Methods for Detecting Chemical and Physical Degradation

Critical for good studies involving the analysis of drugs and their degradants is the establishment and validation of so-called "stability indicating method(s)." Various chroma-tographic methods are best used to detect chemical changes with time under a variety of stress or nonstress conditions. Validated chromatographic separation techniques such as high-performance liquid chromatography (HPLC) and gas chromatography (GC) coupled to sophisticated detectors provide not only useful quantitative information on drug loss but also insight into the number of degradants formed and their quantitation. Based on the order of elution, insight into the properties of the degradants can also be gleaned. When coupled with detection techniques such as photodiode array UV-visible detection616 or mass spectrometry, chromatographic methods are invaluable. Some additional techniques and procedures that are used, especially with complex dosage forms, are described in the following sections.

4.1.1.1. Thermal Analysis

Differential scanning calorimetry (DSC), differential thermal analysis (DTA), and differential thermogravimetry (DTG) are very useful in formulation screening because calorimetric changes and weight changes caused by chemical and physical degradation of pharmaceuticals can be readily detected. For example, DSC was employed in the preformu-lation study of a poorly water-soluble drug substance, a-pentyl-3-(2-quinolinyl-methoxy)benzenemethanol (REV5901). As shown in Fig. 151, the free base exhibited an endothermic peak due to melting that was observed at the same position regardless of storage and measurement conditions. On the other hand, the anhydrous and monohydrate hydrochlo-ride salt forms showed different behaviors depending on measurement conditions. The free base was found to be more physically stable than the hydrochloride salt. Based on these results, the free base was chosen for formulation.617

Figure 151. Application of DSC to preformulation studies of REV5901. The DSC thermogram obtained for REV5901 free base (1) showed no significant change with changes in atmospheric conditions. DSC thermograms were recorded for the anhydrous hydrochloride salt on an open pan without purging with N2 (2), in a pan closed by crimping (3), and in a hermetically sealed pan (4) and for the monohydrate hydrochloride salt on an open pan without purging with N2 (5), on an open pan with purging with N2 (6), in a pan closed by crimping (7) and in a hermetically sealed pan (8). (A) Dehydration; (B) melting endotherms. (Reproduced from Ref. 617 with permission.)

Figure 151. Application of DSC to preformulation studies of REV5901. The DSC thermogram obtained for REV5901 free base (1) showed no significant change with changes in atmospheric conditions. DSC thermograms were recorded for the anhydrous hydrochloride salt on an open pan without purging with N2 (2), in a pan closed by crimping (3), and in a hermetically sealed pan (4) and for the monohydrate hydrochloride salt on an open pan without purging with N2 (5), on an open pan with purging with N2 (6), in a pan closed by crimping (7) and in a hermetically sealed pan (8). (A) Dehydration; (B) melting endotherms. (Reproduced from Ref. 617 with permission.)

20 40 80 120 160 200 temperature (°C)

20 40 80 120 160 200 temperature (°C)

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.621622 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 micro-calorimetry 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

Degradation Aspirin Versus
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.)
Pharmacophore Methaqualone
Figure 153. A natural logarithm plot of heat changes with time produced during the hydrolysis of aspirin at pH 1.1 and 45°C. (Reproduced from Ref. 625 with permission.)

Microcalorimeters are capable of measuring very small amounts of heat flow. This advantage of microcalorimetry was demonstrated in the measurement of the oxidation rate of a-tocopherol saturated with oxygen gas.632 As shown in Fig. 156, the rate constants for the temperature range 23-40°C determined by microcalorimetry were consistent with those extrapolated from the rate constants determined by HPLC at temperatures above 50°C. The rate constant at room temperature was determined rapidly by microcalorimetry, whereas its determination by HPLC would require long-term stability testing over several months. In this case, no change in activation energy was observed in the temperature range studied, indicating that the degradation rate at room temperature could be estimated by extrapolating accelerated data. Microcalorimetry is most effective, however, for degradation exhibiting nonlinear Arrhenius plots. For example, it can be used to determine degradation rates at room temperature when the degradation mechanism and apparent activation energy for degradation vary with temperature. In such cases, extrapolating stability data obtained at elevated temperatures can lead to overestimation or underestimation of the stability at room temperature.

Whereas microcalorimetry is most suitable for the study of degradations that result in relatively large enthalpy changes, such as those seen in the examples of oxidation and

Figure 154. pH-rate profiles for the degradation of ampicillin measured by microcalorimetry (□) and iodometric titration (♦) at 37°C. (Reproduced from Ref. 627 with permission.)

Iodometric Method

Figure 155. Linear relationship between heat flow and degradation of ascorbic acid in aqueous solution (pH 3.0-6.5,25°C). A, •, Glass vials, ascorbic acid concentration: 0.10% w/v; A, glass vials, N2-purged; □, glass vials, EDTA added O, stainless steel vessels; x, stainless steel vessels, EDTA added; +, glass vials, ascorbic acid concentration: 0.01% w/v. (Reproduced from Ref. 628 with permission.)

Figure 155. Linear relationship between heat flow and degradation of ascorbic acid in aqueous solution (pH 3.0-6.5,25°C). A, •, Glass vials, ascorbic acid concentration: 0.10% w/v; A, glass vials, N2-purged; □, glass vials, EDTA added O, stainless steel vessels; x, stainless steel vessels, EDTA added; +, glass vials, ascorbic acid concentration: 0.01% w/v. (Reproduced from Ref. 628 with permission.)

solid-state degradation given above, the technique may provide erroneous results for degradations accompanied by little heat flow. An additional limitation is that the technique is nonspecific and provides little information on the molecular mechanisms of degradation.

In addition to chemical degradation, microcalorimetry has been applied to the detection of physical changes in drug substances and excipients. An example is the change in the hydration of lactose.633

4.1.1.2. Diffuse Reflectance Spectroscopy

Diffuse reflectance spectroscopy (DRS), established by Kortum and co-workers in the 1950s,634 635 was employed by Lach and co-workers to detect the solid-state interactions between various drug substances such as oxytetracycline and various excipients such as

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Figure 156. Arrhenius plots of the oxidation rate constant of a-tocopherol measured by microcalorimetry (O) and HPLC (A). (Reproduced from Ref. 632 with permission.)

Figure 156. Arrhenius plots of the oxidation rate constant of a-tocopherol measured by microcalorimetry (O) and HPLC (A). (Reproduced from Ref. 632 with permission.)

magnesium trisilicate.636 645 The DRS spectrum of an isoniazid-magnesium oxide mixture exhibited a decrease in reflectance r_ with increasing isoniazid content, as shown in Fig. 157. The remission function, calculated by the Kubelka-Munk equation (Eq. 4.1), was proportional to isoniazid content (Fig. 158).640

Thus, the solid-state degradation could be followed quantitatively by DRS. A difficulty with the technique, especially when performed at short wavelengths, is spectral interference from the degradation products. On the other hand, visible color development of solid dosage forms alters spectra at relatively long wavelengths such that quantitative analysis by DRS is possible.640 Color development in an ascorbic acid-lactose mixture exhibited a remission function proportional to the ratio of colored to intact sample for both powders and tablets (Fig. 159), indicating that quantitative analyses are possible.646 The slope of the linear relationship depended on sample density, suggesting that measurement under constant conditions is necessary. DRS is especially useful for detecting small changes occurring locally on solid surfaces.

4.1.1.3. Miscellaneous Methods

NMR and infrared (IR) spectroscopy are also used to investigate the chemical stability of drug substances. Determination of the hydrolysis rate of esters such as atropine by NMR,647 a nondestructive near-IR analysis of aspirin tablets,648 and determination of the hydrolysis rate of diltiazem by polarimetry649 have been reported. Unusual methods, such as measurement of the dielectric properties of dosage forms like gelatin and methylcellulose microcapsules (Fig. 160), have been used to detect physical changes.650 651 These changes

Figure 157. Diffuse reflectance spectroscopy of isoniazid-magnesium oxide mixtures. Isoniazid concentration (mg/g of MgO): (A) 3, (B) 7, (C) 10, (D) 13, (E) 16. (Reproduced from Ref. 640 with permission.)
Medicine Stability Analysis

mole fraction of isoniazid/MgO (xlO-3)

Figure 158. Remission function of isoniazid-magnesium oxide mixture at 268 nm as a function of isoniazid content. (Reproduced from Ref. 640 with permission.)

mole fraction of isoniazid/MgO (xlO-3)

Figure 158. Remission function of isoniazid-magnesium oxide mixture at 268 nm as a function of isoniazid content. (Reproduced from Ref. 640 with permission.)

were then related to changes in drug release rates from these dosage forms. Measurement of weak chemiluminescence has also been applied to a stability study.652

In the formulation screening of solid dosage forms, chemical compatibility is sometimes evaluated using suspensions or slurries.653-656 Although this information may be difficult to relate to the stability of the dosage forms, it may provide some preliminary information on the stability of formulation components.

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