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
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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
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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
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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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Midler, Jr. etal (Merck, 1994)Midler, Jr. etal (Merck, 1994)
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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Lindrud etal (BMS, 2001)Lindrud etal (BMS, 2001)
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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Lindrud etal (BMS, 2001)Lindrud etal (BMS, 2001)
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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Am Ende etal (Pfizer, 2003)Am Ende etal (Pfizer, 2003)
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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Midler, Jr. etal (Merck, 1994)Midler, Jr. etal (Merck, 1994)
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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Midler, Jr. etal (Merck, 1994)Midler, Jr. etal (Merck, 1994)
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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Am Ende etal (Pfizer, 2003)Am Ende etal (Pfizer, 2003)
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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Am Ende etal (Pfizer, 2003)Am Ende etal (Pfizer, 2003)
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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Marchisio etal (2006)Marchisio etal (2006)
Marchisio et al. (2006) AIChE J. v52 p1877
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Marchisio etal (2006)Marchisio etal (2006)
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.