Pharmaceutical cocrystals and amorphous spray-dried dispersions of tenoxicam: Solubility and dissolution enhancement approaches.

摘要

In the present work, crystal engineering and spray drying approaches are applied to tenoxicam Form III, a sparingly soluble active pharmaceutical ingredient (API) (<0.1 ug/ml aqueous solubility) within the oxicam class of non-steroidal anti-inflammatory drugs (NSAID). The primary objectives of the study were to investigate the feasibility of applying crystal engineering and spray drying techniques to identify and characterize cocrystals, and generate a stabilized amorphous dispersions of tenoxicam respectively; and determine whether or not the identified cocrystals or generated amorphous dispersions have impact, if any, on the solubility and/or dissolution and stability of a sparingly soluble model drug, tenoxicam.;An attempt was made to summarize the relevant widespread current literature to understanding the design strategy of cocrystals, preparation techniques and their limitations, cocrystal formation pathways, crystal engineering strategies evaluation and the potential impact of these strategies on the physicochemical properties of an API in question. Recent advances made in the crystal engineering strategies and the innumerable possibilities for designing cocrystals of pharmaceutical and clinical relevance have been exemplified by several cocrystal case studies.;Tenoxicam is a molecule that contains a number of groups capable of hydrogen bonding including amide, pyridyl, phenolic hydroxyl, sulfone, and thiophene functional groups. Therefore, the evaluation of cocrystal design strategy in this study included various carboxylic acids as cocrystal formers representing a wide range of hydrogen bond donors and acceptors. Cocrystals of tenoxicam, were screened, prepared, and characterized using various techniques. Nine phase pure cocrystals of tenoxicam were identified using solvent-drop grinding (SDG) techniques. Structural characterization was performed using powder X-ray diffraction (PXRD), differential scanning calorimetry, and multinuclear solid-state NMR (SSNMR). Solvates and phase mixtures encountered in SDG cocrystal screening were detected using Thermal analysis, PXRD, and 1D SSNMR techniques. Cocrystals formation was confirmed and the structural aspects for the selected cocrystals formed with saccharin, salicylic acid, succinic acid, and glycolic acid are determined using 2D SSNMR methods. Molecular association was demonstrated using cross-polarization heteronuclear dipolar correlation (CP-HETCOR) methods involving 1H and 13C nuclei. The local aspects of the cocrystal structure were revealed by Short-range 1H- 13C CP-HETCOR and 1H-1H double-quantum interactions between atoms of interest, including those engaged in hydrogen bonding. The ionization state and the potential for zwitterionization in the selected cocrystals were assessed by 15N SSNMR. The tenoxicam saccharin cocrystal was found to be similar in structure to a previously-reported cocrystal of piroxicam and saccharin. Comparative evaluation studies on dissolution for four selected cocrystals yielded intrinsic dissolution rates similar or reduced relative to tenoxicam Form III.;Amorphous spray dried dispersions were prepared using L-arginine as a solubilizer. The physical properties of these dispersions were improved by adding Polyvinylpyrrolidone (PVP) as a stabilizer. Results of the study indicated that dispersions containing a 1:2 ratio of tenoxicam:L-arginine with 10% to 50% w/w PVP provided a twofold increase over equilibrium solubility of Tenoxicam at the same pH. Accelerated stability studies performed at accelerated conditions for one month demonstrated that the dispersions exhibit acceptable physical properties with only a minor decrease in chemical stability. In conclusion, for amorphous SDD study, SDDs prepared with tenoxicam, L-arginine and PVP exhibited greatly enhanced dissolution, acceptable physical properties, and sufficient stability for development. SSNMR methods are useful in elucidating structural properties, molecular association, and the formation of a glass solution between tenoxicam, L-arginine and PVP. (Abstract shortened by UMI.).