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Deposition Sciences Inc. - Difficult Coatings - LB - 8/23

Raman Spectroscopy Analysis of Polymorphs

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Polymorph identification is important for the pharmaceutical industry, and Raman spectroscopy can provide a simple way to perform this analysis.

Dr. Robert Alexander, PerkinElmer Ltd.

Some molecules with the same chemical formula can have different crystal structure forms — called polymorphs. There are two ways in which crystal structures can arise: arrangement (or packing) polymorphism and conformational polymorphism. Pseudopolymorphs are crystalline structures that also incorporate solvent molecules and are, therefore, not chemically identical to the true polymorphs.

The differences in the crystalline structure of polymorphs can affect a substance’s characteristics — solubility, dissolution rate, density, hardness, shape — which, in turn, can influence their important pharmaceutical properties, including drug bioavailability and stability as well as formulation of the dosage form.

The formation of polymorphs is a controllable process. Factors such as solvent of crystallization, rate of cooling and degree of supersaturation can affect the crystallographic form produced. Powder processing, especially the pressure from grinding or milling, also can change the form.

In the pharmaceutical industry, it is therefore vital to manufacture the correct polymorphic form and to access its continued viability throughout its formulation, storage and subsequent usage. The polymorphic form present in a drug also is of great commercial importance when a pharmaceutical company files patents for new products.

There are several recognized analytical techniques commonly used to analyze and differentiate among polymorphic forms. Most common are x-ray powder diffraction, thermal analysis and vibrational spectroscopy (IR and Raman).

Raman spectroscopy is one of the most powerful and simple techniques for polymorph analysis, although using a combination of techniques is sometimes advantageous.

Ranitidine hydrochloride is one polymorphic molecule. The histamine type 2 receptor antagonist used in the treatment of peptic ulcers can exist in two distinct forms (Form I and Form II) and in several other pseudopolymorphic forms. The two forms are used by pharmaceutical manufacturers and are available over the counter as coated tablets. The tablets contain a relatively high concentration of one or the other polymorph.

Surface and bulk analysis

Raman spectroscopy can collect spectral data from the surface of samples and, in favorable cases, from several millimeters into the bulk of the sample. In a study of Ranitidine hydrochloride polymorphs, a series of spectra was automatically collected, beginning on the surface coating and progressing into the bulk of a tablet. Each spectrum had a contribution from the coating and the bulk materials, but the relative contribution of each component varied with the depth of penetration. By performing simple spectral subtraction between the spectra, “pure” spectra representing the coating and the bulk material could be generated.

Analyzing tablets from a range of suppliers revealed that each manufacturer chooses one or the other of the two polymorphs as the active ingredient.

The Raman spectra of the two polymorphic forms are shown in Figure 1. Because the molecules are structurally very similar, the spectra also are similar. However, there are enough significant differences to enable an analyst to differentiate among the molecules.

Ohara Corp. - Optical Glass, Polish substrates 10-23

RamanInstitution_PE_figure1.jpg
Figure 1.
These Raman spectra obtained from the bulk of different tablets show the various forms of Ranitidine hydrochloride.


The tablets have a relatively thick protective coating, and the same analysis revealed the Raman spectrum of the coating in addition to that of the active ingredient in the bulk of the tablet. Whereas various manufacturers use different forms of the active ingredient, they all use the same coating material, readily identified as titanium dioxide from its Raman spectrum (Figure 2).

RamanInstitution_PE_figure2.jpg
Figure 2.
The Raman spectrum of tablet coating is compared with reference spectra of the different polymorphic forms of titanium dioxide. The fact that data can be collected down to 100 cm–1 makes Raman an ideal technique for analyzing inorganic structures.


Titanium dioxide is a white, inorganic substance widely used as a protective material in the pharmaceutical industry. Polymorphism also is found among inorganic molecules, and titanium dioxide is an example of such a molecule that can exist in two main polymorphic forms. These two forms give rise to two minerals, rutile and anatase, and, because they have different physicochemical properties, are used to perform various functions within a range of industries. Raman spectroscopy has long been used to identify and differentiate between these minerals because they have significantly different Raman spectra.

Comparing the spectra obtained from the tablet coatings with reference spectra of rutile and anatase revealed that all the tablets have the same coating material: anatase.

This study confirms that Raman spectroscopy is an ideal analytical technique for the identification of organic and inorganic polymorphic forms. Raman spectra have a high degree of specificity and can be used as a “fingerprint” to differentiate among molecules, even those with very similar structures. There is little or no sample preparation required in the analysis, minimizing any danger of the polymorphic forms being changed. The fact that data can be obtained down to low wave number values (below 100 cm–1) means that the Raman technique can readily differentiate between inorganic polymorphs as indicated in this study.

Meet the author

Robert Alexander is Raman technology manager at PerkinElmer Ltd. in Beaconsfield, UK;
e-mail: [email protected].

Published: April 2008
BiophotonicsCoatingscrystal structureFeaturesmoleculespolymorphs

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