Solid-state degradation

Fractional Order. In the decomposition of pure solids, the kinetics of reactions can often be more complex than simple zero- or first-order processes. Carstensen [88] has reviewed the stability of solids and solid dosage forms as well as the equations that can be used in these cases. In addition to zero- and first-order kinetics, solid-state degradations are often described by fractional-order equations. 

These data suggest that the formation of species such as SbX3 may not only be important because of their volatility and flame inhibition, but also for the role they play in the solid state degradation chemistry. 

In conclusion, on the basis of evaluation of the literature and kinetic considerations in conjunction with our stress-testing experience over the last 15 years, temperatures of up to 70°C (at high and low humidities) should provide a rapid, reasonably predictive assessment of the solid-state degradation pathways and relative stabilities of most drug substances at... 

Figure 1 Solid-state degradation models, a—fraction decomposed. A = Prout-Tompkins, kt = ln(-p ), B = 2 dimensional phase boundary kl = l-(l-a)1 2, C=Avrami-Erofeev, kt — [—ln(l — a)] , w=l, D = Avrami-Erofeev, = 0.5.

Calorimetric forms of the Ng equation were used by Willson et al. (7) to analyse the solid-state degradation of L-ascorbic acid. Known amounts (0.5 g) of dry L-ascorbic acid were placed in ampoules along with known quantities of water and the heat changes in the samples were recorded using an isothermal microcalorimeter. The power-time data obtained were analyzed using the calorimetric form of the Ng equation and the parameters obtained are shown in Table 7. It was shown that, at low added quantities of added water, the reaction could satisfactorily be described by solid-state kinetics, but at higher added quantities of water (more than 500 pL) the reaction was best described by solution phase kinetics. 

Table 4 Observed Rate Constant for the Solid-state Degradation of Procaine Penicillin G Stored at 55° C and 67% RH...

In principle, solid state degradation should also take place slowly in surface moisture films at ambient temperatures and humidities. Similar products are to be expected as for solution degradation, but no studies were found that examined this phenomenon. Given the high concentrations of substrate that are present in surface moisture films, there is also the possibility that intermolecular self-aminolysis and polymerization could occur, in addition to the intramolecular reaction reported under anhydrous conditions by Grant and coworkers. 

Shalaev, E.Y. Zografi, G. How does residual water affect the solid state degradation of drugs in the amorphous state. J. Pharm. Sci 1996, 85, 1137-1141. 

Solid state degradation of amoxicillin trihydrate and sodium salt gave qualitative increases in the piperazine-2,5-dione (VI) and in unidentified peaks which were tentatively ascribed to amoxicillin oligomers and their penicilloates [38], Amoxicillin penicilloic acid increased in the trihydrate but not in the sodium salt. 

The solid-state degradation of candidate drugs, particularly in the candidate selection phase, is an important consideration, as degradation rates as slow... 

Argyroponlos, D. S., and Snn, Y, Photochemically induced solid-state degradation, condensation, and rearrangement reactions in lignin model compounds and milled wood iignin, Photochem. andPhotobiol. 64(3), 510-517 (1996). 

DS Argyropoulos and Y Sun. Photochemically Induced Solid-State Degradation, Condensation, and Rearrangement Reactions in Lignin Model Compounds and Milled Wood Lignin. Photochem Phorobiol 64 510-517, 1996. 

Because the radiation in most cases will not penetrate the entire sample, the concentration of the reactant is unlikely to approach zero at infinite time. A plot of remaining concentration vs. time will therefore level off at a value greater than zero. This should be taken into account when selecting the kinetic model for studies of solid-state degradation (Sande, 1996). The solid-state degradation will in some cases appear to consist of a series of consecutive processes with different mechanisms and rates (Carstensen, 1974). Such a stepwise change in reaction rate is most likely caused by an alteration in sample surface and fading of subsequent layers. The concept of reaction order may not be useful for photodecomposition in the solid state (De VUliers et al 1992). 

The fact that molecular movements in the solid state are restricted and that the sample permeability to oxygen and moisture can be low may lead to an alteration in product formation compared to the drug in solution. This is illustrated by formation of new rotamers in the solid-state degradation of tolrestat favoring of the redox product in the solid-state degradation of nifedipine compared to the photo-oxidation product observed in solution or by diversity in degradation products of santonins in solution and in the solid state (Reisch et al., 1986 Lee and Lee, 1990 Marciniec and Rychcik, 1994). These observations emphasize that results obtained on the drug substance in solution are not necessarily valid for the solid state. 

A descriptor rate constant for solid-state degradation can be obtained once a theoretical rate equation has been derived and the data have been tested to see if they conform to the proposed model. However, for solid-state degradation in which the factors affecting the degradation mechanism have not been elucidated, because of the complexity involved, often an apparent constant (or constants) obtained by fitting the observed degradation curve to an empirical equation or equations is utilized. Such constants and the empirical relationships themselves can sometimes be used for stability prediction purposes. This section first discusses various theoretical equations used to describe the solid-state stability of drugs and introduces an empirical equation that can often describe the data adequately. 

Figure 18. Schematic representation of the Jander model for solid-state degradation.

The effect of humidity on the solid-state degradation rates of propantheline bromide and meclofenoxate hydrochloride has been described by... 

Figure 101. Effect of silica gel and moisture content on the solid-state degradation of ascorbic acid during storage at 45°C for 3 weeks, o, 300 mg ascorbic acid , 300 mg ascorbic acid and 80 mg silica gel X, 300 mg ascorbic acid and 640 mg silica gel. (Reproduced from Ref. 451 with permission.)...

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... 

The kinetics of solid-state degradation of peptide and protein pharmaceuticals is difficult to describe for many of the same reasons that it is difficult to describe solid-state inactivation of small molecules. Apparent inactivation of digestive enzymes such as lipase was analyzed empirically using the Weibull equation (Eq. 2.69), as shown in Fig. 209,880-881 whereas apparent inactivation of dry horse serum cholinesterase was adequately described by a first-order equation even for inactivation in the solid state.882... 

Apparent activation energy values have also been reported for solid-state degradation of peptide and protein pharmaceuticals. The reported values include 1-2 kcal/mol for human interferon-P formulated with human serum albumin887 15 kcal/mol for freeze-dried urokinase (Fig. 213)838 and 11-18 kcal/mol for a-chymotrypsin and bromelain tablets, kallikrein capsules, and P-galactosidase powder (Fig. 214).888... 

Solid-state degradation is not straightforward to model and predict as the first step is some sort of disruption of the crystal that has large activation energy. When this is true, although high-temperature studies may show degradation, the rate will decrease rapidly with decreased temperature, perhaps 10-fold per 10°C decrease in temperature. 

Adenosine, as a 2 1 mixture of the R - and (S) isomers, has been synthesized from D-[5- H]xylose. The observed spin-spin coupling between the residual 5 -protons and H-4 showed that the gauche-gauche rotamer is preponderant (ca. 70%) and the gauche-trans rotamer of minor importance (ca. 20%) in aqueous solution, contrasting with the preference for the latter rotamer exhibited by adenosine in the solid state. Degradative studies have established that naturally... 

Polymer degradation can be observed in solution, in melt or in the solid state. Degradation in solution is principally used vith model compounds for kinetics studies, vhereas degradation in melt is frequently associated vith processing con-... 

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