Gary McGeorge

A sensitive, high resolution magic angle turning experiment for measuring chemical shift tensor principal values

A sensitive, high-resolution ‘FIREMAT’ two-dimensional (2D) magic-angle-turning experiment is described that measures chemical shift tensor principal values in powdered solids. The spectra display spinning-sideband patterns separated by their isotropic shifts. The new methods sensitivity and high resolution in the isotropic-shift dimension result from combining the 5π magic-angle-turning pulse sequence, an extension of the pseudo-2D sideband-suppression data rearrangement, and the TIGER protocol for processing 2D data. TPPM decoupling is used to enhance resolution. The method requires precise synchronization of the pulses and sampling to the rotor position. It is shown that the technique obtains 35 natural-abundance 13C tensors from erythromycin in 19 hours, and high quality natural-abundance 15N tensors from eight sites in potassium penicillin V in three days on a 400 MHz spectrometer.

Amorphous Drug-PVP Dispersions: Application of Theoretical, Thermal and Spectroscopic Analytical Techniques to the Study of a Molecule With Intermolecular Bonds in Both the Crystalline and Pure Amorphous State☆

We report the case of BMS-488043-PVP solid dispersions which when analysed using modulated DSC showed compliance with the Gordon-Taylor model, confirming ideal mixing behaviour of the two components. The nature or presence of stabilising interactions between drug and PVP could not be confirmed using this technique. Use of FT-IR, Raman and solid-state NMR spectroscopy confirmed the presence of stabilising hydrogen bond interactions between the drug and PVP. Similar interactions are present as intermolecular bonds in the crystalline and pure amorphous drug system. The Gordon-Taylor equation, as it is not predictive of the presence of intermolecular bonds such as hydrogen bonding in an amorphous dispersion, may underestimate the likely physical stability of solid dispersions which are produced and stabilised by these interactions.

SOLID-STATE 13C CHEMICAL SHIFT TENSORS IN TERPENES. PART I. SPECTROSCOPIC METHODS AND CHEMICAL SHIFT STRUCTURE CORRELATIONS IN CARYOPHYLLENE OXIDE

Principal values of the 13C chemical shift tensor were obtained for the 15 carbons of solid caryophyllene oxide using an improved PHORMAT NMR analysis. The improvements include TIGER processing and improved proton decoupling. TIGER is an alternative to Fourier methods and shortens 2D data collection by incorporating information from a high‐resolution isotropic 1D FID to allow accurate processing of even severely truncated 2D evolution FIDs. In caryophyllene oxide, data collection required less than 1 day, giving significant time savings over comparable 2D Fourier methods. Experimental principal values were assigned with high statistical confidence to specific carbons by comparing them with corresponding calculated values. Correctly assigned values were used to evaluate five different tensor calculation methods. For caryophyllene oxide, the B3PW91 method gave the best correlation with experimental principal values with an RMS error of 2.3 ppm. Refinement of x‐ray positions for hydrogens was shown to improve the calculated RMS error by a factor of >2. Calculated tensors can be used to provide principal value orientations in the three methyl groups of caryophyllene oxide. One of the perpendicular component, δ⊥, is found to exhibit the largest shift variation and dominates the methyl shifts. Sterically unfavorable non‐bonded interactions between proximate hydrogens are shown to correlate with this large upfield shift in the δ⊥ component.

Variation in the Transmission Near-Infrared Signal with Depth in Turbid Media

Transmission near-infrared (NIR) measurements of a 1 mm thick aspirin disk were made at different positions as it was moved through a stack of eight 0.5 mm thick disks of microcrystalline cellulose (Avicel). The magnitude of the first derivative of absorbance for the aspirin interlayer at 8934 cm−1 was lower when the disk was placed at the top or bottom of the stack of Avicel disks, with the largest signal observed when the aspirin was positioned at the central positions. The variation in signal with depth is consistent with that observed previously for transmission Raman spectrometry. In both cases, the trend observed can be attributed to lower photon density at the air-sample interface, relative to the center of the sample, owing to loss of photons to the air. This results in a reduction in the number of photons absorbed or Raman photons generated and subsequently detected when the interlayer occupies a near-surface position.

Analytical Method Development Using Transmission Raman Spectroscopy for Pharmaceutical Assays and Compliance with Regulatory Guidelines—Part I: Transmission Raman Spectroscopy and Method Development

Transmission Raman spectroscopy is a relatively new technique for quantitative analysis of pharmaceutical products, either during manufacturing or as a finished product test. As with any new analytical tool, several things need to be accomplished for widespread application use—assessment of technical capability, fit with quality and manufacturing processes and successful deployment in a quality-controlled environment. The technical capability has been discussed previously, but the practicalities of method development and submission to regulatory authorities have not. In this, one of a series of two papers, the considerations for regulatory submission are discussed. In the second paper, practical method development will be presented and examples provided for data analysis and method development processes.

A Rational Analysis of Uniformity Risk for Agglomerated Drug Substance Using NIR Chemical Imaging

Early risk detection and quick diagnosis of manufacturing challenges are necessary to support the accelerated development pace of drug product in the current competitive environment. Analytical tools, such as near-infrared (NIR) chemical imaging (CI), can be employed for alerting drug substance uniformity risks in intermediates and the final product of solid dosage forms. In this particular study, the ability to characterize the behavior of agglomerated drug substance throughout process development was enabled by NIR CI to identify uniformity risks with small sample sizes and short turnaround time. Using NIR chemical imaging, the drug substance distribution and cluster size in all intermediates were visualized throughout the drug product process. NIR CI enabled rapid identification of the key unit operations that produced the greatest reduction in cluster size for enhanced distribution of the drug substance. The comil acted as a high shear mixing step to disperse soft lumps prior to roller compaction. Shear forces or pressure during roller compaction was sufficient to break down and disperse the agglomerates further. Ultimately, the process was robust against a range of drug substance input properties such that the uniformity of the final blend was consistently achieved and the agglomerated drug substance had no risks to the drug product process.

In-line ATR-UV and Raman Spectroscopy for Monitoring API Dissolution Process During Liquid-Filled Soft-Gelatin Capsule Manufacturing

Complete dissolution of the active pharmaceutical ingredient (API) is critical in the manufacturing of liquid-filled soft-gelatin capsules (SGC). Attenuated total reflectance UV spectroscopy (ATR-UV) and Raman spectroscopy have been investigated for in-line monitoring of API dissolution during manufacturing of an SGC product. Calibration models have been developed with both techniques for in-line determination of API potency. Performance of both techniques was evaluated and compared. The ATR-UV methodology was found to be able to monitor the dissolution process and determine the endpoint, but was sensitive to temperature variations. The Raman technique was also capable of effectively monitoring the process and was more robust to the temperature variation and process perturbations by using an excipient peak for internal correction. Different data preprocessing methodologies were explored in an attempt to improve method performance.

Assessing Hyperspectral Image Content of Pharmaceutical Products Using the Herfindahl–Hirschman Index and Ripley's K-Functions

Hyperspectral chemical imaging technologies are frequently applied in the pharmaceutical industry to assess the distribution of ingredients in product intermediates and finished products. This article discusses two recognized measures of spatial uniformity in the context of pharmaceuticals. Synthetic images are used to introduce the utility of Ripleys K-function and the Herfindahl-Hirschman index (HHI) for describing image content. These metrics were applied to a commercial-like product to demonstrate the practical interpretation for product development. The simple approaches presented here offer the possibility of reporting objective measures of intra-tablet compositional uniformity with minimal supervision.

Applications of MVDA and PAT for Drug Product Development and Manufacturing

Abstract This chapter aims to provide readers with an overview of recent applications of process analytical technology (PAT) and multivariate data analysis (MVDA) in pharmaceutical product development and manufacturing. In-line and at-line PAT tools utilizing spectroscopic techniques, such as near-infrared (NIR) and Raman spectroscopies are discussed. Critical aspects of spectroscopic method design and development, method risk assessment, and validation are described. Calibration design is discussed in detail, including strategies for developing robust partial least squared (PLS) models for active pharmaceutical ingredient prediction in blends and tablets. The chapter highlights two particular applications of PAT and MVDA for two unit operations: blending and tablet compression. An in-line NIR PLS method was implemented to assess blending end-point and homogeneity to support formulation development and scale-up. A second example shows the development and validation of a high-impact at-line NIR method for tablet potency and content uniformity. Implementation and data derived during routine operation are presented to demonstrate the value proposition of applying these tools in commercial manufacturing facilities.

Analytical Method Development Using Transmission Raman Spectroscopy for Pharmaceutical Assays and Compliance with Regulatory Guidelines—Part II: Practical Implementation Considerations

Transmission Raman spectroscopy is a relatively new technique for quantitative analysis of pharmaceutical products, either during manufacturing or as a finished product test. As with any new analytical tool, several requirements need to be met for widespread application. These include assessment of technical capability, integration with quality and manufacturing processes and successful deployment in a quality-controlled environment. In the first paper of a two-part series, regulatory guidelines and method development were discussed for the creation of transmission Raman spectroscopic methods for content uniformity (CU), assay and drug product identity (ID) applications. In this part II, the practicalities of method development are addressed, and an example of the development of a quantitative method for the determination of drug content uniformity in individual tablet cores using partial least-squares is presented.