Particle Size Reduction (Micronization)

Stephen Tindal

Particle Size Reduction

(Micronization)

Formulation Strategies for Oral Delivery of Poorly Soluble Drugs

Session Description and Objectives

Slide 2 www.aaps.org

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.


Particle Size Reduction in Drug

Delivery


Particle Size Reduction in Drug

Delivery (powder)


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


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


Jet Mill Micronization is Great… But… cannot always realize theoretical benefits


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


Post-Particle Size Reduction Downstream Processing & Final Product


Oral Drug Delivery

Multi-compartment Modelling


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)

http://www.apsgb.co.uk/Events/PastEvents/20110609/James Butler.pdf


Technology Fit - Micronization


Successful Technologies Marketed

APIs (by DCS)

Amidon G, et al. Pharm Res. 1995; 12(3): 413-420


Marketed APIs Utilizing Particle Size

Reduction (by DCS)


DCS II Compounds – Technology

Summary


Case Study – DynaCirc®

Micronized Isradipine

Poorly Soluble Compound (DCS IV)

Dharmadhikari NB, et al. U.S. Patent WO2005115092 A2, 2005


Case Study – Utrogestan Micronized Progesterone

Low-solubility compound

(BCS Class II)

Sitruk-Ware R., et. al. Contraception. 1987; 36(4): 373–402


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)


Co-Micronization Provides Improved

Benefits


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


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


Milling Equipment


Introduction

1. Facilities

2. Jet Mill

3. Opposed Jet Mill

4. Containment

5. Project Management


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


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.


Jet Mill (Typically manual feed)

(Optional)


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


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


Jet Mill


Jet Mill


Jet Mill

PFTE inserts can reduce tendency for API build up


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


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.


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


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.


Opposed Jet Mills


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


Optimization of Process Conditions Quality by Design (QbD) Customer Support


Analytical


• 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

Slide 41

www.aaps.org

Biography


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


[email protected]

Catalent, Somerset, NJ, USA

mailto:[email protected]



References


#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


#AAPSMeetings

• Chris Karayiannis (Catalent)

Documents

Particle Size Reduction (Micronization)