| It is estimated that more than 40% of the active pharmaceutical ingredients are poorly water-soluble,which limits the development of pharmaceutical preparations of these active pharmaceutical ingredients and makes it difficult for some drug products with special potency to play its unique effect for the patients.Therefore,to solve the problem of poor solubility of insoluble active pharmaceutical ingredients is particularly important.With the advent of more and more new development lipophilic drugs,many techniques are available to increase the solubility of poorly soluble drugs such as solid dispersions,cosolvents,emulsions,liposomes,and lipids or polymers carrier nanoparticle.However,the usages of large amounts of excipients or organic solvents have toxic side effects to the patients,and the questions of low encapsulation efficiency,poor applicability and complicated operation limit the use of some technologies.Nanocrystal technology refers to the formation of submicron colloidal dispersions of drug particles stabilized by surfactants,polymers,or a mixture of the two.This technique has the advantages of high drug loading,small side effects of excipients and low cost.Drug nanoparticles can also adhere to the gastrointestinal mucosa to prolong the contact time of the drug and enhance the absorption of the drug.In this topic,the experiments were mainly used the combined method of freeze drying and high pressure homogenization to prepare meloxicam nanocrystals,and compared with the traditional method of wet bead milling and high pressure homogenization preparation.The meloxicam nanocrystal with the smallest particle size(88nm)can be obtained by wet bead milling for 4 h,but the preparation time was very long.The lyophilized meloxicam powder can greatly improve the reduction efficiency of drug particle size during high pressure homogenization process compared to meloxicam APIs that have not been modified by freeze-drying process.With only one cycle at 1000 bar homogenization pressure,the particle size of the lyophilized meloxicam sample can be reduced to 342 nm,while that of unmodified drug nanocrystal is 1285 nm under the same conditions.The meloxicam APIs became loose and porous after freeze-drying process.The results of X-ray diffraction also showed the decrease of crystallinity and the polymorphic transformation of the powder after lyophilization.Therefore,the change of drug particle morphology and changes in crystallinity after the FD process may be the reasons to influence the nanosizing processes.Nanocrystals can be transformed to various dosage forms,but most commercially available products which based on nanocrystal technology are oral solid dosage forms.Tablet is the mostly marketed product dosage using this technology to date.And the drying or solidification of nanocrystals is an essential step in the process of making nanocrystals into the final solid oral dosage form.In this experiment,an innovative nanosuspension was directly used as a wetting agent for wet tableting to obtain meloxicam nanocrystalline tablets in one step.At the same time,this experiment first examined the dissolution of small-diameter nanocrystals(<100 nm)and tablets prepared by media milling.And different methods of preparation(medium milling,high-pressure homogenization,and freeze-drying-high pressure homogenization Combination method)effects on the dissolution of pharmaceutical nanocrystals and their tablets were examined.The results obtained are that the meloxicam nanocrystals prepared by the wet bead milling method have the best solubility and the dissolution of the nanocrystals is much higher than the dissolution of the raw drug.And the tablets prepared by using nanocrystals from homogenizer and combination process showed faster dissolution in the first 20 min than the wet bead milling nanocrystal tablets.Meanwhile,the dissolution of the nanocrystal tablets was also significantly better than the dissolution of the drug tablets.It confirms that nanocrystals do improve the solubility of poorly soluble drugs.The reason is that the reduction of the dissolution rate is caused by the agglomeration of the nanoparticles during the tabletting of the polished nanocrystals with a very small particle size.If we want to prepare drugs into nanocrystals and subsequent do some development and application of the nanocrystals,reseachers need to do the experiments about the screening of stabilizers,the optimization of stabilizer ratio,the comparison of preparation methods,the optimization of process parameters and so on.For some of the expensive drugs,which are not suitable for large quantities of multiple batches of research,it requires the researchers to reduce the experimental scale as much as possible under the condition of the existing experimental conditions and under the same assurance of the same experimental effect.This project studies and tests the feasibility of preparing nanocrystals of four insoluble plant-derived compounds(ie,quercetin,rutin,resveratrol and hesperidin)using a ultra-small lab scale(0.5 m L,5 mg drug)method of the wet bead milling.A particle size of ranged from 200 to 500 nm was obtained for nanocrystals of four compounds and the stabilizer selection could be achieved within 2 h by using this ultra-small lab scale bead milling method.By observing the stability of the selected samples,it was confirmed that the nanocrystals prepared by the ultra-small lab scale bead milling method under the optimal conditions had a physical stability of six months.The results of this experiment confirm that ultra-small lab scale preparation can not only achieve the experimental results similar to those of nanocrystals prepared by normal laboratory scale(5 mL),but also shorten the duration of experiment,save the cost and greatly improve the experiment efficiency.At the same time,this topic uses the method of freeze-drying to transform nanocrystals into solid forms,and obtains the lyophilized intermediates with good redispersibility and physical stability for further application. |
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