Ultrasonic spectroscopy for high resolution formulation analysis

1st April 2013

The quality control (QC) of the material and formulation of pharmaceutical manufacturing processes involves a variety of chemical or biological materials, including confirmation of factors such as chemical purity, polymorphism and water content.

Also important are the physical and functional properties that differ between chemical grades. These include dissolution rate, thermal stability (thermal transition), physical state (dispersed/aggregates) and particle size. This is particularly true for biologically active macromolecules such as proteins, polysaccharides and synthesised polymers.
Physical and functional properties can be tested using a selection of methods including UV/visible spectroscopy, laser diffraction, NMR, dynamic rheology and calorimetry. None of the identified techniques are completely satisfactory, each having its limitations and therefore the search for new, fast and more effective methods for wide range characterisation is a popular issue in quality of drug production. This is equally applicable to raw materials, intermediates, excipients and active ingredients.

The benefits of HR-US

High resolution ultrasonic spectroscopy (HR-US) is a new, non-destructive technique with enormous potential for analysis of materials and formulations used in the pharmaceutical industry.

Requiring only small sample volumes (down to 0.03ml) these instruments can be used for the analysis of composition, aggregation, gelation, micelle formation, crystallisation, 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.

The technique is based on precision measurements of parameters of acoustic waves at high frequencies propagating through materials. Unlike current analytical methods, optical transparency is not required as ultrasonic waves propagate through opaque samples and give excellent resolution. Capable of dealing with a wide range of samples and dynamic processes, HR-US generates product quality information in real process time. So it allows fast analysis of factors such as formulation consistency, batch-to-batch variation, and stability assessment. Some examples follow.

Tablet dissolution

To determine drug efficiency, functional characteristics are measured by the dissolution rate of raw material, active ingredients and excipients. The dissolution rate of two different tablets in acidic buffer (to mimic gastric acid environment) was monitored using the HR-US102 spectrometer.

Fig.1 presents the dissolution rate of two tablets determined from ultrasonic velocity data. The ultrasonic velocity changes as the solid drug components gradually dissolve and the solute concentrate grows. Fig.1 shows that tablet one initially dissolves at a much slower rate than tablet two. 50percent of tablet one is dissolved in the first 12minutes, while it takes about 35minutes to dissolve 50percent of tablet two. However, the dissolution rate of both tablets is found to be similar after 20minutes. One of the advantages of the ultrasonic method for measuring the dissolution rate is that it allows measurements of practically any compound in various environments, for example various temperature, pH and solvents.

HR-US can be used to monitor thermal transitions in polymers in different drug formulations. Hydroxypropylmethylcellulose (HPMC) is used to encapsulate hard capsule products. This polymer dissolves slowly in cold water to form a viscous colloidal solution and upon heating becomes insoluble in water forming a thermally reversible gel. This use is petitioned as an alternative to gelatin (animal based) capsules.

In this study, the HR-US102 spectrometer was used for comparative analysis of the gelling transition in two samples (HPMC1 and HPMC2) that differ in the hydroxypropyl content. The solutions of HPMC samples in water (2w/v) were loaded into the ultrasonic cell and their thermal gelling profile was measured from 40 to 90¢ªC at a heating rate of 0.5°C/minute.

Fig.2 shows the change in ultrasonic velocity with temperature in solutions of two different HPMC samples. The change in velocity at low temperature (initial slope) exhibits a linear decrease with increasing temperature and was used as a baseline. The decrease in velocity in this gel transition is caused by a decrease in the hydration level of the atomic groups of the HPMC molecules. According to the ultrasonic data, HPMC1 forms stronger gel networks compared to HPMC2. Thus, HR-US measurements allow analysis of the gelling profiles, detection of the gelling temperatures and characterisation of cross-links in the gel.  

Control of water content in raw material and active compounds is a key issue in drug production. HR-US spectrometers allow analysis of water concentration using precision velocity measurements. The analysis is based on many solutions and mixtures having ultrasonic velocity proportional to the concentration of solute component.

The components’ concentration can be determined from the measured ultrasonic velocity. This approach was applied to measure water content in crystalline and amorphous forms of the drug active compound. Two types of drug compounds, amorphous and crystalline, were dissolved in methanol at concentration 0.13g/cm3 and loaded into ultrasonic cells of the HR-US102 spectrometer. The comparison of ultrasonic parameters in two drugs solutions (at same nominal concentration of drug powder, mg/cm3) at 20°C is given in Fig.3a. The data demonstrates that samples can be easily distinguished by their ultrasonic profiles. The measured difference in ultrasonic velocity is several orders higher than the accuracy of the HR-US 102spectrometer.

Water content was calculated from the measured ultrasonic velocities and the calibration curve, as shown in Fig.3b. The total amount of water in samples is 1–1.5percent. Water content is higher in amorphous form of drug compounds as compared about approximately 0.5percent.

Evgeny Kudryashov, Cormac Smyth and Breda O’ Driscoll are with Dublin-based Ultrasonic Scientific. Vitaly Buckin is with the Department of Chemistry at University College Dublin, Ireland. For more information, visit





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