Pharmaceutical Manufacturing Handbook: Production and

968 ROLE OF PREFORMULATION IN DEVELOPMENT OF SOLID DOSAGE FORMS
should be compared with samples stored in an inert atmosphere. Photolytic degradation
is studied by exposing the sample to UV light (254 and 360 nm) for two to
four weeks and observed for color fading and/or darkening [33] . Color fading may
not always mean drug decomposition. It may be just a physical change which can
be overcome by including dyes in the formulation. As indicated earlier, the solid -
state reactions may be slow, sometimes generating only 1 – 5% of degradation products,
which may be below the detection limit of HPLC [34] . A combination of
qualitative and quantitative analytical tools is helpful to detect drug degradation.
Nevertheless, accelerated stability studies provide an early warning of potential drug
degradation and the preformulation scientist should use discretion in interpreting
and sharing the results with other development teams.
6.2.4.2 Solution - State Stability
Detailed solution - state stability is of limited value if the fi nal anticipated dosage
form is a solid. However, solution - state stability studies can predict the stability of
the drug in the granulating fl uid and the GI fl uids. Solution - state reactions are
faster than the solid - state reactions. This is helpful in generating degradation products
through so - called forced - degradation studies for toxicological screening and
analytical method development. The studies are conducted by exposing the drug
to extreme conditions such as 0.1 N HCl, 0.1 N NaOH, and water at 90 ° C [34] .
Forced - degradation studies are useful to qualify the safety of the degradation
products if it exceeds 0.1 or 0.05% of total daily dose for drugs with < 1 g or > 1 g
dose/day, respectively [6] .
The pH rate profi le is an important parameter that is studied in the solution state.
In early preformulation studies, an approximate pH rate profi le is generated, usually
including the pH encountered in salt selection and in vivo [55] . The studies are later
followed with a detailed pH profi le in the whole pH range of 1 – 10. A typical pH
rate profi le is shown in Figure 18 , which is useful to extract useful information on
K (day –1 )
2 4 6
pH
8 10
FIGURE 18 Representative pH kinetic rate profi le. The drug shows a minimal degradation
at around 2 – 4 and the degradation rate is high in alkaline pH.