# Selected Applications of Terahertz Pulses in Medicine and Industry
## 3 Terahertz Spectroscopy in a Pharmaceuticals  
The terahertz region of the electromagnetic spectrum probes low frequency modes of the solid-state materials. It is unlike mid infrared spectroscopy, where the observed transitions can easily be assigned to chemical functional groups of molecules. These vibrations are governed by intra-molecular vibrations, i.e., atomic bond strengths and mass of the atoms within the molecule. A terahertz spectrum is influenced by weak forces within the crystalline state. This leads the to the observed bands to be determined not so much by the functional groups within the molecule but by the packing density or geometry within the crystalline state, i.e., inter-molecular modes. Because of this sensitivity, terahertz spectroscopy has become a tool to distinguish between polymorphs of chemical substances. Polymorphs are the same chemical substance but have different crystalline forms and, therefore, packing density within the solid state. Understanding the polymorphism of chemical substances is extremely important to the pharmaceutical industry, as these polymorphs may have different dissolution rates, solubility, stability or even biological performance. From an economic perspective, each polymorph represents a unique crystalline state; therefore, it is important to patent each of these states. An example of this is ranitidine hydrochloride developed by Glaxo [34] for the treatment of ulcers. The original patent was based on form I. However, during scale up (from laboratory to manufacturing), as it sometimes happens, a new polymorph was discovered and Glaxo patented this later [35; 36]. Form II was formulated into Glaxo's product Zantac with sales over $3.5 billion in 1991. The original patent [34] expired in 1995, followed by a rush to bring to the market from generic drug companies tablets based on form I. Glaxo took a number of these generic companies to court in breach of their patent claiming that the generic companies were manufacturing tablets with a mixture of form I and II and not just pure form I. The generic company had to, therefore, prove that there was no form II in their tablets or form I. At this time, this was achieved by using X-ray powder diffraction. Glaxo lost the case. Aspirin was the first molecule of pharmaceutical importance to be studied using terahertz spectroscopy in 2001 [37]. In 2003, [PERSON] et al. [38] demonstrated that terahertz pulses could be used to distinguish between polymorphs of ranitidine hydrochloride. Figure 2 shows the terahertz spectra of six different suppliers tablets containing ranitidine hydrochloride as its active ingredient. Figure 2a presents the spectrum of a tablet from the innovator company (Glaxo), showing a single terahertz peak at about 1.14 THz. Glaxo uses form II of the drug, as discussed elsewhere in this paper. The spectra shown in Figure 2b-f are from the tablets obtained from generic companies that use form I. The terahertz spectra of form I is characterised by two peaks at about 0.99 THz and 1.29 THz. Since this original paper, other polymorphs of drug substances have been studied that use terahertz pulsed spectroscopy and these are summarised in Table 1. To demonstrate that terahertz pulse could be used to quantify substances with mixtures, [PERSON] et al. [39] used forms I and III of the drug molecule carbamazepine. The authors mixed the two polymorphs in tablets of polyethylene and were able to obtain a limit-of-detection of 0.44% and a limit-of-quantification of 1.34% between the two substances.