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Nanocrystals of the poorly water-soluble drugs is a promising strategy. To stabilize the drug nanocrystals, stabilizers are usually used; however, the use of common stabilizers is limited by weak stabilization effect and toxicological concerns for long-term treatment. The present work was aimed to investigate the potential of natural silk protein as novel stabilizer for nanocrystal of hydrochlorothiazide, which was a model drug. The nanocrystals of drug with hydrophobic protein stabilizer were prepared by antisolvent precipitation method.Prepared nanocrystals were evaluated for parameters like particle size, zeta potential, DSC, XRD, %crystallinity, SEM, drug content and in vitro dissolution test. Stabilization efficiency of nanocrystals was assessed by their % crystallinity for 3 months. Optimized batch R2 has shown smaller particle size, highest drug content and drug dissolution. Nanocrystals has shown the extended release due to coat of fibroin around the hydrochlorothiazide. From the % crystallinity study it was found that there was not significant change in the nanocrystals prepared using fibroin. So, it was concluded that the fibroin is good stabilizer for drug nanocrystals.