Data Driven Formulation Development Using Material Sparing Methods

Fourth Annual Garnet E. Peck Symposium

Gregory E. Amidon, Ph.D. Enabled Solid Dosage Forms Ann Arbor, MI

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Acknowledgements: Many people at Pfizer Have been involved

Padma Narajan Pam Secreast Bruno Hancock Barbara Spong Glenn Carlson Beth Langdon Jeff Moriarty Matt Mullarney Angela Kong Dauda Ladipo and many others

Data Driven Formulation Development Using Material Sparing Methods

What is the data needed for datadriven decisions? How much material do you need?
A number of us at Pfizer believe that we need limited material and a bunch of data to effectively develop manufacturable formulations.

Data Driven Formulation Development Using Material Sparing Methods

We are moving from seeing is believing to data is predicting.

Traditional Tablet Formulation Development Paradigm

1. Deliver API 2. Conduct drug-excipient compatibility studies ~500-5000g delivery <10 g API

3. Develop Drug Product formulation & manufacturing process

~1 5 kg lot size(s)

4. Manufacture prototype tablets and conduct stability testing

1000 -10,000 tablets

Reliably Manufacture tablets

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Outline
Particle Characterization Particle Size, Shape, Size Distribution, Content Uniformity Dissolution Powder Characterization Bulk, Tapped, True Density Powder flow Compact Characterization Mechanical Properties Tablet Characterization (Formulation Development) Excipient Selection Process Selection Formulation Characterization Manufacturing (MSF approach)
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API Particle Characterization-Microscopy

Method Microscopy Light Polarized LM SEM
Min, m Max, m
Distribution Shape texture
Grams Xtal?

1 3 0.02

1000 1000 1000

Y Y M

Y Y Y

Y Y Y

0.5 0.5 0.5

N Y N

Qualitative Information Best way to get shape, texture, crystallinity information quickly 3 dimensional information possible

API Particle Characterization

Light Scattering and Obscuration

Method Light Scattering Laser
Photon Correlation

Min, m

Max, m

Distribution

Shape

texture

Grams

Xtal?

0.02 0.001 1

2000 1 500

Y Y Y

N N N

N N N

2 2 2

N N N

Light Obscuration

Quantitative Information d50, d10. d90, g (Geometric Std Dev.) Covers wide range of particle sizes Experimental conditions can be critical to obtaining reproducible and meaningful results!

API Particle Characterization

Particle Size Distribution matters

A few big particles (or more) can alter:

Content Uniformity (eg: segregation, potency) Dissolution (slow it down) Processing (eg: powder flow, compressing, granulation)

A few small particles (or more) can alter:

Content Uniformity (eg: segregation) Dissolution (speed it up) Processing (eg: powder flow, compressing, granulation)
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API Particle Characterization

Effects of Particle Size and Distribution on Processing

Content Uniformity (manufacturability issue) Dissolution Rate (drug delivery issue)

API Particle Characterization

Effects of Particle Size and Distribution on Processing

Content Uniformity (manufacturability issue) Dissolution Rate (drug delivery issue)

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Content Uniformity Model

Known particle size distribution Particles end up in a tablet based on random chance

Tablet die
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Key Assumptions in CU model

Log normal distribution is assumed. It is not a

necessary assumption but allows for an analytical solution.

Drug load is low (eg: drug particles are independent) Drug particle size and excipient particle size are similar

(< 5X)

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Theoretical Equation
(BRRohrs, et.al., Pfizer, Inc from Johnson, Yalkowsky & Bolton papers)

d'g = Maximum geometric mean diameter on a weight (or volume) basis required to pass CU. D = dose, mg

g = geometric standard deviation

= true density Cv = Coefficient of variation of the dose (%RSD) to pass CU criteria (eg: Cv = 3.84 to pass USP CU with 99% confidence)

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Maximum Geometric Mean Volume Particle Diameter (d50), m

Particle Size and Distribution Necessary to Pass USP 25 Stage I CU for Tablets

Maximum Mean Volume Particle Diameter, d50 (m) Predicted to Pass USP Content Uniformity Test (99% Confidence) as a Function of Geometric Standard Deviation (g) and Dose (mg)
g d /d 90 50 1.0
1000

1.0 1.7 2.4 3.2 4.1 4.9 5.8

1.5 2.0 2.5 3.0

(Rohrs, Amidon, Secreast, Meury J.Pharm.Sci., 95, 1045 (2006))

1 0.1 1 10 100 1000

Dose, mg
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Micronizing

Examples: 1 mg dose g d50 1.0 (monodispersed) ~150 um 1.5 (narrow) ~110 um 2.0 (moderate) ~ 70 um 3.0 (broad) ~ 25 um 3.5 (very broad) ~ 15 um
.

100

3.5 4.0

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Milling

Content Uniformity Example

(Rohrs, Amidon, Secreas,t Meury, J.Pharm.Sci., 95, 1045 (2006))

Relative standard deviation of content uniformity vs. dose. Symbols are measured values for tablet lots from API Lots A z, and B . Solid lines are calculated using a particle size distribution width for Lots A and B estimated by g = (d84.1/d15.9)0.5, dashed lines are calculated from g = (d97.7/d50)0.5.

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API Particle Characterization

Effects of Particle Size and Distribution on Processing

Content Uniformity (manufacturability issue) Dissolution Rate (drug delivery issue)

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The cocktail party question

What do you say if you are at a cocktail party and some asks you What particle size do I need to achieve an adequate dissolution rate if my drug has an aqueous solubility of 10 ug/mL? A: 1 um B: 10 um C: 100 um D: dont know

Answer: 10 m! Particle diameter in m should be equal to or less than the solubility in g/mL.
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Dissolution: Noyes-Whitney Equation (flat surfaces)

dm D A = (S Cb ) dt h
dm/dt = Dissolution Rate, mass/sec D = Diffusion coefficient ~ 8 x 10-6 cm2/sec A = Surface area, cm2 h = diffusion layer, cm S = Solubility, mass/cm3

Saturated Solution at surface

Solid

Solubility h

bulk

Cb Aqueous
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Dissolution rate for spherical particles

dm 2 dC = D 4r dt dr

a r

dm r = 4DaS dt h
Diffusion Layer, h

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Dissolution Rate for Poly-disperse dm r Systems = 4DaS

dt h

Total dissolution rate =

individual particle dissolution rates

If one knows the particle size distribution, the dissolution rate can be predicted assuming a diffusion layer thickness, h. A pretty good assumption is: a 30m, then h = a (diffusion layer = particle radius) a > 30m, then h = 30m
Ref: Higuchi & Hiestand, J.Pharm.Sci. 52:1 67-71 (1963) Hintz, RJ, Johnson, KC. Int. J. Pharm. 51 9-17 (1988)

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Particle Diameter to Achieve 80% dissolved in 30 minutes

(log-normal dist, sink conditions, spheres)
100

Particle Diameter to Achieve 80% dissolved in 30 Min

10 Monodispersed Sigma = 2.0 Sigma = 3.0 1 1 10 100

Solubility in ug/mL

1000

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Rule of Thumb
100

Particle Diameter to Achieve 80% dissolved in 30 Min

10 Monodispersed Sigma = 2.0 Sigma = 3.0 1 1 10 100

Solubility in ug/mL

1000

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API Particle Characterization

Summary
Particle size, size distribution, shape, and texture (PS)

have an impact on pharmaceutical processing and performance.

This is true for active pharmaceutical ingredients,

excipients and formulations (eg: granules).

Consideration should be given to the impact of these

parameters on formulation processing and robustness.

Appropriate specifications and control (eg: particle

engineering) should be implemented where PS has been identified as impacting processing or performance.

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Outline
API Particle Characterization Particle Size, Shape, Size Distribution, Content Uniformity Dissolution API Powder Characterization Bulk, Tapped, True Density Powder flow API Compact Characterization Mechanical Properties Formulation Development (Tablet Characterization) Excipient Selection Process Selection Formulation Characterization Manufacturing (MSF approach)
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Powder Characterization

Density

Helium pycnometer (true density)

Bulk & Tapped density

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API Powder Characterization

Rotational Shear Cell (Schulze Ring Shear Cell)

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Schulze RST Yield Locus

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Shear Cell Parameters

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Powder Characterization

Summary
True density, bulk and tapped density are useful powder

characteristics Solid fraction matters (in powder and compacts) so true density is needed Bulk & tapped density can be related to processing and powder handling.
Automated powder flow analysis has improved this

century and there are now well-designed, automated systems to characterize powders.
There is plenty of opportunity to improve our

understanding of material properties and how they relate to manufacturing.

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Physical Properties

Mechanical Properties

Physical Properties = properties perceptible especially through the senses and subject to the laws of nature.
(Websters Dictionary)

Mechanical Properties = properties of a material under an applied stress.

Return to Outline
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Mechanical Property Characterization

Triaxial Press

Pendulum Impact Device

Split Die & Punches

Dent measurements

Multifunction Tablet Tester

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Mechanical Property Measurement

A compact of the material is

prepared using a triaxial tablet machine.

This equipment and the long dwell

times we use allow us to make compacts which are essentially free of large defects that might affect test results.

3/4
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Triaxial Tablet Press, Punch and Dies

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Mechanical Properties
As a function of solid fraction
Compression Pressure Plastic Deformation Pressure (Hardness) Tensile Strength Brittle Fracture Index Bonding Index Degree of Viscoelasticity

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Quasi-static Mechanical Property Testing

Out of die measurements at SF = 0.85 Measured Property
Compression Pressure Permanent Deformation Pressure Dynamic Method (Hd) Quasi-static Method (Hq) Tensile Strength (T) Brittle Fracture Index Bonding Index Strain Index Degree of Viscoelasticity

Method Used
Triaxial press

Pendulum Impact Device Multi-function Tester Multi-function Tester = fn(T ,To) = T/Hd = Hd/E = Hd / Hq
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Solid Fraction Affects Mechanical Properties

Example: Deformation Pressure of Hydrous Lactose Spray Process
Reference Solid Fraction = 0.85
100

Tablet Hardness, kN/cm2

10

0.65

0.70

0.75

0.80

0.85

0.90

0.95

Solid Fraction

Compression Pressure

Return to Outline
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Material Sparing Formulations

Material sparing approach to formulations:
Uses a minimalist approach: resource and time savings Improves efficiency of dosage form development by using predictive models and scientific data

1000g 10,000g

100g
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Traditional paradigm

Material sparing paradigm

1. Deliver API

~500-1000g delivery

~100g delivery

2. Conduct drug-excipient compatibility studies

<1g API

Use statistically based approach <1g API

3. Develop Drug Product manufacturing process

~1kg lot size(s)

Material Sparing formulation development <100g lot size(s)

4. Manufacture prototype tablets and conduct stability testing

large number of tablets

~ 33x reduction in number of tablets

Manufacture tablet clinical supplies

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Typical Solid Dosage Platforms

Direct Compression:
(+) simplified process, retains compactibility of materials (-) segregation, flow

Dry Granulation
(+) overcomes poor physical properties of API (particle size, shape) (+) improves flow and content uniformity (-) longer processing time, may compromise compactibility

Wet Granulation
(+) improves uniformity, flow, and compactibility (-) physical and chemical stability, residual solvents (non aqueous granulation)

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Decision making criteria for Material Sparing Formulations

* Physical and chemical stability * Particle size, shape, size distribution, Density * Powder Flow * Solubility * Mechanical properties (Tableting indices) Excipients: * Chemical compatibility with API * Favorable mechanical properties (to match/compensate for API properties, flow) * Compatible size and morphology with API Formulations * Particle Properties * Powder Flow * Mechanical properties
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API:

Excipient Selection Strategy

API + Ductile filler + Brittle filler + Disintegrant + Lubricant

Identify appropriate excipients based on physical & mechanical properties of API (for example) Brittle API
Formulation A: Ductile filler Brittle filler Disintegrant Lubricant

Ductile API
Formulation B: Ductile filler Brittle filler Disintegrant Lubricant

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Predictive Models of Formulations

Placebo component = x% MCC & (100-x)% SDL

0%MCC
600.0 500.0
H d ,M P a

Ductility (Dynamic Hardness), Hd vs %API

25%MCC
600.0 500.0
H d ,M P a

Ductility (Dynamic Hardness), Hd vs %API

400.0 300.0 200.0 100.0 0.0 0 20 40 60 80 100

% API in Blend

400.0 300.0 200.0 100.0 0.0 0 20 40 60 80 100

% API in Blend

0.8

0.85

0.9

0.8

0.85

0.9

50%MCC
600.0 500.0
H d ,M P a

Ductility (Dynamic Hardness), Hd vs %API

75%MCC
600.0 500.0
H d ,M P a

Ductility (Dynamic Hardness), Hd vs %API

400.0 300.0 200.0 100.0 0.0 0 20 40 60 80 100

% API in Blend

400.0 300.0 200.0 100.0 0.0 0 20 40 60 80 100

% API in Blend

0.8

0.85

0.9

0.8

0.85

0.9

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Process Simulation- DC or DG
Small-scale formulation development at Pfizer
Blending Roller Compaction Simulation Milling Tableting Simulation

Twin Shell Blender RCS, EK0 or Hydraulic Press

Small Scale Mill

Compaction Simulator/ Emulator
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Typical material sparing process for dry granulation

100-200g total batch size
Blend formulation in small V-blender Mill/screen through small scale mill Blend & Intragranular Lube in small V-blender Use Roller Compaction Simulation with desired profile at target SF Mill ribbons with small scale mill Extragranular Lube in small V blender Tablet on Compaction Simulator with desired profile, tablet speed and tooling

C h a r a c t e r i z e

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Process steps and predictive tests

API/ Excipient Blend (BMB) RC simulator Mill/Lube Mechanical properties Particle size and distribution Flow tests (shear cell) Tablet simulator Tensile strength solid fraction compression pressure profile Measure friability, disintegration, hardness

Particle size Particle size Periodically and distribution and distribution measure SF Flow tests Flow tests (shear cell) Measure TS vs. SF - Pick best SF

Mechanical Properties

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Mechanical Property Characterization (Quasi-static Out-of-Die Testing)

Triaxial Press

Pendulum Impact Device

Split Die & Punches

Dent measurements

Multifunction Tablet Tester

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Compaction Characterization using Presster (Dynamic mechanical properties)

10 mm flat face round tooling Dwell time 27 msec = 30 rpm

of Killian RTS 16 station tablet press.

Determine:

Compression Stress Solid fraction Tablet tensile strength Out-of-die Heckel analyses

End
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Definitions
Compressibility - a materials ability to undergo volume

reduction as a function of pressure

Compactibility - a materials ability to yield a compact of

adequate deformation resistance when compressed (tensile strength as a function of solid fraction)
Tabletability - tensile strength of a material as a function

of compression force

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Compactibility, Tabletability, Compressibility

Tensile Strength (TS), Compression Pressure (CS), Solid Fraction (SF)

Compactibility: TS vs SF Tabletability: TS vs CP Compressibility: SF vs CP

Ref: Tye, Sun, Amidon, J. Pharm. Sci, 94: 465-472, (2005)

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Compactibility profile of unlubed, Roller Compacted MCC

1.2 Tensile Strength (kN/cm2) 1 0.8 0.6 0.4 0.2 0 0.20

Unlubed Virgin Stock Unlubed SF 0.50 Unlubed SF 0.65 Unlubed SF 0.82

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Solid Fraction

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Compactibility profile of lubed, Roller Compacted MCC

0.7 Tensile Strength (kN/cm2) 0.6 0.5 0.4 0.3 0.2 0.1 0 0.200 Lubed Virgin Stock lubed SF 0.52 lubed SF 0.64 lubed SF 0.84

0.300

0.400

0.500

0.600

0.700

0.800

0.900

1.000

Solid Fraction

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Conclusions
Material sparing approach to formulation development can be successfully
implemented using: - API particle, powder and compact characterization - Predictive tools and scientific data generated on small scale formulation lots. It is important to understand the mechanical properties of API and excipients in order to design robust tablet formulations Useful considerations when scaling up dry granulation processes include: - drug loading in the formulation - ribbon solid fraction and tensile strength - simulation of equivalent parameters on large-scale units

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Data Driven Formulation Development Using Material Sparing Methods

What is the data needed for datadriven decisions? How much material do you need?
A number of us at Pfizer believe that we need limited material and a bunch of data to effectively develop manufacturable formulations.

53

Acknowledgements: Many people at Pfizer Have been involved

Pam Secreast Glenn Carlson Bruno Hancock Angela Kong Dauda Ladipo Barbara Spong Beth Langdon Jeff Moriarty Matt Mullarney Padma Narajan

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