amidon.pdf

0

Data Driven Formulation Development Using Material Sparing

Methods

Fourth Annual Garnet E. Peck Symposium

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

final

1

Acknowledgements:Many people at Pfizer Have been involved

• Beth Langdon• Jeff Moriarty• Matt Mullarney• Angela Kong• Dauda Ladipo• and many others

• Padma Narajan• Pam Secreast• Bruno Hancock• Barbara Spong• Glenn Carlson

2

Data Driven Formulation Development Using Material Sparing Methods

What is the data needed for “data-driven” 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.

3


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

4Reliably Manufacture tablets

1. Deliver API ~500-5000g delivery

2. Conduct drug-excipient compatibility studies

<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

Traditional Tablet Formulation Development Paradigm

5

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)

6

API Particle Characterization-Microscopy

Method Min, µm Max, µm Distribution Shape texture Grams Xtal?

NYN

0.50.50.5

YYM

MicroscopyLight 1 1000 Y Y

Polarized LM 3 1000 Y Y

SEM 0.02 1000 Y Y

• Qualitative Information• Best way to get shape, texture, crystallinity

information “quickly”• 3 – dimensional information possible

7

API Particle CharacterizationLight Scattering and Obscuration

Method Min, µm Max, µm Distribution Shape texture Grams Xtal?

NNN

222

Y

Photon Correlation 0.001 1 Y N NY

Light ScatteringLaser 0.02 2000 N N

Light Obscuration 1 500 N N

• Quantitative Information d50, d10. d90, σg (Geometric Std Dev.)

• Covers wide range of particle sizes

• Experimental conditions can be critical to obtaining reproducible and meaningful results!

8

API Particle CharacterizationParticle 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)

9

API Particle CharacterizationEffects of Particle Size and Distribution on Processing

• Content Uniformity (manufacturability issue)

• Dissolution Rate (drug delivery issue)

10




11

Content Uniformity Model

Known particle size distribution

Tablet die

Particles end up in a tablet based on “random chance”

12

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)

13

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

σg = geometric standard deviationρ = true densityCv = Coefficient of variation of the dose (%RSD) to pass CU

criteria (eg: Cv = 3.84 to pass USP CU with 99% confidence)

14

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

Maximum Mean Volume Particle Diameter, d50 (µm) Predicted to Pass USP Content Uniformity Test (99% Confidence) as a Function of Geometric Standard Deviation (σg) and Dose (mg)

Dose, mg0.1 1 10 100 1000

Max

imum

Geo

met

ric M

ean

Vol

ume

Par

ticle

Dia

met

er (d

50), µ m

1

10

100

1000

Mic

roni

zing

Mill

ing

σg

1.01.5

2.0

2.5

3.0

3.5

4.0

d90

/d50

1.01.7

2.4

3.2

4.1

4.9

5.8

σg d50 .

1.0 (monodispersed) ~150 um1.5 (narrow) ~110 um2.0 (moderate) ~ 70 um3.0 (broad) ~ 25 um 3.5 (very broad) ~ 15 um

Examples: 1 mg dose

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

15

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 , and B . Solid lines are calculated using a particle size distribution width for Lots A and B estimated by σg = (d84.1/d15.9)0.5, dashed lines are calculated from σg = (d97.7/d50)0.5.

16




17

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: don’t know

Answer: 10 µm!Particle diameter in µm should be equal to or less than the solubility in µg/mL.

18

Dissolution: Noyes-Whitney Equation (flat surfaces)

Solubility( )bCS

hAD

dtdm

−××

=S

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

bulk

Cb

AqueousSolid

Saturated Solution at surface

19

Dissolution rate for spherical particles

drdCrD

dtdm 24π×= r

a

⎟⎠⎞

⎜⎝⎛−=

hrDaS

dtdm π4

Diffusion Layer, h

20

Dissolution Rate for Poly-disperse Systems ⎟

⎠⎞

⎜⎝⎛−=

hrDaS

dtdm π4

Total dissolution rate = Σ 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 ≤ 30µm, then h = a (diffusion layer = particle radius)

• a > 30µm, then h = 30µm

Ref: Higuchi & Hiestand, J.Pharm.Sci. 52:1 67-71 (1963)Hintz, RJ, Johnson, KC. Int. J. Pharm. 51 9-17 (1988)

21

Particle Diameter to Achieve 80% dissolved in 30 minutes(log-normal dist, sink conditions, spheres)

1

10

100

1 10 100 1000Solubility in ug/mL

Part

icle

Dia

met

er to

Ach

ieve

80%

di

ssol

ved

in 3

0 M

in

MonodispersedSigma = 2.0Sigma = 3.0

22

Rule of Thumb

1

10

100

1 10 100 1000Solubility in ug/mL

Part

icle

Dia

met

er to

Ach

ieve

80%

di

ssol

ved

in 3

0 M

in

MonodispersedSigma = 2.0Sigma = 3.0

23

API Particle CharacterizationSummary

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.

24

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)

25

Powder CharacterizationDensity

Helium pycnometer(true density) Bulk & Tapped density

26

API Powder CharacterizationRotational Shear Cell (Schulze Ring Shear Cell)

27

Schulze RST Yield Locus

28

Shear Cell Parameters

29

Powder CharacterizationSummary

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.

30

Physical Properties Mechanical Properties

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

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

Return to OutlineReturn to Outline

31

Mechanical Property CharacterizationTriaxial Press

Split Die &

Punches

Pendulum Impact Device

Dent measurements Multifunction Tablet Tester

32

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”

33

Triaxial Tablet Press, Punch and Dies

34

Mechanical PropertiesAs a function of solid fraction

Compression Pressure

Plastic Deformation Pressure (Hardness)

Tensile Strength

Brittle Fracture Index

Bonding Index

Degree of Viscoelasticity

35

“Quasi-static” Mechanical Property TestingOut of die measurements at SF = 0.85Out of die measurements at SF = 0.85

Measured Property Method UsedCompression Pressure Triaxial press

Permanent Deformation Pressure – Dynamic Method (Hd) Pendulum Impact Device– Quasi-static Method (Hq) Multi-function Tester

Tensile Strength (σT) Multi-function Tester

Brittle Fracture Index = fn(σT ,σTo)

Bonding Index = σT/Hd

Strain Index = Hd/E’

Degree of Viscoelasticity = Hd / Hq

36

Solid Fraction Affects Mechanical PropertiesExample: Deformation Pressure of Hydrous Lactose Spray Process

Solid Fraction

0.65 0.70 0.75 0.80 0.85 0.90 0.95

Tabl

et H

ardn

ess,

kN

/cm

2

1

10

100

Reference Solid Fraction = 0.85

Compression Pressure Return to OutlineReturn to Outline

37

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

100g1000g

10,000g

38

Manufacture tablet clinical supplies

Traditional paradigm

1. Deliver API ~500-1000g delivery

2. Conduct drug-excipient compatibility studies

<1g API

3. Develop Drug Product manufacturing process

~1kg lot size(s)

4. Manufacture prototype tablets and conduct stability

testing

large number of tablets

~ 33x reduction in number of tablets

Material Sparing formulation development

<100g lot size(s)

Use statistically based approach <1g API

~100g delivery

Material sparing

paradigm

39

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)

40

Decision making criteria for Material Sparing Formulations

API: * 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

41

Excipient Selection Strategy

API + Ductile filler + Brittle filler + Disintegrant + Lubricant

Formulation B: ⇓ Ductile filler⇑ Brittle fillerDisintegrantLubricant

Ductile API

Formulation A: ⇑ Ductile filler⇓ Brittle fillerDisintegrantLubricant

Brittle API

Identify appropriate excipients based on physical & mechanical properties of API

(for example)

42

Predictive Models of FormulationsPlacebo component = x% MCC & (100-x)% SDL

Ductility (Dynamic Hardness), Hd vs %API

0.0

100.0

200.0

300.0

400.0

500.0

600.0

0 20 40 60 80 100% API in Blend

Hd,

MPa

0.8 0.85 0.9


0.0

100.0

200.0

300.0

400.0

500.0

600.0

0 20 40 60 80 100% API in Blend

Hd, M

Pa

0.8 0.85 0.9


0.0

100.0

200.0

300.0

400.0

500.0

600.0

0 20 40 60 80 100% API in Blend

Hd,

MPa

0.8 0.85 0.9


0.0

100.0

200.0

300.0

400.0

500.0

600.0

0 20 40 60 80 100% API in Blend

Hd,

MPa

0.8 0.85 0.9

0%MCC 25%MCC

50%MCC 75%MCC

.

43

Process Simulation- DC or DGSmall-scale formulation development at Pfizer

Twin Shell Blender Small Scale

MillCompaction Simulator/Emulator

Tableting Simulation

MillingRoller Compaction Simulation

Blending

RCS, EK0 or Hydraulic Press

44

Typical material sparing process for dry granulation100-200g total batch sizeBlend formulation in small V-blender

Mill/screen through small scale mill

Blend & Intragranular Lube in small V-blender

Use Roller Compaction Simulationwith desired profile at target SF

Mill ribbons with small scale mill

Tablet on Compaction Simulator with desired profile, tablet speed and tooling

Extragranular Lube in small V blender

Characterize

45

Process steps and predictive tests

Blend (BMB) Tablet simulatorRC simulator Mill/Lube

• Particle sizeand distribution

• Flow tests (shear cell)

• Measure TS vs. SF - Pick best SF

• Periodically measure SF

• Mechanicalproperties


• Flow tests (shear cell)

• Tensile strength –solid fraction -compression pressure profile

• Measurefriability,disintegration,hardness

API/Excipient


• Flow tests

• Mechanical Properties

46

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

Triaxial Press

Split Die &

Punches

Pendulum Impact Device

Dent measurements Multifunction Tablet Tester

47

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

48

Definitions

Compressibility - a material’s ability to undergo volume reduction as a function of pressure

Compactibility - a material’s 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

49

Compactibility, Tabletability, CompressibilityTensile Strength (TS), Compression Pressure (CS), Solid Fraction (SF)

Compactibility: TS vs SF

Tabletability: TS vs CP

Compressibility: SF vs CP

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

50

Compactibility profile of unlubed, Roller Compacted MCC

0

0.2

0.4

0.6

0.8

1

1.2

0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00

Solid Fraction

Tens

ile S

tren

gth

(kN

/cm

2)

Unlubed Virgin Stock

Unlubed SF 0.50

Unlubed SF 0.65

Unlubed SF 0.82

51

Compactibility profile of lubed, Roller Compacted MCC

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 1.000

Solid Fraction

Tens

ile S

tren

gth

(kN

/cm

2) Lubed Virgin Stock

lubed SF 0.52

lubed SF 0.64

lubed SF 0.84

52

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

53


What is the data needed for “data-driven” 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.

54

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

amidon.pdf

Documents

Transcript of amidon.pdf