Crystal polymorphs are defined as substances that are chemically identical but exist in more than one crystal form, and generally differ in physicochemical properties. The polymorphism is a common phenomenon among pharmaceuticals. It has been shown that about 80% of active pharmaceutical ingredients (API) have polymorphs. 1,2)The optimization of polymorphic forms of an API is an important area of physicochemical research in drug discovery. The impact of polymorphs has been widely reported in the literatures, affecting such properties as dissolution rates, solubility, bioavailability and manufacturability. 3-7)The detection of polymorphs in drug discovery and manufacturing process is very important for assuring sufficient quality of the API. Powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), IR spectroscopy, Raman spectroscopy and solid state NMR measurement are generally applied for polymorph analysis of APIs. Although most of polymorphs are identifiable by these analytical techniques, there are some difficult cases to identify.In a previous paper, 8) we reported on remarkably similar polymorphs, forms A and B of Compound A, which is a novel drug for the treatment of osteoporosis. They were discriminated only by high-resolution powder X-ray diffractometry and thermally stimulated current (TSC) measurements. In particular, the TSC technique was useful for the discrimination of Compound A polymorphs, since both forms gave completely different TSC patterns.The terahertz (THz) region of the electromagnetic spectrum lies between the infrared and millimeter wave regions around 0.3 to 10 THz. THz spectroscopic analysis has been proposed as an analytical technique for crystal polymorphs because of the typical energies characterizing intermolecular interactions in a crystal lattice correspond to the THz region.9) The assignment of spectral features in this regime is still subject to scientific debate and several experiments have been discussed. [10][11][12] Crystalline APIs also have unique phonon modes, and as such, polymorphic forms of solid formulations have different THz spectra. [13][14][15][16] In addition, the absence of distinct modes in amorphous or liquid crystalline forms has been demonstrated. [17][18][19] Thus, THz spectroscopy is thought to be an effective tool for readily discriminating polymorph, even when their crystalline structures are quite similar.In this paper, we demonstrate THz spectroscopy as a novel analytical procedure for the determination of pharmaceutical polymorphs. We have shown that polymorphs of tolbutamide, carbamazepine and Compound A show slight different THz absorption spectra from each other and the second derivative of the THz absorption spectrum is an enormously beneficial tool for discerning different polymorphs.After the polymorph characterization, the optimization of the crystal form is an important step in the development of an API. To avoid the polymorph trouble during manufacturing and storage such as in the Ritonavir nightmare, 20,21) from the view...

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