Real-time monitoring of evaporation crystallization processes of pharmaceutical compounds

Controlling of crystallization processes, and especially polymorph formation, has been an area of great interest and concern for the pharmaceutical industry over decades [1]. The physical properties of the crystals – such as crystal size and shape distribution, purity and polymorph – are influenced by the operating conditions of the crystallization process. Therefore, the ability to control the crystallization process and polymorphism is critical in order to ensure that the desired polymorph is produced. Despite of intensive research, the crystallization mechanisms are still difficult to predict on a theoretical level, which requires much experimental testing for crystal screening, optimization and control [2, 3].Over the past years, process analytical technologies have developed a lot [4]. Enhanced control of crystallization processes appears as better product quality, shorter process times and reduction of compromised batches [5]. Inline Raman spectroscopy and image analysis methods have been shown to be appropriate for on-line monitoring crystallization of several organic and inorganic solids [3, 5, 6]. The level of supersaturation can also be obtained by monitoring with inline Raman spectroscopy [7]. There are, however, several applications where the substances present in the solution or solid phase strongly fluoresce and conventional Raman methods cannot be used due to the main peaks being partially or completely obscured by the fluorescence signal. The present study examines on-line monitoring of evaporation crystallization of piroxicam and carbamazepine, two widely studied pharmaceuticals known to crystallize in different crystalline forms. The research involves controlled studies (aerodynamic conditions, temperature, air humidity and mass transfer between the gas and liquid) using evaporation chamber equipment at ambient pressure with air flow velocity and temperature as controlled variables.In this research, a conventional process analysis 785 nm Raman spectrometer (RXN1, Kaiser Optical Systems Inc., USA) and a time-gated 532 nm Raman spectrometer (Timegate Instruments Oy, Finland) are used to analyze the solid form composition of piroxicam and carbamazepine crystallized by evaporation crystallization. The former is used to online monitor evaporation crystallization process, which provides better understanding of the polymorph formation at different crystallization conditions. The latter involves a picosecond pulsed laser and time-gated detection, enabling fast enough measurement of the Raman spectrum to avoid interference from subsequent fluorescence. This could overcome the problem of fluorescent compounds: for example, piroxicam has yellow colour in the amorphous and monohydrate form, which can exhibit fluorescence with conventional Raman. The obtained polymorphs of piroxicam and carbamazepine crystals and the empirical evaporation rates are assessed and evaluated. X-ray powder diffraction (D8 Advance, Bruker, Germany) is used as a reference method for crystal analysis. The morphology of the crystals is observed with an optical microscope. According to the results obtained, the feasibility of these two Raman analysis methods are compared. The influence of the evaporation crystallization conditions on the crystal formation and crystal structure of the piroxicam and carbamazepine is also discussed.References:[1] Llinàs A, Goodman JM. Polymorph control: past, present and future. Drug Discovery Today, 13, 198-210 (2008).[2] Nagy ZK, Fevotte G, Kramer H, Simon LL. Recent advances in the monitoring, modelling and control of crystallization systems. Chemical Engineering Research and Design, 91, 1903-1922 (2013).[3] Yu ZQ, Chew JW, Chow PS, Tan RBH. Recent advances in crystallization control: An industrial perspective. Chemical Engineering Research and Design, 85, 893-905 (2007).[4] Levent LL, Pataki H, Marosi G, Meemken F, Hungerbühler K, Baiker A, Tummala S, Glennon B, Kuentz M, Steele G, Kramer HJM, Rydzak JW, Chen Z, Morris J, Kjell F, Singh R, Gani R, Gernaey KR, Louhi-Kultanen M, O’Reilly J, Sandler N, Antikainen O, Yliruusi J, Frohlberg P, Ulrich J, Braatz RD, Leyssens T, von Stosch M, Oliveira R, Tan RBH, Wu H, Khan M, O’Grady D, Pandey A, Westra R, Delle-Case E, Pape D, Angelosante D, Maret Y, Steiger O, Lenner M, Abbou-Oucherif K, Nagy ZK, Litster JD, Kamaraju VK, Chiu M-S. Assessment of recent process analytical technology (PAT) trends: A multiauthor review. Organic Process Research & Development, 19, 3-62 (2015).[5] Fujiwara M, Nagy ZK, Chew JW, Braatz RD. First-principles and direct design approaches for control of pharmaceutical crystallization. Journal of Process Control, 15, 493-504 (2005).[6] Févotte G. In situ Raman spectroscopy for in-line control of pharmaceutical crystallization and solids elaboration processes: A review. Chemical Engineering Research and Design, 85, 906-920 (2007). [7] Han B, Sha Z, Qu H, Louhi-Kultanen M, Wang X. Application of on-line Raman spectroscopy on monitoring semi-batch anti-solvent crystallization. CrystEngComm, 11, 827-831 (2009).