Miranda L. Cheney

Coformer selection in pharmaceutical cocrystal development: A case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics

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.

Improving solubility and pharmacokinetics of meloxicam via multiple-component crystal formation.

Meloxicam is a nonsteroidal anti-inflammatory drug prescribed for rheumatoid arthritis, osteoarthritis, postoperative pain and fever. Meloxicam exhibits low solubility in acidic aqueous media and a slow onset of action in biological subjects. An oral dosage form of meloxicam with enhanced aqueous solubility is desired to enable a faster onset of action and its use for mild-to-medium-level acute pain relief. With this in mind, we examine the solubility and pharmacokinetics of 12 meloxicam cocrystals with carboxylic acids. Dissolution studies of meloxicam and its cocrystals were performed in pH 6.5 phosphate buffer solutions at 37 °C. In addition, pharmacokinetic profiles over four hours were acquired after oral administration of a 10 mg/kg (meloxicam equivalent) solid suspension in rats. The majority of meloxicam cocrystals were found to achieve higher meloxicam concentrations in dissolution media and enhanced oral absorption compared to that of pure meloxicam. All meloxicam cocrystals were converted to meloxicam form I when the slurry reached equilibrium. To better understand how cocrystallization impacts the absorption of meloxicam after oral administration, correlations between the in vitro and in vivo data were explored. The results suggest that the meloxicam cocrystals with a faster dissolution rate would exhibit increased oral absorption and an earlier onset of action.

Crystal engineering of multiple-component organic solids: Pharmaceutical cocrystals of tadalafil with persistent hydrogen bonding motifs

Pharmaceutical cocrystals of tadalafil with methylparaben, propylparaben and hydrocinnamic acid have been prepared and characterized. The crystal packing observed in the three resulting cocrystals reveals that tadalafil molecules form persistent hydrogen-bonded chains which accept additional hydrogen bonds from the OH moieties of the respective coformers.

Excited state properties of 9-amino acridine surface adsorbed onto αZr-phosphate particles

In this report the photo-physical properties of 9-amino acridine (9AA) associated with αZr-phosphate particles (αZrP) is examined. In ethanol solution 9AA exhibits absorption maxima at 425 nm, 402 nm and 383 nm as well as emission bands centered at 455 nm and 483 nm (using 423 nm excitation). The corresponding emission decay is monophasic with a lifetime of 16.5 ns. When αZrP is sonicated in the presence of an ethanol solution of 1 mM 9AA the resulting material exhibits a broad absorption band centered at ∼400 nm with shoulders at ∼425 nm and ∼385 nm and emission bands at 462 nm and 485nm (using 423 nm excitation). Interestingly, the emission decay is biphasic with lifetimes of 1.6 ns and 9.8 ns constituting 57% and 43% of the total emission intensity, respectively. The absence of any shifts in the low angle XRD data suggests that 9AA associates via adsorption onto the exterior surfaces of the αZrP particles. Overall, these results are consistent with different modes of 9AA association to αZrP reflecting different degrees of H-bonding which significantly influences the extent of non-radiative decay from the lowest excited singlet state of 9AA.