Douglas Both

Comparison of near infrared and microwave resonance sensors for at-line moisture determination in powders and tablets

In this paper we demonstrate the feasibility of replacing KF for water content testing in bulk powders and tablets with at-line near infrared (NIR) or microwave resonance (MR) methods. Accurate NIR and MR prediction models were developed with a minimalistic approach to calibration. The NIR method can accurately predict water content in bulk powders in the range of 0.5-5% w/w. Results from this method were compared to a MR method. We demonstrated excellent agreement of both NIR and MR methods for powders vs. the reference KF method. These methods are applicable to in-process control or quality control environments. One of the aims of this study was to determine if a calibration developed for a particular product could be used to predict the water content of another product (with related composition) but containing a different active pharmaceutical ingredient (API). We demonstrated that, contrary to the NIR method, a general MR method can be used to predict water content in two different types of blends. Finally, we demonstrated that a MR method can be developed for at-line moisture determination in tablets.

Analytical Method Quality by Design for an On-Line Near-Infrared Method to Monitor Blend Potency and Uniformity

In this work, an example of analytical method quality by design (AQbD) principles applied to an in-line NIR method to monitor blend potency and uniformity in the manufacturing of an oral solid dosage product is presented. An integrated process analytical technology (PAT) method was developed following the AQbD workflow, including risk assessment, design of experiments (DoE), method control strategy, and method maintenance. Several aspects particular to partial least square (PLS) chemometric method development and validation (such as the combined use of DoE, optimization, and multivariate data analysis) are addressed. Results from the risk assessment showed that the active pharmaceutical ingredient (API) particle size was the most significant risk factor due to the presence of aggregates. This risk was reduced by introducing changes in the API crystallization procedure and by including a wide range of calibration blends within the expected range of particle size. Other potential risks related to the instrumentation, the API and excipient properties, and the environment were further studied and minimized. System suitability tests based on Mahalanobis distance and discriminant analysis (DA) techniques were developed to ensure the quality of the spectral data before blend potency calculation. The use of AQbD provided a robust and rugged method that has the potential to be used as part of the product real-time release (RTR) control strategy.

The use of in situ near infrared imaging and Raman mapping to study the disproportionation of a drug HCl salt during dissolution.

NIR imaging and Raman mapping of the dissolution of model pharmaceutical formulations containing the HCl salt of a developmental compound, were carried out using a custom designed flow through cell. The results of this work have shown that NIR imaging and Raman mapping are capable of monitoring the distribution of the components in a formulation during dissolution while also revealing any form changes which may occur in real time. The NIR and Raman data revealed that the drug underwent conversion to the free base when water was used as the dissolution medium. However, in 0.1M HCl this conversion was no longer seen as the medium was below the pHmax (the pH of saturation of both unionised and ionised species and above which the free base can form) of the drug. The data from both approaches broadly agreed demonstrating the applicability of these methods to studying and enhancing our understanding of the complex physical and chemical processes which occur during dissolution in real time.

Stereoisomeric purity determination of captopril by capillary gas chromatography

The GC method developed for the stereoisomeric purity determination of captopril is based on the combined information derived from the analyses of the captopril sample on two GC systems, one with a chiral and the other with an achiral column. The limit of detection has been determined to be 0.02% (w/w) for (R,S) or (S,R) and 0.03% for (R,R), with corresponding minimum quantifiable levels of 0.08% and 0.09%.

Determination of parts per million levels of trifluoroacetic acid in ceronapril bulk substance by headspace capillary gas chromatography

Abstract A headspace capillary gas chromatographic method was developed to determine trifluoroacetic acid (TFA) in a bulk substance (ceronapril). The bulk sample is reacted in a sealed headspace vial with dimethyl sulfate in concentrated sulfuric acid to convert TFA to methyl trifluoroacetate (MTFA). A portion of the headspace of the vial containing the MTFA is chromatographed on a PoraPLOT Q 0.32 mm I.D. capillary column in the split injection mode with flame ionization detection. The limit of detection is less than 10 ppm (w/w).

Process Analytical Technology for High Shear Wet Granulation: Wet Mass Consistency Reported by In-Line Drag Flow Force Sensor Is Consistent With Powder Rheology Measured by At-Line FT4 Powder Rheometer®

Drag flow force (DFF) sensor that measures the force exerted by wet mass in a granulator on a thin cylindrical probe was shown as a promising process analytical technology for real-time in-line high-resolution monitoring of wet mass consistency during high shear wet granulation. Our previous studies indicated that this process analytical technology tool could be correlated to granulation end point established independently through drug product critical quality attributes. In this study, the measurements of flow force by a DFF sensor, taken during wet granulation of 3 placebo formulations with different binder content, are compared with concurrent at line FT4 Powder Rheometer characterization of wet granules collected at different time points of the processing. The wet mass consistency measured by the DFF sensor correlated well with the granulations resistance to flow and interparticulate interactions as measured by FT4 Powder Rheometer. This indicated that the force pulse magnitude measured by the DFF sensor was indicative of fundamental material properties (e.g., shear viscosity and granule size/density), as they were changing during the granulation process. These studies indicate that DFF sensor can be a valuable tool for wet granulation formulation and process development and scale up, as well as for routine monitoring and control during manufacturing.