Evaluating the influence of polymers on nucleation and growth kinetics of pharmaceutical compounds in supersaturated solutions



In clinical practice, oral dosage forms remain the most popular route of drug administration due to patient convenience, low cost, and prolonged stability. Approximately 80% of drugs are sold as tablets; 40% of which suffer from poor bioavailability [1].


Poor oral bioavailability can be due to several factors with poor solubility being of the most common causes. One of the methods to improve transient solubility and dissolution rate is to render the drug amorphous. Thanks to their higher free energy compared to their crystalline counterparts, amorphous materials have higher solubilities. However, this higher solubility is transient since the solution is supersaturated with respect to the crystalline solubility and crystallization is thermodynamically favored. To effectively utilize amorphous formulations, it is therefore necessary to delay crystal nucleation from the supersaturated solution formed upon dissolution. For amorphous formulations, polymers are commonly used to prevent crystallization; thus, enabling supersaturation to be maintained following dissolution of the dosage form. The effectiveness of a given polymer is highly dependent on its interaction with the particular compound under investigation. Herein, we evaluated crystallization from acetaminophen (APAP) supercooled melts and determined which polymers were most effective at reducing the crystal growth rate and at decreasing nucleation rates. The goals of the current work were to determine if there are any correlations between the crystallization inhibition effects of polymers in the solid state and in aqueous supersaturated solutions, as well as to explore methods for assessing the solution nucleation behavior using instrumented small scale crystallization vessels.

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Dr Kaoutar Abbou Oucherif is a senior consultant engineer at Eli Lilly, she also leads the Bioproduct Research and Development team at the Lilly Innovation Center in Cambridge, MA. Dr. Abbou Oucherif received her PhD in 2014 at the Purdue School of Chemical Engineering under Prof. Jim Litster and was co-advised by Prof. Lynne at the School of Industrial and Physical Pharmacy.

 

Reference:

  1. Babu, N. J. & Nangia, A. Solubility Advantage of Amorphous Drugs and Pharmaceutical Cocrystals Published as part of the Crystal Growth & Design 10th Anniversary Perspective. Cryst. Growth Des. 2662–2679 (2011)