Gregory K. Webster

Determination of relative response factors for chromatographic investigations using NMR spectrometry.

In the absence of suitable reference materials for impurity quantitation, laboratories have developed techniques using mass detectors such as the chemical luminescence detector (CLND) and the charged aerosol detector (CAD) to normalize the UV response of each impurity of interest by their molar ratios and thus generate relative response factors without requiring isolated and purified compound-specific standards. While effective, these detectors are limited in response and are effective only with specific mobile phase requirements. Nuclear magnetic resonance (NMR) spectrometry has the advantage of allowing the universal detection of protons while not suffering from the limitations observed for CLND, CAD, and other common detectors. The determination of relative response factors using NMR has been successfully applied to several LC methods. An overview of this technique and representative results are presented.

Use of ionic liquids as headspace gas chromatography diluents for the analysis of residual solvents in pharmaceuticals

Graphical abstract Figure. No Caption available. HighlightsTwo ionic liquids (ILs), 1‐butyl‐3‐methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([BMIM][NTf2]) and trihexyltetradecylphosphonium bis[(trifluoromethyl)sulfonyl]imide ([P66614][NTf2]) were examined as contemporary diluents for residual solvent analysis using static headspace gas chromatography (SHS‐GC) coupled with flame ionization detection (FID).A 25‐fold improvement in limit of detection (LD) was observed with respect to traditional HS‐GC diluents, such as N‐methylpyrrolidone (NMP).The established IL‐based method demonstrated LDs ranging from 5.8 parts‐per‐million (ppm) to 20 ppm of residual solvents in drug substances.The analytical performance was demonstrated by determining the repeatability, accuracy, and linearity of the method.Linear ranges of up to two orders of magnitude were obtained for class 3 solvents.Excellent analyte recoveries were obtained in the presence of three different active pharmaceutical ingredients. Abstract In this study, two ionic liquids (ILs), 1‐butyl‐3‐methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([BMIM][NTf2]) and trihexyltetradecylphosphonium bis[(trifluoromethyl)sulfonyl]imide ([P66614][NTf2]) were examined as contemporary diluents for residual solvent analysis using static headspace gas chromatography (SHS‐GC) coupled with flame ionization detection (FID). ILs are a class of non‐molecular solvents featuring negligible vapor pressure and high thermal stabilities. Owing to these favorable properties, ILs have potential to enable superior sensitivity and reduced interference, compared to conventional organic diluents, at high headspace incubation temperatures. By employing the [BMIM][NTf2] IL as a diluent, a 25‐fold improvement in limit of detection (LOD) was observed with respect to traditional HS‐GC diluents, such as N‐methylpyrrolidone (NMP). The established IL‐based method demonstrated LODs ranging from 5.8 parts‐per‐million (ppm) to 20 ppm of residual solvents in drug substances. The optimization of headspace extraction conditions was performed prior to method validation. An incubation temperature of 140 °C and a 15 min incubation time provided the best sensitivity for the analysis. Under optimized experimental conditions, the mass of residual solvents partitioned in the headspace was higher when using [BMIM][NTf2] than NMP as a diluent. The analytical performance was demonstrated by determining the repeatability, accuracy, and linearity of the method. Linear ranges of up to two orders of magnitude were obtained for class 3 solvents. Excellent analyte recoveries were obtained in the presence of three different active pharmaceutical ingredients. Owing to its robustness, high throughput, and superior sensitivity, the HS‐GC IL‐based method can be used as an alternative to existing residual solvent methods.

Method Development for Pharmaceutical Chiral Chromatography

Abstract Prior to the introduction of thalidomide, approved drugs could be racemic, but experience from that drug has now set new standards for purity assays. Not only must the pharmaceutical analytical chemist be able to separate the active pharmaceutical ingredient (API) from its process impurities and degradation products, but also they must demonstrate enantiomeric purity. This chapter focuses on chiral method development in the pharmaceutical industry. Starting with the historical and regulatory implications of chiral analysis, this chapter proceeds to demonstrate the types of analyses that are currently in use, as well as the columns and phases that are commercially available. Current method development strategies and the hardware that can aid in method development are discussed. The uses and conditions of three different chromatographic techniques, HPLC, SFC, and GC, are discussed.

Use of near-infrared spectrometry for quantitative determinations of selamectin and moisture in topical formulations.

A rapid near-infrared spectrometric (NIR) method was qualified for use with the quantitative analysis of selamectin and moisture in topical formulations. Selamectin is currently marketed as a pet endectocide and is available in several formulations for cats and dogs. The use of NIR in this investigation replaces the in-process testing by liquid chromatography and concurrently provided moisture content that would otherwise only be available with additional Karl Fischer titration investigations. A seven-factor partial least square regression (PLS) of the second derivative spectra encompassing the wavelength region of 1450-2200 nm was used to quantify both selamectin and moisture content. A second three-factor PLS solely for water content was also applied and compared with the full model. This qualification confirms that this method may be used to quantitate selamectin and moisture as a process tool or to examine finished good samples. Each sample can be rapidly analyzed within 5 min on the current bench top system.

Considerations When Implementing Automated Methods into GxP Laboratories

In the increasingly scrutinized pharmaceutical industry, regulatory agencies are demanding validation of any and all analytical instrumentation, including documentation associated with its implementation, qualification, and ability to report accurate and reliable results. Herein, we discuss the qualification and validation of an automated liquid handling system and an automated dissolution method. We describe the comparison of automated experiments versus manual experiments while addressing the pertinent validation and qualification considerations for each. Discussion of documentation and validation required for various regulated laboratories (good clinical practices (GCP), good laboratory practices (GLP), and good manufacturing practices (GMP)) is also reviewed.

Novel Coated Cellulose Carbamate Silica Based Phase to EnhanceSelectivity of Compounds of Pharmaceutical Interest

Modern liquid chromatographic (LC) analyses of targets in complex matrices, even with mass spectroscopic (MS) detection, more commonly are also requiring an orthogonal method to ensure peak purity and resolution of all sample impurities. This is especially true when stereoisomer identity and separation are critical criteria. To help address this gap in orthogonality, a novel coated cellulose carbamate stationary phase was developed using a reoptimized coating density, a type B 500-angstrom silica as its base entity, and a secondary amine to facilitate the coating to the base silica. The chiral phase can be used in reverse phase chromatography but is designed to work with mixed polar eluents in both polar organic and normal phase chromatography. It is also selective for achiral applications as well. A critical difference is the stability of this cellulose carbamate stationary phase at higher alcohol concentrations and the prediction capability of the elution order of analytes. This stationary phase showed greater chromatographic selectivity by requiring less alcohol modifier for elution of chiral compounds, when compared to other cellulose carbamate columns and by the use of acetonitrile (ACN) as a modifier. The Cogent EE phase is also rugged and can easily switch between different pHs without loss of resolution or memory effects. Finally this phase was used to separate optical isomers of gossypol and tramadol, and worked well in a case study where diastereomers were isolated from a previously unknown impurity.