Stability-indicating methodologies

In the typical dmg-excipient compatibility testing program, binary powder mixes are prepared by triturating API with the individual excipients. These powder samples, usually with or without added water and occasionally compacted or prepared as slurries, are stored under accelerated conditions and analysed by stability-indicating methodology, for example, HPLC, CE and so forth. This entire process takes considerable time and resources. 

The stability protocol should include methodology for each parameter assessed during the stability evaluation of the drug substance and the drug product. The protocol should also address analyses and approaches for the evaluation of results and the determination of the expiration dating period, or retest period. The stability-indicating methodology should be validated by the manufacturer and described in sufficient detail to permit validation or verification by FDA laboratories. 

USP<11> USP Reference Standards To ensure that the Reference Standards maintain the properties determined at the initial evaluation, USP maintains a Continued Suitability for Use Program. Abbreviated protocols use the stability-indicating methodology employed in the initial characterization of the material to confirm the consistency of attributes such as appearance, chromatographic purity, or volatiles content... 

The key to any stability analysis will be to select the proper stability indicating methodology to ensure that the critical properties of the material under study do not change overtime. It is crucial that we monitor both the chemical stability as well as the physical stability for a duration that will be long enough so that the... 

Stability of a drug substance and product is monitored throughout the development and clinical phases. This monitoring requires stability-indicating assay methodology, and this is a subject that is separate from performulation per se. In most instances, the major, feasible decomposition products are identified early [51], and as such it is known if the pathways are hydrolytic, oxidative, or photochemical. 

In developing HPLC methodology, these validation requirements stipulate that stability-indicating impurity methods be designed and validated to ... 

Provide analytical methodology with data to support stability-indicating confidence... 

Challenge current analytical methodology with updated KPSS Rugged analytical method with high confidence in stability-indicating ability no further method development activities expected (unless API/ formulation process changes warrant further work)... 

With a knowledge of the methodology in hand, let s review the results of amino acid composition and sequence studies on proteins. Table 5.8 lists the relative frequencies of the amino acids in various proteins. It is very unusual for a globular protein to have an amino acid composition that deviates substantially from these values. Apparently, these abundances reflect a distribution of amino acid polarities that is optimal for protein stability in an aqueous milieu. Membrane proteins have relatively more hydrophobic and fewer ionic amino acids, a condition consistent with their location. Fibrous proteins may show compositions that are atypical with respect to these norms, indicating an underlying relationship between the composition and the structure of these proteins. 

In the micellar region the trend to decreasing colloid stability is arrested and a partial improvement, in line with the enhanced level of polymer adsorption, is noted until the conditions for gross phase separation are reached. Only the intermediate block copolymer BC 42 shows indications of discontinuities in behavior at the solvent composition for micelle formation. The results presented here do not show the sharp transition from stability to instability found experimentally (4,8,17) by Napper and generally expected on theoretical grounds. However, there are important differences in experimental methodology that must be emphasised. 

When one polymorph can be thermally converted to another, differential scanning calorimetry (DSC) analysis cannot be used to deduce the heat of transition between the two forms, and so solution calorimetry represents an alternative methodology. This situation was encountered when evaluating the polymorphs of losartan [140], Enthalpies of transition were obtained in water (A(A//sol) = 1.723 kcal/mol) and in A A-dimethylformarnide (A(A//S0 ) = 1.757 kcal/mol), with the equivalence in results demonstrating the quality of the results. Although enthalpy does not indicate stability, the authors deduced from solution calorimetry that form I was more stable than form II at ambient temperature. 

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