Mixing and Crystallisation - Crystallization Systems · PDF fileAgenda Mixing basics Mixing...

Mixing and CrystallisationDecember 2, 2015

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AgendaMixing basicsMixing and scale downCrystallisation introductionCrystallisationCase studyCase studyFlow Crystallisation

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Mixing BasicsSolutions and slurries need to be stirred to allow good mixing of the various components in thegood mixing of the various components in the mixture and for good heat transferThe type of stirrer / agitator and the shape of the vessel will affect the motion of the solution and / or slurry and so the mixing taking placeLab equipment tends to be spherical – round-bottomed flasksPlant equipment is usually cylindricala t equ p e t s usua y cy d caPlant vessels are usually baffled

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Flow Pattern in an Unbaffled Tank

Vortex

Swirl

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Flow Pattern in a Baffled Tank

Baffles

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Mass Transfer and Agitation

Type of agitation affects motion in solution and effectiveness of mass transferDesign of agitator may be importantg g y p

Impeller, Anchor, Turbine ?Number of bladesDiameterPitch anglePitch angleDistance from bottomWidth of baffle(s)Width of baffle(s)

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Suspending Solids

8Scientific Update course: Physicochemical Concepts in Process Development,presented by Dr N. Powles and Dr M. Stirling (University of Huddersfield).

HCl Neutralisation with KOH:U b ffl dUnbaffled


HCl Neutralisation with KOH:B ffl dBaffled


Mixing Varies Across the VesselThe very best mixing takes place right by the tip of the agitatorof the agitatorPoor mixing zones can be found at the bottom of the vessel and on the surface of the liquidAddition point for chemical reactions, salt formations, and anti-solvent crystallisations can be criticalSub-surface via a dip pipe is often the best option if mixing is criticalopt o g s c t caAddition on to the surface can be improved by using a spray nozzleusing a spray nozzle

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Mixing and AgitatorsThe motion of the liquid / slurry in the vessel will affect the mixingaffect the mixingThe motion of the liquid / slurry is directly affected by the agitator / stirrer being usedHow much radial mixing (sideways) and axial mixing (up and down) takes place in the vessel will depend on the position and design of the agitator

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Impeller

3 radial and curved bladesAssembled axially with 1-2 bafflesA i l ti d di l flAxial suction and radial flowApplication rangeperipheral speedperipheral speed 0.5-10 m/s - turbine flowServiceService

homogenizationsuspension of solids

&liquid-liquid & solid-liquid dispersionheat transferchemical reaction

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Anchor

Anchor agitatorAssembled axially without baffle or with one thermopocketthermopocketAxial suction and radial flow with rotation of product pApplication rangeperipheral speed 0.5-5 m/s -t it l i fltransitory or laminar flowService

homogenizationhomogenizationheat transferchemical reaction

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Radial Turbine

Flat parallel blade to giveFlat parallel blade to give high radial flow and obtain high mix shearhigh mix shear

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Uniflow Axial Turbine

Pitched blades to give high axial flow& l h& low shearTapered blade to minimize radial flow and maintain constant mix velocity at blade tipShear mix minimized3 blades give ease of installation3 blades give ease of installation through centre openingAssembled with or without bafflesApplication range: per speed 2 5 m/sApplication range: per. speed 2-5 m/sService

homogenizationsuspension of solidsliquid-solid & gas-liquid dispersionheat transfer

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chemical reaction

Twin Agitator

Several 2-bladed wheels 90o

drotatedAssembled with or without bafflebafflePrevailing flow axial Application rangeApplication rangeperipheral speed 0.5-12 m/s -laminar or turbulent flowService

homogenizationliquid-liquid & solid-liquidliquid-liquid & solid-liquid dispersionheat transfer

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Pitched Turbine

4 or 6-bladed propellerAssembled axially with 1-4 beaver-tail baffles or eccentrically without baffleeccentrically without bafflePrevailing flow axialApplication rangeApplication rangeperipheral speed 3-20 m/s -turbulent flowService

homogenizationsuspension of solidssuspension of solidsliquid-liquid, solid-liquid & gas-liquid dispersionh t t f

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heat transfer

Disc Turbine

Turbine wheel with 6 radial bladesAssembled axially with or without1-4 beaver-tail baffles. Axial suction and radial flowAxial suction and radial flowApplication rangeperipheral speed 3-10 m/s –transitory or turbulent flowService

homogenizationhomogenizationsuspension of solidsliquid-liquid, solid-liquid & gas-liquid dispersiondispersionemulsionchemical reactionheat transfer

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heat transfer

Loop Agitator

Tubular gate agitatorAssembled axially without baffle or with one thermopocketthermopocketCentripetal and centrifugal radial flowApplication rangeperipheral speed 3-5 m/s -t it l i fltransitory or laminar flowService

homogenization of viscoushomogenization of viscous productsheat transferh i l ti

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chemical reaction

Less Common Impeller Types

StabilizedFlat-Blade

T bi

PerforatedPropeller

Saw-ToothedPropeller

Studded Cage

Turbinep p g

Beater

21Scientific Update course: Secrets of Batch Process Scale Up,given by F. McConville (FXM Engineering).

SpinChem Rotating Flow Cell

22 C.-J. Aurell et al (AstraZeneca), Org. Proc. Res. Dev., 2014, 18, 1116.

SpinChem Rotating Flow Cell

23 C.-J. Aurell et al (AstraZeneca), Org. Proc. Res. Dev., 2014, 18, 1116.

SpinChem Video

24 www.spinchem.com

Impeller Diameters

Ratio of impeller diameter to vessel diameter is an important factor in scale upimportant factor in scale-up

To disperse a gas in a liquid, optimum ratio is approximately 0.25pp yTo disperse 2 immiscible liquids, optimum ratio is approximately 0.40To blend 2 miscible liquids, optimum ratio is > 0.60

Where a gas is introduced to a solid-liquid dispersion a complex situation arisescomplex situation arises.

Gas bubbling may lead to poor mass transfer, whereas in absence of gas, mixing was good with thewhereas in absence of gas, mixing was good with the same agitator.

On scale-up, KEEP GEOMETRIC SIMILARITY!

25Handbook of Industrial Mixing, ed. E.L. Paul, V.A. Atiemo-Obengand S.M. Kresta, Wiley-Interscience, 2004, ISBN 0-471-26919-0

Laminar or Turbulent Flow ?

Osborne Reynolds (1883) distinguished betweenOsborne Reynolds (1883) distinguished between two types of flow

laminar - pressure drop proportional to vp p p pturbulent - pressure drop proportional to v2

The feature of turbulence is formation of lots of eddies of varying sizes, vital for good mixingDegree of turbulence can be characterized by a g yquantity called the “Reynolds number” NReFor scale-up, if pilot vessel designed so that NRep p g Reis the same as in the lab, then equivalent mixing is likely

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Reynolds Number NRe

For agitated vesselN ND2 /NRe = ND2ρ/μ

D = diameter of impeller (m)N = rotation speed of impeller (s-1)ρ = density (kg.m-3)

1 1μ = viscosity (kg.m-1.s-1)NRe has NO dimensionsChange from laminar to turbulent flow usually occurs around same values of NRe

NRe < 4,000 laminarNRe > 10,000 turbulent

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Viscosity and Mass Transfer

For high viscosity applications (NRe up to 5000)g y ( Re )Large scale diameter agitatorLow speedi.e. anchor stirrer

For low viscosity fluidsDiameter of agitator may be as low as one third vessel diameterHi h dHigh speed

Propeller type agitators induce axial flowTurbines induce radial flowTurbines induce radial flowAxial flow component increased by angling turbine blades

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turbine blades

Macromixing (Bulk Mixing)

Achieves a uniform blend on a large scaleAchieves a uniform blend on a large scaleBulk mixing times:

500 ml flask (500 rpm) 2 - 3 seconds( p )40 m3 vessel (25 rpm) 30 - 60 seconds

Before complete mixing occurs there may be“local” excesses of reagentpH differences across mixture

f fThis may cause formation of by-productsparticularly if rate of by-product formation is comparable to that of main reactioncomparable to that of main reaction

Therefore, selectivity may change with scale

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Micromixing

Mechanical agitation will not give a l l h bl dcompletely homogeneous blend

For 2 homogenous fluids, there will be a residual eddy size below which no furtherresidual eddy size below which no further blending takes placeThis is a function of

power input via agitatorviscosity of medium

F l ti dd i iFor aqueous solutions, eddy size range is 10-2 - 10-3 cm.Timescale for homogenization (byTimescale for homogenization (by molecular diffusion) is of the order of 0.1 -1 sec

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Micromixing time can be reduced to a few milliseconds using specially designed static mixers

Ei Mixing Energy Dissipation

A measure of power/unit massput into mixing fluid(dissipation of turbulent kinetic energy)Values range from

0 to ~3.5 W/kgg

3 5PN N dE =

Perhaps most useful parameter

iEV

=

Perhaps most useful parameterfor “scale-down” experiments

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Where: d = impeller diameter (m) N = rotational speed (sec-1)NP = power number V = volume (m3)

Ei Mixing Energy Dissipation

kgw

mdNN

VdNN

massPowerEi PP ====

5353 ρ

Another commonly used quantity:

kgmVmass

Another commonly used quantity:

53 wdNNPowerP P ρ3mVvolumeV

P ===ρ

Where: d = impeller diameter (m) N = rotational speed (sec-1)N = power number V = volume (m3)

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NP = power number V = volume (m3)ρ = density (kg/m3)

Mixing Configuration:S i B t h R tSemi-Batch Reactors

Dip Pipe

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CrystallisationCrystallisation

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Solubility Curve and M t t bl ZMetastable Zone

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Cooling Profiles

a Natural cooling ⎟⎠⎞

⎜⎝⎛−=

−

−

τθθθθ t

ff exp

b Linear cooling

c Controlled cooling

⎠⎝ τθθ fo

( )⎥⎥⎤

⎢⎢⎡

⎟⎠⎞

⎜⎝⎛

Δ−−=

3tTfTTT oog

Natural

( )⎥⎥⎦⎢

⎢⎣ ⎠⎝ Δt

foo

T

b

cC

cooling

Linear

tura

ion

a

ba b c Controlled

supe

rsa

time

a

Temp Time

G Steele (AZ), presentation at Process AnalyticalTechnology Conference, Clearwater FL, November 200736

During CrystallisationNucleation rate affected by

Agitation rateAgitation rateSupersaturation levelSeedinggTrace impuritiesTemperature

Rate of crystal growth affected byAgitation rategDensity and viscosity of solventTemperatureTrace impurities

Optimum temperature for nucleation may

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not be the optimum for crystal growthReview on nucleation: R.J. Davey et al, Angew. Chem. Int. Ed., 2013, 52, 2166.

NucleationSpontaneous appearance of tiny “embryos” of solid phase

< 1 μm; too small for visual detectionClassical nucleation theory (CNT)

B = A exp -16π3γ3ϖ2

B0 = A exp γ

3R3T3(lnS)2

B0 - nucleation rate (m-3s-1)A - pre-exponential factorp e e po e t a actoγ - interfacial tension (dn m-2)ϖ - molecular volume (m3)R - Gas constantT - Temperature (K)

R. Davey & J. Garside; From Molecules to Crystallizers, OUP 2000, pp 17 – 18Angew. Chem. Int. Ed., 2013, 52, 2166

p ( )S - Relative supersaturation (C/Ceq)

g , , ,

Measurement of Induction Time tind(tind = 1 / B0)

Delay between creation of supersaturation andDelay between creation of supersaturation and appearance of detectable particlestind decreases exponentially with increasing S

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Two-Step Nucleation Mechanism

Nucleation occurs inside pre-pformed metastable clusters (several hundred nanometers) C t ti i hi h thConcentration is higher than in the bulk solution, but still no order to the molecules (spinodal phase)Accounts better for observed

t f l ti hi hrates of nucleation, which are about 1010 time lower than CNT would predict pSee P.G. Vekilov, Cryst. Growth Des., 2010, 10, 5007–5019

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5019

Primary Nucleation

HomogeneousS t f lid h f l tiSpontaneous appearance of solid phase from solutionRequires very high degree of supersaturation

HeterogeneousInduced by foreign particles at moderate supersaturation levelsLab solutions contain >106 foreign particles per cm3

b l 1 ibelow 1 micronFiltration removes foreign particles (to below 103 / cm3) thus making primary nucleation more difficultcm3), thus making primary nucleation more difficult

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Primary Nucleation

This paper reports detection of both mechanismsboth mechanismsThe plot induction time against the reciprocal of the square ofthe reciprocal of the square of supersaturationHomogeneousg

Early part of the curve where supersaturation is highI d ti ti i h tInduction time is short

Heterogeneous As supersaturation decreasesAs supersaturation decreases, induction time extendsAt some point, induction time falls

Growth Kinetics of L-Arginine Trifluoroacetate Crystals Liu,*, Xu, Ren, Zhang, Wei, and Wang

and this is thought due to heterogeneous nucleation

a gCryst. Gr. Des. 2010, 3442–3447

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Late Appearance of a Hydrate

NCH3O OCH3

O

N

F

NH

NH

N

4 Solvates and 1 anhydrate known10 Batches of anhydrate produced in a seeded

F

10 Batches of anhydrate produced in a seeded crystallisation

Slurry seeds for 1-2 hours, followed by stirring at room y y gtemperatureGives needles

N d tiNew seed preparationSonicate the seeds for 20 minutes, followed by stirring at room temperaturetemperature

42H. Morrison et al (Amgen), Org. Proc. Res. Dev., ASAPDOI:10.1021/acs.oprd.5b00030, published online on June 26, 2015.

Seeds and Final Cake

Morphology – rods not needlesFaster filtration, lower solubility


Faster filtration, lower solubility

Thermal Analysis


Analysis of the New FormAnhydrate shows no weight lossNew form shows weight loss of 2.6% on heating from room temperature to 130°CKF on new form gives 2.3 wt% waterThis corresponds to a hemi-hydrateThis corresponds to a hemi hydrateThe hemi-hydrate loses water at 77.6°C and then crystallises as a new anhydrous form atthen crystallises as a new anhydrous form at 145.1°CThis melts at 184 2°C and is a new polymorphThis melts at 184.2°C and is a new polymorphThis is confirmed by variable temperature XRPD


Variable Temperature XRPD


Increasing the Dissolution Rate1. Unmilled hydrate2 Pin-milled x 12. Pin-milled x 13. Pin-milled x 44. Jet-milled x 1

Surface area (m2/g)1 0 51. 0.52. 0.83 3 33. 3.34. 3.35. 6.9 (anhydrate)


Metastable Zone WidthVaries with

Cooling rateCooling rateAgitation rateVessel sizeVessel sizeImpuritiesPresence of particlesPresence of particlesThermal history of the solution

Width of metastable zone is independent ofWidth of metastable zone is independent of crystallisation technique

Comparable values for evaporative and cooling p p gcrystallisations

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Effect of Cooling Rate

Crystallisation of L-Glutamic Acid in an oscillatory baffled crystalliserMSZW id t hi h li tMSZW wider at higher cooling rates

X. Ni et al, Cryst. Gr. Des., 2008, 8, 2875-288149

Variation in MSZW

198 experiments at 1 ml scale on solubility of paracetamol at 0.015g/mlMSZ width varies from 7.2°C to 33.8°CStatistically the MSZ width does not change after 150 experiments at 1 ml scale

50 S.S. Kadam et al, Cryst. Growth. Des., 2011, 11, 1271.

Effect of Vessel SizeEmphasises that nucleation is

a random processI 1 L l th h fIn 1 mL volume, the chance of

observing nucleation at 7 degrees is very low perhapsdegrees is very low, perhaps 0.1%

But in 1 litre, the number of molecules is a thousand fold greater, so the chance of b i l ti i l

Probability distribution of the MSZW ∆T for a paracetamolconcentration of 0 015 g/mL in water at a

observing nucleation is also multiplied a thousand fold to around 100% concentration of 0.015 g/mL in water at a

cooling rate of 0.5 C/min:squares, 1mL experiments; circles, 1 L experiments.

around 100%For the MSZW, you really

need a larger reactor

S.S. Kadam et al, Cryst. Growth. Des., 2011, 11, 1271.51

Agitation RateMost agitated solutions nucleate spontaneously at lower degrees of supersaturation thanat lower degrees of supersaturation than quiescent ones (i.e. width of metastable zone is reduced!)reduced!)Increased agitation USUALLY causes additional secondary nucleation by seed proliferation andsecondary nucleation by seed proliferation and attritionFaster agitation may enhance growth kinetics,Faster agitation may enhance growth kinetics, particularly in viscous mediaLarge crystals (e.g. for XRD) normally require a ge c ysta s (e g o ) o a y equ equiescent conditions

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Influence of Addition Rate and Stirring RateStirring Rate

Investigation of an API Crystallisation Zone width decreases slightly at higher agitation rateZone width decreases slightly at higher agitation rateZone width increases at higher addition rate

0 3

0.4

475 rpm - impeller addition location

325 rpm impeller addition location

0.2

0.3

er/g

eth

anol

)

0.1

SZW

(g w

ate

Addition close to impeller

-0.1

0.00 0.1 0.2 0.3 0.4 0.5

MS

53D. O’Grady (Mettler Toledo); PAT in Organic Process R&D,Clearwater FLA, Nov 2007; Chem Eng Res Des, 2007, 85, 945.

Addition Rate (g water/s )

Importance of Point of Addition

0.3

0.4

nol)

475 rpm - wall addition location

325 rpm - wall addition location0.3

0.4

nol)



Additi l t l ll

0.1

0.2

(g w

ater

/g e

than

0.1

0.2

g w

ater

/g e

than Addition close to vessel wall


0 1

0.00 0.1 0.2 0.3 0.4 0.5

MSZ

W (

0.00 0.1 0.2 0.3 0.4 0.5

MSZ

W (g

-0.1

Addition Rate (g water/s )-0.1



Importance of Point of Addition

0.3

0.4

nol)

475 rpm - wall addition location

325 rpm - wall addition location0.3

0.4

nol)



Additi l t l ll

0.1

0.2

(g w

ater

/g e

than

0.1

0.2

g w

ater

/g e

than Addition close to vessel wall


0 1

0.00 0.1 0.2 0.3 0.4 0.5

MSZ

W (

0.00 0.1 0.2 0.3 0.4 0.5

MSZ

W (g

-0.1

Addition Rate (g water/s )-0.1


Computational fluid dynamicsComputational fluid dynamics calculations indicated the difference was due to differingdifference was due to differing levels of turbulence


Anti-Solvent Crystallisation

30

20

25

ml)

Concentration of the solution for crystallisation

10

15

S (g

/100

m

0

5

0 20 40 60 80 100

Temp (°C) Keep Temp fixed while adding anti-solvent

56

g


30

20

25

ml)


10

15

S (g

/100

m

0

5

0 20 40 60 80 100


57

g


30

20

25

ml)


10

15

S (g

/100

m

0

5

0 20 40 60 80 100


58

g

Crystallisation by Anti-Solvent AdditiAddition Anti-solvent

Less control over crystallisation

Uncontrolled crystallisation at the addition point

Manual addition of anti-solvent – operator

i ti

Particle size dependent on reactor size

variationMixing dependentCh i l d i

Solvent recovery more difficultC li t lli tiChanging volume during

the crystallisationCooling crystallisation preferred

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Crystallisation by Anti-Solvent AdditiAddition

Add anti-solvent slowly at the startAdd anti-solvent slowly at the startFaster towards the endOOr add anti-solvent in portions with intermediate seeding

Problem / difficulty:yKnowledge of the change in solubility relative to solvent : anti-solvent compositionsolvent : anti solvent compositionMixing of solvent and anti-solventCh i l i th t lli ti lChanging volume in the crystallisation vessel

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Two AlternativesAdd anti-solvent at ambient temperatureStir and cool to complete crystallisationSeeding best carried out after a small portion of the anti-solvent has been added

Add anti-solvent at elevated temperatureCarry out a standard cooling crystallisationCarry out a standard cooling crystallisation

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OratinibCO2K CO2H

NH

NH

aq HCl

NH

O

NH

Oaq HCl

IPA - H2O

API, coloured, light sensitiveCrystallisation process not robustCrystallisation process not robustVariable amounts of IPA, often exceeding the ICH limit of 5 000 ppmICH limit of 5,000 ppmVariable particle size distribution

62 H. Sato et al (Taiho Pharmaceuticals), Org. Proc. Res. Dev., 2015, 19, 1655.

DoE Study of Crystallisation8 Factors studied in a quarter factorial design, with 2 centre pointwith 2 centre pointAmount of solvent 16.4, 21.4, 26.4 volsSolvent ratio 31, 41, 51: IPA/H2OTemperature 40, 50, 60°CTemperature 40, 50, 60 CAgitation speed 80, 160, 240 rpmHCl concentration 7 12 17%HCl concentration 7, 12, 17%Duration of HCl addition 1, 2, 3 hoursFinal pH 1, 3, 5Additional agitation 0.25, 1, 1.75 hoursg , ,


Variation in Particle Size

16.4 vols, 31% IPA/H2O, 40°C, 80 17% HCl 3 h

26.4 vols, 51% IPA/H2O, 60°C, 80 % HCl 3 h80 rpm, 17% HCl, 3 hour

addition, to pH 5, 0.25 hour stir out

80 rpm, 7% HCl, 3 hour addition to pH 1, 0.25 hour stir out


Key Factors for Residual IPA

Temperature > Amount of solvent > Agitation speed > p g pDuration of HCl addition > Solvent ratioThe high setting of each factor is preferredg g p


Key Factors for PSD

Solvent ratio ≈ Temperature > Duration of HCl addition


Further OptimisationUnimportant factors omitted in next design

HCl t ti fi l H d ti t tiHCl concentration, final pH, and stir out time A further 16 experiment plus 2 centre points, were carried out to upgrade to a response surface analysis

Temperature, solvent volume, solvent ratio, agitation speed, duration of HCl addition

Aim to reduce residual IPA levels and obtain a PSD similar to original API


Ranges ExpandedFactor Original range Expanded rangeTemperature 40-60°C 40-80°CSolvent ratio 31-51% 11-51%Duration of HCl addition 1-3 hours 0.25-3 hoursAmount of solvent 16 4 26 4 volumes 16 4 36 4 volumesAmount of solvent 16.4-26.4 volumes 16.4-36.4 volumesAgitation speed 80-240 rpm 40-280 rpm

Hi h t t i l IPA b t l ti lHigher temperature gives less IPA, but larger particlesLower solvent ratio gives smaller particlesShorter HCl addition gives smaller particlesLarger solvent volume gives less IPAAlthough agitation has no specific effect it was expanded at both ends


Residual IPA


Particle Size


ResultsImpurity levels increase at higher temperature, 80°C or lower solvent ratio (11% IPA/H2O)lower solvent ratio (11% IPA/H2O)Optimum conditions calculated to be:

Temperature 67°CTemperature 67 CSolvent ratio 22% IPA/H2ODuration of HCl addition 2 hoursVolumes of solvent 36 volumesAgitation speed 200 rpm

P di t d t iPredicted to give:Residual IPA 2223 ± 1210 ppm

PSD D 3 2 ± 0 8 μmPSD D10 3.2 ± 0.8 μm

D50 4.9 ± 1.2 μm D 7 4 ± 2 0 μmD90 7.4 ± 2.0 μm


Verification ExperimentsLab scale Actual Predicted

Residual IPA 2138 ppm 1013 3433 ppmResidual IPA 2138 ppm 1013-3433 ppm

D10 1.6 μm 2.4-4.0 μm

D 2 7 μm 3 7 6 1 μmD50 2.7 μm 3.7-6.1 μm

D90 4.2 μm 5.4-9.4 μm

Model improved by adding this data gave newModel improved by adding this data gave new conditions:

Temperature 67°C changed to 70°Ce pe atu e 6 C c a ged to 0 CSolvent ratio 22% changed to 25% IPA/H2ODuration of HCl addition 2 hours no changeVolumes of solvent 36 volumes no changeAgitation speed 200 rpm no change


Second Verification Experiments Parameter Predicted Actual 1 Actual 2R id l IPA 1386 3252 2622 2297Residual IPA 1386-3252 ppm 2622 ppm 2297 ppmD10 2.5-4.1 μm 3.5μm 3.4μmD 3 9 6 1μm 5 6μm 6 0μmD50 3.9-6.1μm 5.6μm 6.0μmD90 5.7-9.3μm 8.6μm 9.7μmYield 94 7% 95 2%Yield 94.7% 95.2%

Process successfully scaled up to produce 3kg of API


Scale Down Then Scale UpTypical lab crystallisation:Everything sets solidThe lab chemist “cranks up” the stirrer to get the slurry moving againOperating at much to high supersaturationOperating at much to high supersaturationLook at mixing parameters comparing 2000 gal reactor with 1 litre lab reactorreactor with 1 litre lab reactor


Matching Power per Unit Mass


Before and After

ORIGINAL PROCESS IMPROVED PROCESS

(Fine, “bridging” needles) (Large, regular needles)


Continuous CrystallisationCritical parameters

Solid loadingSolid density relative to solvent densityParticle sizeFlow rate / residence timeFlow rate / residence timeChoice of reactor typeC fChoice of pumpChoice of connectionsChoice of back pressure regulator (if required)

77

Oscillatory Baffled Reactor (OBR)

S. Lawton et al (AstraZeneca and NiTech), Org. Proc. Res. Dev., 2009, 13, 135778

Mixing in an OBR

Mixing is controlled byMixing is controlled by oscillationsThe baffles oscillate backThe baffles oscillate back and forth orThe fluid pulsatesp

79T. McGlone et al, Org. Proc. Res. Dev., Just acceptedDOI:10.1021/opd.5b00225, published online on Aug 6, 2015.

Continuous OBR Reactor

Mixing is controlled byMixing is controlled by oscillations, not the net flow as in the case of turbulent flowsturbulent flows

Plug flow characteristics are obtained in laminarare obtained in laminar flows

This allows significantly shorter length of reactor and a much more compact reactor setup than conventional systems

X.-W. Ni (NiTech) presentation at The Scale Up Of Chemical Processes, Brussels, July 201480

81 X.-W. Ni (NiTech) presentation at The Scale Up Of Chemical Processes, Brussels, July 2014

Genzyme PlantIncrease in demand for APIPredicted to need 18 tankers per day of acetonitrile for recrystallisationOnly extra space available for expansion / new building was the staff car park2 Years from first discussions to manufacturing

82P. McDonnell (Genzyme) presentation at Process Chemistryin the Pharmaceutical Industry, Durham, NC, Nov 2009.

Commercial API Crystallisation

83 X.-W. Ni (NiTech) presentation at The Scale Up Of Chemical Processes, Brussels, July 2014

Continuous API Crystallisation

World’s largest continuous API plantG H hill UKGenzyme, Haverhill, UKIn production since April 2007Reactor volume reduced by >99%Reactor volume reduced by >99%

84

Lilly Asymmetric HydrogenationOBn OBn1. Rh(COD)2OTf, L,

Zn(OTf)2, MeOH, EtOAc, 70oC, 70 bar

OBn

OOBn

OBn

OOBn

2. Aqueous work up3. Solvent swap to PhCH34. IPA, seed, crystallise

86% >99% ee

H2 - Pd/C, LiBrTHF - EtOH(EtO)3CH, Ac2O

86%, >99% ee

(t-Bu)2P

P(o-Tol)2

Fe

( )3 , 280%

L =

S/C = 2 000:1

O

OH

HO

S/C = 2,000:1

LY500307

85M. Johnson et al (Eli Lilly), Org. Proc. Res. Dev., 2012, 16, 1017;see also J.R. Calvin et al (Eli Lilly), Org. Lett., 2012, 14, 1038.

LY500307

Continuous Crystallisation

(12L) (22L)

MSMPR = Mixed Suspension Mixed Product RemovalLongest continuous run: 91.5 hrNo problems with fouling or plugging

86

p g p gg gProduct 99.6% eeThermodynamic crystallisation (after aging) gives ~95% ee

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