Comparative structural analysis of anhydrous and monohydrated polymorphs of diclofenac diethylammonium: Implications for stability, dissolution, and bioavailability

[Display omitted] •The supramolecular arrangement was studied using Hirshfeld surface analysis.•Physical chemistry properties were investigated using theoretical analysis.•The aqueous solvation effect was carried out using explicit and implicit approaches. Diclofenac diethylammonium belongs to the class of non-steroidal anti-inflammatory drugs, and it is widely used to relieve pain and reduce systemic inflammation. This drug exists in polymorphic forms, which can directly affect the ability to process the drug, as well as drug product dissolution, stability, and bioavailability. Considering the worldwide regulatory guidance for polymorphs in drug substances, a detailed structural analysis of two polymorphs exhibiting the anhydrous and monohydrated structures of diclofenac diethylammonium is presented here, using the supramolecular arrangement and its relationship with structural-physicochemical properties. The polymorph’s structures show conformational differences in the carboxylic group caused by coordinated water molecules presented in the monohydrated polymorphic structure. Both polymorphs have the supramolecular arrangement stabilized by NH···O and CH···Cl intermolecular interactions, but the monohydrated molecule presents a strong OH···O intermolecular interaction due to the presence of a water molecule. Hirshfeld surface analysis showed CH···π and π···π contacts in the anhydrous and monohydrated polymorphs, respectively. Theoretical results, including solvent effect with explicit and implicit approaches for water, indicated the kinetic stability of the diclofenac diethylammonium drug and showed susceptible electrophilic attacks occurring in the region close to the carbonyl oxygen atom.