Solid-State Diversity of Fenofibric Acid: Synthon Polymorphs and Salts with Altered Solubility and Dissolution

Fenofibric acid (hereafter FFA) is a lipid-lowering agent used to treat dyslipidemia, hyperlipidemia, and cardiovascular diseases. The drug belongs to the biopharmaceutical classification system (BCS) Class II category with poor aqueous solubility and high permeability, resulting in improved bioavailability (81%) compared to its prodrug fenofibrate (69%). FFA is marketed in its active form as well as prodrug formulations (fenofibrate and choline fenofibrate) as a sustained-release formulation, because of poor absorption. In order to expand the structural landscape of FFA, solid-form screening resulted in a novel polymorph (FFA-2) along with a reported commercial form (FFA-1). While the crystal structure of FFA-1 maintains an unusual acid···carbonyl heterosynthon-mediated dimer, FFA-2 offers a more robust carboxylic acid dimer, and thus they are designated as synthon polymorphs. Moreover, the novel polymorph (FFA-2) improved its dissolution profile (4-fold) compared to FFA-1 in a neutral pH medium. In order to enhance the aqueous solubility of FFA, further salt screening was carried out that resulted in two ionized forms with heterocyclic amines, specifically piperidine (PPD) and piperazine (PPZ). The crystal structure of the PPZ salt was confirmed by single-crystal XRD, while that of PPD salts was obtained from PXRD data. The FFA-PPZ (1:0.5) salt maintains zigzag packing similar to that of FFA-1, while FFA-PPD (1:1) salt sustains layered packing similar to that of FFA-2. The PPZ salt facilitated much-controlled release, while the PPD salt exceptionally enhanced the solubility and dissolution rate of the drug. Both salts demonstrated exceptional stability in moist environments. Similar to FFA-1, both salts maintained identical cell viability in the human monocyte THP-1 cell line. To summarize, a novel polymorph (FFA-2) and PPD salt can be formulated to improve bioavailability and potentially decrease the required dosage.