Allan S' Myerson

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Crystallization Science and Technology in the
Development in the Pharmaceutical Industry
Allan S. Myerson Department of Chemical
Engineering, Illinois Institute of Technology,
Chicago, IL 60616
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Crystal Solid with short and long range
order with atoms or molecules in a fixed lattice
arrangement. Internal structure of crystals
accessible by x-ray diffraction analysis.
Glycine
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Modern Pharmaceutical Product Tablet
100 mg Prevents nausea and vomiting
Active pharmaceutical ingredient (API)
Ondansetron HCl Dihydrate Equivalent to 4mg
Ondansetron (4) Lactose, microcrystalline
cellulose, pregelatinized starch, hypromellose,
magnesium stearate, titanium dioxide,
triacetin 96mg(96)
API
Excipient, Binding agents
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Crystallization Process Development

• Process Goals
• Purity
• Yield
• Average Size and Size Distribution
• Correct Polymorph or Pseudopolymorph
• Shape

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Polymorphism

• A polymorph is a compound that can crystallise in
  a variety of forms e.g. Carbon (graphite and
  diamond) whilst remaining chemically identical .
• The different forms maybe significantly different
  in terms of both their structures and
  physio-chemical properties.
• Graphite (top and pencil) Diamond (bottom)

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• Basic Information Needed
• Choice of polymorph to be made
• Most stable preferred
• Less stable chosen for solubility or other
  formation reasons
• Monotropic or Eniantiotropic

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Solubility of Polymorphs at Given Temperature
Stability
Solubility
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Polymorphic Properties

• Packing Properties
• Molar volume, density, refractive index,
  conductivity, hygroscopicity
• Thermodynamic Properties
• Melting and sublimation temperature, structural
  energy, enthalpy, heat capacity, entropy, free
  energy and chemical potential, thermodynamic
  activity, vapor pressure, solubility
• Kinetic Properties
• Dissolution rates, rates of solid state
  reactions, stability
• Spectroscopic Properties
• Surface Properties
• Surface free energy, interfacial tension,
  morphology
• Mechanical Properties
• Hardness, tensile strength, compactability,
  handling, flow
• Bioavailability

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Polymorphs of Glycine alpha
beta gamma
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Polymorphs in the Pharmaceutical Industry

• Food Drug Administration
• Requires understanding the system
• Indicates polymorph to be used
• If form changes have to be retested
• Intellectual Property / Patent Rights

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Ritonavir

• Anti-HIV drug
• Initial production based on existence of a single
  form
• In 1998 a second form was detected, which was
  found to be the thermodynamically stable form
• Product recalled
• Reformulation
• Repatenting
• Cost 200-700 million

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Pseudopolymorphism Paroxetine Hydrochloride
(C19H21FNO3.Cl-)
Water
Propan-2-ol
Ibers JA Acta Cryst C55, 1999, 432. Yokota M,
Uekusa H, Ohashi Y, Bull Chem. Soc. Jpn., 72,
1999, 1737.
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Methods Employed to Obtain Unique Polymorphic
Forms

• Sublimation
• Crystallization from a Single Solvent
• Evaporation from a Binary Mixture of Solvents
• Vapor Diffusion
• Thermal Treatment
• Crystallization from the Melt
• Rapidly Changing Solution pH to Precipitate
  Acidic or Basic Substances
• Thermal Desolvation of Crystalline Solvates
• Growth in the Presence of Additives
• Grinding

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Characterization Methods

• Crystallography X-Ray Diffraction
• Single Crystal X-Ray Diffraction
• X-Ray Powder Diffraction
• Morphology Microscopy
• Polarizing Optical Microscopy
• Thermal Microscopy
• Phase Transitions Thermal Methods of Analysis
• Thermogravimetry
• Differential Thermal Analysis
• Differential Scanning Calorimetry
• Molecular Motion Vibrational Spectroscopy
• Infrared Absorption Spectroscopy
• Raman Spectroscopy
• Chemical Environment Nuclear Magnetic Resonance
  Spectrometry

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Patterned Gold Islands
Standard Glass Slide with 725 um Gold Islands
Mesh with 140 um holes
140 um Gold Islands
Hydrophilic Thiol Monolayer
4-Mercaptobenzoic Acid (4-MBA)
Hydrophobic Silane Monolayer
Array of glycerol drops exclusively on
hydrophilic surface
Octadecyl trichlorosilane (OTS)
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Patterned Glycine Crystals on Metallic Islands
(100 µm)
Ordered Array of Glycine Crystals Formed on
Hydrophilic 100 µm Gold Islands
Irregular Leaf-like Shape of Glycine Crystal
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Solid Form Characterization

• two different polymorphs of a given molecule are
  identical except for their distinctly different
  three-dimensional structures
• these structural differences can give rise to
  distinct vibrational frequencies for each moiety
• shift in vibrational frequencies may be on the
  order of 1-20 cm-1

Raman Microscope
y
x
Raman Spectra Acquisition Analysis
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Basic Information Needed

• 1. Solubility Versus Temperature, Solvent
  Composition, and/or pH
• Why Choose solvent system and initial and
  final conditions to obtain yield needed

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Solubility of Ibuprofen
Ibuprofen C13H18O2
A nonsteroidal anti-inflammatory drug that is
used to treat symptoms caused by
arthritis, such as swelling, pain, and
stiffness. Trade Names Advil, Nuprin, and
Motrin
Reference J. Chem. Eng. Data, 47 (6), 1379
-1383, 2002.
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Solubility of Disodium Salt Hemiheptahydrate of
Ceftriaxone
Disodium Salt Hemiheptahydrate of
Ceftriaxone C18H18N8Na2O7S. 3 ½ H2O
A third generation of cephalosporin and is one of
the most important patiently applied antibiotics
Reference J. Chem. Eng. Data, 46 (2), 175 -176,
2001.
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Solubility Measurement Apparatus
Turbidity Light Sources
Multiplexor

Turbidity Probes
Syringe Pump
Chiller Line
Reaction Station
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Solubility Measurement Apparatus

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Accuracy Reproducibility
Paracetamol- Isopropyl alcohol
Roger A.Granberg and Ake C.Rasmuson
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Methods to create supersaturation

• Temperature Change
• Evaporation of solvent
• Reaction
• Addition of miscible non-solvent

• Based on change of solubility of material with
  temperature
• Based on removal of solvent from system thus
  increasing solute concentration
• Addition of reactant which causes the formation
  of a less soluble species
• Addition of a miscible liquid in which the solute
  is not soluble. Causes overall decrease in
  solubility of solute in the mixed solvent system

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Solubility of Polymorphs Solubility ratio of
polymorphs constant at given temperature
regardless of solvent Transition temperature in
enantiotropic system constant regardless of
solvent
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Role of Supersaturation on Polymorphism
Monotropic System
Enantiotropic System
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Lasentec

• Focused Beam Reflectance Measurement

Measurement Particle Size and Population
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Experimental Apparatus Materials
50 ml Vessel
500 ml Vessel
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Basic Information Needed

• How fast does the crystal grow?
• Why Based on average size required gives
  estimate of batch time required to obtain a
  desired size.
• Will primary nucleation or seeding be used?
• Why-Control of crystal size distribution
  depends on control of nucleation process.

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Comparison of the Growth Rate of Hexamethylene
Tetramine Crystals from Water and Ethanol Solution
Hexamethylene Tetramene C6H12N4
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Figure 6.4. Crystal growth rate of glycine-batch
time 7.5 hours
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Batch Seeded Crystallization

• Model Pharmaceutical System
• Cinnarizine (JohnsonJohnson) in 2-Butanone

Formula C26H28N2 MW 368.23,
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Cinnarizine
Monoclinic-B P21/C
Y. Mouille, M. Cotrait, M. Hospital, Acta
Crystallogr. Sect. B Struct. Crystallogr. Cryst.
Chem., Vol31, 1495, 1975
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Batch Seeded Crystallization

• Model Pharmaceutical System
• Non-linear cooling
• Dry seed addition
• On-line monitoring CSD

50mL
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Experiment Results
Volume Weighted CSD Seed mass to yield ratio
0.2
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Experiment Results
Volume Weighted CSD Seed mass to yield ratio
0.2
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Crystal Size Distribution During Cooling and
Seeding of Glycine Crystallization
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Figure 7.2. Bimodal CSD resulting from
insufficient seed addition
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Flufenamic Acid
Formula C14H10F3NO2 MW 281.23
Anti-inflammatory
Form I
Form III
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Raman Monitoring ofDesuperaturation During
Crystallization
1682 cm-1
Normalized to ethanol peak at 881 cm-1
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Raman Monitoring of Crystallization Process
Ethanol
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Combined On-line sensors Raman Lasentec
Isothermal Seeded Crystallization of Flufenamic
Acid
Add seeds
Form III transforms
Completed transformation
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Monitoring Spontaneous Nucleation Lasentec
Raman
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Monitoring Solid Form

• Detect process error at early stage/obtain
  metastable form

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Solution Mediated Transformation
Dissolution
Nucleation
Metastable Form
Solution
Stable Form
Crystal Growth

• Metastable form may exist for a significant
  period of time
• The presence of a more stable form results in
  solution mediated phase transformation
• Sudden appearance of a more stable form which was
  not discovered in the early stages can cause loss
  of time and resources

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Solubility of Each Crystalline Form
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Summary of Transformation Time at 30 º C
at 30 º C in IPA
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Nucleation
Primary
Secondary (Induced by Crystals)
Heterogeneous (Foreign Materials)
Homogeneous
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Agitation Mixing

• Secondary Nucleation
• Nucleation resulting from the presence of
  crystals in supersaturated solutions
• Correlation stirring speed, suspension density
  and supersaturation

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Comparison between vessel in terms of impeller
tip speed
1000 liter _at_ 300rpm Tip speed 5.68 m/s
50 ml _at_ 1000rpm Tip speed 0.70 m/s
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Experimental Apparatus Materials

• Constant Tip Speed in Scale-Up

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Cooling Crystallization
40 ml Vessel 300 ml Vessel

Kinetics
Nucleation at Higher Temperature Nucleation at
Lower Supersaturation Smaller Number of
Nuclei Relatively Longer Growth Time
Hydrodynamics

Smaller Secondary Nucleation Rates
Polymorphism

No Scale-Up Effect on Polymorphic Transition by
Controlled Cooling
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Conclusions

• Measurement of basic physical properties and
  estimation of rates are crucial to
  crystallization process developement
• On-line methods on the lab scale can greatly
  aid obtaining needed data
• Must understand the fundamental differences in
  bench scale, pilot plant and full scale
  experiments

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Related Recent Publications

• Hu, Y., Liang, J.K., Myerson, A.S., and Taylor,
  L.S. (2005). Crystallization Monitoring by Raman
  Spectroscopy Simultaneous Measurement of
  Desupersaturation Profile and Polymorphic Form in
  Flufenamic Acid Systems. Industrial and
  Engineering Chemistry Research, 44, 1233-1240.
• Mukuta, T., Lee, A.Y., Kawakami, T., and Myerson,
  A.S. (2005). Influence of Impurities on the
  Solution-Mediated Phase Transformation of an
  Active Pharmaceutical Ingredient. Crystal
  Growth Design, 5,1429-1436.
• Yi, Y.J., Hatziavramidis, D., Myerson, A.S.,
  Waldo, M., Beylin, V.G., and Mustakis, J.
  (2005). Development of a Small-Scale Automated
  Solubility Measurement Apparatus.
• Industrial and Engineering Chemistry
  Research, 44, 5427-5433.
• Yi, Y.J. and Myerson, A.S. (2006). Laboratory
  Scale Batch Crystallization and the role of
  Vessel Size. Trans IChemE, Part A, Chemical
  Engineering Research and Design, 84, 721-728,
• Lee, A.Y., Lee, I., Dette, S.S., Boerner, J. and
  Myerson, A.S. (2005). Crystallization on
  Confined Engineered Surfaces A Method to
  Control Crystal Size and Generate Different
  Polymorphs. Journal of the American Chemical
  Society, 127, 14982-14983.

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Related Recent Publications

• Mukuta, T., Lee, A.Y., Kawakami, T., and Myerson,
  A.S. (2005). Influence of Impurities on the
  Solution-Mediated Phase Transformation of an
  Active Pharmaceutical Ingredient. Crystal Growth
  Design, 5 1429-1436.
• Lee, A.Y., Lee, I.S., Myerson, A.S. (2006).
  Factors Affecting the Polymorphic Outcome of
  Glycine Crystals Constrained on Patterned
  Substrates. Chemical Engineering Technology,
  29, 281-285.

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Acknowledgements
Particle Technology and Crystallization
Consortium, Pfizer, Mettler-Toledo, ONR, Fujisawa
Pharmaceuticals