Analytical methods are the foundation upon which a comprehensive development program is based because they are the tools by which one understands the behavior of a molecule in a given system. Within our Boston, MA Pharmaceutical Analytical Development laboratory, Pace Analytical Life Sciences develops robust, stage-appropriate methods to address well-defined parameters and support downstream activities in pre-formulation, formulation and process development, and manufacturing. The following sections describe Pace’s pharmaceutical analytical development techniques that support downstream experiments focused on solubility and dissolution, stability, solid form definition and their roles in drug product development.
Pace develops stage-appropriate, robust and accurate chromatographic methods optimized to support development activities as programs advance and warrant additional resources. We clearly define different modes of chromatography from the outset and select the appropriate method(s), based on the characteristics of the molecule and the trait that needs to be evaluated, typically including reversed phase, ion pairing, ion exchange, size exclusion and hydrophobic interaction chromatography. While most compounds can be analyzed using UV detection, alternative detection methods (evaporative light scattering, refractive index, fluorescence, mass spectrometry) may be evaluated as appropriate. The methods must meet certain criteria, which are determined based upon the purpose of the method.
Identification of Related Substances by LC-MS
LC-MS is a valuable tool for the characterization of chemical degradants and impurities. By understanding the structures and sources of these related substances during early development, there is sufficient time to improve various processes, including API manufacturing, formulation and product process development. Depending upon the complexity of the molecule, we may perform additional analyses, either because the number of potential related substances exceeds the number of peaks (multiple co-eluting peaks) or because reasonable structures cannot be proposed based on the collected data.
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Spectroscopic techniques are used for quantitative analysis of small molecules and precipitation behavior in solution as a function of solution composition. Aside from the rapidity and great simplicity of the actual testing, an added benefit to spectroscopic methods is their ability to analyze samples in a non-destructive manner.
We characterize the solid-state properties of a compound through the following methods:
X-ray powder diffractometry (XRPD)
X-ray powder diffractometry is used to characterize the crystalline properties of a molecule.
Differential scanning calorimetry (DSC)
Differential scanning calorimetry (DSC) evaluates thermal properties of the drug substance and the developed formulations through the characterization of salts, polymorphs, and hydrates, which informs formulation and process development. The phenomena to be measured drives the specific experimental design. Commonly observed thermal events are solid-state transitions, glass transition, crystallization, melting, dehydration/desolvation and decomposition. If warranted, analysis by modulated DSC (mDSC) compliments the standard DSC analysis and confirms peak assignments, particularly for putative glass transitions.
Moisture Content by Karl Fischer titration.
In development of lyophilized drug products, Karl-Fisher titration (KF) is used to determine the moisture content of lyophilized product samples. The data informs lyophilization process development as well as specifications for release and stability testing.
Thermogravimetric analysis (TGA)
Thermogravimetric analysis is a thermal technique that determines the moisture content of a drug substance by measuring the weight lost upon heating of a sample. It may also be used to evaluate lyophilized drug products to inform process development and optimization. Unlike Karl Fischer (KF), which is specific for detection of water content in a formulation, TGA detects all volatiles present, differentiating them by the temperatures of the transitions observed on the resulting thermogram. The technique has an advantage over moisture determination by KF titration since it differentiates loosely bound and tightly bound water.
Bright field optical microscopy provides qualitative assessment of particle size and morphology. Cross-polarized microscopy assesses the material for presence of crystalline components by monitoring birefringence.
Particulate Matter Analysis
Particulate matter analysis characterizes the solution properties of the compound and assesses aggregation and association. We use various light scattering techniques for particulate matter analysis, particle size measurement and particle count measurement.