title: Use of enthalpy and Gibbs free energy to evaluate the risk of amorphous formation.
abstract: The control of crystalline and amorphous phases is important during the development of a new drug candidate. Our approach begins with an understanding of the thermodynamics of these two phases. We have developed a quantitative yet practical work flow consisting of three steps towards the analysis of the risk of amorphous material formation. First, we derive the thermodynamic equations to calculate the enthalpy, Gibbs free energy, and the solubility of each phase and their differences as a function of temperature. The enthalpy for each crystalline drug substance at its melting point is selected as the reference state to enable a consistent approach for all analysis. Second, we use data from DSC measurements and the derived thermodynamic equations to construct the enthalpy, Gibbs free energy and solubility diagrams so as to compare the characteristics of these two phases. Finally, we use the results of these calculations to evaluate the potential risk of crystalline-to-amorphous phase conversion during processing of either the drug substance or the drug product. In addition, the impact of amorphous formation on solubility is evaluated. Two drug candidates are used to illustrate this workflow for risk analysis.
authors.affiliation: Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Hsieh
authors.forename: Beth A
authors.initials: BA
authors.lastname: Sarsfield
authors.forename: Martha
authors.initials: M
authors.lastname: Davidovich
authors.forename: Lynn M
authors.initials: LM
authors.lastname: DiMemmo
authors.forename: Shih-Ying
authors.initials: SY
authors.lastname: Chang
authors.forename: San
authors.initials: S
authors.lastname: Kiang
mesh_terms: D003460:Crystallization; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D013816:Thermodynamics; D044366:Transition Temperature
chemical_list: D004364:Pharmaceutical Preparations