Impact of pharmaceutical cocrystals: the effects on drug pharmacokinetics.

INTRODUCTION: Pharmaceutical cocrystallization has emerged in the past decade as a new strategy to enhance the clinical performance of orally administered drugs. A pharmaceutical cocrystal is a multi-component crystalline material in which the active pharmaceutical ingredient is in a stoichiometric ratio with a second compound that is generally a solid under ambient conditions. The resulting cocrystal exhibits different solid-state thermodynamics, leading to changes in physicochemical properties that offer the potential to significantly modify drug pharmacokinetics. AREAS COVERED: The impact of cocrystallization upon drug pharmacokinetics has not yet been well delineated. Herein, we compile previously published data to address two salient questions: what effect does cocrystallization impart upon physicochemical properties of a drug substance and to what degree can those effects impact its pharmacokinetics. EXPERT OPINION: Cocrystals can impact various aspects of drug pharmacokinetics, including, but not limited to, drug absorption. The diversity of solid forms offered through cocrystallization can facilitate drastic changes in solubility and pharmacokinetics. Therefore, it is unsurprising that cocrystal screening is now a routine step in early-stage drug development. With the increasing recognition of pharmaceutical cocrystals from clinical, regulatory and legal perspectives, the systematic commercialization of cocrystal containing drug products is just a matter of time.

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.

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.