giuseppe di benedetto - che 702 - impinging jets

8/6/2019 Giuseppe Di Benedetto - ChE 702 - Impinging Jets

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Precipitation of NanoparticlesPrecipitation of Nanoparticlesby Impinging Jet Mixersby Impinging Jet Mixers

Giuseppe Di BenedettoGiuseppe Di Benedetto

ChE 702ChE 702--002002Modules inModules in

NanoNano--PharmaceuticalsPharmaceuticals

May 3, 2007May 3, 2007

New Jersey Institute of TechnologyNew Jersey Institute of TechnologyOtto H. York

Dept. of Chemical Engineering,Otto H. York Dept. of Chemical Engineering,Newark, NJ 07102Newark, NJ 07102

http://www.polysep.ucla.edu/resear2.jpg


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Giuseppe Di BenedettoGiuseppe Di Benedetto 22

OutlineOutline

The Role of Crystallization in theThe Role of Crystallization in thePharmaceutical IndustryPharmaceutical Industry

Brief Review of CrystallizationBrief Review of Crystallization Impinging Jet MixerImpinging Jet Mixer

Submerged Impinging Jet MixerSubmerged Impinging Jet Mixer

Confined Imp

ing

ing Jet M

ixerConf

ined Imp

ing

ing Jet M

ixer

ConclusionConclusion


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CrystallizationintheCrystallizationinthe

Pharmaceutical IndustryPharmaceutical Industry Over 90% of pharmaceutical drugOver 90% of pharmaceutical drug

compounds (API) are generally incompounds (API) are generally in

crystalline formcrystalline form

Control and operation of crystallizationControl and operation of crystallizationprocesses is one of the mostimportantprocesses is one of the mostimportantchallenges in pharmaceutical developmentchallenges in pharmaceutical development

http://www.kaneda.co.jp/universal/images/solutions/phar_api.jpg


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CrystallizationintheCrystallizationinthe

Pharmaceutical IndustryPharmaceutical Industry Crystallization determines:Crystallization determines:

Drug Chemical PurityDrug Chemical Purity

Physical Propert

iesPhys

ical Propert

ies

Crystal SizeCrystal Size

Crystal StructureCrystal Structure

Degree of Crystal ImperfectionDegree of Crystal Imperfection

Crystal Size Distribution (CSD) affectsCrystal Size Distribution (CSD) affects BioavailabilityBioavailability

StabilityStability

PostPost--Crystallization ProcessingCrystallization Processing

http://www.niroinc.com/images/evap/crystallizer2.jpg


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CrystallizationCrystallization

Crystallization consists of two steps:Crystallization consists of two steps:

= sol id formation begins with= solid formation begins withappearance of very small crystalsappearance of very small crystals Primary nucleationPrimary nucleation

Secondary nucleationSecondary nucleation

= subsequent growth of the= subsequent growth of the

crystals after the nucleation stagecrystals after the nucleation stage

NucleationNucleation

Crystal GrowthCrystal Growth


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Nanoparticle CrystallizationNanoparticle Crystallization

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TypicalCrystallizationTypicalCrystallizationT

echniquesT

echniquesAntiAnti--solvent Crystallizationsolvent Crystallization

Solute (e.g.: API) is deposited from solution bySolute (e.g.: API) is deposited from solution byaddition of antiaddition of anti--solvent (e.g.: water)solvent (e.g.: water)

Sometimes referred to as saltingSometimes referred to as salting--out or wateringout or watering--outout

Reactive CrystallizationReactive Crystallization Solid crystalline product production as a result of aSolid crystalline product production as a result of a

chemical reactionchemical reaction

Gases or liquids act as the reactantsGases or liquids act as the reactants

Gaseous or liquid phase becomes supersaturated withGaseous or liquid phase becomes supersaturated withrespect to reaction productrespect to reaction product


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Time required for homogenously mixed supersaturatedTime required for homogenously mixed supersaturatedsystem depends on mixing techniquesystem depends on mixing technique

When , the final product characteristicsWhen , the final product characteristics

depend on physicodepend on physico--chemical parameters and not onchemical parameters and not onmixing conditionsmixing conditions

When , properties of the final productWhen , properties of the final productare greatly affectedare greatly affected

Mixing vsPrecipitation KineticsMixing vsPrecipitation Kinetics

mixingprecipXX ""

Johnson and Prudhomme (2003) AIChE J. v49 p2264

mixingprecip XX }

mixingprecip XX ""


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Impinging JetMixerImpinging JetMixer

Two jet nozzles arranged diametrically opposedTwo jet nozzles arranged diametrically opposedto each otherto each other

Outlet tips directed to face each otherOutlet tips directed to face each other

The impingement creates an immediate highThe impingement creates an immediate highturbulence impactturbulence impact

DeliverDeliver p ecipmixing XX

Schaer et al (1999) Chem Eng J. v72 p125


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TypesofImpinging JetMixersTypesofImpinging JetMixers

Submerged Impinging Jet MixerSubmerged Impinging Jet Mixer Midler, Jr. et al. (Merck, 1994) USPT #5,314,506Midler, Jr. et al. (Merck, 1994) USPT #5,314,506

Lindrud et al. (BMS, 2001) USPT #6,302,958Lindrud et al. (BMS, 2001) USPT #6,302,958

Am Ende et al. (Pfizer, 2003) USPT #6,558,435Am Ende et al. (Pfizer, 2003) USPT #6,558,435

Confined Impinging Jet MixerConfined Impinging Jet Mixer

Midler, Jr. et al. (Merck, 1994) USPT #5,314,506Midler, Jr. et al. (Merck, 1994) USPT #5,314,506 Am Ende et al. (Pfizer, 2003) USPT #6,558,435Am Ende et al. (Pfizer, 2003) USPT #6,558,435


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SubmergedImpinging JetMixerSubmergedImpinging JetMixer

Collide in a large chamberCollide in a large chamber

Walls have little effect on impingementWalls have little effect on impingement

processprocess Chamber is filled with gas or fluidChamber is filled with gas or fluid

When low viscosity fluid, sometimes referredWhen low viscosity fluid, sometimes referredto as Free Impinging Jet Mixerto as Free Impinging Jet Mixer


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Midler, Jr. etal (Merck, 1994)Midler, Jr. etal (Merck, 1994)

API = Simvastatin (ZocorAPI = Simvastatin (Zocor)) Controls elevated cholesterolControls elevated cholesterol

levelslevels

Solvent = MethanolSolvent = MethanolAntiAnti--Solvent = WaterSolvent = Water

Heated to 85Heated to 85ooCC

Solvent Solution = 55Solvent Solution = 55ooCC Seeded AntiSeeded Anti--Solvent withinSolvent within

vesselvessel 2.5 grams Simvastatin2.5 grams Simvastatin 600 mL water at 70600 mL water at 70ooCC


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Jet Flow Rate = 1.1 L/minJet Flow Rate = 1.1 L/min

Jet Velocity = 23 m/sJet Velocity = 23 m/s

6 L baffled vessel6 L baffled vessel

Diameter = 8 inchDiameter = 8 inch Height = 10 inchHeight = 10 inch

Rushton TurbineRushton Turbine Diameter = 3 inchDiameter = 3 inch

Crystal ParticlesCrystal Particles Surface Area = 3.1Surface Area = 3.10.4 m0.4 m22/g/g

Particle Size = 3 to 20 micronsParticle Size = 3 to 20 microns


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Lindrud etal (BMS, 2001)Lindrud etal (BMS, 2001)

API = (ZAPI = (Z--33--[1[1--(4(4--chorophenyl)chorophenyl)--11--(4(4--methylsulfonylpenyl)methylsulfonylpenyl)methylene]methylene]--dihydrofurandihydrofuran--22--

oneone Solvent = DMSOSolvent = DMSO

AntiAnti--Solvent = WaterSolvent = Water Chilled to 2Chilled to 2ooCC

Solvent Solution = 65Solvent Solution = 65--7575

oo

CC AntiAnti--Solvent within vesselSolvent within vessel

300 mL water at 2300 mL water at 2ooCC


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Sonication at maximumSonication at maximum

Solvent Jet Flow Rate = 0.18 kg/minSolvent Jet Flow Rate = 0.18 kg/minthrough 0.02 nozzlethrough 0.02 nozzle

Water Jet Flow Rate = 0.72 kg/minWater Jet Flow Rate = 0.72 kg/minthrough 0.04 nozzlethrough 0.04 nozzle

Jet Velocity = 12 m/sJet Velocity = 12 m/s

1000 mL jacketed vessel1000 mL jacketed vessel

Rushton TurbineRushton Turbine


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Experiment No. Mean Size %


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BenefitofSonicationBenefitofSonication

Impinging JetsImpinging Jets 101055 W/kgW/kg

SonicationSonication 101099 W/kgW/kg

Atiemo-Obeng & Calabrese (2004)Handbook of Industrial Mixing:Science and Practice,

Rotor-Stator M ixing Devices p500


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Am Ende etal (Pfizer, 2003)Am Ende etal (Pfizer, 2003)

Reactive Crystallization of 5,8,14Reactive Crystallization of 5,8,14--triazatetracyclo[10.3.1.0triazatetracyclo[10.3.1.02,112,11.0.04,94,9]]--hexadecahexadeca--22--(11),3,5,7,9(11),3,5,7,9--pentaenepentaene

First Solvent = Ethyl AcetateFirst Solvent = Ethyl Acetate

Reactant = (L)Reactant = (L)--tartaric acidtartaric acid Second Solvent = MethanolSecond Solvent = Methanol Seeded Solution within vesselSeeded Solution within vessel

20 mg 5,8,1420 mg 5,8,14--triazatetracyclo[10.3.1.0triazatetracyclo[10.3.1.02,112,11.0.04,94,9]]--hexadecahexadeca--22--(11),3,5,7,9(11),3,5,7,9--pentaenepentaene(L)(L)--tartratetartrate

250 mL methanol250 mL methanol 250 mL ethyl acetate250 mL ethyl acetate

Room TemperatureRoom Temperature


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Jet Flow Rate = 20Jet Flow Rate = 20mL/minmL/min

Jet Velocity = 13.4 m/sJet Velocity = 13.4 m/s

Crystal ParticlesCrystal Particles Mean Particle Size =Mean Particle Size =

10 microns10 microns

5% of Particles were less5% of Particles were lessthan 5 micronsthan 5 microns

95% of Particles were less95% of Particles were lessthan 15 micronsthan 15 microns


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ConfinedImpinging JetMixerConfinedImpinging JetMixer

Collide in a small chamberCollide in a small chamber

Walls have large effect on impingementWalls have large effect on impingement

processprocess Chamber can be filled with gas or fluid, orChamber can be filled with gas or fluid, or

left emptyleft empty

Resulting product d

ischarges

into largerResult

ing product d

ischarges

into largervesselvessel


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API = Omeprazole (PrilosecAPI = Omeprazole (Prilosec)) Treatment of gastroesophageal refluxTreatment of gastroesophageal reflux

diseasedisease

Solvent = MethanolSolvent = Methanol AntiAnti--Solvent = Triton XSolvent = Triton X--100 in100 in

waterwater SurfactantSurfactant Heated to 42Heated to 42ooCC

Solvent SolutionSolvent Solution 250 mL Methanol250 mL Methanol

0.25 mL concentrated Ammonium0.25 mL concentrated AmmoniumHydroxideHydroxide

Solution Temperature = 42Solution Temperature = 42ooCC

Jet Flow Rate = 0.7 L/minJet Flow Rate = 0.7 L/min Jet Velocity = 15 m/sJet Velocity = 15 m/s


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Receiving vessel at 42Receiving vessel at 42ooCC

200 mL of water200 mL of water

0.3 mL ofTriton X0.3 mL of

Triton X--100100 0.45 grams Omeprazole0.45 grams Omeprazole

Crystal ParticlesCrystal Particles

CubeCube--like particleslike particles

95% of particles smaller95% of particles smallerthan 3 micronsthan 3 microns


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Reactive Crystallization ofReactive Crystallization ofZiprasidone (Geodon, Zeldox)Ziprasidone (Geodon, Zeldox) Treatment of schizophreniaTreatment of schizophrenia

First Solvent = TetrahydrofuranFirst Solvent = Tetrahydrofuran

(THF)(THF) Maintained at 60Maintained at 60ooCC Reactant = aqueous HCl solutionReactant = aqueous HCl solution

Maintained at 15Maintained at 15ooCC

THF solution JetTHF solution Jet

Flow Rate = 120 mL/minFlow Rate = 120 mL/min Velocity = 9.9 m/sVelocity = 9.9 m/s

HCl solution JetHCl solution Jet Flow Rate = 100 mL/minFlow Rate = 100 mL/min Velocity = 9.5 m/sVelocity = 9.5 m/s


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Receiving vessel at 30Receiving vessel at 30ooCC

Started emptyStarted empty

Crystal ParticlesCrystal Particles Mean Particle Size =Mean Particle Size =

22.5 microns22.5 microns

0% of Particles were less0% of Particles were less

than 1 micronthan 1 micron 90% of Particles were less90% of Particles were less

than 41 micronsthan 41 microns


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Marchisio etal (2006)Marchisio etal (2006)

Reactive CrystallizationReactive Crystallization

Room TemperatureRoom Temperature

2NaCl(aq)(s)BaSO(aq)SONa(aq)BaCl 4422

Marchisio et al. (2006) AIChE J. v52 p1877


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Impinging JetMixerImpinging JetMixerConclusionsConclusions

Very useful when milling is not an optionVery useful when milling is not an option(e.g.: very small crystals for inhalation delivery(e.g.: very small crystals for inhalation deliverysystems)systems)

Rapid precipitation under high supersaturationRapid precipitation under high supersaturationfavors nucleation over growthfavors nucleation over growth

Thus resulting in particles with small averageThus resulting in particles with small averagesizesize

Offers consistent, reproducible crystalOffers consistent, reproducible crystalproduction resultsproduction results


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Impinging JetMixerImpinging JetMixerConclusionsConclusions

The interplay between mixing and precipitationThe interplay between mixing and precipitationis crucialis crucial

Submerged Impinging Jet Mixers alone produceSubmerged Impinging Jet Mixers alone produce

particles only as small as 3 micronsparticles only as small as 3 microns Submerged Impinging Jet Mixers combined withSubmerged Impinging Jet Mixers combined with

Sonication can produce particles as small asSonication can produce particles as small as200 nm200 nm

Confined Impinging Jet Mixers can produceConfined Impinging Jet Mixers can produceparticles smaller than 100 nmparticles smaller than 100 nm


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ReferencesReferences

Am Ende, Dav id J., et al. Reactive Crystallization Method to Improve Particle Size. US Patent 6558435. 6 MayAm Ende, Dav id J., et al. Reactive Crystallization Method to Improve Particle Size. US Patent 6558435. 6 May2003.2003.

AtiemoAtiemo--Obeng, Victor A., and Richard V. Calabrese. RotorObeng, Victor A., and Richard V. Calabrese. Rotor--Stator Mixing Devices.Stator Mixing Devices. Handbook of IndustrialHandbook of IndustrialMixing: Science and PracticeMixing: Science and Practice. Ed. Edward L. Paul, Victor A. Atiemo. Ed. Edward L. Paul, Victor A. Atiemo--Obeng, and Suzanne M. Kresta.Obeng, and Suzanne M. Kresta.Hoboken: John Wiley & Sons, Inc., 2004. 479Hoboken: John Wiley & Sons, Inc., 2004. 479--505.505.

Hacherl, Jean M., et al. Investigation of ImpingingHacherl, Jean M., et al. Investigation of Impinging--Jet Crystallization with a Calcium Oxalate Model System.Jet Crystallization with a Calcium Oxalate Model System.AIChE JournalAIChE Journal 49 (2003): 235249 (2003): 2352--2362.2362.

Johnson, Brian K., and Robert K. Prudhomme. Chemical Processing and Micromixing in Confined Impining Jets.Johnson, Brian K., and Robert K. Prudhomme. Chemical Processing and Micromixing in Confined Impining Jets.AIChE JournalAIChE Journal 49 (2003): 226449 (2003): 2264--2282.2282.

Kirwan, D.J., and C.J. Orella. Crystallization in the Pharmaceutical and Bioprocessing Industries.Kirwan, D.J., and C.J. Orella. Crystallization in the Pharmaceutical and Bioprocessing Industries. Handbook ofHandbook ofIndustrial CrystallizationIndustrial Crystallization. 2. 2ndnd Ed. Ed. Allan S. Myerson. Boston: ButterworthEd. Ed. Allan S. Myerson. Boston: Butterworth--Heinemann, 2002. 249Heinemann, 2002. 249--266.266.

Lindrud, Mark D., et al. Sonic Impinging Jet Crystallization Apparatus and Process. US Patent 6302958. 16Lindrud, Mark D., et al. Sonic Impinging Jet Crystallization Apparatus and Process. US Patent 6302958. 16Oct. 2001.Oct. 2001.

Mahajan, Amarjit J., and Donald J. Kirwan. Micromoxing Effects in a TwoMahajan, Amarjit J., and Donald J. Kirwan. Micromoxing Effects in a Two--ImpiningImpining--Jets Precipitator.Jets Precipitator. AIChEAIChEJournalJournal 42 (1996): 180142 (1996): 1801--1814.1814.

Marcant, Bruno, and RenMarcant, Bruno, and Ren David. Experimental Evidence for and Prediction of Micromixing Effects in David. Experimental Evidence for and Prediction of Micromixing Effects inPrecipitation.Precipitation. AIChE JournalAIChE Journal 37 (1991): 169837 (1991): 1698--1710.1710.

Marchisio, Daniele L., et al. Design and ScaleMarchisio, Daniele L., et al. Design and Scale--Up of Chemical Reactors for Nanoparticle Precipitation.Up of Chemical Reactors for Nanoparticle Precipitation. AIChEAIChE

JournalJournal 52 (2006): 187752 (2006): 1877--1887.1887. Mersmann, A., ed.Mersmann, A., ed. Crystallization Technology HandbookCrystallization Technology Handbook. 2. 2ndnd Ed. New York: Marcel Dekker, Inc., 2001.Ed. New York: Marcel Dekker, Inc., 2001. Midler, Jr., Michael, et al. Crystallization Method to Improve Crystal Structure and Size. US Patent 5314506.Midler, Jr., Michael, et al. Crystallization Method to Improve Crystal Structure and Size. US Patent 5314506.

24 May 1994.24 May 1994. Mullin, J.W.Mullin, J.W. CrystallizationCrystallization. 4. 4thth Ed. Amsterdam: Elsevier ButterworthEd. Amsterdam: Elsevier Butterworth--Heinemann, 2001.Heinemann, 2001. Schaer, Eric, et al. Determination of Local Energy Dissipation Rates in Impinging Jets by a Chemical ReactionSchaer, Eric, et al. Determination of Local Energy Dissipation Rates in Impinging Jets by a Chemical Reaction

Method.Method. Chemical Engineering JournalChemical Engineering Journal 72 (1999): 12572 (1999): 125--138.138.

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