Metastable zone width, crystal nucleation and growth kinetics measurement in anti-solvent crystallization of β-artemether in the mixture of ethanol and water

Abstract The production of β-artemether, (3,12-epoxy-12 h-pyrano (4,3-j)-1,2-benzodioxepin, C16H26O5), an important active pharmaceutical ingredient for the treatment of malaria, uses crystallization as the purification step. This paper investigates the Metastable Zone Width (MSZW), nucleation and crystal growth kinetics of anti-solvent crystallization for β-artemether in ethanol + water system where water is the anti-solvent. Using a turbidity probe, the effect of process variables on MSZW was investigated, including initial the mass ratio of the solute to solvent, temperature, introduction rate as well as introduction location of the anti-solvent. The prediction model for MSZW was calibrated and proved reliable for this system. For anti-solvent crystallization of β-artemether in ethanol + water system, the chord length distribution data was collected using Focused Beam Reflectance Measurement, based on which the nucleation and crystal growth parameters were estimated using the method of moment. The crystal growth mechanism of β-artemether was also studied using a hot stage and imaging system and was found to follow a layer-by-layer growth mechanism.

[1]  B. Glennon,et al.  Application of in Situ FBRM and ATR-FTIR to the Monitoring of the Polymorphic Transformation of d-Mannitol , 2005 .

[2]  Jaroslav Nývlt,et al.  Kinetics of nucleation in solutions , 1968 .

[3]  K. Berglund,et al.  ATR-FTIR for Determining Optimal Cooling Curves for Batch Crystallization of Succinic Acid , 2002 .

[4]  F. Puel,et al.  On-line ATR FTIR measurement of supersaturation during solution crystallization processes. Calibration and applications on three solute/solvent systems , 2001 .

[5]  Ali Abbas,et al.  Model-Based Optimal Strategies for Controlling Particle Size in Antisolvent Crystallization Operations , 2008 .

[6]  Z. Nagy,et al.  Determination of the Kinetic Parameters for the Crystallization of Paracetamol from Water Using Metastable Zone Width Experiments , 2008 .

[7]  R. Braatz,et al.  Parameter Estimation and Optimization of a Loosely Bound Aggregating Pharmaceutical Crystallization Using in Situ Infrared and Laser Backscattering Measurements , 2004 .

[8]  Yu Qian,et al.  On-line concentration measurement for anti-solvent crystallization of β-artemether using UV–vis fiber spectroscopy , 2011 .

[9]  Sohrab Rohani,et al.  Multivariable Real-Time Optimal Control of a Cooling and Antisolvent Semibatch Crystallization Process , 2009 .

[10]  Kevin J. Roberts,et al.  Classifying organic crystals via in-process image analysis and the use of monitoring charts to follow polymorphic and morphological changes , 2005 .

[11]  Antonia Borissova,et al.  In Situ Measurement of Solution Concentration during the Batch Cooling Crystallization of l-Glutamic Acid using ATR-FTIR Spectroscopy Coupled with Chemometrics , 2009 .

[12]  B. Glennon,et al.  In Situ Monitoring of Polymorphic Transitions , 2003 .

[13]  Yu Qian,et al.  Solubility of β-Artemether in Methanol + Water and Ethanol + Water from (288.85 to 331.95) K , 2009 .

[14]  B. Glennon,et al.  Characterizing the metastable zone width and solubility curve using lasentec FBRM and PVM , 2002 .

[15]  B. Glennon,et al.  Supersaturation tracking for the development, optimization and control of crystallization processes , 2010 .

[16]  Zoltan K. Nagy,et al.  Recent advances in the monitoring, modelling and control of crystallization systems , 2013 .

[17]  A. Seidel-Morgenstern,et al.  Application of a recent FBRM-probe model to quantify preferential crystallization of DL-threonine , 2010 .

[18]  Sohrab Rohani,et al.  Kinetics Estimation and Single and Multi-Objective Optimization of a Seeded, Anti-Solvent, Isothermal Batch Crystallizer , 2008 .

[19]  Ali Abbas,et al.  Antisolvent crystallization: Model identification, experimental validation and dynamic simulation , 2008 .

[20]  Reginald B. H. Tan,et al.  Recent Advances in Crystallization control: An Industrial Perspective , 2007 .

[21]  Yang Yang,et al.  Model-Based Systematic Design and Analysis Approach for Unseeded Combined Cooling and Antisolvent Crystallization (CCAC) Systems , 2014 .

[22]  M. Sheikhzadeh,et al.  Real-time optimal control of an anti-solvent isothermal semi-batch crystallization process , 2008 .

[23]  B. Glennon,et al.  The Effect of Mixing on the Metastable Zone Width and Nucleation Kinetics in the Anti-Solvent Crystallization of Benzoic Acid , 2007 .

[24]  Richard D Braatz,et al.  Advances and new directions in crystallization control. , 2012, Annual review of chemical and biomolecular engineering.

[25]  S. Rohani,et al.  Determination of Particle Size Distribution by Par-Tec® 100: Modeling and Experimental Results , 1998 .

[26]  Richard D. Braatz,et al.  First-principles and direct design approaches for the control of pharmaceutical crystallization , 2005 .

[27]  Noriaki Kubota,et al.  An interpretation of the metastable zone width concerning primary nucleation in anti-solvent crystallization , 2008 .