Study On Thermodynamic Properties,Salt Formation And Micronization Of Salbutamol

With the progress in medicinal chemistry,especially the introduction in recent years of combinatorial chemistry and high-throughput screening for identification of new chemical entities,the solubility of new drug molecules has declined dramatically.Salt formation is the most common and effective method to increase the solubility and dissolution rate of acidic or basic drugs.Salbutamol,one of the more commonly used drugs for bronchial asthma,has a low oral absorption and utilization due to its poor water solubility.Therefore,in this paper,SAL was used to prepare drug salts and micronized powders,screen excipient formulations,and its shape,hygroscopicity,fluidity,and inhalation properties were investigated.In this work,the solubility of salbutamol in twelve pure solvents were determined by dynamic method,and the experimental data were correlated with four thermodynamic models,including the modified Apelblat model,λh model,NRTL model and Wilson model,respectively.The results showed that the order of solubility at 293.15 K was:DMSO>N-methyl-2-pyrrolidone>N,N-dimethylacetamide>N,N-dimethylformamide>methanol>ethylene glycol>ethanol>n-propanol>n-butanol>isopropanol>n-pentanol>1,4-dioxane.The model fitting results showed that the modified Apelblat equation has the best fitting effect,with the correlation coefficients R~2 greater than 0.99,and the relative mean deviations were less than 4.0%for all 11 solvents except 1,4-dioxane,and the root mean square deviations were less than 0.001 for all 11 solvents except N-methyl-2-pyrrolidone.In addition,the modified van’t Hoff equation and Gibbs equation were used to explain that both salbutamol dissolution processes were non-spontaneous heat absorption processes.The SAL-GLY micro-powders withβ-cyclodextrin or L-leucine in different proportions were prepared by spray drying.The PXRD results showed that all the SAL-GLY micro-powders prepared in this experiment existed in amorphous form.The DSC showed that the addition of the excipientsβ-cyclodextrin and L-leucine shifted the melting peak of the amorphous drugs to the right by 40～70℃and improved the thermal stability.The particle size of micronized powders were concentrated in the range of 0～7μm,which were in accordance with the requirement of pulmonary inhalation drug delivery.With the increase of excipientβ-cyclodextrin,the particle surface was no longer smooth and the depression became deeper,while the addition of L-leucine caused the particles to form irregular folds or corrugated surfaces.The fluidity,hygroscopicity,inhalation performance and drug content of the micro-powders were tested with different excipients and drug loading ratios.The results showed that when L-leucine as the excipient and drug loading ratio of 1:3,the smallest compressibility of SAL-GLY micro-powders were 17.68%,which was the best fluidity.Compared withβ-cyclodextrin,the excipient L-leucine can reduce the moisture absorption rate at all relative humidity levels,which reduces the possibility of deterioration of SAL-GLY micronized powder due to moisture.In addition,L-leucine played a good role in dispersing the drug molecules,thus increasing their effective lung deposition rate.And the effective lung deposition of the drug micronized powder at the drug loading ratio of 1:3 was 20.20%,and the evacuation rate was 96.75%,with the best nebulization performance of the micronized powder.The SAL-TAR micro-powders with different excipients and drug loading ratios were prepared by spray drying.The results showed that SAL-TAR was methanol solvent,and after spray drying and vacuum drying for 12 h,the micro-powder only had a melting peak,indicating that the prepared drug was SAL-TAR micro-powder.In addition,the SAL-TAR micro-powders prepared by the two excipients uniformly distributed and met the dry powder inhalation requirements.The performance evaluation of SAL-TAR micro-powders were almost the same as that of SAL-GLY micro-powders.The best nebulization performance was achieved when the excipient was L-leucine and the drug loading ratio was 1:3,and the effective deposition in the lung reached 23.65%and the evacuation rate was 96.88%.The amorphous samples of SAL-GLY and SAL-TAR were prepared by grinding and freeze-drying.The dissolution of the two salbutamol salts and their amorphous forms were determined by paddle method.The experimental results showed that compared with SAL,SAL-GLY,SAL-TAR and their amorphous forms disintegrated completely within 6-9 min and the dissolution rates were increased,indicating that salting and amorphous form of drugs could significantly improve the dissolution rate of drugs.