Ultrasonics Beats Optical Methods for Measuring Some Critical Attributes

By Evgeny Kudryashov and Breda O’Driscoll, Ultrasonic Scientific

Pharmaceutical manufacturing is a complex process often utilizing complex scientific and engineering principles. The new Food and Drug Administration (FDA) initiative considers process analytical technology (PAT) to be a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality. The key to the success of PAT is applying the process monitoring tools needed to carry out on-line analysis of each of the critical product attributes.

Process analysis has advanced significantly during the past several decades, due to an increasing appreciation for the value of collecting process data. Available tools have evolved from those that predominantly take univariate process measurements, such as pH, temperature, and pressure, to those that measure different biological, chemical, and physical attributes. Currently, process monitoring is rapidly moving towards non-destructive methods such as new spectroscopic methods. These measurements may be taken off-line, at-line or on-line, before, during or after the steps of the manufacturing process.

Most spectroscopic techniques utilize electromagnetic waves propagating through materials such as optical spectroscopy and its related derivations, such as FTIR, NIR and fluorescence methods. These methods play an essential role in the analysis of chemical attributes of the material (e.g., identity and purity) and in defining parametric end-points for utilized chemical processes.

However, despite these obvious advantages, the applications of traditional ‘electromagnetic’ spectroscopy methods are limited, in particular for process analysis in opaque samples and concentrated dispersions as well as samples without required optical activity (absorption spectrum). Therefore, certain physical and mechanical attributes of pharmaceutical ingredients that are critical to product quality are not easily achievable with standard spectroscopy methods. Consequently, the inherent, undetected variability of raw materials may be manifested in the final product.

Such attributes (e.g. particle size, concentration and their variations within a sample) of raw and in-process materials may pose a significant challenge because of their complexities and difficulties related to collecting representative samples. For example, it is well known that powder sampling procedures can be erroneous.

Several new technologies are now available that can acquire information on multiple attributes non-destructively with minimal or no sample preparation. High-Resolution Ultrasonic Spectroscopy (HR-US) is a novel technique with enormous potential for analysis of a wide range of samples and processes in PAT. This technique is based on precision measurements of the parameters of acoustical waves propagating through materials. It allows fast at/on line analysis of formulation consistency of raw materials, ingredients and intermediates, process impurity analysis, particle sizing, batch-to-batch variation, stability assessment, etc.

Unlike traditional analytical spectroscopy, optical transparency is not required as ultrasonic waves propagate through most types of samples. Moreover, in opaque samples it allows analysis of the interior (bulk properties) of the samples in contrary to many optical techniques, which collect the signal reflected at the surface.

High-Resolution Ultrasonic Spectroscopy generates product quality information in real process time and for a wide range of samples and dynamic processes. It is possible to monitor the manufacturing stages continuously and make adjustments to ensure that the finished product will meet the desired quality and specification.

This article describes some key features of the HR-US technique, which are beneficial for PAT installation, as well as specific advantages of the method in comparison to more traditional spectroscopy methods. This is illustrated using several examples of HR-US applications including real-time monitoring of the sedimentation and particle size evolution in drug suspensions, the effect of drug coating and drug concentration on these processes.

Benefits of HR-US vs. other methods

HR-US is a non-destructive analytical tool based on precision measurements of the velocity and attenuation of acoustical waves at high frequencies propagating through materials. It allows the analysis of composition, aggregation, gelation, micelle formation, crystallization, dissolution, sedimentation, enzyme activity, conformational transitions in polymers, ligand binding, antigen-antibody interactions, and many other processes that play a key role in drug production. Capable of dealing with a wide range of samples and dynamic processes, High-Resolution Ultrasonic Spectroscopy provides real time product quality information.

Two independent parameters, ultrasonic attenuation and ultrasonic velocity are measured in HR-US. Ultrasonic attenuation is determined by the energy losses in ultrasonic waves and can be expressed in terms of the high-frequency viscosity of the medium or its longitudinal loss modulus. This allows analysis of kinetics of fast chemical reactions and microstructure of materials including particle sizing, aggregation, gelation, crystallization and other processes and characteristics.