title: Coformer selection in pharmaceutical cocrystal development: a case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics.
abstract: Meloxicam is a nonsteroidal anti-inflammatory drug with low aqueous solubility and high permeability. Because of its low solubility under acidic conditions (e.g., pH 1-5), it can take more than 2 h for meloxicam to reach its therapeutic concentration in humans. Although the slow onset of meloxicam does not necessarily impact the current label indications, the slow onset does prevent meloxicam from its potential application for the relief of mild-to-medium-level acute pain. Pharmaceutical cocrystallization of meloxicam, which represents a promising approach to generate diverse novel crystal forms, could be used to improve the aqueous solubility and accelerate the onset of action. In this contribution, we describe how a novel method can be used for coformer selection to enable the efficient and effective development of a pharmaceutical cocrystal with desired physicochemical and pharmacokinetic properties. Aspirin was selected as the coformer for meloxicam based upon this alternative route, which combines the supramolecular synthon approach with findings in the previous pharmacological and toxicological studies of meloxicam. The resulting cocrystal of meloxicam and aspirin exhibited superior kinetic solubility and possessed the potential to significantly decrease the time required to reach the human therapeutic concentration compared with the parent drug, meloxicam.
authors.affiliation: Thar Pharmaceuticals Inc, Tampa, Florida 33612, USA.
authors.forename: Miranda L
authors.initials: ML
authors.lastname: Cheney
authors.forename: David R
authors.initials: DR
authors.lastname: Weyna
authors.forename: Ning
authors.initials: N
authors.lastname: Shan
authors.forename: Mazen
authors.initials: M
authors.lastname: Hanna
authors.forename: Lukasz
authors.initials: L
authors.lastname: Wojtas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zaworotko
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000493:pharmacokinetics; D001241:Aspirin / Q000737:chemistry* / Q000493:pharmacokinetics; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004338:Drug Combinations; D007275:Injections, Intravenous; D008297:Male; D000077239:Meloxicam; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared; D013678:Technology, Pharmaceutical / Q000379:methods*; D013843:Thiazines / Q000737:chemistry* / Q000493:pharmacokinetics; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004338:Drug Combinations; D013843:Thiazines; D013844:Thiazoles; D001241:Aspirin; D000077239:Meloxicam