Lighting the way

Paul Smith, of Teraview, discusses the use of terahertz radiation in probing the structure of drug polymorphs

It has long been known that drugs can exist in more than one crystalline form.¹ These polymorphs have the same chemical formula but different crystalline structures, which can lead to different physicochemical properties, such as rates of dissolution or bioavailability, and the drug stability.²

So investigation of crystallographic polymorphism of drugs is of paramount relevance for the pharmaceutical industry. It is also particularly important when patenting a drug when each polymorph is considered to be a different drug, e.g. GSK Paxil/Seroxal.

Polymorphism is very common in drugs and has been observed in 67% of steroids, 40% of sulphonamides and 63% of barbiturates, and can be demonstrated using a variety of experimental techniques ranging from simple measurements to more sophisticated methods of analysis. The techniques include:

• Infra red (IR)³

• Nuclear Magnetic Resonance (NMR) spectroscopy ⁴

• X-ray diffraction⁵

• Raman spectroscopy⁶

• Terahertz Pulsed Spectroscopy (TPS)⁷

• Index of refraction measurements

• Dissolution rate measurements

• Thermal analysis

• Examination on the hot stage polarising microscope

While single crystal X-ray diffraction is still the benchmark method of determining the existence of a polymorph, as it gives the crystalline structure directly, TPS may prove a useful method to assess new drug entities, the effects of processing and storage on the solid-state form of the active substance present in tablets.

In many cases, it is possible to determine the solid state form of a drug present in the dosage form, and even determine if a mixture of forms are present using this technique.

Differences in spectra arise because of differing intermolecular interactions or molecular conformations, or difference in the crystalline structure of the material, giving rise to different phonon vibrations.

clear advantage

This ability to distinguish between solid-state forms has resulted in this technique to be extended to investigate the API in tablets. One clear advantage of TPS for analysing solid dosage forms is that, in the majority of cases, little or no sample preparation is required.

The FDA guidelines indicate that if technically possible, and in cases where drug product performance testing doesn't provide adequate indication of a change in the ratio of polymorphs, the polymorph form should be monitored during stability testing of the drug product. TPS shows promise as a technique which can address this challenge.

Another area of use for this spectroscopy could be in stability testing. While drug companies characterise the bulk drug form of the API, changes in the solid state may occur during processing, and it is envisaged that TPS will follow any crystal structure change during manufacturing process.

Moreover, there is scope for further development in advanced data processing methods such as chemometrics, which will facilitate a greater understanding of solid dose formulations, and several large pharmaceutical companies are now exploring the potential of Terahertz Pulsed Spectroscopy and possible applications in the FDA process analytical technology (PAT) initiative.

Application of method

TeraView Ltd has developed techniques to assist pharmaceutical companies in the rapid characterisation of the stability and polymorphic forms of drugs. Polymorphs can have different solubilities, stabilities or bioavailabilities. These factors may vary between two and five times for different polymorphs. It is important for pharmaceutical companies to understand if their drugs can exist as different polymorphs, and whether there is interconversion between the polymorphs. Terahertz technology provides a rapid technique to identify different polymorphs. Figure 1 shows the Terahertz absorption spectrum of Apo-ranitidine. This contains, as its active ingredient, ranitidine hydrochloride. This molecule can exist as two active forms, known as form 1 and form 2. Apo-ranitidine contains form 1 of the drug, while figure 2 shows the Terahertz absorption spectrum of GSK's Zantac, which contains form 2 as its active ingredient. Figure 3 enhances the difference in the 1-THz region showing clear differences between the two forms. Apotex Inc, Canada, produces Apo-ranitidine.