Solvent-Mediated Polymorphic Transformation of a-Taltirelin by Seeded Crystallization Solvent-mediated polymorphic transformation (SMPT) of the a-form into the b-form of taltirelin (TTL) in seeded crystallization was investigated. The kinetics of polymorph transformation of the TTL was found to be a three-dimensional growth of nuclei mechanism by the Avrami-Erofeev equation. The transformation from the a-form into the b-form was also studied by crystallization adding a-form seeds in solution. The effects of seed loading amount, temperature, super- saturation, and transformation time on polymorph transformation were eval- uated. Seeded crystallization using a-form crystals as a seed nucleated the a-form TTL and then transformed the a-form into the b-form. The transformation rate was controlled by adjusting supersaturation. Keywords: Polymorph transformation, Raman spectroscopy, Solution-mediated crystallization, Solvent-mediated polymorphic transformation, Taltirelin Received: January 16, 2016; revised: April 25, 2016; accepted: April 28, 2016 DOI: 10.1002/ceat.201600043 1 Introduction Polymorphism, a very common phenomenon with active phar- maceutical ingredients (APIs), denotes the existence in two or more structural orientations of a pure substance. Polymorphic forms of the same chemical compound can have different physical and chemical properties such as solubility, melting point, or bioavailability [1]. Therefore, screening and control of API polymorphs in crystallization is crucial. A substance can exist in many forms which have different energies under partic- ular conditions. The stable form is the form having the lowest energy at a particular combination of temperature, pressure, and humidity. The other forms under the same conditions are considered as the metastable forms. A metastable form can also be the stable form under the different conditions. Theoretically, any metastable form can be converted to the stable form under specific conditions, although this conversion will be extraordi- narily slow unless mediated by a solvent [2]. The well-known mechanism in which a metastable form transforms into the stable form in the presence of a solvent is called solution- mediated polymorphic transformation (SMPT) [3]. Recently, various methods of process analytical technology (PAT) have been developed, which can be applied for the in- line measurement of crystallization and transformation of API polymorphs [4–8]. One of the potential in situ measurement technologies is Raman spectroscopy which uses the shift of wavelength caused by the interaction of photons from a mono- chromatic laser source with molecular vibrations. In addition, this technique can be adapted to monitor the transformation between polymorphs in solvent-mediated transformation because the Raman spectra contain information about both the solution phase and the solid phase [9–14]. The target compound in this study is taltirelin (TTL), which is a thyrotropin-releasing hormone analogue with potential neuroprotective and analgesic properties. It is applied as a treatment for neurodegenerative disorders for patients with adult spinal muscular atrophy. TTL has two reported crystal- line polymorphs, namely, a-form and b-form. The crystal structures of a-form and b-form of TTL were detected offline by X-ray powder diffraction (XRD) in previous studies [15–17]. The solubility of both forms is transited at 40 °C, thus the a-form is the stable form at temperatures above the transi- tion point, whilst the b-form is the stable form below this point where stable means lower solubility [15]. Since operating con- ditions in this study are below the transition point, a-form and b-form are the metastable form and the stable form, respective- ly. The mornitoring of TTL in cooling crystallization was per- formed in our previous study [18]. This research focuses on the real-time measurement of SMPT of the a-form into the b-form by Raman spectroscopy. In addition, the differences of the two polymorphs in solid and slurry state were shown by Raman spectra through several characteristic peaks. Generally, in the presence of solvent, the a-form transforms into the b-form along with the occurrence and the shift of some Raman characteristic peaks. Besides, var- Chem. Eng. Technol. 2016, 39, No. 7, 1281–1288 ª 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.cet-journal.com Dang Le Tri Nguyen Kwang-Joo Kim National Research Laboratory for Crystallization Process and Engineering, Department of Chemical Engineering, Hanbat National University, Daejeon, South Korea. – Correspondence: Prof. Kwang-Joo Kim (kjkim@hanbat.ac.kr), National Research Laboratory for Crystallization Process and Engineering, Department of Chemical Engineering, Hanbat National University, Dukmyung-dong, Yuseong-gu, Daejeon 305-719, South Korea. Research Article 1281