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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.
~1 5 kg lot size(s)
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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1 3 0.02
Y Y M
Y Y Y
Y Y Y
N Y N
Qualitative Information Best way to get shape, texture, crystallinity information quickly 3 dimensional information possible
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!
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Tablet die
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(< 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
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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
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
10
Milling
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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Answer: 10 m! Particle diameter in m should be equal to or less than the solubility in g/mL.
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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
Solid
Solubility h
bulk
Cb Aqueous
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dm 2 dC = D 4r dt dr
a r
dm r = 4DaS dt h
Diffusion Layer, h
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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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1000
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Rule of Thumb
100
1000
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Summary
Particle size, size distribution, shape, and texture (PS)
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
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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
Physical Properties
Mechanical Properties
Physical Properties = properties perceptible especially through the senses and subject to the laws of nature.
(Websters Dictionary)
Return to Outline
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Dent measurements
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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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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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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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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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1000g 10,000g
100g
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Traditional paradigm
1. Deliver API
~500-1000g delivery
~100g delivery
<1g API
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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API:
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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0%MCC
600.0 500.0
H d ,M P a
25%MCC
600.0 500.0
H d ,M P a
0.8
0.85
0.9
0.8
0.85
0.9
50%MCC
600.0 500.0
H d ,M P a
75%MCC
600.0 500.0
H d ,M P a
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
C h a r a c t e r i z e
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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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Dent measurements
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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
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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End
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0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Solid Fraction
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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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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.
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