Beverly Nickerson

Enantioseparation of pharmaceutical compounds by multiplexed capillary electrophoresis using highly sulphated α-, β- and γ-cyclodextrins

A multiplexed capillary electrophoresis (CE) system equipped with 96 channels was evaluated for high-throughput screening of enantiomers of solutes of pharmaceutical interest. Using highly (DS approximately 12) sulphated alpha-, beta- and gamma-cyclodextrins under acidic conditions (pH 2.5) only 48 channels could be used because of the high conductivity of the chiral selectors. Method transfer from a single channel to a 48 channel CE system is described. Under optimised conditions, the analysis time on the multiplexed 48 channel CE system is ca. five to eight times the analysis time on the single channel CE system. The figures of merit for the multiplexed system are presented as well as performance evaluation including throughput and productivity gain. Intra-day precision (n=6) ranged from 2.0 to 16.5% and from 2.2 to 15.5% for migration time and resolution, respectively. These values increased with ca. 10% for intermediate precision.

Evaluation of a multiarray system for pharmaceutical analysis by microemulsion electrokinetic chromatography.

A multiplexed capillary electrophoresis (CE) system equipped with 96 channels was evaluated for high-throughput screening in drug discovery by microemulsion electrokinetic chromatography (MEEKC). Method transfer from a single channel to a multichannel CE system is described. Loss of efficiency and reduced migration times could be elucidated to the poor efficacy in Joule heat dissipation by forced air cooling in the multiarray system compared to liquid cooling in the single channel instrument. On the other hand, only 48 channels could actually be used because of the maximum total current of 3 mA. Precision data remained below 8% and 9% for migration times and peak areas, respectively. Some UV-detector cross-talk interference between neighboring capillary channels was noted. Impurities at 0.5% compared to the main peak (100%) could be detected with the multiplexed system which is 10 times lower compared to the single capillary system. Higher efficiency and improved figures of merit (absolute sensitivity and no cross-talk interferences) were obtained by using an array of only 24 capillaries.

Liquid–Liquid and Solid-Phase Extraction Techniques

Liquid–liquid extraction and solid-phase extraction are classical sample preparation techniques that have been used with various types of samples. The fundamentals of these two techniques, as well as several microextraction techniques based on the same principles, are described in this chapter. Application of these techniques to the sample preparation of pharmaceutical dosage forms for analysis is also discussed.

Leveraging elevated temperature and particle size reduction to extract API from various tablet formulations.

Several sample preparation techniques were evaluated for extracting active pharmaceutical ingredient (API) from immediate release (IR) and controlled release (CR) tablet formulations. These techniques utilized either elevated temperature [e.g., accelerated solvent extraction (ASE) and microwave assisted extraction (MAE)] or particle size reduction [e.g., ball mill and homogenizer/Tablet Processing Workstation II (TPWII)]. Results were compared for equivalence to those obtained with the existing standard method for each formulation. For the CR formulations, sample preparation times were significantly reduced when using these techniques compared to the standard method. Advantages and limitations associated with each technique are discussed.

Correlation of dissolution and disintegration results for an immediate-release tablet

The drug release rate of a rapidly dissolving immediate-release tablet formulation with a highly soluble drug is proposed to be controlled by the disintegration rate of the tablet. Disintegration and dissolution test methods used to evaluate the tablets were shown to discriminate manufacturing process differences and compositionally variant tablets. In addition, a correlation was established between disintegration and dissolution. In accordance with ICH Q6A, this work demonstrates that disintegration in lieu of dissolution is suitable as the drug product quality control method for evaluating this drug product.

Sample preparation composite and replicate strategy for assay of solid oral drug products.

In pharmaceutical analysis, the results of drug product assay testing are used to make decisions regarding the quality, efficacy, and stability of the drug product. In order to make sound risk-based decisions concerning drug product potency, an understanding of the uncertainty of the reportable assay value is required. Utilizing the most restrictive criteria in current regulatory documentation, a maximum variability attributed to method repeatability is defined for a drug product potency assay. A sampling strategy that reduces the repeatability component of the assay variability below this predefined maximum is demonstrated. The sampling strategy consists of determining the number of dosage units (k) to be prepared in a composite sample of which there may be a number of equivalent replicate (r) sample preparations. The variability, as measured by the standard error (SE), of a potency assay consists of several sources such as sample preparation and dosage unit variability. A sampling scheme that increases the number of sample preparations (r) and/or number of dosage units (k) per sample preparation will reduce the assay variability and thus decrease the uncertainty around decisions made concerning the potency of the drug product. A maximum allowable repeatability component of the standard error (SE) for the potency assay is derived using material in current regulatory documents. A table of solutions for the number of dosage units per sample preparation (r) and number of replicate sample preparations (k) is presented for any ratio of sample preparation and dosage unit variability.

Sample Preparation for Solid Oral Dosage Forms

Development of extraction and sample preparation methods for solid oral dosage forms for potency and purity analysis can be challenging. Complete extraction of drug and impurities is required using reasonable extraction and sample preparation conditions, and the final prepared sample must be compatible with the analysis method. A systematic approach for the development of extraction and sample preparation methods for potency and purity analysis of solid oral dosage forms is presented. Key steps of the process include the selection of an appropriate diluent to allow complete extraction and solubilization of the analytes of interest and the selection of an appropriate mechanism to disperse the dosage form to facilitate extraction of the analytes. Each step of the method development process is discussed and potential problem areas are highlighted.

Expanding the Application of the Tablet Processing Workstation to Support the Sample Preparation of Oral Suspensions

Sample preparation is the most time-consuming part of the analytical method for powder for oral suspension (POS) assay, purity, and preservative analysis, as this involves multiple dilution and filtration steps. The Tablet Processing Workstation (TPW) was used to automate the sample preparation of a POS formulation. Although the TPW is typically used to automate the preparation of solid oral dosage forms and powders, it contains all of the necessary components to perform POS sample preparation. The TPW exhibited acceptable repeatability in testing 3 lots using 10 replicate preparations per lot. Acceptable linearity of the drug and preservative in the presence of excipients was demonstrated over the range corresponding to 50–150% of intent. Accuracy showed suitable recoveries for all points evaluated. TPW results were shown to correlate to results obtained with the manual method. The TPW method was used to prepare samples in support of manufacturing scale-up efforts. With the efficiencies gained using the TPW, it was possible to analyze a large number of samples generated during process development activities for the POS formulation with minimal human intervention. The extensive data enabled trending of the manufacturing development runs and helped to identify optimization strategies for the process.

Enantioselective analysis for L-pidolic acid in ertugliflozin drug substance and drug product by chiral gas chromatography with derivatization

HighlightsEnantiomeric purity method for L‐pidolic acid in a drug substance and drug product validated.Purge of D‐pidolic acid observed in the drug substance.No racemization of pidolic acid observed in the drug substance or drug product.No chiral testing for pidolic acid is needed for the drug substance or drug product. ABSTRACT L‐pidolic acid is being used as a coformer for ertugliflozin, a sodium‐glucose cotransport 2 inhibitor. A sensitive and rapid two‐step achiral derivatization combined with gas chromatography with flame ionization detection or gas chromatography with mass spectroscopic detection was developed and validated for the enantiomeric purity determination of L‐pidolic acid in the drug substance and drug product, respectively. The method was used to analyze ertugliflozin drug substance forced degradation samples and showed no racemization of pidolic acid in any of the solid or solution stress samples. Analysis of ertugliflozin drug product stability samples showed no significant levels of D‐pidolic acid in the drug product indicating that no significant racemization of pidolic acid occurs in the drug product under normal storage conditions. Based on the data generated, a chiral control for pidolic acid is not necessary for drug substance or drug product, but rather can be controlled in the purchase of L‐pidolic acid.

Sample preparation composite and replicate strategy case studies for assay of solid oral drug products

HIGHLIGHTSSample preparation composite and replicate strategy demonstrated on case studies.Strategy applicable at all stages of solid oral dosage form development.Case studies demonstrate limited data needed to determine replicates and composites.Case studies demonstrate need to reassess strategy as obtain more data. ABSTRACT Drug product assay is one of several tests required for new drug products to ensure the quality of the product at release and throughout the life cycle of the product. Drug product assay testing is typically performed by preparing a composite sample of multiple dosage units to obtain an assay value representative of the batch. In some cases replicate composite samples may be prepared and the reportable assay value is the average value of all the replicates. In previously published work by Harrington et al. (2014) [5], a sample preparation composite and replicate strategy for assay was developed to provide a systematic approach which accounts for variability due to the analytical method and dosage form with a standard error of the potency assay criteria based on compendia and regulatory requirements. In this work, this sample preparation composite and replicate strategy for assay is applied to several case studies to demonstrate the utility of this approach and its application at various stages of pharmaceutical drug product development.