The solid dispersions of a KRAS G12C covalent inhibitor,XNW14010,were prepared by fluidized-bed technology with mannitol particles as the substrates.The type and amount of the carriers and the amount of mannitol particles were optimized by the single factor experiments.The optimal formulation was using poly(vinylpyrrolidone-co-vinyl-acetate)(PVP-VA64)as the carriers,and the mass ratio of l-PVP-VA64-mannitol particles was 1∶1∶1.2.By exploring and optimizing the key process parameters,the process of 1 solid dispersion was scaled up in the GMP workshop.The PXRD characterization results showed that 1 existed in an amorphous state in the solid dispersions.The SEM observation revealed that the solid dispersion particles were spherical in shape and formed an even coating layer around the mannitol substrate.Moreover,the angle of repose of the solid dispersion particles was less than 40°,making it suitable for further mixing and tableting.Based on this,a scale-up production of 1 solid dispersions-based tablets was successfully developed.In the in vitro dissolution test,the dissolution rate at 10 min of 1 from the solid dispersions-based tablets was close to 100％in pH 6.8 PBS.An in vivo experiment was carried out with Beagle dog as a model.The results showed that the drug exposure of 1 from the solid dispersions-based tablets was 8 times higher than that of 1 tablets.
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