Stability-indicating analytical methods, development

In order to assess the stability of a compound, one needs an appropriate method. The development of stability-indicating analytical method, particularly an impurity method, is a chicken and egg type of problem. That is, how does one develop an impurity method to detect degradation products... 

Stress testing is an important part of the drug development process as it provides knowledge about the degradation chemistry of drug compounds. This knowledge is used primarily to develop stability-indicating analytical methods but is also useful for other purposes such as formulation develop-... 

Develop and characterize stability-indicating analytical method. 

Procedures for the development of stability-indicating analytical methods. 

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... 

Outsourcing the development, validation, and performance of analytical methods in recent years has become a popular means to facilitate movement of product through the development process. A recent industry survey reported that the vast majority (86%) of the companies responding say they outsource analytical methods development to contract laboratories. Twenty-five percent of the responding firms indicated that they often or always contract out stability testing on development compounds [37]. There are important criteria to follow in working with contract laboratories to ensure that their methods validation procedures yield results that are consistent with those of the client company [38]. This topic will be discussed later in this chapter. 

Zhang et al. [43] developed and validated a stability indicating HPLC method for the determination of lornoxicam in pharmaceutical formulation. The isocratic procedure was performed in Shimadzu ODS (4.6 mm x 15 cm, 5 pm) column maintained at 25 °C. The mobile phase was degassed mixture of sodium acetate (0.05 mol/L, pH 5.8) and methanol (55 45). The flow rate was 1 ml/min and detection at 290 nm. Selectivity, specificity, linearity, precision, accuracy, and robustness were evaluated to validate the analytical method. Forced degradation studies were performed to provide an indication of the stability-indicating capacity. The stability indicating method for lornoxicam in the injectable dosage was developed and validated. The method can be considered for routine analysis and quality control of lornoxicam in injectable formulation. 

From the current regulatory point of view, tartaric acid as a food additive seems not to have any direct health implications. Toxicity values indicate no potential danger for the population, providing a justification for the fact that the analytical methods developed are focused on the technological effects of the compound (such as cold stabilization in wineries). Antioxidant effects, direct or indirect (via copper and iron complexation or sequestration), might also be of interest in the future, and the developed flow methods presented here and in Chapter 38 have been shown to provide a reliable assessment of these effects. 

The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small but deliberate variations in the analytical procedure parameters. The robustness of the analytical procedure provides an indication of its reliability during normal use. The evaluation of robustness should be considered during development of the analytical procedure. If measurements are susceptible to variations in analytical conditions, the analytical conditions should be suitably controlled or a precautionary statement should be included in the procedure. For example, if the resolution of a critical pair of peaks was very sensitive to the percentage of organic composition in the mobile phase, that observation would have been observed during method development and should be stressed in the procedure. Common variations that are investigated for robustness include filter effect, stability of analytical solutions, extraction time during sample preparation, pH variations in the mobile-phase composition, variations in mobile-phase composition, columns, temperature effect, and flow rate. 

All of the background information discussed in the addendum (Common Functional Groups) will help an analytical chemist with development of a stability-indicating method (SIM) that will assist in the development of an optimized formulation that will become a drug product in the marketplace. Remember, an analytical chemist must be able to provide knowledge, not just data. 

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