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