Effect of OH and F Substitution in Benzoic Acid Coformers on the Solubility and Permeability of Fluorinated Drug Roflumilast

Roflumilast (RML), a difluoromethyl and dichlorophenyl group-containing drug, is a selective phosphodiesterase-4 inhibitor (PDE-4). It is prescribed to mitigate the risk of exacerbations in patients with severe chronic obstructive pulmonary disease and to address plaque psoriasis. The presence of the F atom in drugs and intermolecular interactions and weak hydrogen bonds of fluorine are a contemporary theme in crystal engineering of pharmaceutical cocrystals. The aim of this study is to examine the effect of H ↔ F ↔ OH exchange in coformer molecules and their effect on hydrogen bonding and crystal packing. Three cocrystals of RML were successfully crystallized with 4-hydroxybenzoic acid (4HBA), 4-fluorobenzoic acid (4FBA, H ↔ F), and 3-fluoro-4-hydroxybenzoic acid (3F-4HBA, H ↔ F and F ↔ OH). Their X-ray crystal structures were analyzed for hydrogen bonding synthons and weak intermolecular interactions, notably involving the less common F atom. The presence of an amide tape supramolecular synthon of the N–H···O hydrogen bond along with an auxiliary Cl···O interaction is observed between RML molecules. The crystal structures of RML-4HBA and RML-3F-4HBA contain a Cl···O–(H) halogen bond, while in RML-4FBA, it is replaced by a Cl···F–(C) interaction, indicating OH ↔ F mimicry in cocrystal design. The solubility and dissolution rate of RML were investigated in a physiological environment to show that the cocrystal form exhibited an improved solubility and dissolution rate compared to pure RML. The fluoro coformers enhance drug bioavailability and membrane permeation.