Stability of Drugs and Dosage Forms Sumie Yoshioka

4.1. • Preformulation and Formulation Stability Studies 153
Thermal analysis is often capable of easily detecting drug-excipient interactions. For
example, accelerated degradation of aspirin caused by physical mixture with silica and
aluminum was detected by DSC. 618 Interaction of ibuprofen with magnesium oxide was
detected from changes in DSC thermograms (Fig. 152), 619 as was an interaction between
enalapril maleate and crystalline cellulose leading to decreased stability. 620 Various other
drug–excipient interactions have been detected by this thermal analysis method. 621,622 DSC
can also be employed to investigate the stability of finished dosage forms, as was done, for
example, with aminophylline suppository formulation. 623
DSC, DTA, and DTG are useful for detecting physical changes in addition to chemical
degradation. Crystallization of amorphous drugs and polymorphic transitions (see Chapter
3) have been extensively studied using these methods. 568,580,581
The kinetics of degradation can be studied using isothermal calorimetry, that is,
calorimetry performed at constant temperature. Recently, sensitive thermal conductivity
microcalorimeters useful for detecting even small amounts of degradation at room temperature
have become available. For example, the slow solid-state degradation of cephalosporins
at a rate of approximately 1% per year was successfully measured by microcalorimetry. 624
Microcalorimetry has been employed in studying the kinetics of chemical degradation
of various drug substances. Heat flow produced from the hydrolysis of aspirin in acidic
solution decreased according to first-order kinetics as shown in Fig. 153, indicating that
degradation can be measured by microcalorimetry. 625,626 Apparent first-order rate constants
for ampicillin degradation in aqueous solution measured by microcalorimetry exhibited a
pH–rate profile similar to that obtained from iodometric titrations (Fig. 154). 627 The total
heat flow produced from oxidation of ascorbic acid in aqueous solution measured in various
vessels was proportional to the amount of degraded ascorbic acid, indicating that the
degradation can be easily followed (Fig. 155). 628 The apparent enthalpy change of this
oxidation was calculated to be 224 kJ/mol. Initial heat flow measurements utilizing microcalorimetry
at several elevated temperatures have been used to calculate the energy of
activation for the degradation of drug substances such as tetracycline and phenytoin. The
degradation rate at 25°C was predicted from the rate constant obtained by HPLC and the
activation energy obtained by microcalorimetry. 629 Microcalorimetry has also been used for
determining degradation order and mechanism. 630,631
Figure 152. DSC thermograms showing the interaction between ibuprofen and magnesium oxide. (1:1 mixture).
(a) Before storage; (b) after 1-day storage at 55°C. (Reproduced from Ref. 619 with permission.)