Measurement of Moisture Content in Pharmaceutical Tablets by Handheld Near-Infrared Spectrometer: Adopting Quality by Design Approach to Analytical Method Lifecycle Management.

Control of moisture content in pharmaceutical solids (raw materials and solid dosage forms) is a challenge to pharmaceutical development and manufacturing. Pharmaceutical solids come in several forms and presentations requiring different, and often lengthy, sample preparation methods for moisture determination. Rapid screening of samples for their moisture content calls for an analytical method that can provide in-situ measurement with no or minimal sample preparation. We presented a near-infrared (NIR) spectroscopic method for rapid and non-destructive measurement of moisture content in a pharmaceutical tablet product. A handheld NIR spectrometer was selected for the quantitative measurement because of its ease of use, low cost, and high signals selective to water absorption in the NIR spectral range. Analytical quality by design (QbD) principles were explored during method design, qualification, and continued performance verification to increase robustness and promote continuous improvement of the analytical procedure. The International Council for harmonization (ICH) Q2 validation criteria were followed for validation of its linearity, range, accuracy, repeatability, intermediate precision, and method robustness. Limit of detection and limit of quantitation were also estimated based on the multivariate nature of the method. Practical considerations were also given to method transfer and a lifecycle approach to implementation of the method.

Quantum Cascade Laser Based Infrared Spectroscopy: A New Paradigm for Protein Secondary Structure Measurement.

Mid-infrared spectroscopy is one of the major analytical techniques employed for measurements of protein structure in solution. Traditional Fourier Transform-Infrared (FT-IR) measurement is limited by its blackbody light source that is inherently spatially incoherent and has low optical power output. This limitation is pronounced when working with proteins in aqueous solutions. Strong absorbance of water in protein amide I region 1600-1700 cm-1 restricts light path length to <10 µm and imposes significant experimental challenges in sample and flow cell handling. Emerging laser spectroscopic techniques use high-power coherent laser as light source that overcomes the limitation in FT-IR measurement. In this study, we employed an innovative infrared spectrometer that uses quantum cascade laser (QCL) as light source. Continuous infrared radiation from this laser source can be swiftly swept within the amide I region (1600-1700 cm-1) and amide II region (1500-1600 cm-1), which makes this technique ideal for protein secondary structure study. Protein solutions as low as 0.5 mg/mL were measured rapidly without any sample preparation. Infrared spectra of model proteins were thus collected, and a chemometric model based on partial least squares regression was developed to quantify α-helix and ß-strand motifs in protein secondary structure. The model was applied to measurement of the native secondary structure of commercial therapeutic proteins and bovine serum albumin (BSA) and in thermal degradation studies.