Injectable dosage forms , analysis

N. A. Guzman, H. Ali, J. Moschera, K. Iqbal, and A. W. Malick, Assessment of capillary electrophoresis in pharmaceutical applications — analysis and quantification of a recombinant cytokine in an injectable dosage form, J. Chromatogr., 559 307 (1991). 

J. C. Spell and J. T. Stewart, Quantitative analysis of chloroprocaine and its major impurity 4-amino-2-chlorobenzoic acid in drug substance and injection dosage form by HPTLC and scanning densitometry, JP C, 8 12 (1995). 

The parenteral dosage form constitutes those dosage forms that are administered to patients via injection. They can comprise a powder that is solubilized at the time of administration or a solution or other suitable injectable dosage form that can provide faster action than the solid dosage forms such as capsules and tablets. The development process for parenteral dosage forms is discussed in Chapter 7, with emphasis on the bulk drug substance, excipients, in-process analysis, and final dosage form analysis. 

FIA has also found wide application in pharmaceutical analysis.214,215 Direct UV detection of active ingredients is the most popular pharmaceutical analysis application of FIA. For single component analysis of samples with little matrix interference such as dissolution and content uniformity of conventional dosage forms, many pharmaceutical chemists simply replace a column with suitable tubing between the injector and the detector to run FIA on standard HPLC instrumentation. When direct UV detection offers inadequate selectivity, simple online reaction schemes with more specific reagents including chemical, photochemical, and enzymatic reactions of derivatization are applied for flow injection determination of pharmaceuticals.216... 

For early phase methods, the precision tests only include injection repeatability (also referred to as system repeatability) and method repeatability (also referred to as analysis repeatability). The former is demonstrated by repeating injections of a standard solution and the latter by preparing multiple samples over multiple concentration levels (usually at 80%, 100%, and 120% of the nominal concentration) from the same lot of a composite sample of the dosage form. 

This section will review how physiological factors at the site of injection impact the design of dosage forms and affect choice of excipients. First, pharmacokinetic factors affecting rates of delivery of drug to the blood will be considered. Then, biocompatibility or safety issues will be addressed. This analysis focuses on the intravascular (IV), IM, and SC routes of administration. 

For analytical sample preparation, measurement of the final pH of the sample solution (excipients, API(s), and sample solvent mixed together) will be helpful in the development of any analytical procedure. If an API is known to be stable in acidic pH (pH 1-2), then an analytical chemist will try to utilize a certain sample solvent that has a pH in the required range. However, when a dosage form is dissolved in a sample solvent, the excipients present in the formulation (and even the API) will change the pH of the solution. The final pH of the solution must be measured in order to determine the optimal pH of sample solution to achieve longest solution stability. This is particularly important for a long sequence of injections on autosamplers for analysis, so solutions do not need to be made daily. 

Because the optical rotation detectors only respond to optically active compounds, enantiomeric purity determination to precisions of better than 0.5% can be achieved and is possible in even the complex mixtures. The detection can also be used as part of a flow injection analysis system to determine amount and enantiomeric purity of a drug in dosage form. 

A short discussion of new high-throughput applications of methodologies for solid dosage forms is presented in Chapter 6. Examples include fiber-optic dissolution technology, flow injection analysis, NIR analysis, and robotics. These techniques provide data with less analyst involvement and allow a more thorough batch quality assessment. 

Recently, ICH guidance Q6A has simplified the development of specifications in several ways, not the least of which is the clarification that impurities if already controlled in the API do not have to be controlled in the dosage form unless they are also degradants. For the release assay, this paves the way for simpler, but no less sophisticated methods that require minimal sample preparation. Thus, the future may bring a return to spectroscopic techniques such as ultraviolet/visible (LJV/vis) spectroscopy. There also may be increased use of other high-speed and high-precision techniques such as flow injection analysis (FIA) and near infrared (NIR) analysis. 

Pharmaceutical liquids require very minimal sample preparation they can be injected directly, diluted in mobile phase or other suitable diluent, or extracted into an organic solvent. A diluent is chosen to maintain solubility of the analyte as well as compatibility with the chromatographic system. Pharmaceutical suspensions must be pretreated to dissolve the drug prior to analysis. Another liquid dosage form is an emulsion, in which the liquid is suspended in a second immiscible liquid such as polydimethylsilicone. The sample preparation must break the emulsion. In the analysis of a polydimethylsilicone suspension, a liquid-liquid extraction is generally used to break the emulsion and prepare the sample for simethicone measurement. 

Quantitative analysis of tablets and other dosage forms were also performed early in the current wave of NIR. In 1982, Rose et al. reported the direct analysis of meglumine and meglumine diatrizoate in injectable solutions, for example." In 1986, Whitfield developed a method to measnre the amount of lincomycin in granulations for veterinary purposes. This was the first NIR method accepted by the FDA as a primary method." ... 

In 1977, Zappala and Post [26] investigated the use of NIR in the analysis of meprobamate in four pharmaceutical preparations tablets, sustained-release capsules, suspensions, and injectables. By the publication of the paper, a colorimetric method for the assay of meprobamate in tablets had been adopted in USP XDC. This colorimetric method was more rapid than the previous assay, but still required close control of reagent pH. NIR remained an attractive alternative for determination of meprobamate concentrations in dosage forms. 

Below 200°C, reliable urea thermohydrolysis is very hard to achieve, therefore urea dosage is usually stopped in real-world urea-SCR systems in this temperature regime. Another serious problem connected with the urea injection at low temperatures is the formation of white to yellowish deposits, which are observed when urea solution is injected at very low exhaust gas temperatures or if the urea spray forms a thick film at the walls of the SCR system. The analysis of these deposits [26] showed that they mainly consist of urea and some biuret at low temperatures and of cyanuric acid and some biuret at higher exhaust gas temperatures around 350°C. From laboratory investigations of the urea decomposition, it is known that biuret is easily formed from 150 to 190°C [27], whereas the formation of cyanuric acid is predominant from 200 to 300°C, according to the following reactions [12] ... 

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