Purpose <p>Lurasidone hydrochloride (HCl) is an atypical antipsychotic used for bipolar depression. However, as a Biopharmaceutics Classification System (BCS) Class II drug, it has low solubility, leading to limited oral bioavailability. This study aimed to enhance the dissolution rate and bioavailability of lurasidone HCl by modifying its crystalline structure through co-processing with weak acidic compounds, namely citric acid and nicotinic acid.</p> Methods <p>Lurasidone HCl was co-processed with excipients using the wet co-grinding technique at different molar ratios. The prepared formulations were characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and X-ray powder diffraction (XRD) to investigate solid-state modifications. Dissolution studies were conducted to evaluate the impact of co-processing on drug release. The optimum ratio for each co-former was selected for in vivo assessment of oral bioavailability using the forced swim test (FST) to evaluate antidepressant activity.</p> Results <p>DSC, FTIR, and XRD confirmed the formation of a lurasidone HCl-citric acid co-crystal, while a eutectic mixture was proposed for lurasidone HCl-nicotinic acid formulations. Dissolution studies demonstrated a two-fold increase in dissolution efficiency compared to unprocessed lurasidone HCl. FST evaluation showed increased immobility durations of 1.7-fold for raw lurasidone HCl, 2.9-fold for the marketed product (Elbaluran^®), 2.19-fold for the co-crystal formulation (F3), and 3.08-fold for the eutectic mixture formulation (F7), respectively.</p> Conclusion <p>Citric acid and nicotinic acid effectively enhanced lurasidone HCl dissolution and bioavailability through co-crystallization and eutectic formation, respectively, offering a promising approach for optimizing its therapeutic efficacy.</p>