Process Integration and Product Enhancement Through Crystal Growth Modifiers (CGM )

Transcription

1 Process Integration and Product Enhancement Through Crystal Growth Modifiers (CGM ) iprd Industrial Club Meeting 26 th November 2010 Held at Weetwood Hall Conference Centre Dr Toshiko Izumi Institute of Particle Science & Engineering Institute of Process Research & Development

2 Who is involved in TSB Project Individual personnel Industrial collaborators Prof. Xue Wang (Academic PI) Avantium (Stephan van Banning) High throughput instruments Prof. John Blacker (Academic Project Coordinator) AstraZeneca (Dr. Gerry Steele) Pharmaceutical compounds Dr. Michael Hardie Dr. Toshiko Izumi Prof. Kevin Roberts Dr. Yu Zhou Pfizer (Dr. Ivan Marziano) Pharmaceutical compounds Syngenta (Dr. Neil George Industrial Project Coordinator) Agrochemical compounds 2

3 TSB Project: Work Packages (WP) Work Package WP #1 WP #2 WP #3 WP #4 WP #5 General project management Activity Defining the effects of CGMs on crystal growth of industrial compound via experimental and molecular modelling approaches Development of CGMs screening platform based on 2D imaging and image analysis Development of 3D imaging system and integration with the CGM screening platform Test the reproducibility of the process defined by WP #2 & #4 at 100 s g or litre scale Who is involved in WP #2 Dr. Michael Hardie Dr. Toshiko Izumi Prof. Kevin Roberts All the industrial collaborators 3

4 Aim of WP #2 1. Experimental determination of interaction between industrial compound and its CGMs Nucleation kinetics & crystal growth morphology as a function of heat/cool rate, additive species and additive concentrations 2. Molecular modelling on effects of introducing CGM into crystallising solutions Computational modelling using atom-atom approximation based on surface & interfacial chemistry of the crystal 4

5 Summary of Equipments & Their Use Instruments Description Used for Measuring: Crystal 16 Multi-reactor crystallisation rig 16 parallel ml volume scale 4 independently heated reactor blocks LED & photo sensor for turbidity measurements MSZW Induction Time Crystalline Multi-reactor crystallisation rig 8 parallel 5 ml volume scale 8 independently heated reactor blocks LED & photo sensor for turbidity measurements 4 real time particle visualisation modules Inverted Microscope Optical polarising Olympus microscope integrated with CCD Lumenera camera In-situ microscope glass cuvette cell Cell temperature controlled by submerging in shallow tank of water circulated by a chiller (MSZW) Crystal Growth Rate Calibration on Crystal Growth Rate

6 Molecular Modelling: Atom-Atom Method Summary of Methodology Generate 3D model of crystal by translating a unit cell to a sphere Model assumes that the intermolecular interactions between atoms can be described by van der Waals & electrostatic interactions Calculate charges of each atom in the unit cell (MOPAC program) Calculate lattice energy (E cr ) by summing interactions between central molecule & all surrounding molecules in crystal lattice (HABIT98 program Hopfinger force field) Process continued until summation converges E + att N + A N - E - att B C Lattice planes (hkl) Limiting radius A N + N - B C d hkl central molecule growth normal to planes (hkl) growth normal to planes (-h-k-l) a molecule outside the slice a molecule inside the slice interplanar spacing 6

7 Energy (kcal/mol) Molecular Modelling: Atom-Atom Method for API -80 Energy vs. Limitting radius LATT modes (debug-1) with guide & trend lines Lattice energy Van der Waals Coulombic guide line Summation limitting radius (Angstroms) Initial increase in lattice energy (E cr ) with summation limit (4.0 to 13.0Å) E cr reaches a plateau (ca. -59 kcal/mol) beyond which increasing the summation limit has negligible contribution to the calculated E cr Coulombic (electrostatic) interaction is the dominant force 7

8 Lattice Energy: Partitioning into Slice & Attachment Terms E + att N + d hkl A B C Lattice planes (hkl) A N + N - B C d hkl central molecule growth normal to planes (hkl) growth normal to planes (-h-k-l) a molecule outside the slice a molecule inside the slice interplanar spacing N - E - att Limiting radius E cr E sl E att E att energy released on addition of growth slice to surface of growing crystal E sl energy released upon formation of slice of sickness d hkl Crystal morphology predicted by calculating attachment energies. 8

9 Lattice Energy: Partitioning into Slice & Attachment Terms Face (hkl) d hkl Slice energy (kcal/mol) Attachment energy (kcal/mol) (100) has the lowest attachment energy Slowest growing Most dominant face 9

10 Morphology Simulation via Attachment Energy Calculations (a) (a) Different projections of predicted API (Syngenta compound ) morphology using attachment energy calculation with Hopfinger force field; (b) experimental morphology grown from water (b) (100), (11-2), (1-1-2), (011) and (0-11) dominant faces in a good agreement with the experimental morphology (11-1), (1-1-1), (-1-12), (002), (-112) minor faces 10

11 Temp. ( o C) Comparison of MSZW Systems: API & API*CGM (0.1 w/w%) Solvent = H 2 O mg/g PMG_ MSZW y = -0.72x R² = T diss Meta-Stable Zone Width (MSZW) represents nucleation barrier: T y = x cryst R² = MSZW = T diss -T cryst Heating/Cooling rate ( o C/min) Pure API PMG conc (M) T diss T cryst MSZW API*CGM (0.1 w/w%) PMG conc (M) T diss T cryst MSZW T diss not very much affected by introduction of CGM T cryst decreased by ca. 10 o C (except [API] = 0.18 M) MSZW increased by ca. 10 o C (except [API] = 0.18 M) 11

12 Induction Time Measurements API in water [API] (M) T diss T cryst MSZW Induction time = turbidity start to drop temp start to drop TI# MaxT ( o C) MinT ( o C) Induction time (hrs) Supersaturation ratio, S ti48 BlockA N/A 1.09 ti48 BlockB N/A 1.42 ti149 BlockA ti149 BlockB ti149 BlockC ti149 BlockD ti48 BlockC ti48 BlockD N/A means no change in turbidity observed even after 3 days! Table with 2 induction time implies different induction time observed from the same experimental condition Table with a single induction time means that the repeated experiment did not crystallise out even after 24 hrs Induction time measurements not reproducible More work needs to be done 12

13 Growth Rate Measurements Temperature Control Method using Crystalline on API Experimental conditions: Hook 700 rpm Various cooling rates Nice crystal images captured Image analysis software used to obtain growth rate, however, the software picks up the hook & analyse as particles Images sent to Prof. Wang 13

14 Growth Rate Measurements Microscopic Method on API Experimental conditions: Crystallisation in an in-situ cell Growth rate measurements using an inverted isothermal condition Only a single transparent cubic crystal appeared after ca. 3hrs Very low nucleation rate x-axis: 0.29 S = 1.91 y-axis: 0.36 S =

15 Growth Rate Measurements Microscopic Method on API*CGM(0.1 w/w%) System Experimental conditions: Crystallisation in an in-situ cell Growth rate measurements using an inverted isothermal condition No single crystal appeared even after 17 days Several more days (> 7 days) after (@ r.t.), a single plate-like crystal was present in the original vial, but not in the cuvette. Pure API crystal in a vial API crystal in cuvette API*CGM crystal in a vial Layers of plate-like crystals 15

16 Ongoing Works Continue working on experimental determination of interaction between 5 industrial compounds and their CGMs Nucleation & growth kinetics as a function of heat/cool rate, additive species and additive concentrations Continue with molecular modeling on the effect of introducing CGMs into crystallising solutions Carry out morphology predictions Study of surface chemistry 16