Excipient Impurities

Selective differential UV spectrophotometric method was presented for the determination of niclosamide in bulk and in its pharmaceuticals [43]. The method was based on measuring niclosamide in alkaline solutions against their neutral ethanolic solutions as blanks. The proposed method was sensitive, highly specific, and advantageous over the conventional UV assays, since the interference of the excipients, impurities, degradation products, or other accompanying drugs was nullified. 

Starting materials, solvents, intermediates, degradation products, and by-products are often organic impurities found in drug substances and excipients, while excipient impurities, solvents, by-products, degradation products, and container/closure adducts may be found as organic impurities in drug products. 

Some excipients contain a certain amount of amorphous form such as spray-dried lactose,27 and others are hygroscopic, such as microcrystalline cellulose.28 These excipients will adsorb water, which causes a change in the micro-environment of the formulation. If the drug substance is moisture-sensitive, degradation may occur quickly. Therefore, consider both drug-excipient compatibility and excipient impurity profile in selecting excipients for low-dose drug products. 

Excipient impurity profiles and how to evaluate this important aspect of excipient manufacture, particularly in light of the International Conference on Harmonization (ICH) guidance published in 1999, also are addressed. Care must also be taken that residual solvent levels do not exceed those prescribed in the ICH Guidance for Residual Solvents published in 1999. Solvents are divided into three classes ... 

GL18 Impurities Residual Solvents Impurities residual solvents in new veterinary medicinal products, active substances and excipients... 

Phyllosilicates, in addition to talc and silica, have recently been evaluated for their use as tableting excipients. These compounds include the smectites, pa-lygorskites, and sepiolites [85a]. Although they show some promise, current levels of metallic impurities are currently too high for use in pharmaceutical preparations. 

The validation process begun in Phase I is extended during Phase II. In this phase, selectivity is investigated using various batches of drugs, available impurities, excipients, and samples from stability studies. Accuracy should be determined using at least three levels of concentration, and the intermediate precision and the quantitation limit should be tested. For quality assurance evaluation of the analysis results, control charts can be used, such as the Shewart-charts, the R-charts, or the Cusum-charts. In this phase, the analytical method is refined for routine use. 

Streptokinase is a 48 kDa extracellular bacterial protein produced by several strains of Streptococcus haemolyticus group C. Its ability to induce lysis of blood clots was first demonstrated in 1933. Early therapeutic preparations administered to patients often caused immunological and other complications, usually prompted by impurities present in these products. Chromatographic purification (particularly using gel filtration and ion-exchange columns) overcame many of these initial difficulties. Modern chromatographically pure streptokinase preparations are usually supplied in freeze-dried form. These preparations (still obtained by non-recombinant means) often contain albumin as an excipient. The albumin prevents flocculation of the active ingredient upon its reconstitution. 

If an excipient had been observed, it would need to be identified. In Fig. 13.34, the drug substance standard is applied on lane 1 next to the extracted tablet. The remaining lanes labeled 2-12 are individual excipients in this particular tablet. Only one excipient, number 6, appears and it does in fact have the same R value as the band observed in the tablet. This confirmatory test is commonly used to identify interfering excipients. Now this band can be labeled appropriately, rather than mistakenly labeled as a degradant or impurity. 

From a regulatory standpoint, the FDA s concern regarding safety involves the toxicity, degradants, and impurities of excipients, as discussed in other chapters in this book. In addition, other chapters of this book address types of toxicity concerns, toxicity testing strategies, and exposure and risk assessment of excipients. 

Because of antibody-based selectivity, ELISAs are capable of handling samples that are impure or only semipurihed. It is possible to perform ELISAs in a variety of matrices. This is in contrast to other methods such as HPLC that require relatively pure material. During the development and validation of the ELISA method, it needs to be demonstrated that the ELISA is not affected by interfering substances that could be in the test sample, such as buffers, salts, contaminating proteins, and excipients. It also needs to be demonstrated that the conjugated antibody does not bind nonspecihcally to the coated solid phase. 

FIGURE 19 HPLC separation of the same stability sample shown in Figure 18 under gradient conditions showing better resolution and increased sensitivity of trace impurities, degradants (DG), and excipients (Exc). Reprinted with permission from Reference 19. 

For DP Methods should separate the API and DP degradation products from excipients. DP methods are not required to monitor synthetic process impurities, unless they are also DP degradation products. Methods should be able to detect degradation products present at levels greater than 0.1% relative to the API. Degradation products present at levels greater than 0.2% should be identified and specifications should be placed on limits. 

During early phase development there is limited knowledge about the chemistry of the new chemical entity (NCE) with respect to synthetic impurities and degradation pathways and kinetics. It is, therefore, desirable to develop an array of methods that show applicability to a broad range of potential impurities, degradation products, and excipients. The methods are intended to provide the information necessary to guide the improvement of a synthesis route or a new drug formulation. 

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