Morphologically-Directed Raman Spectroscopy: Uncovering the Good, the Bad, and the Ugly in Drug Formulations

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The pharmaceutical industry is driven by analytical data. New techniques that provide deeper insight are, therefore, crucial, whether the goal is to develop smarter formulation, more rapid deformulation, or for effective counterfeit detection. Morphologically-directed Raman spectroscopy (MDRS) is a powerful technique that combines automated particle imaging with Raman spectroscopy to efficiently deliver particle size, shape, and component-specific chemical identification. Recently highlighted by FDA (1) as pivotal to the approval of a generic version of Nasonex (mometasone), the use of MDRS is growing rapidly as its advantages, applications, and value become increasingly widely recognized.

How it works

MDRS uses measurements of particle size and shape--particle morphology--to guide the application of Raman spectroscopy to chemically identify individual particles. In this way, it delivers component-specific particle size and shape distributions for individual constituents of a blend or suspension, helping researchers to solve complex particle characterization problems (see Figure 1). For example, with MDRS, it is possible to: determine whether the size and shape of an API has been altered during processing and tablet production, measure critical properties of an API within a reference-labeled product as part of deformulation, and/or robustly identify contaminants during manufacture or as part of counterfeiting detection.

Figure 1: Because morphologically-directed Raman spectroscopy (MDRS) can chemically differentiate particles in a sample, it can provide component-specific particle size (and shape) distribution data-as shown here for an active and an excipient.

The workflow associated with MDRS can be broken down into three stages:

• Automated morphological imaging of the particles

• Raman spectral acquisition

• Chemical identification.

Automated particle imaging captures individual images of tens of thousands of particles in a sample within a matter of minutes. Dimensions from these images are used to build up number-based size and shape distributions to describe the sample. These data are often crucial in defining the performance of pharmaceuticals, given that particle morphology can influence critical properties such as solubility and bioavailability, flowability, and processing performance. Automated imaging is well-established within the industry and can be a highly effective tool for formulation, process optimization, and troubleshooting. Independently, however, it cannot differentiate morphologically-similar particles.

In MDRS, Raman spectroscopy is applied to chemically identify each particle of interest, with particles classified and selected on the basis of their size and/or shape. Raman spectroscopy is suitable for the analysis of a wide range of organic materials and offers the specificity to differentiate closely-related chemical species. Typical acquisition times are in the order of 5 seconds to 30 seconds per particle, but the number of particles measured is typically only a relatively small fraction of the sample, reducing overall measurement times.

The final step is to robustly identify the particles selected, by comparing the acquired spectral data with reference spectra. The reference library may be constructed in-house, or the system can interface with established spectral libraries, easing the confident identification of a wide range of substances. A secure identification for a specific particle population makes it possible to generate component-specific particle size and shape distributions.

Comparing MDRS with other techniques

Microscopy can be compared to automated imaging alone; both deliver size and shape data. Automated imaging, however, is significantly faster than microscopy, which can be time-consuming if the number of particles measured is high enough to ensure a representative measurement. Equally importantly, automated imaging delivers results with minimal manual intervention that are consequently independent of the operator subjectivity/human bias that can impact microscopy results. The addition of Raman spectroscopy further sets automated imaging apart from microscopy by conferring the ability to reliably detect, differentiate, and identify morphologically-similar particles.

Compared to bulk Raman, MDRS has the advantage of the potential for heightened sensitivity. Because MDRS is applied to individual particles within a mixture, even very low levels of an API or contaminant can be identified in the presence of a high-volume bulking agent. For example, in a back-to-back comparison of sensitivity, a sample of a powder-based drug, dextromethorphan hydrobromide (DXM), contaminated at 999:1 (weight:weight) with baking soda, produced spectra of the DXM alone with bulk Raman, but was precisely characterized by MDRS (2). MDRS analysis of the individual particles enabled reproducible detection of the baking soda “contaminant” and its quantification, even though the components present were morphologically indistinguishable. This feature is an advantage for contaminant detection in troubleshooting applications or counterfeiting investigations.

Applications of MDRS in the pharmaceutical industry

A notable application was recently highlighted by FDA, which specifically referred to MDRS in information it released about its approval of an abbreviated new drug application (ANDA) for a generic version of Nasonex (mometasone), a locally-acting suspension-based nasal spray for the treatment of allergies (1). Demonstrating the bioequivalence (BE) of a locally-acting product is challenging because traditional pharmacokinetic approaches based on measuring the level of drug in the bloodstream are not valid. FDA accepted in-vitro data measured using MDRS in lieu of a clinical endpoint study, with the technique enabling measurement and comparison of the particle size of the API within the formulation both before and after delivery. Here, MDRS proved pivotal to the success of the submission, setting a precedent for other generics developers to avoid the expense and time associated with a clinical BE determination via analogous analyses.

When it comes to formulating tablets, a particle size and shape specification for the API may be set based on the critical quality attributes (CQAs) of the finished product, such as its dissolution profile. Manufacturing the API to this specification may be relatively straightforward, but ascertaining that size and shape are maintained through any subsequent processing steps--blending, granulation, and tableting, for example--to the point of delivery to the patient, may be far more difficult. A further successful application of MDRS has been to investigate how unit operations such as blending affect the characteristics of the API through measurements of the changes in component-specific particle size and shape distribution associated with different processing conditions (see Figure 2).

Figure 2: Measurements of the particle shape of an API reveal that blending results in a reduction in elongation; this is suggestive of particle chipping (3).

Analogous studies are equally valuable in deformulation, where identifying the APIs present, the composition of the reference drug, and the physical characteristics of key components provides the insight needed to understand how to replicate product performance.

One further application area that can benefit from the unique capabilities of MDRS is counterfeit detection and investigation. Counterfeiting is a major concern for the pharmaceutical industry because of the threat it poses to public health, a company’s reputation, and profitability. MDRS can be used simply to confirm whether an API is present at the correct composition and physical form. In addition, it can detect very low levels of contaminants, and physically differentiate API originating from different sources. This information can provide vital clues to the provenance of counterfeit material, aiding the investigation and prosecution of illegal operations.

Conclusion

Characterizing APIs in isolation is relatively straightforward, but that isn’t how they are encountered in pharmaceutical products. The defining benefit of MDRS is its ability to differentiate the API (the ingredient of interest) from the product matrix and enable measurement. Whether the resulting data are used to show that a generic product is equivalent to a reference-labelled drug, to optimize processing conditions, to detect contaminants, or to help identify the source of a counterfeit, the net effect is the same. By efficiently generating component-specific data, MDRS accelerates and enhances key activities within the industry, and is consequently establishing itself as a powerful and valuable analytical tool.

References

1. R. Lal, FDA embraces emerging technology for bioequivalence evaluation of locally acting nasal sprays, FDA/CDER SBIA Chronicles (May 2016 Issue), accessed Feb. 13, 2017.
2. D. Huck-Jones, A. Koutrakos, and B. Kammrath, Introducing morphologically directed Raman spectroscopy, accessed Feb. 13, 2017. 
3. J. Gamble et al., International Journal of Pharmaceutics 470 (1-2) 77-87 (2014).

About the Author

Cathryn Langley, PhD, is associate product manager, analytical imaging, Malvern Instruments Ltd, Enigma Business Park, Grovewood Road, Malvern, Worcestershire, WR14 1XZ, UK ; Tel: +44 (0) 1684 892456; Fax: +44 (0) 1684 892789; www.malvern.com.

Article Details

Pharmaceutical Technology
Vol. 41, No. 4
Pages: 60–61, 73

Citation

When referring to this article, please cite it as C. Langley, “Morphologically-Directed Raman Spectroscopy: Uncovering the Good, the Bad, and the Ugly in Drug Formulations," Pharmaceutical Technology 41 (4) 2017.