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Approaches to the Investigation ofApproaches to the Investigation of Dissolution Testing Changes and Failures
Jianmei Kochling, PhDGenzyme, a Sanofi Company
AAPS Webinar, May 23, 2013
Acknowledgements
AAPS APQ Dissolution Focus Group Q p Vivian Gray: V.A. Gray Consulting Alger Salt: GSK pharmaceuticals Greg Martin: Complectors Consulting, LLC Raimar Loebenberg: University of Alberta Jian-Hwa Han: Abbvie Inc. Juan Castaneda-merced: Genzyme, a Sanofi
CompanyCompany
Purpose
Understand possible factors that can cause dissolution changes and failuresg
Investigate that whether the dissolution changes are g gcaused by drug product or dissolution method
Solid Dosage Formulation Development ProgressionProgression
Phase 1: first in man, oral solution, suspension, drug in bottle, capsules, p , g , p ,or tablets
Phase 2: more mature oral dosage forms Phase 2: more mature oral dosage forms Phase 3: oral dosage form optimization
toward commercializationtoward commercialization
Dissolution Mechanism
DisintegrationGranules
DisintegrationTabletsSmall particles
Disintegration Disintegration
Very limitedLimited
di l ti BestVery limited dissolution
dissolution Best dissolution
Drug in solutionsolution
Factors That Affect the Dissolution of a Drug ProductDrug Product Intrinsic Property
of APIGeneral
of API Solubility Wettability Dissolution Particle size Polymorphs Morphology Disintegration Intrinsic rate Morphology Surface area Density
F l iAPI Intrinsic Formulation
Disintegration or Erosion of API
Solubilization
Formulation Excipients Hardness
PropertyProcess, and Excipients
S ifi Q lit Att ib t Process
Specific Quality Attributes
Modified from C. Tong, Pharmaceutical Technology, 2009
Outline for Case Studies
Drug Product Dissolution MethodDrug Product Drug load Particle size
Dissolution Method Coning and gelling Agitation speed
Tablet hardness Disintegration
E i i i i
Sinker Buffer (composition
and pH) Excipient composition Gelatin capsules
(cross-linking)
and pH) Deaeration Surfactant amount and ( g)
Polymorph change on stability
type
Biopharmaceutical Compound ClassificationClassification
BCS I: high solubility, high permeability BCS II: low solubility, high permeability BCS III: high solubility, low permeability BCS III: high solubility, low permeability BCS IV: low solubility, low permeability
Drug Load Affects BCS I and BCS II Compound Dissolution DifferentlyCompound Dissolution Differently
Dissolution Profile Did Not Change, BCS I Dissolution Profiles Change, BCS II
80%
100 %
C.)
0.1N HCI75 RPM80%
100%
% Dissolved
.)
40%
60%
olve
d (L
.C
0.6% SDS in water75 RPMPaddle
60%
80%
olve
d (L
.C.
20%
40%
%D
isso
Yellow: 30% drug load
Purple: 50% drug loadDash line: 50 mg Capsules (17%)Solid Line: 100mg Capsules (34%)20%
40%
%D
isso
0%0 20 40 60
Purple: 50% drug load g p ( )
0%0 5 10 15 20 25 30 35 40 45
Ti ( i ) Time (min)Time (min.)
Drug Load Effect on Dissolution
Correct method can differentiate drug load difference
10
Courtesy of Greg Martin
Particle Size Effect-Drug Substance Process Change Resulting in a Dissolution Profile ChangeChange Resulting in a Dissolution Profile Change
Drug Substance Characterization After Process ChangeProcess Change
Differentiating Particles Using Biorelevant MediaMedia
Hardness vs Dissolution
Hardness change impacts dissolution profiles Hardness change impacts dissolution profiles What changes tablet hardness?
E i i i t Exicipients Process Storage (when hardness is affected by moisture
penetration)
Hardness Impact on Dissolution
Process Change Formulation Excipients Change
olut
ion
80
15 m
in d
isso
40Hardness kP4.6 9.7 16.1 Hardness, kP
Hardness, kP
Pharmaceutical Development Case Study: “ACE Tablets”, Conformia, CMC-IM working groupwww.ispe.org/pqli/case-study-ace-tablets.pdf
Impact of Tablet Hardness on Dissolution
Drug Product #12 (25 mg)Drug Product (25 mg tablet)Drug Product #12 (25 mg)
100120
6080
100
%
10 kp15 kp5 kp
02040
5 kp7 kp11 kp
00 20 40 60 80 100
min
13 kp
Courtesy of Greg Martin
Process Changed the Disintegration of TabletsTablets
y = 6.6833x + 10.328R2 = 0.9155
25 00
30.00
35.00
min
]
1.60
1.80
2.00
m2]
Katja Schmid1,2 and Raimar Löbenberg2
`y = 0.4183x + 0.2421
R2 = 0.983515.00
20.00
25.00
grat
ion
time
[m
1 00
1.20
1.40
e st
reng
th [N
/m
0 00
5.00
10.00
disi
nteg
0 40
0.60
0.80
1.00
tens
ile
0.001.00 2.00 3.00
compaction force [t]
0.40
Courtesy of Raimer Loebenberg
No Relationship Between Tablet Dissolution and Disintegration TimeDisintegration Time
Close diamond: disso at 15 minOpen square: disso at 30 minOpen square: disso at 30 min
The 24 set of tablets prepared using different filler, binder, and disintegrating agent and compressed into tablets to different hardness showed large variation in the dissolution
Abhay Gupta et al, AAPS PharmSciTech, Vol. 10, No. 2, June 2009 495-499
p gand disintegration time.
Relationship Between Disintegration Time and the Tablet Dissolution When Changing LMH and DCPTablet Dissolution When Changing LMH and DCP
in 15 min (closed symbols)in 15 min (closed symbols) and at 30 min (open symbols) as function of filler used in the formulation (red squaresformulation (red squares-Lactose Monohydrate (LMH); blue diamonds-Dicalcium phosphate Dihydrate (DCP)) ResultsDihydrate (DCP)). Results are expressed as mean ±standard deviation for n=6
Type of filler affects dissolution rate and disintegration time.
Abhay Gupta et al, AAPS PharmSciTech, Vol. 10, No. 2, June 2009 495-499
Dissolution Impacted by Varying Levels of an ExcipientExcipient
MK-4965 62% Drug Load Tablets for PMF DevelopmentpH 6.8 Phosphate Buffer (50 mM) with 3% Tween and Japesese Basket Sinkers at 150 rpm Paddle Speed
100
120
60
80
solv
ed
40
60
% D
iss
♦ 4% Poloxamer
■ 6% Poloxamer
0
20
0 10 20 30 40 50 60 70 80 90 100
Error bars represent Min/Max values
Time (min)
20
Courtesy of Greg Martin
Example of Gelatin Cross Linking
21Courtesy of Greg Martin
Cross-linking
USP Descriptionp
Cross-linking (Pellicle) can be caused by agents or impurities present in the capsule shell thereby rendering the entire shellpresent in the capsule shell, thereby rendering the entire shell matrix insoluble under conditions that normally would dissolve the gelatin shell. One of the strongest and most common types of cross-linking involves the covalent bonding of the amine group of a lysine side chain of one gelatin molecule to a amine group on anotherside chain of one gelatin molecule to a amine group on another molecule. This reaction generally is caused by trace amounts of reactive aldehydes. Formaldehyde, glutaraldehyde, glyoxal, and reducing sugars are the most common cross-linking agents. The covalent bonding produced with this type of cross-linking is, for allcovalent bonding produced with this type of cross linking is, for all practical purposes, irreversible, and dissolution of the shell must involve the breaking of other bonds such as the enzyme- mediated breaking of the peptide bonds in the protein chains.
S USP Ch t 1094 1724 d 711See USP Chapter <1094>, <1724>, and <711>
Current <711>
F h d ft l ti l d l ti t d For hard or soft gelatin capsules and gelatin-coated tablets that do not conform to the Dissolution specification, repeat the test as follows. Where water p por a medium with a pH of less than 6.8 is specified as the Medium in the individual monograph, the same Medium specified may be used with the addition ofMedium specified may be used with the addition of purified pepsin that results in an activity of 750,000 Units or less per 1000 mL. For media with a pH of 6.8
t ti b dd d t d tor greater, pancreatin can be added to produce not more than 1750 USP Units of protease activity per 1000 mL.
Dissolution Testing with and without Pepsin AddedAdded
Pepsin added% Dissolved RT 6m
80%
100%
RT, 6m
No pepsin60%
80%
Pepsin added for the crossed linked
40% RT storage, 6m not crossed
40C/75% RH, 6m, Crossed-linked
0%
20%
0 5 10 15 20 25 30 35 40 45
pH 1.20 5 10 15 20 25 30 35 40 45
Time (min.)
Enzyme Function Depends on the Degree of Cross-linkingof Cross-linking
Courtesy of Dr. Jian-Hwa Han, Abbvie Inc
Enzyme Pepsin Behavior at Different pHs
Suggestions for QC Dissolution Testing
Tier1:Tier1: Use the current dissolution method as is Continue to stages 2 and 3 testing if failing stage 1 test
due to cross linking.
Tier 2 If fails Tier 1, then go to Tier 2 test by adding enzymes
to remove cross linking.
If stability at previous time has already failed go If stability at previous time has already failed, go to Tier 2 directly.
Crystalline Formation from Amorphous Spray DispersionSpray Dispersion
Increased bioavailability
www.bendresearchlab.com
A Discrimination Dissolution Method :Detect Crystalline Polymorphs at ~5%
120.0%
:Detect Crystalline Polymorphs at 5%
100.0%
60.0%
80.0%
ed
40.0%
% A
PI D
isso
lve
Crystalline%0.5%1.0%2.5%
0.0%
20.0%
%
<1% SDS meida, 50 RPM, Paddle
5.0%10.0%15.0%
0 10 20 30 40 50 60 70
Time (Min)
Tablet Dissolution Change due to Amorphous Crystalline ConversionAmorphous Crystalline Conversion
Outline for Case Studies
Drug Product Dissolution MethodDrug Product Drug load Particle size
Dissolution Method Coning and gelling Agitation speed
Tablet hardness Disintegration
E i i i i
Sinker Buffer (composition
and pH) Excipient composition Gelatin capsules
(cross-linking)
and pH) Deaeration Surfactant amount and ( g)
Polymorph change on stability
type
Coning or Gelling During Dissolution
Formulation dependent Formulation dependent Method dependent
i i d Two are intertwined Investigation can result in a leading cause
depending on which factor is dominant
Coning: Method DependentChanging Apparatus is ImportantChanging Apparatus is Important
95
Oneway Analysis of %Dissolved 30 min By Apparatus12
Oneway Analysis of Cone By ApparatuDissolution results at 30 min Cone formation
80
85
90
ed 3
0 m
in
6
8
10
ne
7,8,11
USP I: BasketUSP II Paddle
65
70
75
%D
isso
lve
0
2
4Con
8
7
11
USP II Paddle
60paddle basket
Apparatus
Quantiles
-2paddle basket
Apparatus
7
100 RPM50 RPM100 RPM50 RPM
paddlebasket
Level80.561.8
Minimum80.773.1
10%81.275
77.1
25%83.3584.4
Median84.52590.85
75%85.992.4
90%87.293.1
Maximum
Quantiles
Use Statistical Design to Examine Method RobustnessRobustness
%Dissolved 30 min: Parameter AnalysisScaled Estimates yNominal factors expanded to all levels
I t tTerm
83 6
ScaledEstimate
0 366125Std Error
228 34t Ratio
0001*Prob>|t|
Scaled Estimates
Height(20,30)SLS(0.5,0.7)Air[yes]Air[no]
-0.7145834.2520833
0.51250 5125
0.3914040.3914040.3661250 366125
-1.8310.861.401 40
0.0735<.0001*0.16740 1674
Intercept 83.6 0.366125 228.34 <.0001*
Air[no]Speed[low]Speed[high]Temp(35,39)
-0.5125-2.48752.4875
0.96875
0.3661250.3661250.3661250.391404
-1.40-6.796.792.48
0.1674<.0001*<.0001*0.0166*
Ranking of Impact on Method Robustnessamount of surfactant > agitation speed > temperature
Coning - Formulation and Method
50 RPM PEAK
solv
ed
60%
80%
100%
Infinity speed
50 RPM PEAK
% D
iss
50 RPM 20%
40%
60%
50 RPM PEAK vessel50 RPM USP II
Infinity speed after this time
Data extrapolated from
Heavy insoluble excipients causing coningChanging method speed is important
0%0 5 10 15 20 25 30 35
Time (min)
50 RPM USP II
preal exptl data
Schematic of the Perturbation Study Demonstrating the Existence of a Dead Zone at the Bottom of the USP Vessel
Tahseen Mirza, et al, Dissolution Technology, FEBRUARY 2005, 11-16.
Dissolution Rate Comparison
Tahseen Mirza, et al, Dissolution Technology, FEBRUARY 2005, 11-16.
Gelling
Usually is formulation dependent Usually is formulation dependent Selection of apparatus is important
A ( i b k ) i Apparatus I (rotating basket) issues Granules get caught inside the basket Formulation gels up and get caught inside the
basket
Lactose Gelling Effect
100 RPM Basket
Lactose vs Lactose Free Formulations100 Lactose vs Lactose-Free Formulations
708090
100
ed3040506070
Dis
solv
epH 1.2 LactosepH 1.2 Lactose-freepH 4 5 LactosepH 6.8
0102030%
pH 4.5 LactosepH 4.5 Lactose-freepH 6.8 LactosepH 6.8 Lactose-free
Cotton Ball0
0 10 20 30 40 50 60 70min
Examples of Sinkers
O-Ring Style3-prone O Ring Style Sinker, 316 SS
3-prone
Spiral Capsule Sinker, Coated Music Wire 1 10" L
Spiral Capsule Sinker, 316 SS 84" L x 385" WCoated Music Wire, 1.10" L
x .41" W capacity, 6.5 coils 316 SS, .84 L x .385 W capacity, 5 coils
8 Mesh Basket Sinker 8 Mesh Basket Sinker, 1.06"CAPWHT-Breath Film 8 Mesh Basket Sinker, .90" L x .51" W capacity
8 Mesh Basket Sinker, 1.06 L x .62" W capacity
CAPWHT Breath Film cSinker, PC 316 SS
WWW.DISS0LUT10NACCESS0RIES.COM
Same Type of Sinker but Fit Differently Can Results in Different Dissolution Results
Sotax spring style chosen
80%
100%100 mg
60%
80%
Disso
lved
Sotax spring style too snuggle
20%
40%
% D
3-prong Sinker3-prone
0%0 5 10 15 20 25 30
Time (min )
Spring Style Sinker size 18 D6mm
Spring Style Sinker Size 19 D7mm
Time (min.)
Buffer Effect : Formulation Change Requires a Correct Method to Detect DifferenceCorrect Method to Detect Difference
Buffered pH with surfactant removed the dissolution differentiation power
80.0%
100.0%
L.C
.)
20 0%
40.0%
60.0%
ssol
ved
(L
0.0%
20.0%
0 20 40 60 80 100 120 140Time (min)
%D
is
Time (min)30% drug load, 0.6% SDS pH 6.8 30% drug load, 0.6% SDS
50% drug load, 0.6% SDS 50% drug load, 0.6% SDS pH 6.8Surfactant
In waterpH 6.8 buffered surfactant media
same amount of surfactant
pH Effect: Same Drug in Different pH Dissolution MediaDissolution Media
100 0%
Understand the Property of Each Component in Formulation
pH 4.5-6.890.0%
100.0%
70.0%
80.0%
C.)
pH 2
Form lation composition iss e
50.0%
60.0%
ssol
ved
(L.C Formulation composition issue:
One of the excipients has low solubility at acidic condition
40.0%
0 20 40 60 80 100 120 140
% D
is tablets
0 20 40 60 80 100 120 140
Time (min)
Dissolution of a BCS I Compound, Gelatin Capsule at pH 1 2 4 5 and 6 8Capsule at pH 1.2, 4.5, and 6.8
75 RPM
80%
100%
60%
80%
solv
ed
20%
40%% D
is
85% Dissolved
100mg capsule, pH 1.2
0%
20%
0 5 10 15 20 25 30 35 40 45Time (min )
100mg capsule, pH 4.5
100mg Capsule, pH 6.8
Time (min.)
Tablet Example: No Dissolution Difference at pH 1 0 4 5 and 6 8at pH 1.0, 4.5, and 6.8
Drug X Dissolution, pH 4.5 BufferRobert LionbergerOffice of Generic Drugs, FDA
40
60
80
100
120
% D
isso
lved
GenericRLD
Drug X; Highly soluble, IR tabletThe test and reference list drug
ACPS-CP MeetingJuly 23, 2008
0
20
0 20 40 60 80Time (min)
The test and reference list drug products have the same formulations, qualitatively and quantitatively
Drug X Dissolution, 0.1 HCl
80100120
olve
d
Drug X Dissolution, pH 6.8 Buffer
80
100
120
olve
d
0204060
0 20 40 60 80
% D
isso
GenericRLD
0
20
40
60
0 20 40 60 80
% D
isso
GenericRLD
Time (min) Time (min)
Bubbles in Dissolution Medium
Variability in Dissolution Data
To eliminate this source of variability, the dissolution medium should be degassed or deaerated.
Guidance for IndustryBubble and coning 1
Guidance for Industry The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 –Current Good Manufacturing Practice (cGMP)
CLIP1584.AVI
Bubble and Coning 2(cGMP)
USP <711> CLIP1582.AVI
DeaeratedCourtesy of Raimer Loebenberg
Deaerated
Deaeration Removes Dissolved Oxygen
Dissolution <711> suggests heated vacuum filtration as one method of deaerationdeaeration
He Dissofillmanual
nonmanual
Levels of dissolved oxygen remaining after various stages of a dissolution run using (1) Manual vacuum filtration, (2) Dissofill automated filtration (3) Helium sparging, and (4) Non-deaerated media.
Owen S. Degenhardt et al., Dissolution Technology, FEBRUARY 2004, 6-11
From left to right
Degasing and Reaeration for a Surfactant-containing Dissolution Mediumcontaining Dissolution Medium
For method validation and transfer, equilibrate the media before test is recommended.
Fliszar, KA, Forsyth, RJ, Li, Z, Martin, GP., Dissolution Technology, Aug, 2005
Drug Solubility vs Surfactant Concentration
2
2.5
3
mL)
SDSTween 80
1
1.5
2
ubili
ty (m
g/m
0
0.5
1
Solu
0.00% 0.20% 0.40% 0.60% 0.80% 1.00%Surfactant Percent (w /w)
Solubility of Griseofulvin with and without Different SurfactantsDifferent Surfactants
Ff: drug molecules that are free in solutionFm: drug molecules that are micelle-incorporatedn: number of drug molecules per micelle
Aggregation Weight, g/mol of micelles
Balakrishnan, A, Rege, B.D., Amidon, G.L., Polli, J.E., J. Pharm. Sci., 2004, 93, 2064.
Aggregation Weight, g/mol of micellesSDS< CTAB<Tween 80< Cremophor EL
Effect of Different Surfactants on Dissolution
Drug Product #5
0 3% SLS5% Tween 800.3% SLS Tween 80
1% Arlacel 60 (Sorbitan Stearate)
No surfactant
(Sorbitan Stearate)
51
Honary, S., Majidian, A., Naghibi, F., Iranian J. Pharm. Res. (2007), 6, 25-33
Conclusion
Dissolution results changes or failures can be caused gby many factors
Need to investigate the root cause: Drug product Drug product Excipients Process Dissolution method Dissolution method
General guideline for dissolution trouble shooting Failure mode effect analysis (FMEA) for root cause analysis
U t ti ti l ft t f DOE d d t l i Use statistical software to perform DOE and data analysis Identify leading factors that contribute to the method
robustness
Thank You
Any Questions ?y