Precipitation of Nanoparticles

by Impinging Jet Mixers

Giuseppe Di Benedetto
ChE 702-002
Modules in
Nano-Pharmaceuticals

http://www.polysep.ucla.edu/resear2.jpg May 3, 2007

New Jersey Institute of Technology

Otto H. York Dept. of Chemical Engineering,
Newark, NJ 07102 1
 Outline
 The Role of Crystallization in the
Pharmaceutical Industry
 Brief Review of Crystallization
 Impinging Jet Mixer
– Submerged Impinging Jet Mixer
– Confined Impinging Jet Mixer
 Conclusion

Giuseppe Di Benedetto 2
 Crystallization in the
Pharmaceutical Industry
 Over 90% of pharmaceutical drug
compounds (API) are generally in
crystalline form
 Control and operation of crystallization
processes is one of the most important
challenges in pharmaceutical development

Giuseppe Di Benedetto http://www.kaneda.co.jp/universal/images/solutions/phar_api.jpg 3

 Crystallization in the
Pharmaceutical Industry
 Crystallization determines:
– Drug Chemical Purity
– Physical Properties
 Crystal Size
 Crystal Structure
 Degree of Crystal Imperfection
 Crystal Size Distribution (CSD) affects
– Bioavailability http://www.niroinc.com/images/evap
/crystallizer2.jpg

– Stability
– Post-Crystallization Processing
Giuseppe Di Benedetto 4
 Crystallization
 Crystallization consists of two steps:
– Nucleation = solid formation begins with
appearance of very small crystals
 Primary nucleation
 Secondary nucleation
– Crystal Growth = subsequent growth of the
crystals after the nucleation stage

Giuseppe Di Benedetto 5
Nanoparticle Crystallization

http://www.matsceng.ohio-state.edu/mse205/lectures/chapter10/chap10_slide5.gif

Giuseppe Di Benedetto 6
 Typical Crystallization
Techniques
 Anti-solvent Crystallization
– Solute (e.g.: API) is deposited from solution by
addition of anti-solvent (e.g.: water)
– Sometimes referred to as “salting-out” or “watering-
out”
 Reactive Crystallization
– Solid crystalline product production as a result of a
chemical reaction
– Gases or liquids act as the reactants
– Gaseous or liquid phase becomes supersaturated with
respect to reaction product

Giuseppe Di Benedetto 7
Mixing vs Precipitation Kinetics

 precip   mixing

Johnson and Prud’homme (2003) AIChE J. v49 p2264

 Time required for homogenously mixed supersaturated
system depends on mixing technique
 When  precip   mixing , the final product characteristics
depend on physico-chemical parameters and not on
mixing conditions
 When  precip   mixing , properties of the final product
are greatly affected

Giuseppe Di Benedetto 8
 Impinging Jet Mixer
 Two jet nozzles arranged diametrically opposed
to each other
 Outlet tips directed to face each other

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

 The impingement creates an immediate high
turbulence impact
 Deliver  mixing   precip
Giuseppe Di Benedetto 9
Types of Impinging Jet Mixers
 Submerged Impinging Jet Mixer
– Midler, Jr. et al. (Merck, 1994) USPT #5,314,506
– Lindrud et al. (BMS, 2001) USPT #6,302,958
– Am Ende et al. (Pfizer, 2003) USPT #6,558,435

 Confined Impinging Jet Mixer

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

Giuseppe Di Benedetto 10
Submerged Impinging Jet Mixer
 Collide in a large chamber
 Walls have little effect on impingement
process
 Chamber is filled with gas or fluid
– When low viscosity fluid, sometimes referred
to as “Free Impinging Jet Mixer”

Giuseppe Di Benedetto 11
Midler, Jr. et al (Merck, 1994)
 API = Simvastatin (Zocor®)
– Controls elevated cholesterol
levels
 Solvent = Methanol
 Anti-Solvent = Water
– Heated to 85oC
 Solvent Solution = 55oC
 Seeded Anti-Solvent within
vessel
– 2.5 grams Simvastatin
– 600 mL water at 70oC

Giuseppe Di Benedetto 12
Midler, Jr. et al (Merck, 1994)
 Jet Flow Rate = 1.1 L/min
 Jet Velocity = 23 m/s
 6 L baffled vessel
– Diameter = 8 ¼ inch
– Height = 10 inch
 Rushton Turbine
– Diameter = 3 inch
 Crystal Particles
– Surface Area = 3.1±0.4 m2/g
– Particle Size = 3 to 20 microns

Giuseppe Di Benedetto 13
Lindrud et al (BMS, 2001)
 API = (Z-3-[1-(4-
chorophenyl)-1-(4-
methylsulfonylpenyl)
methylene]-dihydrofuran-2-
one
 Solvent = DMSO
 Anti-Solvent = Water
– Chilled to 2oC
 Solvent Solution = 65-75oC
 Anti-Solvent within vessel
– 300 mL water at 2oC

Giuseppe Di Benedetto 14
Lindrud et al (BMS, 2001)
 Sonication at maximum
 Solvent Jet Flow Rate = 0.18 kg/min
through 0.02” nozzle
 Water Jet Flow Rate = 0.72 kg/min
through 0.04” nozzle
 Jet Velocity = 12 m/s
 1000 mL jacketed vessel
 Rushton Turbine

Giuseppe Di Benedetto 15
 Lindrud et al (BMS, 2001)
Experiment No. Mean Size % <0.5000 m 95th percentile

42216-157-20 0.5090 microns 99.011 0.5086 microns

42216-158 0.5124 98.097 0.5087

42216-195 0.5376 92.224 0.9373

44032-006-12 0.5164 97.499 0.5087

44032-006-18 0.5178 97.093 0.5088

44032-006-27 0.5129 97.987 0.5087

Giuseppe Di Benedetto 16
 Benefit of Sonication
Impinging Jets ≈ 105 W/kg

Sonication
≈ 109 W/kg

Atiemo-Obeng & Calabrese (2004)

Handbook of Industrial Mixing:
Science and Practice,
“Rotor-Stator Mixing Devices” p500

Giuseppe Di Benedetto 17
Am Ende et al (Pfizer, 2003)
 Reactive Crystallization of 5,8,14-
triazatetracyclo[10.3.1.02,11.04,9]-
hexadeca-2-(11),3,5,7,9-pentaene
 First Solvent = Ethyl Acetate
 Reactant = (L)-tartaric acid
 Second Solvent = Methanol
 Seeded Solution within vessel
– 20 mg 5,8,14-
triazatetracyclo[10.3.1.02,11.04,9]-
hexadeca-2-(11),3,5,7,9-pentaene
(L)-tartrate
– 250 mL methanol
– 250 mL ethyl acetate
 Room Temperature

Giuseppe Di Benedetto 18
Am Ende et al (Pfizer, 2003)
 Jet Flow Rate = 20
mL/min
 Jet Velocity = 13.4 m/s
 Crystal Particles
– Mean Particle Size =
10 microns
– 5% of Particles were less
than 5 microns
– 95% of Particles were less
than 15 microns
Giuseppe Di Benedetto 19
 Confined Impinging Jet Mixer
 Collide in a small chamber
 Walls have large effect on impingement
process
 Chamber can be filled with gas or fluid, or
left empty
 Resulting product discharges into larger
vessel

Giuseppe Di Benedetto 20
Midler, Jr. et al (Merck, 1994)
 API = Omeprazole (Prilosec®)
– Treatment of gastroesophageal reflux
disease
 Solvent = Methanol
 Anti-Solvent = Triton X-100 in
water
– Surfactant
– Heated to 42oC
 Solvent Solution
– 250 mL Methanol
– 0.25 mL concentrated Ammonium
Hydroxide
– Solution Temperature = 42oC
 Jet Flow Rate = 0.7 L/min
 Jet Velocity = 15 m/s
Giuseppe Di Benedetto 21
Midler, Jr. et al (Merck, 1994)
 Receiving vessel at 42oC
– 200 mL of water
– 0.3 mL of Triton X-100
– 0.45 grams Omeprazole
 Crystal Particles
– Cube-like particles
– 95% of particles smaller
than 3 microns

Giuseppe Di Benedetto 22
Am Ende et al (Pfizer, 2003)
 Reactive Crystallization of
Ziprasidone (Geodon, Zeldox)
– Treatment of schizophrenia
 First Solvent = Tetrahydrofuran
(THF)
– Maintained at 60oC
 Reactant = aqueous HCl solution
– Maintained at 15oC
 THF solution Jet
– Flow Rate = 120 mL/min
– Velocity = 9.9 m/s
 HCl solution Jet
– Flow Rate = 100 mL/min
– Velocity = 9.5 m/s

Giuseppe Di Benedetto 23
Am Ende et al (Pfizer, 2003)
 Receiving vessel at 30oC
– Started empty
 Crystal Particles
– Mean Particle Size =
22.5 microns
– 0% of Particles were less
than 1 micron
– 90% of Particles were less
than 41 microns
Giuseppe Di Benedetto 24
 Marchisio et al (2006)
 Reactive Crystallization
BaCl2 (aq)  Na 2SO 4 (aq)  BaSO4 (s)  2NaCl(aq)
 Room Temperature

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

Giuseppe Di Benedetto 25
Marchisio et al (2006)

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

Giuseppe Di Benedetto 26
Marchisio et al (2006)

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

Giuseppe Di Benedetto 27
 Impinging Jet Mixer
Conclusions
 Very useful when milling is not an option
(e.g.: very small crystals for inhalation delivery
systems)
 Rapid precipitation under high supersaturation
favors nucleation over growth
 Thus resulting in particles with small average
size
 Offers consistent, reproducible crystal production
results

Giuseppe Di Benedetto 28
 Impinging Jet Mixer
Conclusions
 The interplay between mixing and precipitation
is crucial
 Submerged Impinging Jet Mixers alone produce
particles only as small as 3 microns
 Submerged Impinging Jet Mixers combined with
Sonication can produce particles as small as
200 nm
 Confined Impinging Jet Mixers can produce
particles smaller than 100 nm

Giuseppe Di Benedetto 29
 References
 Am Ende, David J., et al. “Reactive Crystallization Method to Improve Particle Size.” US Patent 6558435. 6 May
2003.
 Atiemo-Obeng, Victor A., and Richard V. Calabrese. “Rotor-Stator Mixing Devices.” Handbook of Industrial
Mixing: Science and Practice. Ed. Edward L. Paul, Victor A. Atiemo-Obeng, and Suzanne M. Kresta.
Hoboken: John Wiley & Sons, Inc., 2004. 479-505.
 Hacherl, Jean M., et al. “Investigation of Impinging-Jet Crystallization with a Calcium Oxalate Model System.”
AIChE Journal 49 (2003): 2352-2362.
 Johnson, Brian K., and Robert K. Prud’homme. “Chemical Processing and Micromixing in Confined Impining Jets.”
AIChE Journal 49 (2003): 2264-2282.
 Kirwan, D.J., and C.J. Orella. “Crystallization in the Pharmaceutical and Bioprocessing Industries.” Handbook of
Industrial Crystallization. 2nd Ed. Ed. Allan S. Myerson. Boston: Butterworth-Heinemann, 2002. 249-
266.
 Lindrud, Mark D., et al. “Sonic Impinging Jet Crystallization Apparatus and Process.” US Patent 6302958. 16
Oct. 2001.
 Mahajan, Amarjit J., and Donald J. Kirwan. “Micromoxing Effects in a Two-Impining-Jets Precipitator.” AIChE
Journal 42 (1996): 1801-1814.
 Marcant, Bruno, and René David. “Experimental Evidence for and Prediction of Micromixing Effects in
Precipitation.” AIChE Journal 37 (1991): 1698-1710.
 Marchisio, Daniele L., et al. “Design and Scale-Up of Chemical Reactors for Nanoparticle Precipitation.” AIChE
Journal 52 (2006): 1877-1887.
 Mersmann, A., ed. Crystallization Technology Handbook . 2nd Ed. New York: Marcel Dekker, Inc., 2001.
 Midler, Jr., Michael, et al. “Crystallization Method to Improve Crystal Structure and Size.” US Patent 5314506.
24 May 1994.
 Mullin, J.W. Crystallization. 4th Ed. Amsterdam: Elsevier Butterworth-Heinemann, 2001.
 Schaer, Eric, et al. “Determination of Local Energy Dissipation Rates in Impinging Jets by a Chemical Reaction
Method.” Chemical Engineering Journal 72 (1999): 125-138.

Giuseppe Di Benedetto 30