Accuracy excipients

A number of oral solution or suspension products are included in the EPARs. Apart from the usual points of consideration for active ingredients and excipients, particular mention is made of possible precipitation of active ingredient when a solution is in use, the inclusion of excipients having a major impact on bioavailability, the need for flavoring to mask the taste of the active ingredient, relative potency compared with other routes of administration, preservation issues, dosing devices and the precision and accuracy of the dose delivered, and bioequivalence where formulations have been modified during the development process. 

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. 

Accuracy samples are prepared by spiking bulk drug and excipients in the specified volume of dissolution fluid. The concentration ranges of the bulk drug spikes are the same... 

Unlike the previous techniques, sensitivity is not an issue for AAA. There are few interfering substances because the method involves hydrolysis, derivatization, and chromatography with detection at a unique wavelength. Most excipients will not affect the hydrolysis step, but one has to be careful to ensure that the amino acids used to quantitate the protein are not destroyed. In addition, it must be determined if the excipients interfere with the derivatization chemistry or the chromatography. A BSA standard in the same buffer formulation is routinely run in parallel to the target protein to ensure the accuracy of the method. 

The extent of revalidation required for formulation changes should be determined on a case-by-case basis. Slight adjustments to the formulation may not require further validation work. This would include an adjustment of the excipient ratios, a change in tablet shape, etc. Specificity and accuracy should be re-evaluated for the inclusion of a new excipient into the formulation (e.g., antioxidants, dyes, preservatives). A change in the formulation such as going from a tablet to a capsule or from a liquid to a solid would mean a significant change to the formulation and complete validation should be performed. 

Diclofenac sodium, famotidine and ketorolac were analysed utilising their formation of a coloured charge transfer complex with 2,4 dichloro-6-nitrophenol. The complexes were detected by UV/visible spectrophotometry at 450 nm. The method was not affected by the presence of common excipients in the formulations analysed. The precision and accuracy of the method was comparable to that of HPLC methods used to analyse the same samples. ... 

Experimental Requirements. Solutions of known concentrations are used to determine the linearity. A plot of peak area versus concentration (in percent related substance) is used to demonstrate the linearity. Authentic samples of related substances with known purity are used to prepare these solutions. In most cases, for the linearity of a drug product, spiking the related substance authentic sample into excipients is not necessary, as the matrix effect should be investigated in method accuracy. 

The accuracy of the method related to the excipient is achieved by assay of three preparations at 50%, 100%, and 150% of the proposed concentration by spiking the excipient. The mean recovery at each level should be between 97 and 103% (Table 6.2). 

Murakami et al. [82] developed and validated a sensitive HPLC technique to quantify omeprazole in delayed release tablets. The analysis was carried out using a RP-Cig column with UV-VIS detection at 280 nm. The mobile phase was diluted with phosphate buffer (pH 7.4) and acetonitrile (70 30) at a flow-rate of 1.5 ml/min. The parameters used in the validation process were linearity, range, quantification limit, accuracy, specificity, and precision. The retention time of omeprazole was about 5 min with symmetrical peaks. The linearity in the range of 10-30 ng/ml presented a correlation coefficient of 0.9995. The excipients in the formulation did not interfere with the analysis and the recovery was quantitative. Results were satisfactory and the method proved to be adequate for quality control of omeprazole delayed-release tablets. 

The same authors also applied capillary electrophoresis to the study of benazepril hydrochloride and several angiotensin-converting enzyme inhibitors [43]. Separation of the compounds was performed by means of two phosphate buffers (each 0.1 M) at pH 7 and 6.25, respectively [42], Due to the highest selectivity of the first mentioned running buffer, the same system has been applied for the quantification of benazepril and other compounds in their corresponding pharmaceutical formulations. It was found that the possibility of simultaneous identification and quantification of the active ingredient in the finished products was especially attractive, and that excipients do not adversely affect the results. This article deals with the validation of some parameters of the quantitative analysis, namely linearity, precision, accuracy, and robustness [43],... 

Liquid or semisolid preparations may require the presence of ancillary excipients to effect solvation or dispersion of the active ingredient. In particular, formulations containing drugs in the suspended state may require viscosity-enhancing agents or other additives to ensure that the drug remains homogenously dispersed. Otherwise, the accuracy of the dose may be compromised. 

Excipients that aid powder flow in tablet or capsule manufacture. Materials such as colloidal silica improve flow from hopper to die and aid packdown in the die or capsule shell. Accuracy and consistency of fill and associated dose is thereby improved. 

The effect of dosing vehicle excipients such as PEG400, propylene glycol. Tween 80, and hydroxypropyl-P-cyclodextrin on the accuracy of pharmacokinetic analysis by LC-MS was investigated as well [89-90]. Due to matrix effects, the analysis may indicate a 2-5-fold increase in the calculated plasma clearance. This would result in a false rejection of the compound in a drag discovery screen. Similar effects of dosing vehicle excipients were also investigated via post-column infusion studies by others [79, 85, 91]. 

From the electropherogram in Fig. 2, no interference from the formulation excipients could be observed at the migration times of ENX and IS. The limit of the detection (LOD) was 3.85 x 10 M, while the limit of quantification (LOQ) was 1.16 X 10 M. The results indicate good precision. Method accuracy was determined by analyzing a placebo (mixture of excipients) spiked with ENX at three concentration levels (n = 6) covering the same range as that used for linearity. Mean recoveries with 95% confidence intervals are given in Table 3. 

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