Preformulation stage chemical stability

In the early stage of preformulation, characterization of the drug molecule involves ionization constants and partition coefficient determinations, aqueous and nonaqueous kinetic and equilibrium solubility determination, pH solubility profile, chemical stability assessment, and salt and polymorph screening. Assessment of biopharmaceutics and toxicological screening are also essential... 

Early on in product development, the potential for the successful development of a solid oral dosage form is assessed, based on the physicochemical properties of the API (1). Prior to solid dosage form development, it is necessary to anticipate the physicochemical properties that can have a major influence on product manufacture and performance. The early development (preformulation and early formulation development) studies should focus on these properties so as to avoid problems at later stages of development. While the molecular properties dictate the intrinsic solubility and the chemical stability of the compound, by controlling the physical form of the compound and by modifying physical properties (e.g., particle size), the dissolution rate can be enhanced with the potential for improving bioavailability. This chapter will focus on physical properties including particle characteristics, and most importantly, the physical form (i.e., solid state) of the API. 

Data considered to be important for suspensions at the preformulation stage include solubility, particle size and propensity for crystal growth and chemical stability. Furthermore, during development, it will be important to have knowledge of the viscosity of the vehicle to obtain information with respect to settling of the suspended particles, syringibility and physical stability (Akers et al. 1987). In a report on the preformulation information required for suspensions, Morefield et al. (1987) investigated the relationship between the critical volume fraction as a function of pH. They noted that it is usually desirable to maximize the volume fraction of solids in order to minimize the volume of the dose . 

---