Disintegration Test a SurrogateDisintegration Test a Surrogateforfor

Dissolution TestingDissolution TestingSome Practical ConsiderationsSome Practical Considerations

Vilayat A. Sayeed, Ph.D.Director, Division of Chemistry III

Office of Generic DrugsOPS/CDER/FDA

April 28-30, 2008Crystal City, Arlington, VA

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Objectives• To understand the influence of formulation and

processing variables on the dissolution and disintegration time of IR tablets

• To determine the relationship, if any, between dissolution and disintegration time for IR tablets of a highly soluble drug

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Disintegration vs. Dissolution

De-aggregation

Dissolution

Tablet

Granules or Aggregates

Particles

Drug in Solution (in-vitro/in-vivo)

Disintegration

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ICH Q6A Decision Tree 7(1)• Disintegration acceptance criteria with an upper

time limit are acceptable if the following conditions are satisfied:

Dosage form is not designed to produce modified releaseDose/ solubility < 250 mL through out the physiological pH range (pH 1.2 - 6.8) at 37°CDissolution > 80% in 15 min at pH 1.2, 4.0, and 6.8A relationship has been determined between disintegration and dissolution

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Drug Selection• Verapamil HCl used as model drug

– Product Classification– Dose / Solubility < 250 mL at pH range 1.2 - 6.8

• Solubility at different pH (Analytical Profiles)Solvent Water/pH solubility (mg/mL)pH 2.32 82pH 3.05 78pH 4.65 89pH 4.86 82pH 5.59 76pH 6.35 83pH 6.54 46pH 6.76 11pH 7.32 0.44

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Experiment Design• Verapamil HCl used as model drug

– Product Classification– Dose / Solubility < 250 mL at pH range 1.2 - 6.8

• Formulation ingredients– Drug 10.0%– Filler 75.0%– Binder 4.0% – Disintegrating agent (or absent) 10.0% (0%)– Magnesium stearate 0.5%– Talc 0.5%

• 2x2x3x2 (24 batches) full-factorial design used

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Variables and Batch Codes• Different batches of IR tablets prepared by varying

– Filler DCP / LMH– Binder PVP / HPMC– Disintegrating Agent NaCMC / MCC / None– Tablet hardness 6 Kgf / 10 Kgf

• Each batch assigned a five digit alpha-numeric code V*1*2*3*4, where – *1 = D for DCP L for LMH – *2 = P for PVP H for HPMC– *3 = A for NaCMC M for MCC X for None– *4 = 1 for 6 Kgf 2 for 10 Kgf (tablet hardness)

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Manufacturing Process• Drug + filler blended for 5 min in a planetary mixer• Granulation performed in a fluidized- bed

granulator• Aqueous binder solution sprayed at constant rate• Dried granules blended with the disintegrating

agent (if present), talc and magnesium stearate for 5 minutes in a V-blender

• Granules compressed on a tablet press to obtain tablets with 6 and 10 Kgf hardness

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Test Procedures• USP30 <701> Disintegration procedure for

uncoated tablets. n = 6• USP30 Dissolution test procedure for Verapamil

HCl tablets. n = 6– USP method II (Paddle method) at 50 rpm– Media: 900 mL 0.01 N HCl– UV analysis at 278 nm at 15 and 30 minutes – USP limit: Q NLT 75% in 30 min

• Dissolution test also performed in pH 4.0 and pH 6.8 phosphate buffers for selected batches

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Results• Disintegration Time ranged from <1 to >60 min• Dissolution @ 30 min ranged from 18.1 to 100.5%• Q < 75% for 14 batches (failed as per USP criteria)• Variable analysis of the 14 failed batches:

DCP: LMH 12:2 NaCMC: MCC: None 4:4:6PVP: HPMC 6:8 6 Kgf: 10 Kgf (Hardness) 7:7

• Dissolution @ 15 min at pH 4.0, 6.8 & 0.1N HCL– Q > 80% for VLHA1 and VLHA2 – Q < 80% for at least one tablets at all pHs for VLPA1,

VLPA2, VLPX1 and VLPM1

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Variation in Disintegration Time

0

10

20

30

40

50

60

A1 A2 M1 M2 X1 X2Disintegrating Agent and Tablet Hardness

Dis

inte

grat

ion

Tim

e (m

in)

DH LH DP LPFiller - Binder

Dark color: DCP; Light color: LMH; Ξ (Horizontal): HPMC; [|] (Vertical): PVP

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Dissolution (at 30 min)

0

20

40

60

80

100

120

A1 A2 M1 M2 X1 X2Disintegrating Agent and Tablet Hardness

Dis

solu

tion

at 3

0 m

inut

es (%

w/w

)

DH LH DP LPFiller - Binder

USP limit

Dark color: DCP; Light color: LMH; Ξ (Horizontal): HPMC; [|] (Vertical): PVP

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Dissolution vs. Disintegration

0

20

40

60

80

100

0 4 8 12 16 20Disintegration Time (minutes)

Dis

solu

tion

(%w

/w)

30 min

15 min

>

USP limit

ICH Q6A Dicision Tree 7(1)

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Q ≥ 80% @ 15 minutes

70

75

80

85

90

95

100

105

0 1 2 3 4 5 6Disintegration Time (minutes)

Dis

solu

tion

(%w

/w)

VLHA1VLHA2

VLPA1

VLPA2 VLPM1

VLPX1

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Effect of Filler

0

20

40

60

80

100

0 4 8 12 16 20Disintegration Time (min)

Dis

solu

tion

(%w

/w)

DCP 15 min LMH 15 min

DCP 30 min LMH 30 min

>

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Effect of Disintegrating Agent

0

20

40

60

80

100

0 4 8 12 16 20Disintegration Time (min)

Dis

solu

tion

(%w

/w)

A-15 M-15 X-15

A-30 M-30 X-30

>

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Effect of Binder

0

20

40

60

80

100

0 4 8 12 16 20Disintegration Time (minutes)

Dis

solu

tion

(%w

/w)

H-15 P-15H-30 P-30

>

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Variable Effect Analysis• Dissolution (at 15 and 30 min) influenced by

– Filler L > D p < 0.0001– Disintegrating agent A > M > X p = 0.002– Binder P > H p = 0.02

• Disintegration time influence by– Disintegrating agent A > M > X p < 0.0001– Filler L > D p = 0.0002– Binder P > H p = 0.004– Hardness 1 > 2 p = 0.02– Filler * Disintegrating Agent p = 0.0004– Filler * Binder p = 0.008– Binder * Disintegrating Agent p = 0.03

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Conclusions• Dissolution influenced by formulation variables• Disintegration time influenced by all four variables• Filler and disintegrating agent showed most

significant influences on both test parameters• No relationship observed between dissolution and

disintegration time • Only two test batches (out of 24) met the criteria for

using disintegration test for drug release

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Acknowledgement

Abhay Gupta, Robert Hunt, Mansoor A. Khan,

Gary Buehler, Helen Winkle