Impact of Crystal Nuclei on Dissolution of Amorphous Drugs.

Amorphous drugs are used to improve bioavailability of poorly water-soluble drugs. Crystallization must be managed to take full advantage of this formulation strategy. Crystallization of amorphous drugs proceeds in a sequence of crystal nucleation and growth, with different kinetics. At low temperatures, crystal nucleation is fast, but crystal growth is slow. Therefore, amorphous drugs may generate dense but nanoscale crystal nuclei. Such tiny nuclei cannot be detected using routine powder X-ray diffraction (PXRD) and polarized light microscopy (PLM). However, they may negate the dissolution advantage of amorphous drugs. In this work, for the first time, the impact of crystal nuclei on dissolution of amorphous drugs was studied by monitoring the real-time dissolution from amorphous drug films, with and without crystal nuclei, and the evolving crystallinity in the films. Three model drugs (ritonavir/RTV, posaconazole/POS, and nifedipine/NIF) were chosen to represent different crystallization tendencies in the supercooled liquid state, namely, slow-nucleation-and-slow-growth (SN-SG), fast-nucleation-and-slow-growth (FN-SG), and fast-nucleation-and-fast-growth (FN-FG), respectively. We find that although the amorphous films containing nuclei do not show obvious differences from the nuclei-free films under PLM and PXRD before dissolution, they have inferior dissolution performance relative to the nuclei-free amorphous films. For SN-SG drug RTV, crystal nuclei have negligible impact on the crystallization of amorphous films, dissolution rate, and supersaturation achieved. However, they cause earlier de-supersaturation by inducing crystallization in solution as heterogeneous seeds. For FN-SG drug POS and FN-FG drug NIF, crystal nuclei accelerate crystallization in the amorphous films leading to lower supersaturation achieved with POS, and elimination of any supersaturation with NIF. Dissolution profiles of amorphous films can be further analyzed using a derivative function of the apparent dissolution rate, which yields amorphous solubility, initial intrinsic dissolution rate, and onset of crystallization in the amorphous films. This study highlights that although crystal nuclei are undetectable with routine analytical methods, they can significantly negate, or even eliminate, the dissolution advantage of amorphous drugs. Hence, understanding crystal nucleation process and developing approaches to prevent it are necessary to fully realize the benefits of amorphous solids.

Dissolution changes in drug-amino acid/biotin co-amorphous systems: Decreased/increased dissolution during storage without recrystallization.

Co-amorphous systems have been proven to be a promising strategy to address the poor water solubility of poorly water-soluble drugs. Generally, the initial dissolution behaviors after co-amorphous system preparation and the potential recrystallization during storage are used to evaluate the performance of co-amorphous systems. However, this study reveals that decreased dissolution and unexpected increased dissolution were observed during storage though the co-amorphous systems maintained amorphous form. Three drugs (valsartan, tadalafil, mebendazole) and three co-formers (arginine, tryptophan, biotin) were used to prepare co-amorphous systems and the samples were stored for different times. After stored for 80 d, most of the co-amorphous systems maintained amorphous form, however, decreased and increased intrinsic dissolution rates (IDRs) were both observed in these non-recrystallized co-amorphous systems. The moisture changes of the systems during storage and the possible drug-co-former molecular interactions showed no effect on the dissolution changes, while phase separation might play a role in it. In conclusion, more attention should be paid to the dissolution changes of co-amorphous systems during storage. Focusing on the initial dissolution behaviors after sample preparation and the physical recrystallization during storage is not enough for the development of co-amorphous systems in future.

An interlaboratory investigation of intrinsic dissolution rate determination using surface dissolution.

The purpose of this study was to conduct an interlaboratory ring-study, with six partners (academic and industrial), investigating the measurement of intrinsic dissolution rate (IDR) using surface dissolution imaging (SDI) equipment. Measurement of IDR is important in pharmaceutical research as it provides characterising information on drugs and their formulations. This work allowed us to assess the SDI's interlaboratory performance for measuring IDR using a defined standard operating procedure (see supporting information) and six drugs assigned as low (tadalafil, bromocriptine mesylate), medium (carvedilol, indomethacin) and high (ibuprofen, valsartan) solubility compounds. Fasted State Simulated Intestinal Fluid (FaSSIF) and blank FaSSIF (without sodium taurocholate and lecithin) (pH 6.5) were used as media. Using the standardised protocol an IDR value was obtained for all compounds and the results show that the overall IDR rank order matched the solubility rank order. Interlaboratory variability was also examined and it was observed that the variability for lower solubility compounds was higher, coefficient of variation >50%, than for intermediate and high solubility compounds, with the exception of indomethacin in FaSSIF medium. Inter laboratory variability is a useful descriptor for understanding the robustness of the protocol and the system variability. On comparison to another published small-scale IDR study the rank ordering with respect to dissolution rate is identical except for the high solubility compounds. This results indicates that the SDI robustly measures IDR however, no recommendation on the use of one small scale method over the other is made.