.88%and 0.50%,respectively.Among them,the van't Hoff equation was the best prediction model in mixed solvents.In the 4,4'-difluorobenzophenone-pure solvent system,the average values of the RAD of Apelblat,Van't Hoff,?h,NRTL,Wilson and UNIQUAC models were 0.33%,0.91%,0.45%,2.07%,0.87%and 2.36%,among them,the Apelblat equation was the best prediction model in pure solvents.In the 4,4'-difluorobenzophenone-mixed solvent system,the average values of the RAD of Apelblat,Van't Hoff,?h,NRTL,Wilson,Jouyban-Acree model,and the modified Jouyban-Acree model were 0.66%,0.84%,0.38%,3.38%,2.80%,1.98%and 1.60%,and the ?h equation was the best prediction model in mixed solvents.(6)According to the investigation results of powder properties,it was determined that microcrystalline cellulose(MCC),mannitol(MNT),and cross-linked polyvinylpyrrolidone(PVPP)were the main auxiliary materials for direct compression;the vial method was the method for determining the disintegration time limit;The prescription for direct compression premixed excipients was:25%MCC,55%MNT,15%PVPP,3%effervescent,1%aspartame and 1%micronized silica gel.The drug-containing excipients had good powder properties,and the appearance and hardness were suitable,the disintegration time was within 30 s,and the difference in friability and tablet weight reached the requirements;when the pre-mixed excipients the capacity of cinnarizine was less than 10%,the disintegration time and friability met the requirements;the cumulative dissolution rates within 30 minutes all reached more than 95%.4 Conclusion of this thesis(1)The solubility of flunarizine hydrochloride and 4,4'-difluorobenzophenone in pure solvents and mixed solvents increase with the increase of temperature.Flunarizine hydrochloride has the largest solubility in methanol and the smallest solubility is in methyl acetate.The solubility data provides a theoretical basis for the study of its dosage form improvement and the pre-prescription study.The dissolution processes of them are both enthalpy-driven and non-spontaneous endothermic and entropy-increasing processes.(2)The solubility of flunarizine hydrochloride and 4,4'-difluorobenzophenone in ten pure solvents are correlated and fitted using six thermodynamic models of Apelblat,Van't Hoff,?h,NRTL,Wilson,and UNIQUAC.Seven models of Apelblat,Van't Hoff,?h,NRTL,Wilson,Jouyban-Acree model and the modified Jouyban-Acree model are used for correlation fitting in the mixed solvent,all of which have good correlation fitting effects.The parameters are obtained by correlation fitting,which are used to estimate and predict the solid-liquid equilibrium data of them at more temperatures,and provide a basic reference for the optimization of crystallization process conditions.(3)The best prescription of premixed excipients prepared by direct compression method is:25%MCC,55%MNT,15%PVPP,3%effervescent,1%aspartame and 1%micronized silica gel.Cinnarizine crystals have good adaptability and tolerance.The fast-release effect of flunarizine hydrochloride orally disintegrating tablets made in this experiment is obvious and the dissolution uniformity is good,and the dissolution rate meets the requirements.