Particle Processing and Modeling in
the Pharmaceutical Industry
B. J. Glasser
Department of Chemical and Biochemical Engineering
Rutgers University
Piscataway, New Jersey 08854
1
Drug
A drug product consists of therapeutics and excipients combined in a
delivery system. A drug product’s success lies in its ability to deliver
the drug at a certain rate in a certain environment in the body.
Discovery
http://www.sciencebase.com
/images/epothilone_anticanc
er_compound.jpg
Delivery
Manufacture
http://www.medgadget.com/archives/img
/benephit.jpg
2
Regulations
“FDA’s responsibility is to protect the American public. In terms
of products that are developed by a technology--whether it's a
new technology or a conventional technology--our role is to
ensure that the products are safe. Our role is not really to make
a judgment about whether they should be placed in the
marketplace or not. . . . We are here as the gatekeeper to close
the gate if a product is not going to be safe for consumers. . . . “
GMP
regulations
address issues
including record
keeping,
personnel
qualifications,
sanitation,
cleanliness,
equipment
verification,
process
validation, and
complaint
handling.
http://www.fda.gov/
3
www.fda.gov/cder/reports/rtn99-3.htm
Growth of Pharmaceutical Industry in USA
US Sales
www.research.ibm.com/journal/sj/441/cortada.html
4
World Pharmaceutical Market
http://www4.dr-rath-foundation.org/PHARMACEUTICAL_BUSINESS/pharmaceutical_industry.htm 5
Comparison of Annual Sales Per Person
ANNUAL SALES PER PERSON OF PHARMACEUTICALS (2004, £ )
http://www.abpi.org.uk/publications/publication_details/annualReview2005/ar2005_leader.asp
6
Growth of Pharmaceutical R&D Expenditure
http://www.pharmafocusasia.com/knowledge_bank/articles/images/graph1.gif
7
Comparison of Pharmaceutical R&D
WORLD VOLUME OF PHARMACEUTICAL R&D (2004 £m)
http://www.abpi.org.uk/publications/publication_details/annualReview2005/ar2005_leader.asp
8
Employment by Establishments
Total: 291000
employees in USA
9
www.bls.gov/oco/cg/images/cgc009_1.gif
Pharmaceutical Employment by Position Level
Employment, 2004
Occupation
Total, all occupations
Num
ber
291
100
53
18.2
85
29.3
34
11.6
79
27
9
3
13
4.5
13
4.4
5
2
Management, business, and financial occupations
Professional and related occupations
Office and administrative support occupations
Production occupations
Percent
Sales and related occupations
Installation, maintenance, and repair occupations
Transportation and material moving occupations
Others
www.bls.gov/oco/cg/cgs009.htm
10
New Drug Discovery
http://www.nature.com/nbt/journal/v22/n10/t
humbs/nbt1004-1215-F1.jpg
http://www.syagen.com/images/drug_di
scovery.jpg
11
Dosage Forms
Tablets/Capsules
Injectables
Inhalants
Transdermal products
and implants
Drug
Skin
http://www.avmed.com/im
ages/c_rx-capsule.jpg
http://www.indiamart
.com/cscpharma/gifs
/injectable.jpg
http://www.bath.ac.uk
/pr/releases/images/v
ectura-inhale.gif
http://www.lifetech.com/pm/nb1app3.
12
jpg
Types of Tablets (>80% of Total Products)
• Compressed tablets
– Multiple compressed
tablets
• Sugar - Coated tablets
• Film - Coated tablets
– Enteric coated tablets
• Buccal or sublingual
tablets
• Chewable tablets
Advantages
• convenience of
consumptiom
• shelf-life
(stability)
• economics of
manufacturing
• patient
acceptance
• Effervescent tablets
• Hypodermic tablets
13
Product/Process Development Paradigm
Raw Chemicals
Drug Synthesis
Drug is converted into Particles
(sub-optimal delivery properties)
Formulation
Adjusted particle properties
Preliminary process
(unknown manufacturability)
Process Development
& Scale up
Adjusted process
(unknown scalability)
Manufacturing
14
Product
Pharmaceutical Engineering
•
•
•
•
Around 15 years to bring a new drug to market
Blockbuster drug - $1B annual sales
Product development and scale-up
Hiring of chemical engineers
• Muzzio, Shinbrot, & Glasser, “Powder Technology in the Pharmaceutical Industry:
The Need to Catch Up Fast”, Powder Tech., 124,1-7, (2002).
• Glasser, Cole & Muzzio, “Pharmaceutical Engineering Training”, Pharmaceutical
Technology, 25:12, 34-36, (2001).
15
Flow Sheet for Tablet Manufacture
Source: F. Muzzio
16
Synthesis
http://www.u-tokyo.ac.jp/coe/images/pic_list03_004.JPG
http://www.chemsoc.org/chembytes/ezine/images/1999/persp_apr99_2.jpg
Improvement in organic synthesis allow
us to make larger and larger molecules.
17
Crystallization
Spheres
Needles
Cubes
18
http://aiche.confex.com/aiche/2005/techprogram/images/21810-0.jpg
Agitated Drying of Crystals
Drying Parameters:
Drying Temperature
Agitation Speed
Drying time
Vacuum
Crystal Size Distribution:
Attrition decreases the size.
Lekhal et al. Powder
Technology (2003)
Agglomeration increases the size.
19
Drying
• Freeze Drying
• Spray Drying
solvent
evaporation
Spray drying consists of the following unit operations:
Pre-concentration of liquid
Atomization (creation of droplets)
Drying in stream of hot, dry gas (usually air)
Separation of powder from moist gas
Cooling
Packaging of product
20
http://www.malvern.com/ProcessEng/images/processes/spray_drying_overview1.gif
Milling and Granulation
Three Main Granulation Mechanisms
Create a desired particle size
Improve flow and handling
Increase flow rate
Increase uniformity in finished
product
Increase density
-reduce volume required for
processing and storage
-Increase batch size
Reductions in dust
Improve appearance
Decrease ingredient segregation
Can improve dissolution (surfactant
effects)
21
Milling/Granulation Equipment
High shear granulators use both an impeller to
provide vigorous mechanical agitation and a
chopper to break large agglomerates and
promote the growth of small ones. Typically, they
produce hard granules less than 2 mm in size.
http://www.tollcompaction.com/POWDER.jpg
A Pulva mill is used for fine
grinding of dry or wet materials
ranging from 180 microns (80 U.S
mesh) to 45 microns (200 U.S.
mesh).
22
http://www.tollcompaction.com/POWDER.jpg
Blending
Three main mechanisms for mixing (J.C.
Williams)
Convection
•Driven by bulk flow
•Fast macromixing
•Easy to scale up
•Limited by segregated flow structures
(incomplete mixing)
Dispersion
•Driven by individual particle motion
•Always slow
•Leads to complete macroscopic homogeneity
•Scale-up criteria unknown
Shear
•Caused by velocity gradients
•Required for micromixingof cohesive systems
•Scale-up criteria unknown
23
Powder Blenders
24
Source: F. Muzzio
Problems in Mixing - Segregation
Segregation occurs if particles differ in size, density,
shape, or other characteristics.
25
Source: F. Muzzio
Fluidized Bed Drying
Vo: fluid velocity
ut: particle terminal velocity
VOm: minimum fluidization
velocity
* Kunii and Levenspiel, 1991
26
Application of FBs in Pharmaceutical Industry
•Blending
•Drying
•Spray-drying
•Granulation
•Coating
•Pelletizing
•Adsorption
• High mass and heat transfer
• Billions of dollars on fluidized bed processes each year
http://www.uic.edu/depts/chme/UnitOps/Fluidized%20Beds.jpg
27
Classification of Gas-Fluidized Beds
28
Problems in Fluidized Bed Processing
Packed
bed
Uniform
expansion
• Different Flow Regimes
• Flow Instability
• Voidage Waves
Bubbling
• Drying or Reaction Rate
• Selectivity
• Product Yield
• Safety
Increasing • Environmental Impact
Clustering
Gas Flows
Streamer
29
Tableting
Compaction Mechanism
• Particle re-arrangement (low pressure
densification). Particles move into closer
packing, air leaves the powder plug.
Spherical particles move less than irregularly
shaped particles
• Deformation occurs as pressure is
increased, enlarging the area of contact
between particles
• Fragmentation, which gives high yield
stress, occurs next as pressure increases.
New surfaces and bonding points are created
• Bond formation then takes place between
previously existing and newly created
30
http://www.sripharmacare.com/gifs/tablet-capsule1.jpg
surfaces
Tableting Machines
Four main stages for tableting : Die fill, weight
adjustment, compression, and ejection
Rotary tablet presses
http://www.capsule-filling-machine.com/rimages/131/tablet-h01.jpg
31
Problems in Tableting
32
Coating
There are several types of coating method that are divided into two main categories:
the single layer and the multi-layer coating methods. The first category is most
commonly used for the pharmaceutical patches
Some of the main variables involved in the selection of the appropriate method are:
The number of layers
Layer thickness
Viscosity
Solids content
Accuracy
Solvent systems
Surface treatment and so on
33
http://www1.istockphoto.com/file_thumbview_approve/344351/2/istockphoto_344351_multi_macro.jpg
Coating Equipment
http://www.medicaldesign.com/
http://www.sono-tek.com/images/_biomedical/medicoat_header.jpg
Talwar Pharma
manufactures a wide
range of pellet products,
mainly omeprazole and
lansoprazole pellets, and
offers stage wise quality
tests at drug coating
stage, sub-coating stage
and enteric coating stage
The surface profile of a drugeluting coating on a stent
examined with an optical
interferometer reveals some
waviness in the coating,
along with a lower region in
the middle of the area
examined
http://www.pharmaceuticaltechnology.com/contractor_images/ta
34
lwar/3.jpg
Sampling
• Accurate sampling is a key technical
need for quality control and process
characterization
Stratified Sampling
• In pharmaceutical manufacturing,
batch sampling is increasingly
becoming a regulatory expectation
• Standard tools (thief probes) are
extremely unreliable, often resulting in
samples of uncertain size and
composition
Three Assumptions
Source: F. Muzzio
• Random Mixtures (Normal Distributions)
• Unperturbed Sampling (no thief error)
35
• Unchanging Mixtures (no segregation)
Sampling Machines
Globe-Pharma Sampler
•Cavities can be filled with solid dies
36
•Only lower cavity used
Challenges in Pharmaceutical Industry
• Development cost is rising – 50% increase in five years
• Why is this happening?
– New drugs are harder to formulate
– Products are increasing in complexity
– “Regulation is inefficient”
• Health care cost is rising rapidly
• Uninsured, underinsured, and third world populations
cannot afford many new drugs
• Many drugs do not get developed because the economic
incentive is not there
• Number of new drugs has decreased 50% in 10 years 37
Source: F. Muzzio
The Barriers – and the Opportunity
• Three inter-related barriers
– Lack of synergy between fundamental science and
domain knowledge
– Lack of predictive models
– Lack of the properly trained human resource
• A major opportunity
– Develop the predictive science
– Create inter-disciplinary training programs
– Provide a forum for science-based regulation
38
Source: F. Muzzio
2016 – Imagine if ……
• Product development only took six months
• Cost of development and manufacturing could be cut in half
• Products and processes could be designed in the computer
(like airplanes, microchips)
• Regulation promoted continuous improvement
• Pharmaceutical manufacturing was
Mature
Portable
Highly reliable (2.5s  6s)
Could manufacture finished pharmaceuticals in a
compact device, such as a modified ink-jet printer?
– Greatly reduced facilities cost
– Reduced batch size and stock
– Personalized dosage based on weight
39
– Scalable, flexible
Source: F. Muzzio
Significance of Particle Processes
• Essential for 60% of manufactured
products
Bridgwater,
Gran. Matt.,
2002
• Numerous, recurring industrial problems
Knowlton,
et al Chem
Eng. Prog.,
1994
– 40-50% operations below design
specifications
– Commissioning delays & productivity delays
– No strong theoretical design basis
– Design strategies are usually empirical
 Erratic flow and inhomogeneity
• Acute for pharmaceutical industry
– 80% of drug products are capsules, pills or
tablets
– 18% FDA recalls for “potency/content
Wall Street
uniformity”
Journal, 2003
– Uncertain, rudimentary scale-up
– Manufacturing efficiency lags other industries
FDC, The
Gold Sheet,
2002
40
Granular Materials Not Yet Understood
• Extreme
behavioral
regimes
GEA
Buck,
Inc.,
2004
Jenike and
Johanssen,
2004
• Curious
phenomena
Makse
et al,
Nature
1995
Umbanhowar et al,
Nature 1996
• Scale-gap between particle-level and macroscopic
Michaels,
models
Powhder Tech.,
2003
41
Inhomogeneity in Granular Flows
• Uniform flows often desirable,
but “cluster” spontaneously
– Mesoscale structures
– Interstitial fluid negligible
– Determines performance
Jaworski,
Dyakowski,
– Segregation potential?
Powder
Tech. 2002
• Examination of instabilities
illuminates:
– Underlying physics
– Flow transitions, onset of Goldfarb,
Shinbrot,
Glasser,
chaos?
Nature,
2002
• Fluid analogies exploited
Pipe Flows
Liss,
Conway,
Glasser,
Phys.
Fluids,
2002
Channel Flows
Forterre
and
Pouliquen,
Phys. Rev.
Lett., 2001
42
Segregation in Granular Materials
• Treated as
unpredictable, inevitable
• Dominated by rules-ofthumb
• Broad application
hampered:
– Numerous qualitative
mechanisms
– Little agreement,
eg. Brazil nut effect
Alexander, Muzzio, Shinbrot,
Chem. Eng Sci 2003
Breau et al, Phys. Rev.
43
Lett., 2003
Granular Flows in Different Geometries
Goldfarb, Glasser and
Shinbrot, Nature, (2002)
Liss, Conway, Zega, and
Glasser,
Pharmaceutical
Technology, (2004)
Conway, Lekhal, Glasser,
Khinast AIChE J. (2006)
Conway, Shinbrot and
Glasser, Nature, (2004)
Lekhal, Conway, Glasser, Khinast
Chem. Eng. Sci. (2006)
Dry Solids
Wet Solids
44
Introduction to Nanoparticles
• Nanoparticles are ultra fine powders
whose particle sizes are in the range
of 1-100 nm.
• Applications in materials and
manufacturing, health care,
medicine, electronics, environment,
energy, chemical and pharmaceutical
biotechnology, agriculture,
information technology.
• Nanoparticles in the range of 1-5 nm
have potential applications in
nanoscale electronics.
• Nanoparticles below 5 nm exhibit
unique physical and chemical
properties.
45
http://www.brighamandwomens.org/publicaffairs/Images/nanoparticles%20attack%20prostate%20cancer
%20cells.jpg
Contd.. Introduction to Nanoparticles
• Difference in the range of structural chemistries between bulk and
nanoscale particles make nanoparticles unique in vast applications.
• Properties of nanoparticles vary considerably with size
• Activity and selectivity can be greatly influenced by nanoparticles.
• Particle size is critical in determining the properties of
nanoparticles.
• Synthesis of nanomaterials over a range of chemical composition
and sizes has been a challenge.
• An ordered geometry and structure is of interest in nanoparticles
(control of shape, size and structure).
• Spherical nanoparticles were of interest due to their high surface
area.
• Due to high surface area, metal oxide nanoparticles have wide
range of applications in sensors, catalysis and electronics.
46
Drug Nanoparticles
• In pharmaceutics, active ingredient is in the form of solid particles.
• Application of nanotechnology for treatment, diagnosis, monitoring,
and control of biological systems has been determined by NIH as
nanomedicine.
• Drug nanoparticles can be used with the development of
nanotechnology.
• For example, in 2005, FDA approved 130 nm albumin nanoparticles
loaded with paclitaxel.
• Several polymeric, metal nanoparticles, liposomes, micelles,
quantum dots, dendrimers, microcapsules, cells, cell ghosts,
lipoproteins, and many different nanoassemblies play a major role in
diagnosis and therapy.
• Nanoparticulate pharmaceutical carriers enhance the vivo efficiency
of many drugs
http://nano.cancer.gov/objects/img_resource/nanoparticles.jpg
47
Importance of Nanosize in Drug Delivery
Object
Size (nm)
Carbon atom
0.1
DNA double helix (diameter)
3
Ribosome
10
Virus
100
Bacterium
1,000
Red blood cell
5,000
Human hair (diameter)
50,000
Resolution of unaided human eyes
100,000
Ref:
Gupta R.B, Kompella U.B, Nanoparticle Technology for Drug Delivery, Drugs
48
and Pharmaceutical Sciences. 2006; 159: 2-3.
Cond.. Importance of Nanosize
• Size matching is important for drug delivery.
• Drug delivery aimed at influencing the biochemistry of the body.
• Nanoparticles are of great interest in drug delivery due to
comparable sizes to the human cells.
• Biological systems are in the nanometer range
• To treat the disease, one needs to use the same nanoscale.
• For example correcting faulty gene, killing leprosy bacteria in the
blood cells, blocking multiplication of viral genome, killing cancer
cell, repair cellular metabolism etc.
http://www.aist.go.jp/aist_e/museum/science/7/7_4.jpg
49
Importance of Nanoparticle Surface
Particle size (nm)
Surface molecules (%)
1
100
10
27.1
100
2.97
1,000
0.3
10,000
0.03
Ref:
Gupta R.B, Kompella U.B, Nanoparticle Technology for Drug Delivery, Drugs
50
and Pharmaceutical Sciences. 2006; 159: 3-4.
Cond.. Importance of Nanoparticle Surface
• Small size nanoparticles are suitable for variety of drug
delivery applications.
• As the particle size decreases, number of molecules present on
particle surface increases.
• Increased contact area can increase adhesion
• For spherical solid particle of diameter d, surface area per unit
mass, Sg, is
 d
S g  
 4
2
 d  s

 6
3



1
3

2d s
(Gupta et.al, 2006)
51
Nanoparticle Flow for Drug Delivery
• Nanoparticle flow can be facilitated by
– Convective flow induced by the flow of blood, lymph or
interstitial fluid
– Influence of the interaction of nanoparticles with themselves or
with biological components
– Diffusion and particle movement of particle suspensions in
interstitial tissue
• Advantages of nanoparticle flow
– Small dimension allows them to interact more effectively with
cells
– Can be safely injected
– Diffuse further into tissues
– Diffuse through individual cells
• Larger particles are vulnerable to detachment by shear
forces
52