Some applications of near-infrared reflectance analysis in the pharmaceutical industry.

A non-comprehensive overview of near-infrared (NIR) reflectance analysis in the pharmaceutical industry is presented. This survey will include background information defining NIR (i.e. spectral region and spectral features), the spectroscopic measurement, and the merits of this technique. This presentation comprises selected pharmaceutical applications of NIR used within Wellcome. One use of NIR is for the identification of tablets in bulk and non-invasively inside individual blister pack cells using several sample presentations including a fibre-optic probe. NIR has been used to determine moisture in freeze-dried parenterals by non-invasively measuring spectra through the bases of product vials. The viability of transferring moisture measuring equations between different instruments within the same site and between two different sites is examined. Another application of NIR involves a rapid assay of the active in whole tablets without any sample preparation. Finally, the use of NIR to validate blending processes for solid formulations is briefly discussed. There are many other applications of NIR in the pharmaceutical industry which are beyond the scope of this presentation. The applications presented here are those being pursued within our company, and provide an indication of the capabilities of NIR.

Suitability of near-infrared methods for the determination of moisture in a freeze-dried injection product containing different amounts of the active ingredient.

A near-infrared reflectance (NIR) method for determination of moisture in an experimental freeze-dried injection product was developed and validated. NIR spectra were collected through the bases of unopened product vials using a horizontal instrument accessory, before generating primary reference data on the same individual vials by Karl-Fischer titration. Data were collected for product containing different concentrations of the active ingredient in the same matrix. NIR calibrations were developed with second derivative spectral data using regression facilities within the NIR software, and validated using independent test sets. An assessment is given of the applicability of moisture calibrations developed on product at one active ingredient level to the prediction of moisture contents in the product containing a different concentration of active ingredient.

The determination of the preservative, chlorocresol, in a pharmaceutical formulation by flow injection analysis.

A flow injection analysis (FIA) procedure is described for the determination of chlorocresol in a parenteral pharmaceutical formulation. The product is directly injected into a carrier stream of water and subsequently reacted with a reagent stream of nitrous acid. The resulting brown nitro-derivative is determined spectrophotometrically at 400 nm. The method has been validated and should be applicable to chlorocresol in other pharmaceutical products and to compounds containing a phenolic ring, assuming absence of matrix interference.

The determination of pentavalent antimony in sodium stibogluconate in a pharmaceutical formulation by flow injection analysis.

A flow injection analysis (FIA) procedure is described for the determination of pentavalent antimony (Sb5+) in the drug, sodium stibogluconate, in a parenteral pharmaceutical formulation. The sample solution is injected directly into a carrier stream of iodide ion which is then mixed with an acid stream in situ. Sb5+ is determined by the redox reaction with acidified iodide to liberate iodine, which is monitored spectrophotometrically at 350 nm. The closed conditions prevent interference from atmospheric oxygen and the rapid reaction time assists in minimizing interference from side reactions. The use of tartaric acid as a solvent for sample and standard solutions ensures obedience of Beer's law over the Sb5+ concentration range 0.01-0.2% (w/v). The method is specific for the higher oxidation state in an ionic mixture of Sb5+ and Sb3+, and has been fully validated for use in a pharmaceutical preparation. Assuming absence of matrix interference it is applicable to Sb5+ from other sources and should be applicable to other reducible ionic species.

Near-infrared methods for the identification of tablets in clinical trial supplies.

Near-infrared reflectance analysis (NIR) methods have been developed for the confirmation of the identity of blister-packed tablets for clinical trial supplies. Three approaches are described: (1) presentation of single exposed tablets from blisters directly to the optical window; (2) presentation of unopened opaque blister-packed tablets directly to the optical window of the NIR instrument; and (3) use of a fibre-optic accessory to examine tablets through unopened opaque blister packs. For clinical purposes, all tablets in this trial were manufactured to match the appearance of one another. Tablets containing four strengths of an experimental drug (2, 5, 10 and 20% w/w of the active), a marketed product as a clinical comparator (80% w/w of the active), and a placebo were investigated. The NIR methods were developed by chemometrically building a library with second derivative spectra for each tablet type. Library validation and test data are presented along with a comparison of the three sample presentation techniques. The scope and limitation of each sample presentation technique are discussed.

Development and transferability of near-infrared methods for determination of moisture in a freeze-dried injection product.

Near-infrared reflectance (NIR) methods for non-invasive and non-destructive measurement of moisture in a lyophilized product were developed independently at two sites. NIR spectra were collected with the same model instrument at each site. The spectra were scanned through the bases of unopened glass vials using a horizontal instrument accessory. The primary reference data for moisture content were generated using Karl-Fischer titration on the same individual vials. The NIR calibration equations were developed with second derivative spectral data using regression programs within the NIR software. These calibration equations were validated using independent test data from additional vials of product from the original site, and cross tested against similar data from the other site to check their robustness. This cross comparison demonstrated that a calibration equation from one site could satisfactorily be used for predicting moisture contents in product manufactured at the other site. Expected variations arising from differences in vial material, manufacturing process, analysts and instruments appeared to be satisfactorily accommodated. Finally, two test data sets were obtained by scanning a set of samples on two spectrometers at one site. The results from these data sets were comparable using the calibration equation developed solely on one of the two instruments. The results from all calibration and test sets are presented and discussed, and an assessment of the method transferability between instruments and sites is given.