The role of pH and dose/solubility ratio on cocrystal dissolution, drug supersaturation and precipitation.

Cocrystals that are more soluble than the constituent drug, generate supersaturation levels during dissolution and are predisposed to conversion to the less soluble drug. Drug release studies during cocrystal dissolution generally compare several cocrystals and their crystal structures. However, the influence of drug dose and solubility in different dissolution media has been scarcely reported. The present study aims to investigate how drug dose/solubility ratio (Do=Cdose/Sdrug), cocrystal solubility advantage over drug (SA=Scocrystal/Sdrug), and dissolution media affect cocrystal dissolution-drug supersaturation and precipitation (DSP) behavior. SA and Ksp values of 1:1 cocrystals of meloxicam-salicylic acid (MLX-SLC) and meloxicam-maleic acid (MLX-MLE) were determined at cocrystal/drug eutectic points. Results demonstrate that both cocrystals enhance SA by orders of magnitude (20 to 100 times for the SLC and over 300 times for the MLE cocrystal) in the pH range of 1.6 to 6.5. It is shown that during dissolution, cocrystals regulate the interfacial pH (pHint) to 1.6 for MLX-MLE and 4.5 for MLX-SLC, therefore diminishing the cocrystal dissolution rate dependence on bulk pH. Do values ranged from 2 (pH 6.5) to 410 (pH 1.6) and were mostly determined by the drug solubility dependence on pH. Drug release profiles show that maximum supersaturation (σmax=Cmax/Sdrug)and AUC increased with increasing Do as pH decreased. When Do>>SA, the cocrystal solubility is not sufficient to dissolve the dose so that a dissolution-precipitation quasi-equilibrium state is able to sustain supersaturation for the extent of the experiment (24 h). When Do<

Cocrystallization as a novel approach to enhance the transdermal administration of meloxicam.

Despite its large effectiveness, the long-term oral administration of high doses of meloxicam (MLX) may lead to gastrointestinal events such as abdominal pain, diarrhea, dyspepsia, ulceration, hemorrhage, and gastrointestinal perforation. Moreover, the pH-dependent solubility of MLX makes the development of new oral formulations even more challenging. As an alternative to overcome these limitations, the transdermal delivery of this drug has been purposed. Although various physical and chemical approaches to enhance the absorption of MLX may be found in literature, the use of cocrystallization has not been reported so far. Cutaneous permeation of MLX and 1:1 meloxicam-salicylic acid cocrystal (MLX-SLC) were evaluated using Franz diffusion cells. Cocrystal was suspended in an aqueous solution and in a gel to evaluate the vehicle effect on permeation parameters. In aqueous medium, the cocrystallization showed to enhance the drug permeation coefficient from 1.38 to 2.15 × 10-3 cm/h. MLX-SLC generated supersaturation with respect to the drug during dissolution studies simulating the conditions in the Franz cell donor chamber. This greater amount of free drug in the solution could contribute to explain the higher transdermal absorption and shorter lag time of this system. In addition, the acidic coformer ionization led to a pH reduction from 7.4 to 5.8, which, in turn, provided an increase in the unionized species of the drug, enhancing its permeation rate. The gel containing cocrystals reduced MLX permeation rate significantly (P = 0.42 × 10-3 cm/h), which was attributed to its higher viscosity.