Salts, Cocrystals, and Salt Cocrystals Consisting of Papaverine and Dicarboxylic Acid

In pharmaceutical drug development, selecting appropriate solid-state forms of active pharmaceutical ingredients (APIs) is crucial. Focusing on the API papaverine, we conducted screening studies of its crystalline salts and cocrystals synthesized using eight dicarboxylic acids with different pK_a values as counterions/coformers, followed by crystal structure analysis. We identified two crystalline salts, one salt cocrystal, five cocrystals, and one intermediate form on the salt–cocrystal continuum. We examined the correlation between crystal form and ΔpK_a value between the API and counterions/coformers (where ΔpK_a = pK_a(papaverine) – pK_a(acid)). Cocrystals were obtained when ΔpK_a was approximately 2 or less, while crystalline salts were obtained when ΔpK_a was approximately 4 or greater. With fumaric acid (ΔpK_a ≈ ca. 3), two distinct crystal forms were obtained despite the identical molecular combinations. One, an intermediate-state crystal, exhibited a donor–acceptor (···N···O···) distance (<2.6 Å) that was shorter than the other. Through systematic screening using the various counterions/coformers, we demonstrated that the ···N···O··· distance alone may be a useful predictor for the formation of intermediate-state crystals. This highlights the importance of comprehensive crystal screening with a wide range of counterions and coformers. This study emphasizes the importance of accurate crystal structure analysis during API development, particularly when ΔpK_a values indicate the potential for multiple solid forms.