(30c) Evaluation of the Ability of Different Polymers to Inhibit Drug Crystallization Upon Rapid Solvent Evaporation – Development of a Small Scale Screening Method

As a result of the recent trend whereby potential new drug candidates are frequently characterized by having a low aqueous solubility and/or dissolution rate, the application of solid dispersion technology has become increasingly important as a formulation tool in pharmaceutical development. Currently, however, (i) there is a lack of knowledge in what polymers are best suited in inhibiting crystallization for a specific API during subsequent storage, and (ii) no system has been described enabling a screening of the crystallization inhibiting performance of different polymers upon rapid solvent evaporation using small amounts of API. In this study, the ability of 7 chemically diverse, pharmaceutically relevant polymers [Eudragit® E100, poly(acrylic acid), poly(vinylpyrrolidone), poly(vinylpyrrolidone-vinyl acetate), poly(styrene sulfonic acid), hydroxypropylmethylcellulose and hydroxypropylmethylcellulose acetate succinate] to inhibit the crystallization of 8 readily crystallizable model APIs (benzamide, phenacetin, flurbiprofen, flufenamic acid, chlorpropamide, chlorzoxazone, bifonazole and lidocaine) was investigated. Films of the different drug-polymer combinations were prepared by rapid evaporation from solution, using a spin coating method. The spin coating method was selected as the process is characterized by (i) rapid solvent evaporation kinetics, showing similarity to scaled-up processes such as spray drying, and (ii) low sample consumption, making it attractive as an evaluation method in early development settings. A total of 7 different drug/polymer weight ratios [90/10, 75/25, 60/40, 50/50, 40/60, 25/75 and 10/90 (w/w)] were evaluated for each drug-polymer combination. The crystallization behavior of the films was monitored using polarized light microscopy over 7 days of room temperature storage under dry conditions. It was observed that compounds having a higher crystallization tendency for the pure compound [1] tended to be more difficult to stabilize using the polymeric additives; more polymer was required. In addition, the stabilizing ability of the polymers varied considerably for the individual APIs, with the acidic polymers PAA and PSSA showing the most extreme behavior. The acidic polymers were good stabilizers for the drugs with basic and amide functional groups, but extremely poor stabilizers for acidic drugs. A reasonable correlation between crystallization inhibition in spin coated films versus bulk powders (prepared by rotary evaporation) was observed. The small scale screening method is thus a potentially useful technique to evaluate the role of drug-polymer chemistry in the stabilization of amorphous solid dispersions.

Acknowledgements:

The National Science Foundation Engineering Research Center for Structured Organic Particulate Systems is acknowledged for financial support (NSF ERC-SOPS)(EEC-0540855).

Reference: [1] Van Eerdenbrugh B, Baird JA, Taylor LS. 2010. Crystallization Tendency of Active Pharmaceutical Ingredients Following Rapid Solvent Evaporation ? Classification and Comparison with Crystallization Tendency from Undercooled Melts. J Pharm Sci. In press.