Stephen Tindal
Particle Size Reduction
(Micronization)
Formulation Strategies for Oral Delivery of Poorly Soluble Drugs
Session Description and Objectives
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A summary review of micronization technology, it’s
place in drug delivery, and application in oral,
poorly small molecule development. A review of
more common equipment for micronization.
• Describe micronization in relation to DCS.
• Why doesn’t micronization always work?
• Review equipment and operating principles.
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Particle Size Reduction in Drug
Delivery
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Particle Size Reduction in Drug
Delivery (powder)
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Need for Oral Bioavailability
Enhancement
BCS I
BCS III
BCS II
BCS IV
Marketed Drugs Pipeline Drugs
BCS I
BCS III
BCS II
BCS IV
BCS I
BCS III
BCS II
BCS IV
BCS I
BCS III
BCS II
BCS IV
Limited bioavailability can lead to inter-patient variability/inconsistent treatment, can delay the onset of action and ultimately be the reason for the discontinuation of development programs.
R. Lipp; The Innovator Pipeline: Bioavailability Challenges and Advanced Oral Drug Delivery Opportunities, Am. Pharm. Rev., 2013
CHALLENGES OF INNOVATOR PIPELINE
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Why use Micronization?
Benefits:
• Improve Performance
• Increase surface area to deliver faster dissolution rate for poorly soluble compounds to improve Bioavailability
• Right particle size for inhaled drugs
• Reduced grittiness for topic or oral liquid suspensions.
• Narrower particle size distribution
• Improve Process
• Better content uniformity for low dose drugs
• Reduce segregation/sedimentation of formulation blends
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Jet Mill Micronization is Great… But… cannot always realize theoretical benefits
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Co-Micronization
• Simultaneous micronization of pre-blended API / Excipient
• Benefits:
• Improve Performance
• Ensure actual particle size target is achieved
• Ensure theoretical surface area increase is realized
• Improve wet-ability of particles
• Improve solubility (and maybe permeability)
• Improve Process
• Improve flow of resulting powder
• Simpler / Lower cost option
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Post-Particle Size Reduction Downstream Processing & Final Product
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Oral Drug Delivery
Multi-compartment Modelling
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Proposed Dose Form Selection Model: Developability Classification System (DCS)
Source: Butler, J. The optimal use of biorelevant media & simple modeling for the prediction of in-vivo oral behaviour (http://www.apsgb.co.uk/Events/PastEvents/20110609/James%20Butler.pdf)
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Technology Fit - Micronization
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Successful Technologies Marketed
APIs (by DCS)
Amidon G, et al. Pharm Res. 1995; 12(3): 413-420
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Marketed APIs Utilizing Particle Size
Reduction (by DCS)
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DCS II Compounds – Technology
Summary
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Case Study – DynaCirc®
Micronized Isradipine
Poorly Soluble Compound (DCS IV)
Dharmadhikari NB, et al. U.S. Patent WO2005115092 A2, 2005
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Case Study – Utrogestan Micronized Progesterone
Low-solubility compound
(BCS Class II)
Sitruk-Ware R., et. al. Contraception. 1987; 36(4): 373–402
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Case Study –
Co-Micronized Fenofibrate
•Poorly Soluble Compound (BCS Class IIb)
•Non-micronized fenofibrate (fed-state) only had a 60% dose absorption (Lipanthyl® 300mg)
•Co-micronizing fenofibrate with surfactant SLS (sodium lauryl sulfate) improved the D50% time
•Authors provide data showing bioequivalence of 200mg dose to unmicronized 300mg dose.
US Patent 4,895,726 B Curtet, et al. (1990)
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Co-Micronization Provides Improved
Benefits
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Inhalation Drug Delivery
• Benefits of Pulmonary Drug Delivery:
– Large surface area (100 m2) – alveoli
– Rapid absorption of drug into systemic circulation
– Avoid first-pass hepatic metabolism
Cheng Y. AAPS PharmSciTech. 2014
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Effect of Aerodynamic Particle Size
Distribution
MMADs – mass aerodynamic diameters DPI – Dry Powder Inhaler
MMDs – mass median diameters FPM – Fine Particle Mass
pMDI – pressurized metered dose inhaler FPFs – Fine Particle Fractions
Mitchell J, et. al. AAPS PharmSciTech. 2007; 8(4): E1-E12
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Milling Equipment
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Introduction
1. Facilities
2. Jet Mill
3. Opposed Jet Mill
4. Containment
5. Project Management
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Facilities
• GMP Processing Bays
• Separate cleaning rooms
• Single pass air –no re-circulation
• Temperature and humidity
monitored/controlled
• Nitrogen capabilities
• Containment capabilities
• Automated product collection systems
• Analytical support
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Spiral Jet Mill
• Very commonly used for GMP processing
• A flat round horizontal grinding chamber with a ring of evenly spaced
tangential nozzles. The gas emerging from these jets forms a high velocity
grinding circle and a free vortex
• Powder is introduced by a fluidized venturi jet into the grinding zone at a
tangent through the top plate. Particles are subjected to a combination of
forces resulting in particle to particle collisions and ultimately size reduction
• The free vortex keeps the larger particles in the grinding zone by centrifugal
force whilst allowing finer particles to migrate to the centre outlet – thus
providing narrower output range
• Milled material is collected by a filter system
• Gas can be air or nitrogen. No significant heat build up.
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Jet Mill (Typically manual feed)
(Optional)
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Jet Mill Factors affecting the micronized product particle size distribution
• Microniser design (chamber size and geometry)
• Design, number and placement of jet nozzles
• Particle size, brittleness and flow of feed material (batch to batch variability)
• Material can be passed through mill a second time
• Final material specification may be a
compromise of particle size and flow properties
• Operational parameters: • Mill pressure
• Venturi pressure
• Feed rate
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The benefits of Jet Milling
• High throughput, simple and reproducible
• Narrow particle size distribution
• Easy scale up from R&D to Production
• Production yields consistently over 90%
• Industry standard for API particle reduction for dissolution rate improvement
• No moving parts and minimal product contact (liners)
• No heat generation
• Easy to clean
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Jet Mill
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Jet Mill
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Jet Mill
PFTE inserts can reduce tendency for API build up
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Opposed Jet Mills
• Design - Opposed jet systems (arrowed)
• Collides streams of particles together
• Includes more sophisticated particle
classifier
• Capable down to 5 µm
• Suitable for APIs requiring very narrow,
well defined particle size distribution
• Incorporates screw feed allowing
processing of powders that flow less
well
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Opposed Jet Mill
Opposed Jet Mills with forced vortex classifiers are used when narrow particle
size distributions are required.
The process gives a greater control of the top end of the size distribution
curve.
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Hosokawa AFG 100 Classifier
• Fine particles are carried
upwards by a gas stream
where they meet the vortex
classifier.
• The rotation speed of the
classifier governs the exit of
particles through it into the
collection system
• Particles that are too big are
excluded by centrifugal forces
and retained in the grinding
zone
Opposed Jet Mills
Section through a classifier wheel
The classifier wheel spins at high speed and creates a vortex around the outer edge.
As particles travel upward in the airstream towards the wheel, they are either pulled through the wheel gaps if they are small and light enough (in spec) or thrown out if they are too large and have lower velocity, dropping back down into the mill for further milling.
The classifier is very efficient and ensures a narrower particle size distribution
Fine particles pass through the classifier wheel into the centre and off to the collection system
Coarse particles rejected by the classifier pass back into the milling zone
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Opposed Jet Mills
Potential downsides:
• It requires a minimum batch size larger than equivalent
spiral jet mill.
• Recycling of coarse material can cause powder to build-
up in the grinding zone.
• Recycling of coarse material can increase the amount of
amorphous content in some powders.
• Classifier does not tolerate sticky materials which block
the wheel.
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Opposed Jet Mills
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Factors which affect the particle size distribution are:
• Jet nozzle size
• Jet nozzle pressure
• Air Flow
• Speed of classifier
In practice the top end of the particle size distribution is usually
controlled by adjusting the classifier speed
Micronization for Highly Potent
Compounds
• Increasing trend of highly potent compounds being developed
• Micronizing potent compounds presents unique challenges for
product containment
• High Potent compound processing
− Supports all milling operations
− R&D isolator and Commercial scale
− Operator Exposure Limit (“OEL”) <1μg/m3 for any quantities
− Operators in air-supplied suits for highest level of protection
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Optimization of Process Conditions Quality by Design (QbD) Customer Support
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Analytical
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• Sampling / Sample Size!
• Optical Microscopy
• Laser Light Scattering
• Scanning Electron Microscopy
• Surface Area
• XRPD
• DSC
• TGA
• DVS
• FTIR
• Kinetic Solubility
• Content Uniformity (HPLC)
Conclusion
• Particle Size Reduction is an integral process in the manufacturing of APIs and is commonly used for the development of oral, inhalation, topical, and ocular dosage forms
• Mechanical milling is commonly used to improve content uniformity for solid oral dosage forms
• Micronization is commonly evaluated for bioavailability enhancement of:
• Poorly Soluble Compounds for Oral Drug Delivery
– BCS Class IIa (dissolution rate limited)
– BCS Class IIb (solubility limited)
– BCS Class IV (solubility and permeability rate limited)
• Small Molecules for Inhalation Drug Delivery
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www.aaps.org
Biography
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Degree in Chemistry and Analytical Science
30 years with Catalent
Mostly R&D Formulation, but some QC and 3 years as Director of Operations for clinical & commercial
Pharmaceuticals since 1997
Currently Director, Science & Technology, USA.
Contact Information
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Catalent, Somerset, NJ, USA
References
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#AAPSMeetings
• R. Lipp; The Innovator Pipeline: Bioavailability Challenges and
Advanced Oral Drug Delivery Opportunities, Am. Pharm. Rev.,
2013
• Source: Butler, J. The optimal use of biorelevant media & simple
modeling for the prediction of in-vivo oral behaviour
(http://www.apsgb.co.uk/Events/PastEvents/20110609/James%20
Butler.pdf)
• Amidon G, et al. Pharm Res. 1995;
• Sitruk-Ware R., et. al. Contraception. 1987; 36(4): 373–402
• Cheng Y. AAPS PharmSciTech. 2014
• Mitchell J, et. al. AAPS PharmSciTech. 2007; 8(4): E1-E12
Acknowledgements
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#AAPSMeetings
• Chris Karayiannis (Catalent)