Precision 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. 

Besada et al. [13] described spectrophotometric methods for determination of penicillamine in pure and dosage forms. Penicillamine was measured spectrophoto-metrically in 0.1 M HC1 (at 195 nm) or in 0.1 M NaOH (at 238 nm). Both methods gave recoveries of 100% with good precision. For determination of the drug in tablets, in the presence of excipients, ground samples were extracted with each of these solvents and the difference in absorbance at 238 nm between the two solutions were measured. The recovery of the drug from commercial tablets was 99.8%, with a coefficient of variation of 0.38%. The three methods were suitable for 4—130 ppm of the drug. 

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. 

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. ... 

The batch size ranged from 3.75 up to 60 kg. To obtain precise scale-up measurements, the excipients which were used belonged to identical lots of primary material [10% (W/W) corn starch, 4% (W/W) polyvinylpyrrolidone as binder, and 86% (W/W) lactose]. As can be seen from Figure 4, the amount of granulating liquid is linearly dependent on the batch size. During the scale-up exercise, the rate of addition of the granulation liquid was enhanced in proportion to the larger batch size. Thus the power profile, which was plotted... 

Inject the excipient standard solution at the working concentration specified in the method. The relative standard deviation (% RSD) of five or six consecutive injections is NMT 2%. The requirement for % RSD may be modified depending on the properties of the analyte and the test method. In the analysis of Polysorbate 80 in Nasonex, 5% RSD for system precision was acceptable, due to its very low concentration in the formulation. 

Excipient compatibility studies are a form of preliminary stability assessment. It is important that they be executed appropriately. The precise details of the testing will probably be different for each organization carrying out such studies. However, certain general assumptions are implicit in this approach. The underlying principle is the Arrhenius relationship ... 

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. 

Initial attempts at selecting PEs have identified certain surfactants, such as bile salts and fatty acids, which appear to facilitate oligonucleotide absorption. The advantages of these components are many, in that they are endogenous to foods and body constituents, plus the literature is rich with information about the use and exposure of these two classes of compounds [56]. The precise mechanism of action for these PEs is unknown, but is believed to involve a disruption of the mucus layer barrier, an increase in the fluidity of the mucosal membrane, and potentially an opening of the paracellular tight junctions. The mucolytic effect coupled with the increased membrane fluidity imparted by these excipients appears to allow in-... 

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],... 

A 15 mM borate buffer has been extensively validated 113] for the analysis of a wide range of acidic drugs, excipients and raw materials. Internal standards were used to improve injection precision and peak identification. Fig. 3.5 shows a separation of warfarin with two reference compounds P-naphthoxyacetic acid and aminobenzoic acid. Extensive method validation included linearity, sensitivity, solution stability, recovery... 

Excellent accessibility to the buccal mucosa makes application of the dosage form painless, precisely located, and easily removable without discomfort at the end of the application period. The oral cavity consists of a pair of buccal mucosae. Thus, a drug-delivery system can be applied at various sites either on the same mucosa or, alternatively, on the left or right buccal mucosa on different applications. This is particularly advantageous if the delivery system contains a drug or excipient that mildly and reversibly damages or irritates the mucosa. 

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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