Formulation development performance rating

Relative humidity can have a significant impact on drying behavior and film quahty. Water-based formulations that perform weU when apphed under dry conditions may be deficient under high humidity apphcation conditions. The rate of water evaporation is much slower at high humidity, but solvent evaporation continues. This results in solvent depletion during the critical phases of film formation and consequent poor film development. 

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. 

In almost all studies, a reference formulation is needed, either as a comparator for assessment of relative performance compared to the test formulation, or as a simple vehicle, to characterise the drug substance pharmacokinetics. If the aim is to investigate the influence of certain formulations on the rate and extent of absorption, which is the case in early development or IVIVC studies, an oral solution of the drug is the first choice as a reference formulation. Stability of the solution, regarding drug compound degradation and precipitation, is an important factor to verify before study start. Inclusion of a parenteral reference formulation, if feasible, provides additional information, as will be further discussed below. 

The literature is lacking of experimental and numerical studies of these binary mixtures. It is, however, crucial to investigate performance losses due to these mixtures. Experimental investigations can be used to outline the magnitude of their effects. The experimental measurements can then be used to outline a more comprehensive study for tertiary or higher order mixtures. Further, they are used to formulate the reaction rates for the purpose of developing a numerical model. 

Strain rate sensitivity of (or the effect of press speed on) the formulation is of primary concern in scale-up. Whether the product development work was performed on a single-stroke press or a smaller rotary press, the objective in operations will be to increase efficiency, in this case the tablet output rate and, therefore, the speed of the press. For a material that deforms exclusively by brittle fracture, there will be no concern. Materials that exhibit plastic deformation, which is a kinetic phenomenon, do exhibit strain rate sensitivity, and the effect of press speed will be significant. One must be aware that although specific ingredients (such as calcium phosphate and lactose) may exhibit predominately brittle fracture behavior, almost everything has some plastic deformation component, and for some materials (such as microcrystalline cellulose) plastic deformation is the predominant behavior. The usual parameter indication is that target tablet hardness cannot be achieved at the faster press speed. Slowing the press may be the only option to correct the problem. 

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