(88c) Crystallization Tendency of Active Pharmaceutical Ingredients and the Ability of Polymeric Additives to Alter Crystallization Behavior From Undercooled Melts

BACKGROUND AND SIGNIFICANCE The overall goal of this research is to gain a better understanding of the underlying mechanisms controlling the crystallization tendency of organic molecules from the undercooled melt and glassy state, and to investigate the influence of polymeric additives on crystallization behavior. Current understanding of the inherent crystallization tendency of organic molecules upon cooling from the undercooled melt (glass-forming ability or GFA) and the relationship between this and the long term physical stability of any resultant glass (glass stability or GS) is marginal at best. Hence it is essential to develop a more fundamental understanding of how the molecular properties influence the GFA and GS of organic compounds as well as the ability of polymeric additives to disrupt crystallization from both the undercooled liquid and glassy solid at a mechanistic level.

In an era of drug discovery where a large percentage of new chemical entities have a low aqueous solubility, dispersing the active pharmaceutical ingredient (API) in a hydrophilic polymer to form an amorphous solid dispersion is becoming of increasing interest as a formulation technique to improve bioavailability. An important criterion in assessing if an API is a potentially suitable candidate for an amorphous formulation is its physical stability, both during the processing operation and during storage. Understanding the interplay between molecular properties, formulation, and processing parameters will enable development of robust predictive models to rationally assess the crystallization tendency of new chemical entities, enabling early decision about whether delivering the drug as a solid dispersion is a viable formulation option.

METHODS The crystallization tendency of 51 organic molecules from the undercooled melt was screened using differential scanning calorimetry (DSC). Samples were prepared in hermetically-sealed pans, heated at 10°C min^-1 through the melting temperature, held isothermally for 3 minutes, rapidly cooled at 20°C min^-1 to -75°C, and reheated at 10°C min^-1 through the melting temperature. The compounds were separated into three distinct classes based on their crystallization behavior: class (I) ? crystallization observed during cooling from the undercooled melt prior to the T_g event, class (II) ? crystallization not observed upon cooling from the undercooled melt to below T_g, however crystallization was observed during reheating above T_g, and class (III) ? crystallization not observed upon either cooling to below T_g or upon subsequent reheating up through the melting point. Drug:polymer mixtures of varying wt% ratios were prepared by cryomilling and the same heat/cool/heat cycle described above was performed in the DSC, observing the wt% polymer required to inhibit crystallization upon either cooling and/or reheating. A principal component analysis (PCA) was performed using various thermal (T_melt, T_g, ΔH_fus, ΔS_fus, ΔG_v) and molecular (MW, # rotatable bonds) input parameters from the set of organic molecules to investigate the potential link between a molecule's physiochemical properties and its crystallization tendency.

RESULTS From the DSC screening study, 23 molecules were classified as class (I), 11 as class (II), and 17 as class (III). A PCA model was generated from the data with 3 principal components, and could explain 97.8% of the variation in the input parameters. Contribution plots of the descriptors used in the model show that on average compounds with higher crystallization tendency [class (I)] tend to be lower MW, simpler structures compared to compounds with lower crystallization tendency [class (III)]. Additionally, both ΔH_fus and ΔS_fus tend to be higher for class (I) molecules [and lower for class (III) molecules]. These results show that multiple physicochemical properties appear to play a role in dictating crystallization tendency. The ability of polymeric additives to alter crystallization tendency varied depending on the inherent crystallization tendency of the molecule. Data collected showed that compounds with high crystallization tendency [class (I)] require significantly more polymer to inhibit crystallization from the undercooled melt compared to compounds with lower crystallization tendency [class (II)]. This indicates that the ability of a polymer to inhibit crystallization is dependent on the inherent crystallization tendency of a molecule. Additionally, the relative effectiveness of a polymer to inhibit crystallization varied between drug compounds, believed to be in part due to the ability of the polymer to specifically interact with the drug through hydrogen bonding.

CONCLUSIONS The screening method developed in this study and the resulting classification scheme is a potentially useful tool to rationally assess the crystallization tendency of new chemical entities, greatly reducing unneeded experiments and thus allowing more well-informed decisions on formulation strategies. The effect of polymeric addition on altering crystallization behavior varied depending on the inherent crystallization tendency of the drug as well as the presence of specific drug-polymer interactions. The National Science Foundation Engineering Research Center for Structured Organic Particulate Systems (NSF ERC-SOPS)(EEC-0540855) is acknowledged for financial support.