Stability-indicating capabilities

According to the ICH guideline on stability testing, the purpose of stress testing is twofold [45]. First, it can be used to predict the stability of the molecule and from the degradation products establish degradation pathways. Second, it can validate the stability-indicating capability of the analytical... 

QIE Evaluation of Stability Data Page 2 Factors that can cause an apparent lack of mass balance should be considered, including, for example, the mechanisms of degradation and the stability-indicating capability and inherent variability of the analytical procedures... 

The scope of ICH QIE addresses the evaluation of stability data that should be submitted in registration applications for new molecular entities and their associated drug products. A systematic approach should be adopted in the presentation and evaluation of the stability information. The stability information should include, as appropriate, results from physical, chemical, biological, and microbiological tests. Mass balance should be assessed and the factors that can cause an apparent lack of mass balance the mechanism of degradation and the stability-indicating capability and inherent variability of the analytical procedures. 

A stability-indicating assay of econazole nitrate in cream and lotion formulations has been reported9. Samples of cream or lotion are dispersed in tetrahydrofuran and extracted into methanolic and aqueous methanolic solutions. They are then filtered prior to analysis. Chromatography was performed on a Waters uBondapak C18 Column (30 cm x 3.9mm) and UV detection at 220 nm was used. The mobile phase consisted of 780 ml of methanol, 20 ml of tetrahydrofuran and 200 ml of ammonium carbonate solution (0.1% w/v), at a flow rate of 2.0 ml/min. The method was shown to be capable... 

A reliable analytical method must be available before preformulation studies are started and hence method development activities must precede preformulation activities. The analytical method should be capable of separating the active and any major degradation product(s) and thus be stability-indicating. Analytical methods such as titration and ultraviolet (UV) spectroscopy are not used since they are not considered to be stability-indicating. Only HPLC has been widely used as the method of choice in recent years because of its efficiency, applicability for a wide range of chemical compounds, and ease of... 

An HPLC method for the estimation of potency and determination of degradation products is an integral part of release testing. The analytical method should be stability indicating and capable of separating the active ingredient peak from degradation product, process impurity, and excipient-related peaks (Fig. 1). 

In the early stages of product development, there is usually a bottleneck in the analytical department. Most companies work on the basis of allowing two analysts per formulator, but this ratio is often inadequate. It is of paramount importance that the analytical department be involved in the early stages of the formulation process. These are the people who will have to analyse the prototype formulations and look for evidence of stability problems as soon as possible. They are, of course, capable and equipped to do this, but time will be saved if they know precisely what materials the formulator is putting into the prototypes. There is no substitute for a fully validated stability indicating assay, but initial rough analytical methods can be extremely useful for determining what excipients to avoid and what conditions, such as pH, are critical to the formulation. 

Stability aspects of SLMs were investigated in DC18C6-facilitated, diffusion-limited transport of uranyl ion across a flat-sheet SLM. Solvent effects on the cation flux and diffusion coefficients were evaluated (44). The results of this study indicated that the stability and transmembrane fluxes depend on the physico-chemical characteristics of the carrier-diluent combination, not on the characteristics of the diluent alone. The physico-chemical properties of some diluents tested in the study are given in Table 5. Greater membrane stability was obtained with a membrane solvent of low volatility and aqueous solubility. Among the various diluents tested, a mixture of o-dichlorobenzene and toluene (3 7 by volume) gave the best combination of stability, regeneration capability, and transport rates. 

As seen in the preceding section, the discoloration of degraded poly(vinyl chloride) is due to the formation of polyene sequences. Some stabilizers are capable of restoring the original colour of the polymer, indicating reaction with the polyenes present. For example, dibutyltin maleate undergoes a Diels-Alder reaction with polyenes [15]. Thus the sequence of conjugated double bonds is shortened. 

N-Nitrosamine inhibitors Ascorbic acid and its derivatives, andDC-tocopherol have been widely studied as inhibitors of the N-nitrosation reactions in bacon (33,48-51). The effect of sodium ascorbate on NPYR formation is variable, complete inhibition is not achieved, and although results indicate lower levels of NPYR in ascorbate-containing bacon, there are examples of increases (52). Recently, it has been concluded (29) that the essential but probably not the only requirement for a potential anti-N-nitrosamine agent in bacon are its (a) ability to trap NO radicals, (b) lipophilicity, (c) non-steam volatility and (d) heat stability up to 174 C (maximum frying temperature). These appear important requirements since the precursors of NPYR have been associated with bacon adipose tissue (15). Consequently, ascorbyl paImitate has been found to be more effective than sodium ascorbate in reducing N-nitrosamine formation (33), while long chain acetals of ascorbic acid, when used at the 500 and lOOO mg/kg levels have been reported to be capable of reducing the formation of N-nitrosamines in the cooked-out fat by 92 and 97%, respectively (49). 

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