A dissolution-enhancing strategy for clopidogrel napadisilate: surfactant-assisted wet granulation and particle size engineering

Clopidogrel napadisilate hydrate is a stable clopidogrel salt, but its low aqueous solubility limits dissolution. This study developed a spray-drying-free tablet using surfactant-assisted wet granulation and jet milling. Among four surfactants screened at pH 2.0, polysorbate 80 (PS80) yielded the highest similarity factor (f2 = 74.6 vs. 19.5–59.8; n = 3 tablets). Response surface methodology identified PS80 concentration as the main determinant of f2. At pH 4.5, API particle size was dominant: reducing D90 from 208.2 to 16.2 μm increased f2 from 31.9 to 82.8 with acceptable flowability, whereas 6.6 μm impaired flowability without further benefit. The model-predicted optima (0.84 mg PS80; D90 11.9 μm) were not prepared as batches; the selected conditions (1.0 mg PS80; D90 16.2 μm) yielded f2 values exceeding the predictions (74.6 vs. 70.3; 82.8 vs. 80.0). PXRD and DSC detected no crystalline transformation, although hydrate water content was not determined. In an exploratory parallel-group beagle dog study (n = 6 per group), Cmax and AUC0–24 of parent clopidogrel did not differ significantly from Plavix® (p = 0.774 and 0.910); bioequivalence and active-metabolite exposure were not assessed. These results identify API particle size as critical for pH 4.5 dissolution and support conventional wet granulation with jet milling as a practical alternative to amorphous or spray-dried approaches.