Crystallization Tendency of Amorphous Pharmaceuticals Prepared by Rapid Solvent Evaporation: Classification, Comparison with Undercooled Melts and Interpretation in Terms of Physico-Chemical Drug Compound Characteristics

Thursday, November 11, 2010: 9:55 AM
Grand Ballroom D (Salt Palace Convention Center)
Bernard Van Eerdenbrugh1, Jared Baird2 and Lynne Taylor2, (1)Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, (2)Industrial & Physical Pharmacy, Purdue University, West lafayette, IN

Knowledge of the crystallization tendency of pure amorphous active pharmaceutical ingredients (APIs) yields information that is key to the evaluation of the use of amorphous solid dispersions as a formulation platform. However, to date, systems enabling the classification of the crystallization tendency of amorphous APIs are lacking. This presentation describes the development of such a classification system for APIs prepared by rapid solvent evaporation. Initial screening to determine model compound suitability was performed using a structurally diverse set of 51 compounds in 3 different solvent systems. Of this starting set of 153 drug-solvent combinations, 93 (40 compounds) were selected for further evaluation based on solubility, chemical solution stability and processability criteria. These systems were spin coated and their crystallization tendency was monitored using polarized light microscopy. The crystallization behavior of the samples could be classified as rapid (Class I, 39 cases), intermediate (Class II, 23 cases) or slow (Class III, 31 cases). The solvent system employed influenced the classification outcome for only four of the compounds. The various compounds showed very diverse crystallization behaviors. Upon comparison of classification results with those of a previous study [1], where cooling from the melt was used as a preparation technique, a good similarity was found whereby 68 % of the cases were identically classified. Principal component analysis (PCA) was performed using a set of relevant physicochemical compound characteristics (melting point, glass transition temperature, heat of fusion, entropy of fusion, the free energy difference between the crystalline and amorphous states, molecular weight and the number of rotatable bonds). It was found that a number of these parameters tended to differ between the different classes. These could be further interpreted in terms of the nature of the crystallization process. Additional multivariate analysis on the separate classes of compounds indicated some potential in predicting the crystallization tendency of a given compound.


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

Reference: [1] Baird JA, Van Eerdenbrugh B, Taylor. LS 2010. A Classification System to Assess the Crystallization Tendency of Organic Molecules from Undercooled Melts. J Pharm Sci. DOI: 10.1002/jps.22197

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