Non-destructive Raman Method Development for Quantifying Active Pharmaceutical Ingredient in an Oral Suspension Through Plastic Dosing Syringes.

For liquid drug products, e.g., solutions or suspensions for oral or parenteral dosing, stability needs to be demonstrated in primary packaging during storage and in dosing devices during in-use periods per quality guidelines from the International Conference on Harmonisation (ICH) and the European Agency for the Evaluation of Medicinal Products (EMEA). One aspect of stability testing for liquid drug products is in-use stability, which typically includes transferring the liquid samples into another container for further sample preparation with extraction diluent and necessary agitation. Samples are then analyzed with traditional chromatography methods, which are laborious, prone to human errors, and time-consuming, especially when this process needs to be repeated multiple times during storage and in-use periods. Being able to analyze the liquid samples non-destructively would significantly improve testing efficiency. We investigated different Raman techniques, including transmission Raman (TRS) and back scatter Raman with a non-contact optic (NCO) probe, as alternative non-destructive tools to the UHPLC method for API quantitation in in-use liquid samples pulled into plastic dosing syringes. The linearity of the chemometric methods for these two techniques was demonstrated by cross-validation sample sets at three levels over an API concentration range of 60 to 80 mg/mL. The accuracy of the chemometric models was demonstrated by the accurate prediction of the API concentrations in independent samples from four different pilot plant batches manufactured at different sites. Both techniques were successful in measuring a signal through a plastic oral dosing syringe, and predicting the suspension API concentration to within 4% of the UHPLC-measured value. For future work, there are opportunities to improve the methodology by exploring additional probes or to expand the range of applications by using different sample presentations (such as prefilled syringes) or formulation matrices for solutions and suspensions.

New suppressor technology improves the ion chromatographic determination of inorganic anions and disinfection by-products in drinking water.

This paper describes a new suppressor technology for analyzing water samples using United States Environmental Protection Agency (EPA) methods 300.0 and 300.1. The Alltech DS-Plus suppressor improves and simplifies anion analysis in drinking water. In addition to suppressing the carbonate mobile phase and enhancing the analyte signal like conventional ion chromatography (IC) suppressors, the DS-Plus suppressor removes carbonic acid (as dissolved carbon dioxide) from the suppressor effluent before detection (US patent Nos.: 6444475; 6468804; others pending), lowering the background conductivity to near zero. Anions are detected in water background, improving sensitivity and lowering detection limits. The water-dip often seen with conventional suppressors is greatly reduced, improving fluoride quantification. The DS-Plus suppressor operates continuously without the need for external regenerants or switching valves. The performance of this new suppressor for analyzing water samples has been found to meet the EPA methods specifications.

Alternative approach to enhancing cation selectivity in ion chromatography.

A new approach to enhance cation selectivity in ion chromatography (IC) is described. Two packings, one carrying a conventional carboxylate cation exchanger and the other carrying a crown ether (CE) phase are packed into two separate columns and used in series. The resolution between sodium and ammonium and between ammonium and potassium is increased significantly. The two stationary phases may also be mixed and packed into a single column. The selectivity of the cations can be adjusted easily by varying the dimensions of the carboxylate and CE columns (in the two-column configuration), or by changing the ratio of the carboxylate cation exchanger to the CE packing (in the single-column configuration). These new systems separate ammonium and sodium, even when the sodium concentration is 5000 times higher. Amines such as ethanolamine and triethanolamine can also be separated from the alkali and alkaline-earth cations.

Recent advances in ion chromatography suppressor improve anion separation and detection.

The Alltech DS-Plus suppressor improves and simplifies anion analysis by suppressor-based ion chromatography (IC). In addition to suppressing the mobile phase and enhancing the analyte signal, the DS-Plus suppressor removes carbonic acid from the suppressor effluent when carbonate-hydrogencarbonate mobile phases are used, reducing the water dip that interferes with early eluting peaks, increasing detection sensitivity, and enabling carbonate-hydrogencarbonate gradients. The ability to operate with carbonate-hydrogencarbonate gradients places exceptional separating power in the mobile phase, forgoing the need for expensive columns with special selectivity. Continuous operation and solid-phase chemistry eliminates the need for external regenerants, switching valves, and multiple operating modes.

New suppressor technology improves trace level anion analysis with carbonate-hydrogencarbonate mobile phases.

Sodium carbonate-hydrogencarbonate mobile phases are preferred over sodium hydroxide for anion analysis by suppressor-based ion chromatography (IC). Unlike hydroxide, carbonate-hydrogencarbonate has strong eluting power and its buffering capacity can be used as a selectivity tool for controlling separations. However, carbonate-hydrogencarbonate mobile phases fell out of favor for trace level analysis because the carbonic acid suppressor effluent has some background conductivity, which reduces sensitivity compared to sodium hydroxide. This paper describes a new suppressor technology that improved anion analysis with carbonate-hydrogencarbonate mobile phases. In addition to converting the carbonate-hydrogencarbonate buffer to carbonic acid like other traditional IC suppressors, the new DS-Plus suppressor also removed carbonic acid from the suppressor effluent. Anions are now detected in water background, just like when using sodium hydroxide as the mobile phase. The lower background conductivity improves sensitivity and reduces detection limits. The water-dip often seen with conventional suppressors is greatly reduced, improving fluoride quantification.

Solving complex anion separation problems with a carbonate-hydrogencarbonate gradient.

This paper describes the application of a new suppressor to solve complex anion separation problems with carbonate-hydrogencarbonate gradients. In addition to suppressing the mobile phase and enhancing the analyte signal like any other ion chromatography suppressor, the new DS-Plus suppressor removes carbonic acid from the suppressor effluent when carbonate-hydrogencarbonate mobile phases are used. This greatly reduces the background signal, enabling carbonate-hydrogencarbonate gradients. Since carbonate-hydrogencarbonate mobile phase has stronger eluting power than hydroxide or tetraborate, only dilute concentrations are needed to separate most anions. By adjusting the carbonate-hydrogencarbonate ratio in the mobile phase, various anion mixtures including those containing organic and inorganic anions with -1 to -3 charges can be separated on one or two columns, eliminating the needs for columns with special selectivity.