Crystal Engineering to Solidify and Chemically Stabilize Oily dl-Butylphthalide

dl-3-n-Butylphthalide (dl-NBP) is a well-known neuroprotective drug used for the treatment of ischemic stroke. It is oily in appearance and vulnerable to oxygen and light, resulting in the only developed oral product being NBP soft capsules. However, this conventional dosage form suffers from unsatisfactory absorption due to water insolubility and extensive metabolism. This work aimed to solidify and stabilize dl-NBP through cocrystallization and then combine crystalline NBP with solubilization technologies for solid dosage forms to enhance systemic exposure. Cocrystals of dl-NBP with 2,5-dihydroxybenzoic acid (NBP-2,5HBA), 3,5-dihydroxybenzoic acid (NBP-3,5HBA), gallic acid (NBP-GAA MH), and 5-hydroxyisophthalic acid (NBP-5HPA) were first discovered using liquid-assisted grinding and comprehensively characterized. The edible cocrystal NBP-GAA MH with a melting point of 67 °C exhibited higher chemical stability than the parent drug. The developed formulation of NBP-GAA MH showed considerable improvement in dissolution rates than NBP soft capsules at pH 2.0 and 4.5. In in vivo study, the cocrystal formulation yielded 1.7 and 1.9 times higher Cmax and AUC0–8h in rats than the commercial product. Therefore, cocrystallization promises to solidify and stabilize oily/liquid compounds and enriches their dosage forms in drug development.