Themechanism Research Of Drug Nanosuspension Preparation Process And Miniaturization Of Drug Nanosuspension

With the development of new technologies,such as high throughput screening,combinatorial chemistry,proteomics,the number of candidate drugs has been increasing,but about 40% of these candidates are difficult soluble drugs.The number of new chemical entities from chemical synthesis is also gradually increasing,but about 60% drugs from chemical synthesis are indissolvable.Reduceing particle size of the difficult soluble drugs to 100~1000 nm forming nanocrystals is a feasible method.By reducing particle size,which changes saturated solubility and dissolution rate,drug nanosuspension eventually,improve the bioavailability of drugs.This technology not only can be used for indissolvable drugs,for those drugs who is poorly insolvent in water and insoluble in oil also applies.At present,the preparation methods of nanosuspension are precipitation,medium grinding method,high pressure homogeneous method and combination method,etc.The price of some drugs is expensive and some drugs are synthetic difficult,those drugs can't satisfy batches of nanocrystalline research,especially the stabilizer screening work,the supply and demand of the drug is insufficient.This topic was in the study of drug nanosuspension preparation process mechanism,at the same time designed a kind of miniaturization grinding method,whichwas used to filter the stabilizer screening work.Firstly,this topic on the basis of existing instruments in the laboratory designed an miniaturization method to prepare nanosuspension,in a rare drug active pharmaceutical ingredients screen different stabilizers: scatter of API 5 mg in 0.5 m L water contains stabilizers,preparing nanosuspension by milling with the oscillation of the shaking table.This miniaturization was magnified ten time,and compared the particle size results and stability of nanosuspensions,the results showed that the miniaturization was effective in this topic,greatly improving the efficiency of the nanocrystalline research,so it can be used in the research of nanosuspension on screening multiple stabilizers in the future.In addition,this subject adopted “Bottom-up” to prepare nanosuspension,through researching on two majoraffecting factors,determined the optimum parameters: Firstly,the volume ratio of antisolvent(AS)to solvent(S)is 1:15~1:20;Secondly,the solventsof most drugs need to drip into antisolvent in a slowly speed.The particle size distributionof nanosuspensionprepared with “Bottom-up” is wide,and easy toresidual organic solvents,unstable in preservation,but the ability to quickly reducing the drug particle size is superior to others.The nature of the drug itself plays an important rolein the preparation of nanosuspension,which determines the final particle size and production efficiency.Drug properties can be divided into several aspects such as crystallinity,particle microstructure,etc.Which one specific drug properties determines the result,there is no system research.Therefore,and to study the mechanism process of particle size reducing is particularly important.In this topic,hesperitin and meloxicam were transformed through spray drying,rotary evaporation,quenching cooling,freeze-dried,forming drug particles different from drug APIs on morphology and crystallinity,then prepared nanosuspensions with grinding or high pressure homogeneous.The results of SEM,PCS/LD,X-ray diffraction and DSC showed that the active pharmaceutical ingredients with the modification processing will get different microstructure and crystallinity.For HPT,modified with spray drying,particle size of the nanosuspension prepared with high pressure homogeneous was the smallest,the result showed the reducing of drug crystallinity can't help to follow-up process of homogeneous,and the changed particle microstructure shall be the important reasons.MLX was modified with freeze-drying processing,PCS of the nanosuspension grinded with 30 min was better than that of initial API grinded with 120 min,the particle size distribution was also narrower;For MLX modified with freeze-drying,the LD and PCS of nanosuspension prepared with 10 times homogeneous in 500 bar low pressure was superior to that of nanosuspension produced from initial API with 20 times homogeneous in 1300 bar high pressure;SEM photographs showed drug modified with freeze-drying will become porous in microstructure speculation,speculating that was the important reason for size reduction efficiency.