August 2010Joost Strasters
Particle Size Method Development and Validation in Support of NanoCrystal Colloidal Dispersion® Formulation Characterization
Webinar Sponsored By:
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Overview
Background: NanoCrystal Colloidal Dispersion® Compositions
Relevance of particle size analysis
Particle size method development and validation
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Advances in Drug Discovery (e.g. High Throughput Screening) produce 30%-50% poorly water soluble leads
Formulation Approaches Inadequate to Overcome:
Poor Bioavailability
Food Effects
Slow Absorption
Safety Issues for IV
Background
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• Most dosage forms possible (e.g. oral, parenteral and nasal)• Increases oral bioavailability & fed/fasted variability• Decreases time to onset of action• High drug loading possible (up to 30-40% active)• Combine with other technologies (e.g. controlled release)• Low viscosity liquid preparations• Potential for improved chemical stability compared to solutions• Uses standard pharmacopoeial materials
A proprietary formulation and manufacturing approach for the delivery of poorly water- soluble drugs
NanoCrystal® Technology | What is it?
NanoCrystal® technology involves reducing drug particles to the nanometer size. By reducing particle size, we increase the drug’s exposed surface area. We then stabilise the particles to maintain the formulation’s particle size.
NanoCrystal® technology involves reducing drug particles to the nanometer size. By reducing particle size, we increase the drug’s exposed surface area. We then stabilise the particles to maintain the formulation’s particle size.
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Total surface area6 square inches
Total surface area12 square inches
Total surface area24 square inches
NanoCrystal® Particles Increase Surface Area
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1.0 um
Morphology of NanoCrystal®
Suspensions
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Ball or Media Mill
Rotating Impeller
AttritionMedia
Drug Slurry
How are they Made?
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NanoCrystal® Technology
Stable nanoparticles of poorly soluble drugs typically less than 2,000 nanometres
(nm) in diameter
can be produced using various approaches such as wet milling, homogenisation,
precipitation and supercritical fluid techniques.
The wet-milling size reduction process utilizes high energy ball milling with
agitator bar
Wide range of stabilizers including surfactants and polymers
Worked on a broad range of insoluble actives
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NanoMill® Media Mill 0.3L
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NanoMill® Zeta Mill 10L
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NanoCrystal Colloidal Dispersion®
Manufacturing Process
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Equipment vs. Development Stage
1000NanoMill®-Z60Commercial
5-1050-100
NanoMill®-Z10/NanoMill®-Z60
Phase III
5-10NanoMill®-Z10Phase II
1NanoMill®-Z2Phase I
Min. API required per batch (kg)MillStage
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SugarBead
NanoCrystal® Particles on Drug Coating
NanoCrystal®Particles
Dispersed Throughout Sugar Bead
NanoCrystal Colloidal Disperson® Formulation
Spray Coat OntoSugar Beads
Spray Dry WithSugar Solution
Low Loading
Uniform Dosage Units
High Loading
Suitable for incorporationinto final dosage form
NanoCrystal Colloidal Dispersion®
formulation to Solid Dosage Form
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Analytical Challenges
Particle size characterization
• static light scattering (laser diffraction)• emphasis on precision
Solid dosage forms: dissolution vs. re-dispersability
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Characterization of Particle Size Distributions
Summarize observed distribution with a small number of characteristic values:
1) Dmean; mean diameter, center of gravity2) Mode; diameter corresponding to maximum3) Median; 50% point (50% of area above and below)
2 3 1
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Characterization of Particle Size Distributions: Percentiles
0
0.005
0.01
0.015
0.02
0.025
0.03
0.035
0.04
0.045
0 100 200 300 400 500 600 700 800size (nm)
frequ
ency
D5 D10 D50 D95D90
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0
5
10
15
20
25
30
0.01 0.1 1 10 100 1000
Size (μm)
f (%
)
76543210
Time (h)
Change in Particle Size Distribution during Milling
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In-process particle sizing
Particle Size Reduction
0
100
200
300
400
500
600
0 100 200 300 400 500 600 700
Process Time (min)
Mea
n Pa
rticl
e Si
ze (n
m)
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0
100
200
300
400
500
600
700
800
900
1000
Hor
iba
Part
icle
Siz
e (n
m)
LMZ-2 LMZ-4 LMZ-10 LMZ-60LMZ Media Mill Scale
NanoCrystal Colloidal Dispersion®Formulation Scale-up
D50D90
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Monitoring Formulation Stability
100
120
140
160
180
200
220
0 1 2 3 4 5 6 7
Time (months)
Dm
ean
(nm
)
5 oC25 oC
40 oC
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complete redispersibility
incomplete redispersibility
Redispersibility of Spray Processed NanoCrystal® Particles
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NanoCrystal Colloidal Dispersion composition in Redispersibility Medium
Non-Optimized NanoCrystal®
Solid composition in Redispersibility Medium
Optimized NanoCrystal Solid composition in Redispersibility Medium
Redispersibility of Spray Processed NanoCrystal® Particles
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Dispersant
Concentration Optimization
Agitation/Circulation
Particle sizing: Method Development
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Concentration Optimization
150160170180190200210220230240250260270
68 73 78 83 88 93 98
% Transmittance
Dm
ean
(nm
)
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Instrumental Conditions
Exp # Agitation Circulation Dmean (nm) D10 (nm) D90 (nm)
1 1 1 187.03 137.5 245.7
2 1 3 184.23 135.9 242.1
3 3 1 187.28 137.8 245.8
4 3 3 184.61 136.1 242.5
5 1 1 185.32 136.3 243.7
6 1 3 184.04 135.8 241.8
7 3 1 184.13 135.8 241.9
8 3 3 184.98 136.4 242.9
Parameters Selected: Agitation: 2 Circulation: 2
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Precision
• instrument• inter-assay• intermediate
Selectivity
Robustness
Particle sizing: Method validation
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Particle Sizing: Precision
Design of Intermediate Precision Experiments1 N = 6 Assays Day-1 Analyst-1 Instrument-12 N = 6 Assays Day-1 Analyst-2 Instrument-13 N = 6 Assays Day-1 Analyst-1 Instrument-24 N = 6 Assays Day-1 Analyst-2 Instrument-25 N = 6 Assays Day-2 Analyst-1 Instrument-16 N = 6 Assays Day-2 Analyst-2 Instrument-17 N = 6 Assays Day-2 Analyst-1 Instrument-28 N = 6 Assays Day-2 Analyst-2 Instrument-2
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Particle Sizing: Intermediate Precision LA910Grand RSD
Analyst Day Instr.# Replicate Dmean (nm) D5(nm) D10(nm) D50(nm) D90(nm) D95(nm)1 1 1 1 107 45 56 95 171 2111 1 1 2 107 45 56 95 171 2101 1 1 3 106 45 56 94 168 2061 1 1 4 107 45 56 95 170 2091 1 1 5 106 45 55 94 169 2081 1 1 6 103 45 55 93 163 1951 1 2 1 102 44 53 88 165 2001 1 2 2 101 44 53 87 163 2061 1 2 3 101 44 53 87 162 2021 1 2 4 100 44 53 87 161 2011 1 2 5 101 44 53 87 161 2021 1 2 6 98 44 53 87 152 1881 2 1 1 108 45 56 96 172 2121 2 1 2 108 45 56 96 171 2101 2 1 3 106 45 56 95 168 2051 2 1 4 107 45 56 95 169 2081 2 1 5 107 45 56 95 169 2081 2 1 6 106 45 56 95 168 2061 2 2 1 103 44 53 89 166 2111 2 2 2 103 44 53 88 167 2101 2 2 3 102 44 53 89 165 2071 2 2 4 102 44 53 88 164 2061 2 2 5 102 44 53 88 164 2061 2 2 6 101 44 53 88 163 2052 1 1 1 107 45 55 94 172 2142 1 1 2 107 45 55 94 173 2162 1 1 3 105 45 55 93 168 2072 1 1 4 106 45 55 93 170 2122 1 1 5 106 45 55 93 171 2132 1 1 6 106 45 55 93 169 2082 1 2 1 102 44 53 88 164 2092 1 2 2 100 44 53 87 161 2022 1 2 3 100 44 53 87 158 1982 1 2 4 100 44 53 86 158 1992 1 2 5 100 44 53 87 159 2002 1 2 6 99 44 53 87 157 1972 2 1 1 109 45 56 97 176 2162 2 1 2 108 45 56 96 174 2142 2 1 3 107 45 56 95 170 2082 2 1 4 106 45 55 94 169 2082 2 1 5 106 45 55 94 170 2092 2 1 6 106 45 56 94 169 2072 2 2 1 103 44 54 89 165 2092 2 2 2 104 44 53 89 169 2172 2 2 3 103 44 53 88 167 2122 2 2 4 102 44 53 88 165 2102 2 2 5 101 44 54 88 162 2032 2 2 6 101 44 54 89 161 200
Dmean (nm) D5(nm) D10(nm) D50(nm) D90(nm) D95(nm)Average 104 45 54 91 166 207STDEV 3.0 0.5 1.3 3.5 5.0 5.8% RSD 2.8 1.1 2.4 3.9 3.0 2.8RSD limit 6% 10% 10% 6% 10% 10%
Grand RSD
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Instrument to instrument variability LA910:Formulation samples
Formulation Dmean D10 D50 D90 Dmean D10 D50 D90sd (nm) sd (nm) sd (nm) sd (nm) rsd (%) rsd (%) rsd (%) rsd (%)
A 2.8 2.1 3.5 2.1 2.8 3.4 3.6 1.5B 4.5 7.1 4.7 6.9 2.6 6.0 2.8 2.9C 9.5 6.5 9.5 12.2 6.1 6.5 6.5 5.4D 10.6 7.9 10.1 18.2 5.9 7.0 5.9 7.0E 8.7 5.4 8.7 19.4 5.4 5.5 5.7 8.1F 9.2 10.0 9.5 14.6 6.0 10.7 6.6 6.4
6-8 Instruments:
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Particle Sizing: Precision (Repeatability) LA950
Formulation 1 Dmean D5 D10 D50 D90 D951 156 113 120 154 195 2092 155 112 119 153 194 2083 155 112 119 153 194 2084 156 113 119 154 195 2095 154 111 119 152 193 2076 155 112 119 152 194 208
Average 155 112 119 153 194 208Std Dev 0.8 0.8 0.5 1.0 0.8 0.7
RSD 0.5 0.7 0.4 0.6 0.4 0.4
Formulation 1 Dmean D5 D10 D50 D90 D951 154 112 119 152 192 2082 154 112 119 152 192 2083 155 113 119 152 192 2084 155 113 119 152 193 2085 154 112 119 152 193 2076 155 112 119 153 193 208
Average 155 112 119 152 192 208Std Dev 0.5 0.5 0.0 0.6 0.3 0.5
RSD 0.3 0.5 0.0 0.4 0.1 0.3
Instrument 1:
Instrument 2:
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Instrument to instrument variability LA950:Formulation samples
Formulation 1 Dmean D5 D10 D50 D90 D95Average (nm) 155 112 119 152 193 208Std Dev (nm) 0.8 0.8 0.7 1.0 1.1 0.7
RSD (%) 0.5 0.7 0.6 0.6 0.6 0.3
4 Instruments:
Formulation 2 Dmean D5 D10 D50 D90 D95Average (nm) 193 136 147 187 247 264Std Dev (nm) 1.5 0.5 0.4 0.6 0.4 1.1
RSD (%) 0.8 0.4 0.3 0.3 0.2 0.4
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Selectivity LA950: Formulation 1
120
140
160
180
200
220
240
260
280
300
320
340
360
380
400
60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 100
%Transmittance
Dm
ean
(nm
)
Target Analysis Range
‘small’
‘medium’
‘large’
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Selectivity LA950: Formulation 2
95
115
135
155
175
195
215
235
60.0 65.0 70.0 75.0 80.0 85.0 90.0
% Transmittance
Mea
n Pa
rtic
le S
ize
(nm
)Target Analysis
Range
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Robustness LA950 Method
Parameter
A B C D E F G
Mean Particle Size (nm)
DOE Pattern Agitation Circulation Waiting
Time Sampling
Times % Transmittance Temperature of Dispersant *
194 ----+++ -1 -1 -1 -1 +1 +1 +1
185 --++--+ -1 -1 +1 +1 -1 -1 +1
185 -+-+-+- -1 +1 -1 +1 -1 +1 -1
193 -++-+-- -1 +1 +1 -1 +1 -1 -1
194 +--++-- +1 -1 -1 +1 +1 -1 -1
187 +-+--+- +1 -1 +1 -1 -1 +1 -1
184 ++----+ +1 +1 -1 -1 -1 -1 +1
195 +++++++ +1 +1 +1 +1 +1 +1 +1
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Robustness LA950 Method
Key
Agitation Level
Setting
Circulation Level
Setting
Waiting Time (Sec)
Sampling Times
% Transmittance Temperature
(oC) *
Method Value 2 2 30 5000 83-87 Ambient *
Max (+1) Value 3 3 40 6000 87-90 Ambient + 4OC *
Min (-1) Value 1 1 20 4000 80-83 Ambient - 4OC *
Particle Size Measurement Main Effect (D value)
1 -1 1 0 8 1 *
Standard Deviation (SD) of Main Effects
5
SD x √2 7
Main Effect Considered Significant [(P<0.05) if ⏐D⏐> (SD x √2)] (Y/N) No No No No Yes No *
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In-Process Particle Sizing
150
200
250
300
350
400
450
0 30 60 90 120 150 180 210 240 270 300 330 360
Time (min)
Part
icle
Siz
e (n
m)
Dmean
D90
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In-Process Particle Sizing
150.0
200.0
250.0
300.0
350.0
400.0
450.0
500.0
0 30 60 90 120 150 180 210 240 270 300 330 360
Time (min)
Part
icle
Siz
e (n
m)
Dmean
D90
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Conclusion
Particle size analysis of NanoCrystal Colloidal Dispersion® Formulations by means of static laser light scattering is successfully used for:
• Process control for manufacture• Monitoring formulation stability• Characterizing formulation performance• Technology Transfer
Crucial method characteristics:• Intermediate precision• Robustness
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Elan Drug TechnologiesThe World’s Leading Drug Delivery Company
For more information go to our website www.elandrugtechnologies.com
SUMMARY
Top Drug Delivery Company of the Decade-Drug Delivery Technology Survey, May 2010
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