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