Influence of the pK(a) Value of Cinnamic Acid and P-Hydroxycinnamic Acid on the Solubility of a Lurasidone Hydrochloride-Based Coamorphous System

[Image: see text] Coamorphization of a poorly water-soluble active pharmaceutical ingredient (API) has been proven to be effective in improving its solubility. Generally, API can form multiple coamorphous systems with different coformers. However, it remains unclear how the pK(a) value of different coformers influences the solubility of the API. In this study, structurally related cinnamic acid (CA, pK(a) = 4.37) and p-hydroxycinnamic acid (pHCA, pK(a) = 4.65) were chosen as coformers for the coamorphization of lurasidone hydrochloride (LH). To investigate the influence of the pK(a) value of the coformers on the solubility of LH, LH-CA/pHCA coamorphous systems were prepared by the vacuum rotary evaporation method and characterized by powder X-ray diffraction and differential scanning calorimetry. Fourier-transform infrared spectroscopy, Raman spectroscopy, and molecular dynamics (MD) simulations were employed to investigate the intermolecular interaction of the coamorphous systems. It was found that the solubility of LH in the coamorphous LH–pHAC with a higher-pK(a) coformer was higher than that of the coamorphous LH-CA. In addition, according to the solubility product principle-based formula derivation, we established the functional relationship between the solubility of LH and the pK(a) of the coformers at different-pH buffering solution. It was found that the coformer with a larger pK(a) value would be more beneficial to improve the solubility profile of LH. Collectively, the current study offers an effective strategy to improve the poor solubility of drugs by increasing the pK(a) value of the coformer in coamorphous systems.