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Accentus C3 Technology

Harwell, Oxfordshire, U.K.

Crystallization Control using Power Ultrasound - Process Development and Scale-up

Graham Ruecroft PhD graham.ruecroft@accentus.co.uk

www.sonochemistry.co.uk

Chemsource 2004, Amsterdam, June 23rd

New Technologies for Scale-Up

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Agenda

Crystallization – key issues, problems Ultrasound in crystallization - sonocrystallization Application of ultrasound – R&D equipment Nucleation, polymorphism, crystal size distribution-

pertinent examples Equipment for large scale Benefits of Sonocrystallization Future of Sonocrystallization

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The Need for Crystallization Control

Almost every chemical process that produces a solid product involves at least one crystallization step, either for intermediate separation, final product purification, or for the removal of key impurities.

Products are made to increasingly stringent physical specifications.

Crystallization processes can be difficult to control per se. Control of the nucleation event is often difficult but is key to

process control. Some products such as fats, triglycerides, oligomers, proteins,

oligonucleotides, newer complex drug compounds are extremely hard to nucleate and can have extreme habit.

It’s a fact…..

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Generation of Supersaturation(unstructured solution)

Prepare saturated solution at at T1 then cool to T2EvaporationAnti-solvent addition

Nucleation Define solubility curve and metastable zone widthDefine metastable supersaturationPrimary homogeneous, heterogeneousSecondary heterogeneous (shear, contact, fracture, attrition, needle)

Crystal growthComplex processSupersaturated solution composed of variety of units (atoms, molecules, ions, hydrates, dimers, trimers, clusters, polymers)Driving forces is supersaturation – units transported by diffusion then built into surface of crystal

Key Issues of Crystallization

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Problem Areas

Attrition

Solidshandling

Polymorphism

Encrustation

Habit

Solvation Sizedistribution

Purity

Yield

Agglomeration

Growth

Nucleation

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Ultrasonic Processing

The concept of ultrasonic processing is not new……but perhaps the ability to use it on industrial scale is.

Power ultrasound is already proven to have significant effects on the rate of various processes such as:

Mixing and Homogenisation CrystallizationReaction Rate Enhancement HydrogenationEmulsification FiltrationHigh Shear ExtractionDecontamination Degassing, DefoamingSolid / Liquid Separation Wax DispersionBiological Cell Disruption De-agglomerationAnaerobic digestion (environment) Particle Disruption

Secondary metabolism rate increase SievingSize Reduction

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Sonocrystallization – what is it?

The application of high-intensity (100 W/L), low-frequency (20 – 60 kHz) ultrasound to promote and control crystallization.

The main effect of ultrasound is to promote nucleation via transient cavitation

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Sonocrystallization Origins

The first application of ultrasound to crystallization in 1927 predates by decades any serious application to chemistry1.

There is a considerable literature from the former Soviet Union in the 1950s to the 1970s, albeit dealing with small-scale applications2.

1. Richards, W. T.; Loomis, A. I. J. Am. Chem. Soc. 49 3086 (1927).2. Kapustin, A. P. ‘The Effects of Ultrasound on the Kinetics of Crystallisation’.

USS Academy of Sciences Press. Engl. Trans. Consultants Bureau, New York, 1963; Martynovskaya, N. V. Akust. Ul'trazvuk. Tekh. 1970 (6), 14; Reshetnyak, I. I. Akust. Zh. 21 99 (1975).

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Key Principles of Cavitation Application of ultrasound to a liquid produces Cavitation (microscopic

gas/vapour bubbles) caused by successive compression and rarefaction (just a few acoustic cycles).

Transient cavitation bubble collapse produces regions of extreme excitation, temperature (5000K) and pressure (2000 atm) to create surface and energy for nuclei to form - but why?

- Local temperature increase effects?- Concomitant shockwaves?- Rapid local cooling rates of 107-1010 K.s-1?- Overcome energy barriers to nucleation?

Intensity of cavitation depends on factors such as frequency, power, temperature, viscosity.

Bubble expansion

Bubble collapseNucleus formation

Crystal growth

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Solvent Cavitation Parameters

Imax Maximum intensity relative to water = 100

Tmax Temperature for maximum intensity

T1/T2 Range for >70% of Imax

Solvent I max Timax (oC) (T1/T2)

Water 100 35 (20/50)

Toluene 71 29 (10/40)

2-Propanol 38 16 (0/30)

Ethanol 46 21 (15/27)

Methanol 52 19 (4/23)

Dichloromethane 38 -40 (-60/–25)

Ethyl acetate 45 9 (-15/16)

Acetone 44 -36 (-50/-20)

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Why use Sonocrystallization?

The use of ultrasound provides a non-invasiveway of improving crystal properties and process control

Non-invasive means no added chemicals or additional mechanical treatment – maintain a sterile closed loop in seeded processes

By controlling the nucleation event and therefore the crystal size and crystal size distribution, yield, purity, habit and product handling (including filtration) may be improved

Avoidance of encrustation Manufacture better quality products and improved productivity

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Application of Ultrasound – R&DUltrasonic Probe / Horn

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Application of UltrasoundProcess R&D Ultrasonic Micro-Reactor

1 – 2 ml capacity for use when material is very limited Ultrasound probe on back, glass front for viewing Can be used as batch reactor or flow-cell

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Recent LiteratureParticle Engineering using Ultrasound

Dennehy, R. D., “Particle Engineering Using Power Ultrasound”, Proc. 4 th Sci. Update Int. Symp.: ‘Aspects of Polymorphism and Crystallization – Chemical Development Issues’, Chester, UK, April 2003 and Org. Pro. Res. Dev. 2003, 7, 1002 (GSK)

Kim, S.; Wei, C.; Kiang, S. “Crystallization Process Dev. and Particle Engineering”, Org. Pro. Res. Dev. 2003, 7, 997 (BMS)

Crystallization of various drug compounds using batch and anti-solvent addition processes using probe-based flow-cells.

Particle size control to avoid of milling. Consistent Particle size distribution Sonocrystallization in the Process Chemist’s toolkit. Some probe erosion issues – the challenge for scale-up.

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Particle engineering using ultrasound

Ultrasound generator

US Horn / Probe

Product solution

Anti-solvent

Product slurry

Vessel and flow-cell not in proportion

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Process Research and Development:Simple laboratory set-up

Product solution

US Horn / Probe

Ultrasound generator

Alternate withdrawal of slurry

Vessel and flow-cell not in proportion

Lasentec / turbidity probe

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Define solubility curve

Define metastable supersaturation (first appearance of nuclei / crystals):Hence metastable zone width

Aim to control and induce nucleation by judicious application of power ultrasound

Nucleation

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Induction of Nucleation [1]

10

12

14

16

18

20

22

24

30 32 34 36 38 40 42 44

Point of nucleation Insonated Uninsonated

Critical sub-cooling Insonated Uninsonated

Crit

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sup

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atu

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n

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Solubility cu

rve

Temperature (oC)

Sor

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Reduced metastable zone width induced by insonation forsorbitol hexaacetate in solution in methanol

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Control of Crystal SizeSorbitol hexaacetate

Cooling crystallization

No Ultrasound

Same magnification

Cooling crystallization

Ultrasound to initiate nucleation

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Induction of Nucleation [2]Phenylalanine in water

4

4.5

5

5.5

6

6.5

7

7.5

50 55 60 65 70 75 80

Temperature deg.C

Co

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Solubility

Withultrasound

Noultrasound

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Crystal Size Distribution (CSD)

The CSD is determined by:• The operation of the crystallizer throughout the

supersaturation time profile• The use of seeds ……or ultrasound• The agitation conditions etcand is defined by Growth and Nucleation rates, which

depend in turn on supersaturation history The size distribution which is generated will affect the

performance of both the immediate downstream processing operations and also the subsequent performance of the material during storage, formulation and use.

Expect problems with fines and wide CSD.

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Control of Crystal SizeGeneral Rules on the Effects of Cavitation

Continuous insonation produces many nuclei resulting in small crystals

Using insonation to only initiate reaction allows larger crystals to grow

Pulsed insonation gives a combination effect

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0

20

40

60

80

100

120

140

Wai

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)

90th centile No U/S

75th centile NoU/S

50th centile No U/S

25th centile No U/S

10th centile No U/S

90th centile 2s U/S

75th centile 2s U/S

50th centile 2s U/S

25th centile 2s U/S

10th centile 2s U/S

Insonated(tightlygrouped)

Uninsonated(wide spread)

Data for a pharmaceutical product (amino acid derivative) driven out of solution (Aq) by addition of an acetone anti-solvent (drowning out crystallization)

Induction Times for Nucleation

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Polymorphism

Polymorphism common amongst organic materials. Small-molecule drugs are very flexible Difficult to predict how a large floppy molecule might behave in the solid state

Isolation of the “wrong” polymorph brings substantial problems in some applications. i.e Ritonavir (Abbott) – new more stable polymorph produced at various sites

Polymorphs differ in bioavailability, solubility, dissolution rate, chemical and physical stability, Mpt, colour, filterability, density, flow properties

Stable polymorphs are thermodynamically favoured (least soluble, most stable but form slowly)

One problem is the very small energy differences between polymorphs Metastable polymorphs are kinetically favoured (fast growth and

nucleation)

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Polymorphism and Ultrasound

Ultrasound induced nucleation of potentially polymorphic systems may assist in producing the ground state polymorph or one near the ground state i.e insonate a saturated solution of the most stable polymorph known – check

for nucleation and crystal growth; thus more stable polymorph Judicious application of US (nucleate when you want to!) at the right

level of supersaturation, temperature, concentration can assist in getting polymorph A over polymorph B

Some caution though: seeds of A might predominantly secondary nucleate to produce A but equally can seed for polymorph B

With ultrasound there are a number of control options i.e:- Frequency: Changes size of cavitation event affecting unit cell formation Amplitude: Affects ground state selection Cavitation Threshold: Acoustic streaming can influence crystal growth

whereas Transient cavitation influences nucleation

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Sugars are very difficult to crystallize Seeding used (use seeds suspended in IPA) Benefits of ultrasound

Autonucleation without the need for seeding Obviates requirement for IPA Control of crystal size Saves steam energy in process plant

Full Scale Development Program underway

Sononucleation – Sugars

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Sononucleation - Sugars

Solute. Quantity dissolved in 10g water

Temp. (oC) at which solid appeared

Without With

Ultrasound ultrasound

D-xylose 25 36 43

D-sucrose 18 <40 47

D-lactose 5.5 41 43

D-maltose 13 <20* 40

D-cellubiose 2.0 <20* 42

Saturated 50 oC, cooling 0.2K /min. 20kHz u/s, 2-6 s, ~35 W/L

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Crystallization of ProteinsExciting Developments

In C3 laboratories ultrasound has been used to induce the separation of DNAse I from aqueous solutions as crystalline particles.

The objective was to develop a method to produce particles in a narrow size distribution with aerodynamic diameters in the range 3 – 5 as a model system for inhalation.

More-recently one client has demonstrated potential benefits of ultrasound even with a ‘probe-in-a-beaker’ for predictable and rapid crystallization of a protein analogue for diabetes, reducing process time by 50%.

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Crystallization of Aspartame from Water

Ref: McCausland, L. J. Accentus plc. Brit. Patent GB 02 12626.6, 5 May 2002.

No ultrasoundAmorphous-looking lumpy solid

UltrasoundUniform crystalline product

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Control of CSD for an API(1) Non ultrasound (US) controlled(2) Single nucleation (1 W / mL for 30 sec) of aliquot (20 mL) at medium supersaturation (SS) then

return to batch(3) Periodic aliquot insonation every 1 o from medium to high SS then return each aliquot to batch –

cool to ambient(4) Recirculation (20 mL flow-cell) with constant ultrasound 0.5 W / mL from medium to high SS-

sampled at ambient(5) As (4) but sampled at 5o – no further US

Particle Size Distribution

0.01 100.01 200.01 300.01 400.01 500.01 600.01 700.01 800.01 900.01

Particle Size (µm)

0

5

10

15

20

25

30

Vol

ume

(%)

UCB34714 C3-005-50 slurry 1.5h @ 10C, 29 January 2004 17:31:01UCB C3-005-52 10 degrees for 0.5h, 03 February 2004 17:33:50UCB C3-005-53 recirc insonation 9 degrees internal, 05 February 2004 17:33:10UCB C3-005-53 recirc insonation 19 degrees 1.2h, 05 February 2004 15:53:37UCB34714 ex 40 IPAcetate slurry, 16 January 2004 15:35:25

(4)

(5)

(2)

(3)

(1)

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(1) Standard batch cooling crystallization (160 g/L)(2) Continuous 50 W/L batch insonation (flow-cell in batch mode 160 g/L); sampled at 5o

(3) Continuous 50 W total on probe recirculation insonation 250 g/L; sampled at 5o

API Formulated for Inhalation

Particle Size Distribution

0.01 30.01 60.01 90.01 120.01 150.01 180.01 210.01 240.01

Particle Size (µm)

0 2 4 6 8

10 12 14 16 18 20

Vol

ume

(%)

Fenoterol recryst 2.1L scale C3-005-28, 17 December 2003 09:18:53Fenoterol recryst 2.1L scale C3-005-28 with ultrasound 1757h, 17 December 2003 17:54:34Fenoterol recryst 2.1L scale C3-005-28 with ultrasound 0816h o'night 6 deg, 18 December 2003 08:13:41

(2)

(3-blue)

(1)

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Ultrasonic Probe Based TechnologyProbe systems have serious disadvantages for scale-up

10-150 W cm-2 at face (@ 20-60 kHz) Creates very high intensity field It is not possible to transmit an intense cavitation field more

than 5 - 10 cm beyond the end of the probe (geometric losses)

- Cannot transmit into large process volume,i.e. low W/L and hence precludes scale-up

Large transducer displacements- Increased stress on material, more likely to fail- Good for laboratory studies

CAN NOT be used at large commercial scale. Previously cited pilot scale studies (1 L flow-cell) illustrate limit of practicality.

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Probe Problems:Cavitational Erosion

After 30 hrs of non-continuous use

Jet impact

Bubble implosionLiquid in-flow

Vessel wallProbe tipSolid surface

Bubble collapseLiquid jet penetrates bubble during asymmetric collapse

Damage to a solid caused by jet impact and emission of shock waves as a result of repetitive bubble implosions

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C3 Ultrasonic Flow CellPerkins, J. P. AEA Technology plc. World Patent WO0035579 B1, 22 Jun. 2000

Modular 5 litre cell, shown in batch mode (with bottom plate) Can also operate in continuous mode and units can be combined in a

modular fashion for ‘scale-out’ and increased residence time Plurality of low [electrical and acoustic] power (~3 W/cm2) transducers

giving 25 – 150 W/L; ideally 40 – 80 W/L Use in continuous and pulsed mode Flexible arrangement using non-coherent ultrasound patterns

Side Top

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C3 Scale-Out Philosophy

Generator module

37 litre cell module5 rows, each with 12 transducers

n x modulesstacked to give

desired residence time

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Ultrasound via process flow-cell applied here toremove key saltimpurities

Bulk Inorganic Process > 1000MT paHighly simplified and little changed since first operation in late 1800’s!

CausticDigestion

ConcentrationPrecipitation Calcination

BulkProducts

ImpurityRemoval

Insoluble Residue Disposal

CausticLiquor

Recycle

Feed-stock

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Impurity Removal BenefitsSignificant opportunity for Sonocrystallization in ‘old’ inorganic bulk processes

Application of C3 technology can facilitate:

Increased liquor productivityLower consumable chemical consumption Increased refinery outputLower capital cost per tonne of productBetter energy efficiency from increased concentrationFewer residues, lower environmental impactUse of lower grade feedstockLess degradation of product quality over time Increase in profitability of plant

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Pilot Flow-cell InstallationPiloted at 1/30th scale over 6 months

• 5-10 m length ultrasonic flow-cell / duct estimated for full scale• Start up Q1 2005

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Benefits of Sonocrystallization

The controlled delivery of power ultrasound facilitates: Nucleation of troublesome systems, narrow the metastable

zone and make nucleation predictable Crystallization without using external seeds in difficult-to-

nucleate systems Formation of the desired polymorph Increased productivity - from pharma to bulk inorganics Improved crystal purity and physical properties Removal of secondary unit operations (milling etc) Generation of new intellectual property

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Future of Sonocrystallization? Many more applications of Sonocrystallization expected, evolving to

become a core platform technology It has broad chemical industry applicability for superior particle size

control – easy scale-out/up An improved autonucleation method for non-invasive seeding in GMP

production, potentially becoming the standard seeding method of choice

Production technology for assisting in the manufacture of new ‘complex’ APIs, proteins, macromolecules

Emergence of new small scale equipment linked to PC coupled with turbidity measurement, Lasentec etc, scale-out process equipment

Process intensification and continuous crystallization Application in nanotechnology (nucleate nanophases) and

biotechnology

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Acknowledgements

David Hipkiss (C3) Linda McCausland (C3) Peter Cains (University College, London) John Perkins (Sonic Systems) Rob Perkins (Sonic Systems) C3 Technology customer base

For more information visit www.sonochemistry.com