Stability of Drugs and Dosage Forms Sumie Yoshioka

108 Chapter 2 • Chemical Stability of Drug Substances
shaped crystals. 409 Solid-state hydrolysis of carbamazepine from needle-shaped crystals
with a higher Crystalline order is faster than that of beam-shaped and prismatic forms. 410
Reactivity of carbamazepine to light also depends on the crystalline form of the drug. 411
Differences in reactivity among different crystalline forms have also been reported for
photodegradation of furosemide. 412
The stability of drugs in their amorphous form is generally lower than that of drugs in
their crystalline form, because of the higher free-energy level of the amorphous state. The
relationship between degradation rate and crystallinity determined from heats of dissolution
for ß-lactam antibiotics such as sodium cefazolin indicates that a drug with low crystallinity
tends to have decreased chemical stability. 413
Decreased chemical stability of solid drugs brought about by mechanical stresses such
as grinding is said to be due to a change in crystalline state. For example, grinding of aspirin
increased its degradation rate in suspension form. A relationship between the stability and
grinding time was reported 414 (Fig. 92) and was attributed to the increased solubility of
aspirin due to a change in its crystalline state rather than to any increase in surface area.
The chemical stability of solid drugs is also affected by the crystalline state of the drug
through differences in surface area. For reactions that proceed on the solid surface of the
drug, an increase in the surface area can increase the amount of drug participating in the
reaction. For example, in a study of the reaction between solid-state sulfacetamide and
phthalic anhydride, the percent of the drug that reacted within 3 h increased with increasing
surface area, as shown in Fig. 93. 415
2.2.12. Effect of Moisture and Humidity on Solid and Semisolid Drugs
Drug degradation in heterogeneous systems such as solids and semisolid states is
affected by moisture. The effect of moisture and humidity on the degradation kinetics of
various drug substances including ascorbic acid, 416,417 thiamine salts, 418,419 aspirin, 420 vitamin
A 421 (Fig. 94), and ranitidine hydrochloride, 422 to name a few examples, has been
reported.
Moisture plays two primary roles in catalyzing chemical degradation. First, water
participates in the drug degradation process itself as a reactant, leading to hydrolysis,
Figure 92. Effect of grinding time on the degradation of aspirin in suspension at 40°C. , Zero-order rate constant;
, solubility. (Reproduced from Ref. 414 with permission.)