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Dynamic Image Analysisand pharmaceutical multi-particulates
Particle size distributionsCoat thickness and drug release
Swelling during drug release
G. Heinicke© Horiba Instruments Webinar, June 2009
TopicsWhat are multi-particulates and what is DIA?Representative samplesApplications
Raw materialsDrug layeringMeasuring coat thicknessInvestigating drug release
Future opportunities
G. Heinicke© Horiba Instruments Webinar, June 2009
Multi-particulatesInert CoreDrug + BinderPolymer CoatingDrug release
Sugar Sphere Plus Drug Layer Plus Polymer Layer
Ghost After Dissolution,
Expansion Noticeable
Sugar Sphere Plus Drug Layer
Sugar Sphere
G. Heinicke© Horiba Instruments Webinar, June 2009
G. Heinicke© Horiba Instruments Webinar, June 2009
Standard for beads Common, conceptually easy
Sizes 500,600,710,850,1000,1180,1400 µm
Sieving facts
Tolerances on sieves (e.g. 850 µm)–Mean opening 850 ± 35 µm, NMT 5% > 925 µm, max individual 970 µm
–Sieve-to-sieve differencesInfinite shaking, lengthwise passage
G. Heinicke© Horiba Instruments Webinar, June 2009
Alternate PSDs
MicroscopesLabor intensive, small sample size, which dimension to measure if irregular
Dynamic Image AnalysisImage dimensions irrespective of orientationAverage is larger, conceptually and measured
G. Heinicke© Horiba Instruments Webinar, June 2009
Dynamic image analysis
Screen
Light Source
Sample Collection
Vibrating Chute and Sample
G. Heinicke© Horiba Instruments Webinar, June 2009
Measuring shadows
G. Heinicke© Horiba Instruments Webinar, June 2009
A typical PSD
G. Heinicke© Horiba Instruments Webinar, June 2009
Particle sizes and distributions
G. Heinicke© Horiba Instruments Webinar, June 2009
Raw materials, drug layering
G. Heinicke© Horiba Instruments Webinar, June 2009
Zoom camera images
G. Heinicke© Horiba Instruments Webinar, June 2009
DistributionsAbsolute homogeneity – 1 particle is sufficientDegree of heterogeneity
Span from smallest to largest particleShape consistency
Typical multi-particulatesDrug layered seed cores (sugar spheres or MCC)Extruded productsHigh shear granulations
Adequate representation
G. Heinicke© Horiba Instruments Webinar, June 2009
Representative measurements
Different distributionsSize of sampleMethod of samplingHow representative is the sample?Reproducibility of measurement
Data from a given sample is reproducible
Heinicke & Schwartz, Pharm Dev Tech, 9 (4), 359, 2004
G. Heinicke© Horiba Instruments Webinar, June 2009
Fluid bed sampling
PSD is steady at about 15,000 particles for layered sugar spheres (10-30 g depending on D50 and density)Sample port equivalent to thiefSample port samples represent the processing
Heinicke & Schwartz, Pharm Dev Tech, 9 (4), 359, 2004
G. Heinicke© Horiba Instruments Webinar, June 2009
Typical data
Applications
G. Heinicke© Horiba Instruments Webinar, June 2009
Multi-particulates
Sugar Sphere Plus Drug Layer Plus Polymer Layer
Ghost After Dissolution,
Expansion Noticeable
Sugar Sphere Plus Drug Layer
Sugar Sphere
G. Heinicke© Horiba Instruments Webinar, June 2009
Drug layering
Heinicke et al., Pharm Dev Tech, 10, 85, 2005
G. Heinicke© Horiba Instruments Webinar, June 2009
Resolve polymer coat addition
G. Heinicke© Horiba Instruments Webinar, June 2009
These are the particles
13% 15%
G. Heinicke© Horiba Instruments Webinar, June 2009
Series of coat thickness
G. Heinicke© Horiba Instruments Webinar, June 2009
G. Heinicke© Horiba Instruments Webinar, June 2009
900
910
920
930
940
950
960
970
980
990
D50
Mes
(um
)
0 5 10 15 20TPCW (%)
Linear Fit D50Mes (um) = 891.86135 + 4.7723849 TPCW (%) Summary of Fit RSquare 0.993486RSquare Adj 0.992183Root Mean Square Error 1.777776Mean of Response 955Observations (or Sum Wgts) 7
G. Heinicke© Horiba Instruments Webinar, June 2009
Drug release
0
20
40
60
80
100
0 240 480 720 960 1200
Time (min)
% R
elea
sed
7%CW9%CW11%CW13%CW15%CW17%CW19%CW
G. Heinicke© Horiba Instruments Webinar, June 2009
TPCW and drug release
R2 = 0.9986
y = 58.608x - 99.382
0
200
400
600
800
1000
1200
5 10 15 20
TPCW (%)
T50
(min
)
G. Heinicke© Horiba Instruments Webinar, June 2009
Coat thickness & drug release
y = 23.637x - 86.566R2 = 0.9917
0
200
400
600
800
1000
1200
0 10 20 30 40 50
Coat Thickness (um)
T50
(min
)
T50 (min)Linear (T50 (min))
G. Heinicke© Horiba Instruments Webinar, June 2009
700
750
800
850
900
950
1000
1050
1100
D50
Mes
0 5 10 15 20TPCW
Heinicke et al., Pharm Dev Tech, 10, 85, 2005
How real is it?
Supporting evidence for meaningful data
G. Heinicke© Horiba Instruments Webinar, June 2009
Effect of batch surface area
Adjust by altering core charge weightRatio of weights is ratio of area (different weights of same substrate)Normalize for TPCW and look at drug release
Effect of raw material PSD (SA) on coat thickness, a contribution to lot-to-lot variation
G. Heinicke© Horiba Instruments Webinar, June 2009
Experiment with batch size
600, 650, 700, 750 and 800 g core chargesOne coating solutionSame coating solution weight additions of 425, 559, 699, 845, 998, 1158, and 1326 g to each core chargeComparison of coat thicknessComparison of drug release
G. Heinicke© Horiba Instruments Webinar, June 2009
Core charge & change in D50
960
970
980
990
1000
1010
1020
1030
1040
D50
6 8 10 12 14 16 18 20Nominal CW
Linear Fit Bx ID=="600g"Linear Fit Bx ID=="650g"Linear Fit Bx ID=="700g"Linear Fit Bx ID=="750g"Linear Fit Bx ID=="800g"
G. Heinicke© Horiba Instruments Webinar, June 2009
Normalize to TPCW
960
970
980
990
1000
1010
1020
1030
1040
D50
5 10 15 20TPCW
Linear Fit Bx ID=="600g"Linear Fit Bx ID=="650g"Linear Fit Bx ID=="700g"Linear Fit Bx ID=="750g"Linear Fit Bx ID=="800g"
G. Heinicke© Horiba Instruments Webinar, June 2009
TPCW and T50
100200300400500600700800900
10001100
T50
(min
)
5 10 15 20TPCW
Linear Fit Bx ID=="600g"Linear Fit Bx ID=="650g"Linear Fit Bx ID=="700g"Linear Fit Bx ID=="750g"Linear Fit Bx ID=="800g"
G. Heinicke© Horiba Instruments Webinar, June 2009
Explain the single line
G. Heinicke© Horiba Instruments Webinar, June 2009
Different experiments marked
100200300400500600700800900
10001100
T50
(min
)
5 10 15 20TPCW
Linear Fit Bx ID=="600g"Linear Fit Bx ID=="650g"Linear Fit Bx ID=="700g"Linear Fit Bx ID=="750g"Linear Fit Bx ID=="800g"
G. Heinicke© Horiba Instruments Webinar, June 2009
Novel use of DIA
small
medium
large Low potency
High potency
Heinicke et al., Pharm Dev Tech, 10, 85, 2005
G. Heinicke© Horiba Instruments Webinar, June 2009
Different SS sieve cuts
G. Heinicke© Horiba Instruments Webinar, June 2009
Expt 1: Coating constant PSDsSame sized particles700 g core charge of each (separately)Same coating solution weight additions of 425, 559, 699, 845, 998, 1158, and 1326 g to each core chargeSample, measure D50 at each TPCW, plotQ: Are the lines coincident, parallel or diverging?
G. Heinicke© Horiba Instruments Webinar, June 2009
Constant coat thickness
small
medium
large Low potency
High potency
G. Heinicke© Horiba Instruments Webinar, June 2009
10
15
20
25
30
35
40
45
Coa
tTh
ickn
ess
(um
)
6 8 10 12 14 16 18 20TPCW
Expt 1: Slopes aren’t equal
Linear Fit Core=="15"Linear Fit Core=="45"Linear Fit Core=="64"
G. Heinicke© Horiba Instruments Webinar, June 2009
DensityD
ensi
ty
0.65
0.7
0.75
0.8
0.85
15% 45% 64%
Potency at Same Size
All PairsTukey-Kramer 0.05
Heinicke et al., Pharm Dev Tech, 10, 85, 2005
G. Heinicke© Horiba Instruments Webinar, June 2009
Adjust for surface area
CddC 1
1
2
1
22 ρρ
=
Cx = Core Charge Weight (1 or 2)
ρx = Bulk Density of Cores
dx = Diameter of CoresHeinicke et al., Pharm Dev Tech, 10, 85, 2005
G. Heinicke© Horiba Instruments Webinar, June 2009
Expt 2: Adjust Core ChargeSame sized particles636g, 700 g, 775 g sprayed separatelySame coating solution weight additions of 425, 559, 699, 845, 998, 1158, and 1326 g to each core chargeSample, measure D50 at each TPCW, plotQ: Are the lines coincident, parallel or diverging?
G. Heinicke© Horiba Instruments Webinar, June 2009
Expt 2: Slopes are equal
10
15
20
25
30
35
40
Coa
t Thi
ckne
ss (u
m)
6 8 10 12 14 16 18 20 22TPCW (%)
Linear Fit Core ID=="15"Linear Fit Core ID=="45"Linear Fit Core ID=="64"
G. Heinicke© Horiba Instruments Webinar, June 2009
Investigating drug releasePolymer insolubleSwelling and stretchingCoat thickness effectsCore dependent
G. Heinicke© Horiba Instruments Webinar, June 2009
Coat thickness and swelling
G. Heinicke© Horiba Instruments Webinar, June 2009
Constant coat thickness
small
medium
large Low potency
High potency
G. Heinicke© Horiba Instruments Webinar, June 2009
Core dependence: release & size
0
20
40
60
80
100
0 240 480 720 960
Time(min)
% R
elea
sed
Drug release in 0.1N HCl, same sized cores and same
coat thickness
Starting PSDs and ghost PSDs after drug release
Heinicke & Schwartz, Pharm Dev Tech, 12, 473, 2007
G. Heinicke© Horiba Instruments Webinar, June 2009
Future opportunities for DIA
Count, mass per particle, uniformitySurrogate dissolution testSurface area of core chargeBimodal distributions Density of drug layer or coating layer as appliedApplication to other multi-particulates
G. Heinicke© Horiba Instruments Webinar, June 2009
Acknowledgements
Horiba instrumentsThe late Dr. J.B. Schwartz & USPDr. Garth Boehm and Dr. Kristin ArnoldAnchen Pharmaceuticals Inc.
Questions?