Design and modeling of pharmaceutical polymorphic crystallization processes

DESIGN AND MODELING OF PHARMACEUTICAL POLYMORPHIC CRYSTALLIZATION PROCESSES NICHOLAS KEE CHUNG SHEN NATIONAL UNIVERSITY OF SINGAPORE 2008 DESIGN AND MODELING OF PHARMACEUTICAL POLYMORPHIC CRYSTALLIZATION PROCESSES NICHOLAS KEE CHUNG SHEN (B. Eng. (Hons.), NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMICAL AND BIOMOLECULAR ENGINEERING NATIONAL UNIVERSITY OF SINGAPORE 2008 ACKNOWLEDGEMENTS I would like to express my deepest gratitude to my advisors, A/Prof. Reginald B. H. Tan from the National University of Singapore (NUS) and Prof. Richard D. Braatz from the University of Illinois at Urbana-Champaign (UIUC) for their guidance, patience and support. I would also like to thank Prof. Charles F. Zukoski (UIUC), A/Prof. Paul J. A. Kenis (UIUC), and Prof. Farooq Shazuzamman (NUS) for being part of the thesis committee. I am grateful to Dr. Ang Ee Lui, Yusua Agabus, Paul Arendt, Mickie Bailot, Cheok Bee Khim, Cheong Kim Seng, Chew Lee Chee, Dr. Ann Chow, Gavin Chua, Chua Eng Kiong, Ashlee Ford, Dr. Mitsuko Fujiwara, Goh Kia Hoe, Dr. He Guangwen, Daniel Heller, Doris How, Sister Janice Keenan, Dr. Li Shaohai, Dr. Jim Mabon, Ng Yeap Hung, Sarah Perry, Dr. Sendhil Poornachary, Maya Ramesh, Ronnie Tan, Dr. Effendi Rusli, Siah Tiong Seng, Tan Thiam Teck, Tang Weng Ling, Sumitro Joyo Taslim, Teo Shi Wee, Dr. Scott Wilson, Wuang Shy Chi, Dr. Woo Xing Yi, Dr. Yu Zaiqun, and Yun Chee Yong for their friendship and assistance during my stay in Singapore and the United States. Financial support for this work was provided by the Agency of Science, Technology and Research (A*STAR). Finally and most importantly, I dedicate this thesis to my family; my parents, parents-in-law, siblings, siblings-in-law, and particularly my wife Li May for her incredible support, encouragement, patience, and love. i TABLE OF CONTENTS Acknowledgements i Table of Contents ii Summary iv List of Tables v List of Figures vi List of Symbols …………………………………………………………………… .x General Introduction Literature Review .6 2.1 Direct Design of Pharmaceutical Crystallization Processes ………………… .6 2.2 Direct Design of Pharmaceutical Polymorphic Crystallization Processes … .11 2.3 Techniques for Solubility Measurement …………………………………… .16 2.4 Modeling of Polymorphic Crystallization and Transformation ………………18 Selective Crystallization of the Metastable Polymorph in a Monotropic Dimorph System ……………………………………………………………………………… .22 3.1 Introduction ………………………………………………………………… .22 3.2 Experimental Procedures …………………………………………………… 24 3.2.1 Materials and Instruments ………………………………………………24 3.2.2 Calibration for Solution Concentration …………………………………26 3.2.3 Solubility and Metastable Limit Measurements ……………………… 27 3.2.4 Seeded batch crystallization …………………………………………….29 3.3 Results and Discussion ……………………………………………………….30 3.3.1 Solubility and Metastable Limit Measurements ……………………… 30 3.3.2 Concentration Controlled Batch Crystallization ……………………… 32 3.4 Concluding Remarks ………………………………………………………….40 Semi-Automated Solubility Measurement for an Enantiotropic Pseudo-Dimorph System ……………………………………………………………………………… .41 4.1 Introduction ………………………………………………………………… 41 4.2 Experimental Procedures …………………………………………………… 43 4.2.1 Materials and Instruments ………………………………………………43 4.2.2 Calibration for Solute Concentration ………………………………… .45 4.2.3 Solubility Measurements ……………………………………………….46 ii 4.3 Results and Discussion ……………………………………………………….49 4.3.1 Method ……………………………………………………………… 49 4.3.2 Method ……………………………………………………………… 53 4.4 Concluding Remarks ………………………………………………………….57 Selective Crystallization of the Metastable Polymorph in an Enantiotropic Pseudo-Dimorph System …………………………………………………………… 59 5.1 Introduction ………………………………………………………………… .59 5.2 Experimental Procedures …………………………………………… ………60 5.2.1 Materials and Instruments ………………………………………………60 5.2.2 Calibration for Polymorph Composition using PXRD …………………62 5.2.3 Calibration for Solute Concentration ………………………………… .63 5.2.4 Solubility and Metastable Limit Measurements ……………………… 65 5.2.5 Seeded Batch Crystallization ………………………………………… .66 5.3 Results and Discussion ……………………………………………………….67 5.3.1 Solubility and Metastable Limit Measurements ……………………… 67 5.3.2 Concentration Controlled Batch Crystallization ……………………… 72 5.4 Concluding Remarks ………………………………………………………….80 Estimation of Kinetics for L-Phenylalanine Hydrate and Anhydrate Crystallization ……………………………………………………………………… .82 6.1 Introduction ………………………………………………………………… .82 6.2 Experimental Data for Modeling …………………………………………… 83 6.3 Mathematical Model of L-phe Crystallization ……………………………… 86 6.3.1 Model Equations ……………………………………………………… 86 6.3.2 Relationship between CSD and CLD Moments ……………………… 91 6.3.3 Parameter Estimation ………………………………………………… .94 6.3.4 Confidence Intervals for the Parameter Estimates …………………….104 6.3.5 Model Validation …………………………………………………… .107 6.4 Staged vs. Simultaneous Parameter Estimation ………………………… …115 6.5 Concluding Remarks ……………………………………………………… .117 Conclusions and Recommendations …………………… .……………………….118 7.1 Conclusions ………………………………………………………………….118 7.2 Recommendations for Future Work .………………………………………120 Bibliography ……………………………………………………………………… .123 iii SUMMARY The objectives of this research are: (i) to design and control pharmaceutical crystallization processes aimed at the selective production of metastable polymorphs, applicable to various types of polymorphic systems; (ii) to develop a semi-automated procedure for solubility measurement of both polymorphic forms, and (iii) to model polymorphic crystallization processes and elucidate the kinetic parameters pertaining to both polymorphic forms. Chapter introduces several aspects of polymorphic crystallization, including its relevance to pharmaceutical crystallization. This will be followed by Chapter which gives a review of recent developments particularly on the use of Process Analytical Technology (PAT) in this field. Chapter describes the implementation of concentration feedback control for selective crystallization of the metastable polymorph in a monotropic dimorph system, using L-glutamic acid as the model compound. A similar demonstration is given in Chapter for a different polymorph system, L-phenylalanine, which is an enantiotropic pseudo-dimorph system. Prior to this, a semi-automated scheme for solubility measurement is described in Chapter 4, also using L-phenylalanine as the model compound. Chapter describes the simulation of the polymorphic crystallization processes from Chapter 5, to estimate the nucleation and crystal growth kinetic parameters of both forms of L-phenylalanine. Lastly, the conclusions and future directions are provided in Chapter 7. iv LIST OF TABLES Table 3.1 ATR-FTIR calibration samples for solute concentration measurement. ……………………………………………………………………………………… 26 Table 3.2 Initial solute concentrations in the metastable limit experiments. ……… 29 Table 3.3 Fitting parameters for α and β-form L-glu acid solubility curves. ……… .31 Table 3.4 PXRD analysis of seed and product crystals. …………………………… .34 Table 4.1 ATR-FTIR calibration samples for solute concentration measurement. … 46 Table 4.2 Fitting parameters for anhydrate and monohydrate form L-phe solubility curves. ……………………………………………………………………………… .52 Table 5.1 PXRD calibration samples for polymorph composition. ………………… 63 Table 5.2 ATR-FTIR calibration samples for solute concentration measurement. … 64 Table 5.3 Initial solute concentrations in the metastable limit experiments. …………66 Table 5.4 Fitting parameters for anhydrate and monohydrate form L-phe solubility curves. ……………………………………………………………………………… .68 Table 5.5 PXRD analysis of seed and product crystals. …………………………… .76 Table 6.1 Summary of operating conditions and results for the concentration controlled runs. ………………………………………………………………………………… .84 Table 6.2 Segments of experimental data pertaining to different crystallization kinetics. ……………………………………………………………………………………… .86 Table 6.3 Variants of power law growth model for anhydrate L-phe. ……………….98 Table 6.4 Variants of power law nucleation model for anhydrate L-phe. ………… 101 Table 6.5 Parameter estimates with 95% confidence intervals. …………………….105 Table 6.6 Comparison of simulated and experimental results: mean La and product composition. …………………………………………………………………………109 v LIST OF FIGURES Figure 1.1 Solubility curves of dimorphs I and II (Csat,I and Csat,II respectively) in a (a) monotropic system and (b) enantiotropic system. ……………………………………. Figure 2.1 Crystallization apparatus with various in situ sensors. ……………………. Figure 2.2 Schematic of FBRM sensor. ………………………………………………. Figure 2.3 Direct design of a batch crystallization recipe using ATR-FTIR and FBRM. ………………………………………………………………………………………….9 Figure 2.4 Schematic of selective crystallization operations for (a) Form II and (b) Form I, in a monotropic dimorph system based on the solubility diagram. …………………………………………………………………………… ………… 13 Figure 2.5 Schematic of selective crystallization operations for Form I, in an enantiotropic dimorph system based on the solubility diagram with different metastable limits. ……………………………………………………………………. 14 Figure 3.1 Scanning electron micrographs of L-glu acid crystals (scale bar 100 µm): (a) α-form and (b) β-form. ………………………………………………………………. 23 Figure 3.2 PXRD patterns of α (bottom) and β (top) forms of L-glu acid. …………………… 25 Figure 3.3 Representative ATR-FTIR spectra of the calibration samples and regression coefficients of the calibration model relating absorbance to solute concentration (the regression coefficients for the temperature and the intercept are not shown). ……….26 Figure 3.4 Total counts/sec (-) and temperature (x) profiles in the metastable limit experiment. ………………………………………………………………………… .29 Figure 3.5 L-glu acid solubility curves compared to: (a) previously published data (Ono et al., 2004a) and (b) metastable limit for cooling rate at 0.4 °C/min. …………32 Figure 3.6 Preliminary seeded batch crystallization run: (a) implemented supersaturation profiles, (b) temperature profile (seeding at min), and (c) microscopy image of the α-form product crystals with β-form crystals observed on the α-form crystal surfaces (scale bar 180 µm). ………………………………………………… 34 Figure 3.7 PXRD patterns of the seed and product crystals. …………………………34 Figure 3.8 Seeded batch crystallization Runs 1-3: (a) implemented supersaturation profiles, (b) temperature profiles with seeding at min, and (c) total counts/sec profiles. ……………………………………………………………………………….36 vi Figure 3.9 Microscopy images of seed and product crystals (scale bar 180 µm): (a) αform seed crystals, (b) α-form product crystals from Run with wide size variation, (b) α-form product crystals from Run with agglomeration, (d) α-form product crystals from Run 2, and (e) α-form product crystals from Run 3. ……………………………37 Figure 3.10 Size distribution of L-glu acid α-form seeds (based on the largest diagonal length measurable from the microscopy images) and product crystals (based on dimension indicated in Figure 3.9e); sample size of 100 crystals for each distribution. ……………………………………………………………………………………… .38 Figure 4.1 Microscopy images of L-phe crystals: (a) anhydrate form as is from Sigma Aldrich (>98.5%), (b) monohydrate form, and (c) the anhydrate form with a more well-defined habit as rhombic platelets obtained through recrystallization. …………43 Figure 4.2 PXRD patterns of anhydrate (-) and monohydrate (-) forms of L-phe. … 45 Figure 4.3 Representative ATR-FTIR spectra of the calibration samples and regression coefficients of the calibration model relating absorbance to solute concentration. The regression coefficients for the temperature and the intercept are not shown. ……… .45 Figure 4.4 Total counts/sec profiles as a function of temperature at different heating rates. The non-zero baseline value was due to the presence of bubbles caused by the high stirring rate. …………………………………………………………………… .48 Figure 4.5 (a) Solute concentration and temperature profiles and (b) total counts/sec profile in the solubility experiment for anhydrate form L-phe using Method 1. …… 50 Figure 4.6 (a) Solute concentration and temperature profiles and (b) total counts/sec profile in the solubility experiment for monohydrate form L-phe using Method 1. The open circles indicate erroneous concentration values; the solid circles indicate correct measurements. ……………………………………………………………………… .50 Figure 4.7 L-phe solubility curves compared to previously published data (Mohan et al., 2001) for the anhydrate form, Csat,a, and monohydrate form, Csat,m. …………… 52 Figure 4.8 Schematic of Method and L-phe solubility points using Method compared to the fitted solubility curves from Method 1. …………………………….54 Figure 4.9 Solute concentration, anhydrate form ( ) and monohydrate form ( ), and temperature (+) profiles in the solubility experiment using Method 2. The concentration profile is not shown entirely for parts (c) and (d) because of erroneous measurement due to interference from monohydrate needles. The open circles indicate erroneous concentration values, and the solid circles indicate correct measurements. 54 Figure 4.10 Total counts/sec profile in the solubility experiment using Method with the anhydrate form (-) referencing the left axis and the monohydrate form (-) referencing the right axis. …………………………………………………………….55 vii Figure 4.11 PVM images from the solubility experiment using Method (scale bar 100 µm): at the anhydrate form saturation, the recrystallization of the monohydrate form, and the eventual dissolution. ………………………………………………………….57 Figure 5.1 Scanning electron micrographs of L-phe crystals: (a) anhydrate form and (b) monohydrate form. ……………………………………………………………………59 Figure 5.2 (a) PXRD patterns of calibration samples (the largest peak at 2θ ≈ 5.54° was normalized to the same value in all the patterns to better illustrate the variation in the characteristic peaks of the monohydrate form), and (b) PXRD calibration line for polymorph composition. …………………………………………………………… .62 Figure 5.3 Representative ATR-FTIR spectra of the calibrations samples and regression coefficients of the calibration model relating absorbance to solute concentration. The regression coefficients for the temperature and the intercept are not shown. ……………………………………………………………………………… .64 Figure 5.4 Solubility curves of L-phe: Csat,a ( ) and Csat,m ( ) in mixed solvent from isothermal studies, Csat,m ( ) in mixed solvent from slow heating. ………………… .69 Figure 5.5 Run 2m experimental profiles with seeding at min: (a) solute concentration and temperature and (b) total counts/sec. …………………….……… 70 Figure 5.6 PVM images (scale bar 100 µm) from Run 2m at: (a) 41 min, at first detection of crystals of the monohydrate form and (b) 52 min, at onset of increase in FBRM total counts/sec. ……………………………………………………………….70 Figure 5.7 Run 4m experimental profiles with seeding at min: (a) solute concentration and temperature and (b) total counts/sec. ………………….………… 71 Figure 5.8 PVM images (scale bar 100 µm) from Run 4m: (a) at 43 min, onset of increase in FBRM total counts and (b) at 63 min, first detection of monohydrate form crystals. ……………………………………………………………………………….71 Figure 5.9 L-phe solubility and seeded metastable limits. ………………………… .72 Figure 5.10 Supersaturation profiles implemented in the seeded batch crystallization runs. ………………………………………………………………………………… .72 Figure 5.11 Experimental profiles in the seeded batch crystallization runs (with seeding at min): (a) temperature and (b) total counts/sec. ………………………….73 Figure 5.12 PVM images (scale bar 100 µm) from Run at (a) 36 min, onset of increase in FBRM total counts, (b) 104 min, first detection of monohydrate form crystals, (c) 243 min, and (d) 296 min. ……………………………………………….74 Figure 5.13 Microscopy images of seed and product crystals (scale bar 200 µm, unless stated otherwise): (a) seeds – anhydrate form, (b) Run products – monohydrate form crystals observed on the anhydrate crystals surfaces, (c) Run products – agglomerates viii designs in which all crystallization phenomena occur simultaneously, forcing the simultaneous estimation of all of the parameters. It should be possible, however, to add constraints in the crystallization phase diagram to the D-optimal approach so that staged experimental designs can be implemented that minimize the uncertainties in the parameters while retaining the advantages of stage design. This would combine the best features of the two approaches. 6.5 Concluding Remarks A process model for the polymorphic crystallization of L-phenylalanine, an enantiotropic pseudo-dimorph system, was developed. The kinetic parameters for nucleation and growth for both the anhydrate and monohydrate forms were estimated using in situ probes (solute concentration obtained from ATR-FTIR spectroscopy and CLD moments measured using FBRM) from experiments in which feedback controlled motion in the crystallization phase diagram suppressed certain kinetic events (for example, cross nucleation) in particular segments of the experimental data. This simplified the crystallization model and reduced the number of parameters to be estimated simultaneously, by focusing on the relevant segments of the experimental data pertaining only to certain kinetics. This facilitated the estimation of the parameters in a stage-wise manner for each set of kinetics. Such an approach is advantageous for crystallization models with a large number of parameters such as for polymorphic systems. The predictive ability of the crystallization model was evaluated based on the model properties of the product crystals and metastable limit which were in good agreement with that from independent characterization and experiments. It is hoped that this combination of experimental design and process modeling will facilitate process modeling and development for other polymorphic pharmaceutical compounds. 117 CONCLUSIONS AND RECOMMENDATIONS 7.1 Conclusions The following conclusions are drawn based on the research work and results presented in this thesis: • A systematic methodology is presented for the selective crystallization of the metastable form of a monotropic dimorph, L-glutamic acid, for batch cooling crystallization. Attenuated Total Reflection-Fourier Transform Infrared (ATRFTIR) spectroscopy coupled with chemometrics was used to determine the solute concentration and solubility curves of both α and β-forms of L-glutamic acid in aqueous solution. The metastable limit associated with secondary nucleation for a seeded system was determined using laser backscattering (Focused Beam Reflectance Measurement, FBRM). Batch crystallizations seeded with the metastable α-form crystals following various preset supersaturation profiles were implemented using concentration feedback control which regulated the cooling rate based on in situ measurement of solute concentration. Batch crystallizations operated at constant relative supersaturation in an appropriate temperature range prevented secondary nucleation of both polymorph types and were successful in selectively growing large metastable crystals with uniform size. • The same direct design approach was applied to different polymorphic system; a batch recipe for the selective crystallization of the metastable anhydrate form of an enantiotropic pseudo-dimorph system, L-phenylalanine (L-phe), in a mixed solvent system (75 wt% water and 25 wt% 2-propanol) was implemented by controlled tracking of a designed trajectory in the phase 118 diagram. The solubility curves of both the anhydrate and monohydrate forms and the seeded metastable limit were determined in similar fashion using ATRFTIR spectroscopy and FBRM respectively. The nucleated forms identified using in situ video microscopy. Anhydrate form seeded batch operations were implemented following various preset supersaturation profiles; undesired secondary nucleation of both forms at the metastable limit provided the operating constraints in terms of the maximum allowable supersaturation. Batch crystallization implemented at low constant absolute supersaturation with respect to the unwanted monohydrate form was successful in preventing cross nucleation and in selectively growing large anhydrate crystals with relatively more uniform sizes. This methodology extended the useful range of the phase diagram to temperatures below the transition point, where the anhydrate form is metastable, to increase product yield compared to operations utilizing only the temperature range above the transition temperature, where this form is stable. • A semi-automated procedure for measuring the solubility of both enantiotropes in a dimorphic system was developed using the same in situ instruments. The approach was demonstrated for L-phe. The procedure involves the determination of the anhydrate form solubility from in situ IR spectroscopy of an equilibrated slurry, followed by the dissolution of the anhydrate form by heating. The monohydrate form is then recrystallized, and its solubility determined from slow heating until complete dissolution is detected by FBRM. The solubility of the monohydrate form was determined differently from the anhydrate form due to the interference on the IR measurements from small needle-like monohydrate crystals. This single-experiment approach allows for 119 more efficient solubility measurement of both forms and is applicable to other enantiotropic dimorph systems • A process model for the crystallization of L-phe crystals from mixed propanolwater solution, an enantiotropic system, is developed with kinetics estimated for the anhydrate and monohydrate forms using in situ ATR-FTIR spectroscopy and laser backscattering. A challenging aspect of estimating kinetics for this system is the formation of large numbers of small crystals under certain conditions, which result in biases in the data collected from in situ ATR-FTIR and FBRM probes. Batch experiments were designed to follow particular trajectories in the phase diagram so that some kinetic phenomena are suppressed (for example, cross nucleation) in some runs, which enabled the estimation of sets of kinetic parameters in stages, reducing the number of parameters to be estimated simultaneously. The model was validated by comparison of model predictions and experiments for the product crystals and metastable limits obtained from independent characterization and experiments. It is hoped that this combination of experimental design and process modeling will be emulated to facilitate process modeling and development for other polymorphic pharmaceutical compounds. 7.2 Recommendations for Future Work The successful demonstration in using the direct design approach applied with Process Analytical Technology (PAT) for the control, design and modeling of crystallization processes in non-polymorphic and dimorphic systems highlights its potential and applicability for more complex operations. Selective crystallization processes in multiple polymorphs systems and enantioseparation processes are of particular importance in the pharmaceutical industry. PAT has not yet been rigorously 120 applied in these systems because of their inherent complexity; it is expected that the implementation of more advanced modeling and control strategies will have a large impact. Example applications on such systems will be highly beneficial, particularly for industrial users. • Stearic acid is an example of a multiple polymorph system. It is applied to many industrial processes such as detergent and insulation industries and also for suppositories, coating enteric pills and ointments (Mirmehrabi and Rohani, 2004); it is often considered a model compound in the series of long-chain compounds (Sato and Boistelle, 1984). Stearic acid has four known polymorphs, A, B, C, and E; polymorph A is triclinic, whereas forms B, C and E are monoclinic (Sato and Boistelle, 1983; 1984). The crystals of form A are elongated, while the B and C forms are lozenge-shaped, exhibiting acute angles of 75° and 55° respectively. Previous studies on the relative stability of each form revealed the enantiotropic relationship of forms B and C; the transition point is at 32°C and form B is the stable polymorph below this temperature (Sato and Boistelle, 1984; Sato et al., 1985). Form A is always metastable throughout the given temperature range (18-40°C) (Sato et al., 1985; Beckmann et al., 1984). Earlier works in preferential crystallization of certain modifications identified suitable occurrence domains / operating conditions for primary nucleation of each polymorph in terms of the solvent, temperature, supersaturation, and stirring condition (Sato and Boistelle, 1983; 1984; Garti et al., 1980b). • Enantioseparation processes from solution are of large interest because more than 50% of pharmaceutical active substances are known to be chiral (Lorenz and Siedel-Morgenstern, 2002). Enantioseparation and racemate resolution are 121 frequently by means of crystallization methods, as there are the manual sorting of crystals (for conglomerates), resolution by entrainment (preferential crystallization), separation via diastereomic salt formation and crystallization from optically active substance. 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(Liotta and Sabesan, 2004; Barrett and Glennon, 2002; Parsons et al., 2003; Yi et al., 2005); these have been demonstrated for non -polymorphic systems One of the objectives of this research is to develop such schemes for polymorphic systems 2.4 Modeling of Polymorphic Crystallization and Transformation The direct design approach reviewed and proposed for selective crystallization processes in polymorphic. .. recent years PAT is the design and control of manufacturing processes through real-time measurements with the goal of ensuring final product quality (Yu et al., 2004); it includes not just the use of in situ sensors and data analysis but also process automation, first-principles modeling and simulation, and design of optimized processes A typical experimental apparatus for batch crystallization may utilize... sensors as part of Process Analytical Technology (PAT) also extends towards more efficient measurement of useful properties such as the solubility and also in the development of predictive crystallization models The focus of this thesis is (i) to design and control pharmaceutical crystallization processes aimed at the selective production of metastable polymorphs, applicable to various types of polymorphic. .. pertaining to the application of concentration feedback control in more complex systems such as enantiomeric systems 5 2 LITERATURE REVIEW 2.1 Direct Design of Pharmaceutical Crystallization Processes There has been increasing emphasis on the design, control and operation of pharmaceutical crystallization processes to produce a consistent crystal product (Yu et al., 2004) Industry batch crystallization recipes... monitoring, design and control of pharmaceutical crystallization processes, which functions as the main separation and purification process for the manufacturing of drug substances The aim is to reduce time to market, increase the efficiency of drug manufacturing, and improve product consistency; the pharmaceutical product pharmacokinetics and 3 efficiency are determined by the size distribution and the... motivation of this research In the efficient design of robust and reliable crystallization processes for complex systems, a more integrated approach based on 15 underlying physical experimentation mechanisms Designing and is needed controlling rather than by trial -and- error pharmaceutical polymorphic crystallization processes is an area where the implementation of more advanced control strategies can have... a direct design approach to design batch recipes without determining crystallization kinetics The feasibility of this methodology in relation to selective crystallization is discussed along with existing methods of effecting preferential crystallization A review of common techniques and schemes for solubility measurement and modeling studies on polymorphic crystallization and transformation is also... et al., 1985; Profir and Rasmuson, 2004; Mirmehrabi and Rohani, 2005; Trifkovic and Rohani, 2007)) necessary for the selective crystallization of the metastable form The implementation is often system or property specific and its suitability in other polymorphic systems is unknown Other methods of selective crystallization involve determining cooling temperature or solvent addition profiles, typically... direct design approach; (ii) to develop a semi-automated procedure for solubility measurement in polymorphic systems, and (iii) to model polymorphic crystallization processes and elucidate the kinetic parameters pertaining to both polymorphic forms Chapter 2 provides a detailed literature review of recent developments in industrial pharmaceutical crystallization particularly on the use PAT in a direct design. .. process boundary and is an important property that needs to be characterized before applying the direct design approach Chapter 6 describes the simulation and modeling of the seeded batch crystallization of L-phenylalanine from Chapter 5 The crystallization model is developed based on the population balance equation (PBE) and the method of moments, and is used to estimate the nucleation and crystal growth . Literature Review 6 2.1 Direct Design of Pharmaceutical Crystallization Processes ………………… 6 2.2 Direct Design of Pharmaceutical Polymorphic Crystallization Processes … 11 2.3 Techniques for. REVIEW 2.1 Direct Design of Pharmaceutical Crystallization Processes There has been increasing emphasis on the design, control and operation of pharmaceutical crystallization processes to produce. objectives of this research are: (i) to design and control pharmaceutical crystallization processes aimed at the selective production of metastable polymorphs, applicable to various types of polymorphic