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Continuous Crystallization of Pharmaceuticals
Allan S. Myerson
Dept. of Chemical Engineering
Novartis-MIT Center for Continuous Manufacturing
Massachusetts Institute of Technology
Process Goals
Purity
Yield
Average Size and Size Distribution
Correct Polymorph or Pseudopolymorph
Shape
Crystallization Process Development
Technological Approaches and Innovation
Crystallizer Process Design and Attainable Regions
New Operational Approaches and Configurations of MSMPR Crystallizer Cascades
New Crystallizer Designs
Crystallization for Process Intensification
Work flow for MSMPR design MSMPR cascade design
Given: API, solvent system
API characterization Dynamic simulation Process Optimization
Experimental validation
• Determine analytics
& calibration
• Solubility measurement
• Conduct steady state
MSMPR experiments
• Estimate kinetic
parameters
• Run simulation, track
control variables
• Conduct experiments to
validate dynamic model
prediction
• Set control objectives &
limitations
• Operational window
• Verify feasibility
• Determine the optimal
operating conditions
Case study: operation windowThe case of p-aminobenzoic acid in water
Control objective: yield > 0.9, polymorph purity > 0.95
(contour: yield, white lines: polymorph purity)
• Two stage MSMPR
• τtotal=120 mins
• T2=5˚C
Constraints:
• T1, τ1
Operating variables:
Barriers to Implementation
Significant Amounts of Kinetic Data required with long experimental times if steady state experiments are performed
Minimum amount of API needed is typically above 20grams
Knowledge of population balance modeling and parameter estimation required
6
New Operational Approaches and Configurations Using MSMPR Cascades
Crystallization with Solution Concentration and Recycle
Crystallization with Solid Recycle
Crystallization with Impurity Removal and Solute Concentration Using Nanofiltration Membrances for Solution Recycle
Crystallization with Impurity Complexation for Purity Improvement
Continuous Single Stage MSMPR with Recycle for Cooling Crystallization
Crystallizer
Feed
Condensation
Acetone
Removal
Waste
Filter
unit
Evaporation
Waste
Recycle
Filter
unit
Feed Crude
solutionMSMPR Separator
Pure API
(solid only)
Concentrated
Mother liquor
Vac. Evaporation Acetone
155mL (mother liquor
only)
Waste
Crystallization with Solid Recycle
|9
Objectives
• Improve yield with a short residence time
• Control crystal size and purity
Solids recycle
• Higher suspension density Larger surface area
• More crystal mass deposition Higher yield
Cooling crystallization of cyclosporine
Supersaturation
Crystal surfaces
Nucleation
Crystal growth
MSMPR with Membrane Concentration
Membrane
ModulePermeate:
Ideally Solvent
And Impurity
Additional Purgestream?
Depleted API
Concentrated Impurity
MSMPR with Membrane
Membrane Unit
Filter Unit
Feed
Antisolvent
Crystallizer, RT = 1 hFBRM (for CLD)
Combined MSMPR with Membrane Recycle
BatchMSMPR,
no MembraneMSMPR with
1:2-PP-XMSMPR with
1:3-PP-X
Yield* 89.22% 70.29% 98.03% 98.71%
4HBA in crystals, ppm*,** 0.32 0.13 0.15 0.22
*Novartis process (batch): Yield = 92%, limit of 4HBA in crystals = 3 ppm** values below reporting limit (defined by HPLC method)
0
0.5
1
1.5
2
2.5
3
3.5
4
0 2 4 6 8 10
% w
/w
Time, h
CrystallizerRecyclePurge
0
0.5
1
1.5
2
2.5
3
3.5
4
0 2 4 6 8 10
% w
/w
Time, h
Crystallizer
Retentate
Permeate
0
0.5
1
1.5
2
2.5
3
3.5
4
0 2 4 6 8 10
% w
/w
Time, h
CrystallizerRetentatePermeate
Without Membrane 24-P84-1:2-PP-X 24-P84-1:3-PP-X
New Crystallizer Designs
13
Oscillatory Baffled Crystallizer
Continuous Flow Tubular Crystallization in Slugs
Pressure Driven Mini MSMPR
COBR (Continuous Oscillatory Baffled Reactors)
Eddies
Forward strokeBack stroke
Net flow Oscillation
• Series of periodically spaced orifice baffles, superimposed oscillatory motion of a fluid (with a net flow)
• Decouples mixing from net flow thus reduced processing time
• Reduced average shear (when compared to localized shear from impellers)
• Enhancement in processes such as rapid heat transfer, particle mixing and mass transfer.
• Plug flow reactor
Fig 1. Example of a typical COBR set-up
Fig 3. Flow interaction with baffles
Fig 2. Various baffle types: single orifice, multiple
orifice, smooth constrictions.
Nucleation method: Indirect ultrasonication
Nucleation Growth
Sonication
bath
Air
Air Slurry Air Slurry Air SlurryHot
solution
Slug formation
Sonication
probe
Sonication probe
Sonication converter
Water bath
Silicone tubing
15
Pressure-driven flow crystallizer (PDFC)
No
Stage 1
TV-1
Reagent Stream 2
Transfer Line 1Pump 1
L1a
L2a
Stage 2
Transfer Line 2
L1b
L2b
Reagent Stream 1
Collection Vessel
Pressure Release Opening
TV-2Vacuum
NoNc
No
NoNc
Crystallization For Process Intensification
17
Combined Salt Formation and Crystallization
Crystallization of Crystalline Excipients
Crystallization of Polymer Excipients.
Salt Formation and Crystallization in a Single Step
Ratio of Fumeric Acid to Free Base Crucial Parameter
0.00%
1.00%
2.00%
3.00%
4.00%
5.00%
6.00%
0.3 0.5 0.7 0.9 1.1 1.3
C13 c
on
cn
etr
ati
on
in
th
e m
oth
er
liq
uo
r, m
ass/m
ass
Molar Ratio of fumaric acid/C11
ALISKIREN (SPP-100) SALTC12(FUMARIC ACID)
+
C11 (SPP-100 FREE BASE)
a) HCl-gas, iPr2O
b) NaOH, Me-THF
OO
ONH2
OHHN NH2
O O
C11 92%
a) HCl-gas, iPr2O
b) NaOH, Me-THF
OO
ONH2
OHHN NH2
O O
C11 92%
. 1/2
Continuous Crystallization of On Excipients
API
Excipient
M
Feed
Vessel
MSMPR
Crystallizer
Feed SolutionInlet Solution
Acetaminophen
Ethanol P1
TTTC
Solid Excipient Feed
D-mannitol
M
Acetaminophen
Ethanol
D-mannitol
TC TT
Product
Acetaminophen
Ethanol
D-mannitol P2
To Filter
From Films to Tablets