Improving Dissolution Rate and Solubility of Palbociclib Salts/Cocrystal for Anticancer Efficacy

Abstract

Palbociclib (PBC) is a highly effective drug for the treatment of breast cancer, but its full potential is hindered by limited bioavailability due to poor water solubility and severe adverse reactions in some patients. To address these challenges, our research focused on creating novel PBC salt/cocrystal with Generally Recognized As Safe (GRAS) coformers to enhance solubility and dissolution rate. We successfully synthesized three distinct PBC salts: methane sulfonic acid (MSA), benzene sulfonic acid (BSA), and ethane sulfonic acid (ESA). We also explored forming a cocrystal with adipic acid (ADA) through evaporation/slurry crystallizations. Although obtaining single crystals for PBC-ADA was challenging, our analytical techniques, including diffraction, spectroscopy, and thermal analysis, confirmed the creation of salts or cocrystals, providing valuable structural insights. Single-crystal X-ray diffraction revealed proton transfer from sulfonic acid coformers to PBC, forming sulfonate-ammonium hetero-synthons in the salt adducts. Even without single crystals, alternative characterization methods indicated interactions between carboxylic acid and amine groups in PBC-ADA. These newly developed salts and cocrystal, in anhydrate and hydrated forms, significantly improved PBC's solubility and dissolution rates in phosphate buffer media. Notably, PBC-ESA salt and PBC-ADA cocrystal exhibited remarkable 63-fold and 56-fold increases in solubility, respectively, compared to pure PBC. Our research presents a promising strategy to enhance PBC's absorption efficiency as a breast cancer treatment. The newly developed PBC salts offer a potential alternative to current formulations, effectively addressing solubility and adverse reaction issues, potentially improving patient outcomes.