Establishing a Relationship between Disintegration and Dissolution

Establishing a Relationship between 

Disintegration and Dissolution 

AAPS: DISSOLUTION WORKSHOP 

Rhodes University, Grahamstown 

December 09-10, 2009 

Dr. Johannes Krämer 

Relationship between 

Disintegration and Dissolution.... 

Content 

• The scientific rationale 

• The chance to waive dissolution testing: ICH Q6A 

• Methods of establishing a relationship 

• Results for specimen under investigation 

• Extension to complete product line 

• Setting specifications for disintegration testing 

© PHAST GmbH, www.phast.de 2 

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Risk evaluation mandatory 

prior to start 

To include 

• Vital medical indication (e.g. antiepileptic drug) 

• Narrow therapeutic index (e.g. Annex to SUPAC IR) 

• Extended BCS 

– stability in the GI tract 

– enterohepatic cycle 

– absorption window… 

• Dosage form evaluation 

– excipients 

• …. 


Goals of Dissolution Testing 

• prediction p of changes g of bioavailability, y, the 

surrogate-parameter of therapeutic efficacy 

• evaluation of robustness as a parameter of drug 

product- related safety 

critical manufacturing variables 

• in QC (quality control) to prove uniformity of 

product quality within the technological range 

of manufacturing processes 


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Prediction of Bioperformance 

based on BCS 


Biopharmaceutics 

Classification Scheme (BCS) 

• solubility of drug 

substance under 

physiological pHconditions 

• permeability of drug 

substance in an 

isolated segment of 

human jejunum at pH 

6.5 


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BCS - a base to establish specifications 

for in vitro dissolution testing 

definition of solubility 

"high solubility" if dose/solubility volume < 250 ml 

highest unit dose of drug is dissolved in buffer solutions at 

within physiological range (pH 1.2 – 8.0) at 37°C. The 

quotient of highest unit dose and lowest concentration 

obtained in buffer solutions is determined 

e.g.: drug substance x has it’s lowest solubility at pH 1.2 with 

1.5 mg/mL. 

Tablets are available in dosage strengths 200 and 300 mg. 

300 mg / 1.5 mg/mL = 200 mL -> high solubility drug 


Biopharmaceutics Drug 

Classification Scheme (BCS) cont’d 

solubilityy permeability 

p y 

case 1 high high 

case 2 low high 

case 3 high low 

case 4 low low 


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Dissolution Spec’s … 

IR Dosage Forms according to US FDA: 

An IR product is considered rapidly dissolving if 

≥ 85% of the labeled amount dissolves 

within 30 min 

Apparatus @ 100/150 or Apparatus @ 50/75 rpm 

in 900 mL in each of the following media: 

1) 0.1N HCl or SGF without enzymes and 

2) buffer pH 4.5 and 

3) buffer pH 6.8 or SIF without enzymes 


Using ICH Q 6A Guideline … 

Decision Tree # 7: 

Setting Acceptance Criteria for Drug Product Dissolution 

1. What type of drug release acceptance criteria are 

appropriate? 

Is the dosage 

form designed to produce 

modified release? 

NO 

General single-point dissolution 

acceptance criteria with a 

lower limit are acceptable 

Is drug solubility 

at 37 ± 0.5°C high throughout 

the physiological pH range? 

(Dose/solubility ≤ 250 mL 

( (pH H 11.2 2 - 68)) 6.8)) 

YES 


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Using ICH Guideline … 

IIs dosage d form f 

dissolving rapidly? 

(Dissolution >80%/15min 

at pH 1.2, 4.0, and 6.8) 

NO 

General single-point dissolution 

acceptance criteria with a 


YES General single-point dissolution 

acceptance p criteria with a 


Has a relationship been 

determined between 

disintegration and dissolution? 

General disintegration 

acceptance criteria with an 

upper time limit are acceptable 


Relationship between disintegration 

and dissolution 

per se not a correlation: 

• disintegration in QC is defined as time of completeness of a 

kinetic process 

• dissolution in QC is amount of completeness at a specified 

time 

• no analogous parameters for a correlation available 

Has a relationship been 

determined between 

disintegration and dissolution? 


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disintegration and dissolution 

disintegration an integral part of and / or 

prerequisite for dissolution for IR dosage forms 

dissolution a composite process 

• dissolving from the surface of tablet 

• disintegration a surface enlarging process 

• deaggregation and separation of excipients and API 

• dissolution of API particles 


Dissolution - a composite 

process 

#D # Drug molecules l l 

 

• • •• 

release 

 

 

 

 

•• 

• 

• • 

• • • • 

• • • • 

⌫⌫ ⌫ 

⌫⌫ 

⌫ 

USP: fundamentals of dissolution, 2009 


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Sigmoid Dissolution Curve of 

Solid Dosage Forms 

100% 

% Drug Dissolved 

0% 

Mechanical Lag 

+ 

WWetting tti 

Deaggregation 

Disintegration 

Occlusion, 

instability… 

Time 

USP: fundamentals of dissolution, 2009 




A Case Report for a BCS Class I Drug 


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study protocol: 

• prove that disintegration is the prerequisite for dissolution 

• defining comparable parameters 

– i.e. amount dissolved at the time of complete disintegration in 

the dissolution apparatus 

• comparing analogous parameters for 

– freshly manufactured batches 

– ffor samples l after f accelerated l d stability bili treatment 

– extension to historical data of batches successfully released 

• proof of assumption: amount dissolved at the time of 

complete disintegration in the disintegration apparatus is 

comparable to process analyzed for the dissolution 

apparatus 


M containing IR products 

under investigation 

tablet shape 

special*1 special* special* special*1 special*1 

*1 *2 

C-excipient/mg p g 

per tablet 

1.0 5.0 

*2 

tablet mass / mg 174 174 174 174 174 174 

*1 investigated with dissolution method 1 to 3 

*2 investigated with dissolution method 1 only 

= round tablet 

special = anisodiametric 

= round tablet with cross-standing braking notches 


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Methods: Dissolution n=12 

apparatus 

medium pH 1.2 pH 4.5 pH 6.8 

medium degassed degassed degassed 

volume 500/900 mL 500/900 mL 500/900 mL 

agitation 100 rpm 100 rpm 100 rpm 

temperature 37°C 37°C 37°C 

sampling 

at 5, 10, 15, 20, 25, 30, and 45 min 

at the time of complete disintegration 


Methods: Disintegration 

according to USP 

• with n=12 

• use of water 

sampling 

• at the time of complete disintegration 

• at a zone validated prior to testing 

• pooled sampling for n=6 


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Methods: chemical analysis, 

data evaluation 

chemical analysis 

• derivative spectroscopy 

data evaluation 

• disintegration time 

– with regard to dossier / compendial requirements 

– using g Statistical Moment Theoryy 

• dissolution profiles 

– with regard to ICH spec’s 

– using the Statistical Moment Theory 


Statistical Moment Theory: 

Mean Times 

MDT vitro = tM(t)dt / M(t)dt 

0 0 

⎡ ⎤ 

⎢ ⎥ 

⎣ ⎦ 

⎡ 

∞ ∞ 

⎤ 

∫ ⎢∫ 

⎥ 

⎣ ⎦ 

M = drug released 

MDT MDTvitro = MMean Di Dissolution l ti Ti Time iin vitro 

it 


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Additivity of Mean Times 

Mean Times: data reduction taking g into account curtosy y and skewness of 

distributions. 

•The processes are overlapping and therefore, distributions do also overlap. 

• According to the theory of statistical moments the statistical moments are 

adding up 

MDT pH 1.2 = MDgT_Dissol1.2 + MDislnT 1.2 

MDT pH 1.2 the mean dissolution time in dissolution apparatus @ pH 1.2 

MDgT_Dissol1.2 the mean disintegration time in dissolution apparatus @ 

pH 1.2 

MDislnT 1.2 the mean terminal dissolution time after disintegration in the 

dissolution appartus @ pH 1.2 


Results: Solubility 

pH 1.2 125 103.1 

pH 1.2 250 97.2 

pH 4.0 125 106.3 

pH 4.0 250 97.0 

pH 6.8 125 100.5 

pH 6.8 250 104.3 

highest dose is soluble in NMT 250 mL 


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Establishing a relationship: 

Results BCS 

Solubility: 

• data prove good solubility 

Permeability: 

• data prove good permeability 

therefore, substance M is a BCS class I compound 


Results: Dissolution kinetics 

product name 

/ geometry 

pH 5 10 15 20 25 30 45 

M / 1.2 102.8 103.1 103.3 102.6 102.4 102.9 102.6 

4.5 86.5 90.9 94.3 96.7 96.5 96.8 99.4 

6.8 92.3 96.7 98.3 100.2 101.1 100.4 101.9 

1.2 102.8 103.1 103.3 102.6 102.4 102.9 102.6 

4.5 86.5 90.9 94.3 96.7 96.5 96.8 99.4 

dissolution >> 80% in 30 min and in 15 min 


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Results: amount dissolved at 

time of disintegration at pH 1.2 

tablets 

in the 

dissolution 

apparatus 

at pH 1.2 

product d t name/ / 

geometry 

index 

disintegration 

time dissolution 

apparatus [s] 

amount 

dissolved [%] 

M 1.25 / 1 60.0 64.8 

2 65.0 89.2 

3 60.0 87.5 

4 60.0 78.9 

5 60.0 91.7 

6 60.0 79.0 

7 55.0 86.2 


Amount dissolved app. 

pH 1.2, 4.5, and 6.8 vs. disintegration 

time in water (mean, n=12) 

dissolved API [%] 

120 

100 

80 

60 

40 

20 

8 55.0 87.8 

9 55.0 91.5 

10 60.0 98.3 

11 65.0 85.7 

12 65.0 89.6 

Dissolution [%] / Disintegration time [s] (dissolution apparatus) 

0 

0 50 100 150 200 250 

Disintegration time [s] 

pH 6.8 

pH 4.5 

pH 1.2 


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Findings 

• MDgT MDgT_Disint Disint shows higher variability than MDT @ pH 11.2 2 - 

6.8. 

• This identifies the disintegration method as more variable. 

• From the MDgT_Dissol at pH 4.5 and 6.8 it can be 

concluded that the disintegration process is the most 

variable sub sub-process process, whereas the MDislnT at pH 4.5 4 5 and 

6.8 are much less variable. 


Summary 

Conclusions: 

• Disintegration is the prerequisite for dissolution 

• At the time of complete disintegration a rather constant 

amount of drug is being dissolved 

• This is valid for the dissolution apparatus and the 

disintegration apparatus 

• The sub-processes are overlapping, with the help of 

statistical moment theory the sub-processes can be clearly 

ddescribed ib d 

• Disintegration is the most variable sub-process 

The relationship of disintegration and dissolution is 

a cause and effect relation 


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ICH Q6A decision tree #7 

criteria are met 

No modified release dosage form 

Solubility is high throughout the physiological range pH 1.2 to 6.8 

Dissolution is rapid and complete. Under all experimental 

conditions > 80 % in 15 min 

No analogous data result form dissolution and disintegration 

No linear stochastical relationship is feasible 

A relationship of disintegration as the rate limiting step for 

dissolution was described 

The findings for the dissolution tester were confirmed for the 

disintegration tester (data not shown) 

Disintegration was found to be the more variable process 

The data generated for actual production lots represent the 

properties of the drug product (historical data) 

As a consequence: 

The dissolution test may be waived for batch release testing for all 

formulations included in the study 


Finally: Setting Specifications 

Dissolution testing as a biopharmaceutically 

relevant test procedure may be waived! 

• Disintegration is prerequisite for dissolution recommended 

for batch release testing 

• Comparison of the disintegration results together with the 

dissolution results for the disintegration apparatus allows 

tightening of spec’s to 5 min (Ph,Eur. / USP: 15 min) 

For all immediate release dosage strengths of that 

M containing product, the spec’s for 

disintegration time were set: NMT 5 min 


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Thank you 

www www.artofdissolution.com 

artofdissolution com 


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Establishing a Relationship between Disintegration and Dissolution

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