Physical Properties for Novel Cilostazol Co-amorphous; Effect of Preparation Method and Molar Ratio on the Co-amorphous

Abstract

Co-amorphous materials have gained special attention in the pharmaceutical field due to their high potential to enhance the oral bioavailability of poorly aqueous soluble drugs. In co-amorphous studies, few reports have examined the physical properties and molecular states of different active pharmaceutical ingredients (APIs) : co-amorphous former (CF) molar ratios and preparation methods. Therefore, we investigated the effect of molar ratio and preparation method on the physical properties of a novel co-amorphous system consisting of cilostazol and l-tryptophan, which we identified through screening. Co-amorphous consisting of molar ratios of 1 : 1 (co-milling (CM) 1 : 1), 1 : 1.5 (CM 1 : 1.5), and 1 : 2 (CM 1 : 2) were prepared by the CM method, while samples with a molar ratio of 1 : 1 (spray drying (SD) 1 : 1) were prepared by the spray drying method. CM 1 : 1.5 and CM 1 : 2 showed the highest solubility. Storage stability was excellent for CM 1:1.5, CM 1 : 2, and SD 1 : 1, whereas physical properties were improved by co-amorphization. To investigate the factors responsible for the improved physical properties, the molecular state of the co-amorphous system was evaluated, and it was inferred that hydrogen bonds were formed between cilostazol and l-tryptophan. Solid-state ¹³C-NMR showed several new peaks specific to the solid state in the co-milled sample compared to SD 1 : 1 and cilostazol amorphous, suggesting that the molecular state may differ depending on the preparation method. As described above, different physical properties and molecular states were observed in the novel co-amorphous system consisting of cilostazol and l-tryptophan when the molar ratio of APIs and CF, and the preparation method differed.