Solid-state forced degradation studies

TABLE 9-25. Solid-State Forced Degradation Studies... 

Forced Degradation Studies (Solid State and Solution)—Drug Substance and Drug Product... 

Forced degradation studies are carried out either in the solution state and/or in the solid state. Usually the forced degradation testing is carried out on one batch of drug substance and/or one formulation blend (capsules and tablets). This forced degradation testing should not be part of a formal stability program. 

The temperature/humidity conditions used may be more severe than the typical accelerated stability testing conditions in order to generate potential degradation products in a reasonable time. The typical forced degradation conditions include thermolytic, hydrolytic, oxidative, photolytic (in excess of ICH conditions), high pH (alkaline conditions), and low pH (acidic conditions). Outlined in Table 9-25 and Table 9-26 are some solid-state and solution forced degradation studies, respectively, that could be conducted. In the following... 

Forced degradation studies of API and DP include appropriate solid-state and solution-state stress conditions (e.g., acid/base hydrolysis, heat/humidity, oxidation, and light exposure) in accordance with ICH guidelines (Figure 2, Steps 2 and 3). Forced degradation studies should be conducted whenever a stability-indicating... 

The adsorption of proteins from aqueous solution to solid surfaces is the result of a combination of hydrophobic, steric, and electrostatic interactions between the protein, solid surface, and solution [ 1-3]. Numerous studies have been conducted to identify the driving forces governing protein adsorption and dynamics at liquid-solid interfaces and have been reviewed elsewhere [4—8], In the adsorbed state, protein stmcture is likely to be perturbed (Figure 15.1). The unfolded or partially unfolded protein can then adopt various flexible conformations depending on the natures of the solid surface the protein [1, 4, 9-13]. While this has been exploited for various applications [12], uncontrolled adsorption can cause protein degradation, compromised function, and even life-threatening immunogenic responses. The molecular mechanisms of protein adsorption have not been fully elucidated and remain a current area of research [ 10]. 

As can be seen in this figure, a polymer behaves differently compared with substances having small molecules. There is a crystalline phase in addition to the amorphous solid and liquid phases. By the time the temperatures that are needed to vaporize the polymer are achieved, in practice they may degrade or depo-lymerize. The rest of the chapter is devoted to the study of the equations of state that can be used to describe the behavior of polymer systems. Negative pressures must be watched for in these systems. One feature that comes out clearly from the analysis presented in Sections 2.1.1 and 2.1.2 is that pressure in a box filled with gas molecules is the force exerted by the gas molecules on the walls of the container. The minimum pressure achievable is zero Nm". This can happen at very low temperatures when the velocity of the molecules reaches a state of rest or zero velocity. At this juncture, or at some time prior to this juncture, the force exerted by the molecules on the walls of the container will be zero and hence the pressure is zero. Any value of pressure lower than 0, such as negative pressure, cannot accurately describe real substances. It could be that it derives from a mathematical model that is no longer valid to describe the system in that range of conditions. 

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