particle size method development and validation in support of nanocrystal … · 2019-03-11 ·...

August 2010Joost Strasters

Particle Size Method Development and Validation in Support of NanoCrystal Colloidal Dispersion® Formulation Characterization

Webinar Sponsored By:

DOCNAME_DATE_Elan_Author’s Initials

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Elan Drug Technologieswww.elandrugtechnologies.com

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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



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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particle size method development and validation in support of nanocrystal … · 2019-03-11 ·...

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