Preventing crystallization in amorphous oral administration or transdermal drug delivery

Nowadays, many of the drugs developed tend to have very low solubility, asserting challenges in their development. In an oral administration, the active pharmaceutical ingredient needs to reach the site of action/absorption. Implicitly, solubility and dissolution rate are key factors to ensure sufficient oral bioavailability/absorption in the gastro-intestinal tract.

Amorphous solid drug dispersion in a polymer matrix is one widely used method to improve solubility and dissolution rate of low soluble drugs (1). However, a crystalline form of a drug is thermodynamically favored over a high free energy amorphous form (2). Polymers and additives are most commonly used to inhibit the crystallization in the amorphous solid formulations (3-5).

Have you ever wondered what happened during Nucleation Rate Measurements?

Have a look on the movie below!

Lynne Taylor and her group at Purdue University have intensively studied the influence of polymers on nucleation and growth of different active pharmaceutical ingredients. She and several other researchers emphasize how addition of polymers clearly affects nucleation and growth rates from supersaturated aqueous solutions (6). Two different crystallization instruments, Crystal16® and Crystalline™, were extensively used to determine the nucleation behavior. Induction time for nucleation was determined by using the Crystal16® Parallel Crystallizer. To obtain nucleation rates as the systems precipitate, the Crystalline™ Particle Viewer was the most suitable instrument to run the experiments. In her latest publication, Lynne Taylor shows how in solution two polymers, PVP and PVPVA having the greatest effect on nucleation were also the most effective inhibiting the growth (7). In contrast with the polyvinyl polymers, PAA showed to increase the nucleation rate; a behavior one wants to know while developing such an amorphous formulation (8-9). Polymers are typically expected to reduce nucleation and therefore this different behavior of the different polymers possibly suggests that using combinations of polymers with similar mechanism could effectively inhibit growth.

This conclusion extremely important in the development of a drug could only be drawn by understanding the nucleation induction time and rate with the use of the most intensively used crystallization systems. Crystal16® Parallel Crystallizer is an extremely useful instrument in elucidating primary nucleation kinetics, while Crystalline™ Particle Viewer allows one to determine both primary and secondary nucleation kinetics. The above mentioned brings the two systems once again to the front line as the most useful technology solutions for studying crystallization behavior.

 

1 K. Kawakami, Adv. Drug Deliv. Rev., 2012, 64, 480-495.
2 D. Alonzo, G. Zhang, D. Zhou, Y. Gao and L. Taylor, Pharmaceutical Research, 2010, 27, 608-618.
3 I. Weissbuch, M. Lahav and L. Leiserowitz, Crystal Growth & Design, 2003, 3, 125-150.
4 V. Y. Torbeev, E. Shavit, I. Weissbuch, L. Leiserowitz and M. Lahav, Crystal Growth & Design, 2005, 5, 2190-2196.
5 D. E. Alonzo, S. Raina, D. Zhou, Y. Gao, G. G. Z. Zhang and L. S. Taylor, Crystal Growth & Design, 2012, 12, 1538-1547.
6 B. A. Hendriksen and D. J. W. Grant, Journal of Crystal Growth, 1995, 156, 252-260.
7 N.S. Trasi, K. A. Oucherif, J. D. Litster and L.S. Taylor, CrystEngComm, 2015, 17, 1242-1248.
8 G. A. Ilevbare, H. Liu, K. J. Edgar and L. S. Taylor, Crystal Growth & Design, 2012, 12, 3133-3143.
9 D. D. Patel and B. D. Anderson, Mol. Pharm., 2014, 11, 1489-1499.