WHO workshop on

Theo Dekker -- Jiaxing, China --September 20072 |

WHO workshop on

Quality, good manufacturing practice and bioequivalence with a focus on antituberculotics

Jiaxing, China

5 to 9 November 2007

Comparative dissolution testingand applications

Theo Dekker, D.Sc.Research Institute for Industrial Pharmacy

North-West University, Potchefstroom, South Africa


What is dissolution testing?Tablets and capsules (conventional IR)

It measures the portion (%) of the API that1. has been released from tablets/capsules and2. has dissolved in the dissolution medium during

controlled testing conditions within a defined period

– The tablet thus first disintegrates– Then the API will be able to dissolve– Slow disintegration ➜ slow dissolution– The % API dissolved is determined with an appropriate

validated method: UV/VIS, HPLC, AA, GC, etc


Oral suspensions &powders for oral suspensions

Dissolution also applicable to the following oral preparations

Oral suspensions– Use unit dose (e.g. 5 ml) of well mixed suspenion– Example: Ibuprofen Oral Solution USP

Powders for oral suspensions– Sample: reconstituted suspension– Using unit dose of well-mixed reconstituted suspension

Principle– No disintegration (like tablets) - only rate of API dissolution– Important for APIs of low solubility (BCS)


GlossarySolid oral dosage forms

Immediate release (IR) typically means that 75% of the API is dissolved within 45 minutes– Rapidly dissolving: ≥ 85% in ≤ 30 minutes– Very rapidly dissolving: ≥ 85% in ≤ 15 minutes

Modified-release dosage forms (consult IntPh, PhEur/BP, USP)– Formulation deliberately changes release (slows down)

• Extended-release (prolonged-release)Slower release throughout the gastro-intestinal tract

• Delayed-release (enteric coated tablets)Resists gastric fluid & disintegrates in intestinal fluid

– Not part of presentation


What is multi-point dissolution?

In multipoint dissolution– multiple (≥ 3) samples are withdrawn from the dissolution

medium during dissolution testing– at pre-determined time points (intervals) and– each sample is analysed for the % API dissolved

A graph of % API dissolved against time= the dissolution profile


Multi-point dissolutionExample of dissolution profile

ACTIVE INGREDIENT: CLARITHROMYCINMEDIUM: PHOSPHATE BUFFER pH 6.8

0

20

40

60

80

100

120

0 10 20 30 40 50

WITHDRAWAL TIME IN MINUTES

Dis

solu

tion

(%)

Clarithromycin 250 mg tablets


Comparative dissolution testingThe principle

Two or more products or batches containing the same API are compared by means of multipoint dissolution

The strength of products / batches may or may not be the same (depending on purpose of test)

The dissolution conditions are similar, e.g.• Apparatus, medium, volume, rotation speed & temperature• Minimize possible experimental differences in conditions

Samples are taken at the same time points and the data (dissolution profiles) compared

Calculations: correct for volume change of dissolution medium


Comparative dissolution testingExample


0

20

40

60

80

100

120

0 10 20 30 40 50


Dis

solu

tion

(%)

PRODUCT B 500 mgPRODUCT B 250 mg


Comparative dissolution testing

When are dissolution profiles similar?


Comparative dissolution testingProfile similarity determination

1. If both the test and reference product show more than 85% dissolution within 15 minutes,– the profiles are considered to be similar

• No calculations are required

If this is not the case, apply point 2

2. Calculate the f2 value (similarity factor): – If f2 ≥ 50

• the profiles are regarded similar


Comparative dissolution testingSimilarity factor f2

n = number of time points

Rt = % API dissolved of reference product at time point x

Tt = % API dissolved of test product at time point x Minimum of 3 time points (zero excluded) 12 units (one / vessel) for each batch (for “official” purposes) Only one measurement should be considered after the comparator

product has reached 85 % dissolution (or asymptote is reached) RSD: ≤ 20% at early time point &

≤ 10% at higher time points


Comparative dissolution testingf2 calculation – spread-sheet design


Comparative dissolution testingDissolution conditions (study design)

Apparatus(choice)

• Paddle, 75 (or 50) rpm or • Basket, 100 rpm

Dissolution media(All three media for full comparison)

1. pH 6.8 phosphate buffer2. pH 4.5 acetate buffer3. Buffer pH 1.2 or 0.1 M HCl

Volume of media900 ml or less

Temperature37°C ± 0.5°C

Sampling points10, 15, 20, 30, 45, (60, 120) min. (short intervals)

Units (individual)12 for “official” studies


Typical time pointsImmediate release tablets (capsules)

Rationale:

1. Condition 1– ≥ 85% dissolution of both products within 15 min.– 15 minute time point thus essential

2. Condition 2, for calculation of f2– a minimum of 3 points are required– Only one measurement should be considered after

85 % dissolution– 20 minute time point thus first possible one

(if 15 minute fails 1st condition)

PointTime

110

215

320

430

545


Comparative dissolution testingComparison of products

When are the dissolution properties of two products (batches) regarded similar?

When the dissolution profiles are similar– in all three media

• Statements of instability or insolubility are not acceptable, but should be demonstrated / justified (literature?)


Example 1Determination of similarity of profiles

Example 1-B% API dissolved

Time(min)

Tablet D (Ref)

Tablet E (Test)

10555715727820859130971004510210060102101

f2 required?Yesf2 (n = 3 ?)64 (similar)

Example 1-A% API dissolved

Time(min)

Tablet A (Ref)

Tablet B (Test)

108794159699209999301009945101996010199

f2 required?No, ≥ 85% in 15 minf2 (n = N/A ?)profiles similar


Example 1 Determination of similarity of profiles (cont.)

Example 1-D% API dissolved

Time(min)

Tablet D(Ref)

Tablet A (Test)

10558715729620859930971004510210160102101

f2 required?Yesf2 (n = 3 ?)31 (not similar)

Example 1-C% API dissolved

Time(min)

Tablet X(Ref)

Tablet Y(Test)

102934153841204750306364458079609591

f2 required?Yesf2 (n = 6 ?)74 (similar)


Example 2Ciprofloxacin: two batches of same product

Apparatus paddle at 50 rpmMedia: 1 pH 1.2 HCl solution (900 ml)

2 pH 4.5 acetate buffer (900 ml) 3 pH 6.8 phosphate buffer (900 ml)

Temp.: 37°C ± 0.5°C (start, middle, end)Units: Twelve tablets per medium, each batchSampling: Manual, through in-line filter (0.45 μm PVDF)

at 10, 15, 20, 30 and 45 minutesAnalysis: HPLC

ProductManufacturerBatch NrExpiry dateStatusCipro 500ABC Ltdxxx06/2008TestCipro 500ABC Ltdzzz07/2008Reference


Example 2Ciprofloxacin: two batches (cont.)

Conclusion: The profiles in all three media can be regardedsimilar / not similar, since …………

Medium►pH 1.2Buffer pH 4.5Buffer pH 6.8% dissolved% dissolved% dissolved

Time (min)b/n xxxb/n zzzb/n xxxb/n zzzb/n xxxb/n zzz10838093962831

15959297993436209997991003839301021011001003940451021021021013941

similarity ?n = 5 ?

≥ 85%in 15 min.

≥ 85%in 15 min.

f2 = 83(≥ 50)



ACTIVE INGREDIENT: CIPROFLOXACINMEDIUM: ACETATE BUFFER pH 4.5

0

20

40

60

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100

120

0 5 10 15 20 25 30 35 40 45 50


Dis

solu

tion

(%)

BATCH NO: zzz

BATCH NO: xxx

ACTIVE INGREDIENT: CIPROFLOXACINMEDIUM: pH 1.2

0

20

40

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0 5 10 15 20 25 30 35 40 45 50


Dis

solu

tion

(%)

BATCH NO: zzz

BATCH NO: xxx

pH 1.2Acetate buffer pH 6.8



ACTIVE INGREDIENT: CIPROFLOXACINMEDIUM: PHOSPHATE BUFFER pH 6.8

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40 45


Dis

solu

tion

(%)

BATCH NO: zzz

BATCH NO: xxx

Phosphate buffer pH 6.8

Why is only 40% dissolution

reached in buffer pH 6.8?


Questions:1. May change in particle size affect the dissolution rate at pH

6.8?2. What dissolution level should ciprofloxacin 250 mg tablets be able to

reach in pH 6.8 medium?

X. Yu et al. Pharm. Research, 11, 522-527 (1994)

Ciprofloxacin (cont.)Solubility is pH dependent:

“Highly soluble” at pH < 6 100% dissolution obtained in pH

4.5 and pH 1.16

At pH 6.8 and 40°C the solubility is about 0.2 mg/ml this explains 40% dissolution for

500 mg dose !!

40°C ▼


Example 3Clarithromycin tablets – Proportional formulations 2 strengths prepared

from same granulate

f2 = 31

Profiles not similar !

Solubility of the API in buffer pH 6.8 “low” according to BCS

Do you expect that particle size or polymorphism may have effect on the profiles?


0

20

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120

0 10 20 30 40 50


Dis

solu

tion

(%)

PRODUCT B 500 mgPRODUCT B 250 mg


Example 4Isoniazid/Ethambutol tablets

Purpose of study– Part of quality testing according to PhInt monograph

Samples studied– Note that the Product A is double strength

• (though it has fastest dissolution rate !)

ProductIsoniazid / Ethambutol 2HClA300mg / 800mgB150mg / 400mgC150mg / 400mgD150mg / 400mg


Example 4Isoniazid/Ethambutol tablets

Conditions and requirement according to– Monograph for Isoniazid and Ethambutol hydrochloride tablets in– International Pharmacopoeia (PhInt)

ApparatusPaddle, 75 rpm Dissolution mediumpH 6.8 phosphate bufferVolume of medium500 mlDegassed?No (undegassed)Temperature37°C ± 0.5°CSampling points10, 15, 20, 30, 45, an 60Requirement≥ 85% of label claim dissolved in 30 min


Isoniazid/Ethambutol tablets (1)Medium: pH 6.8 phosphate buffer

Product B

0

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100

120

0 10 20 30 40 50 60 70

Withdrawal time in minutesD

isso

lutio

n (%

)

Ethambutol HClIsoniazid

Product A

0

20

40

60

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100

120

0 10 20 30 40 50 60 70

Withdrawal time in minutes

Dis

solu

tion

(%)

Ethambutol HCl

Isoniazid



Product C

0

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60

80

100

120

0 10 20 30 40 50 60 70


Dis

solu

tion

(%)

Ethambutol HCl

Isoniazid

Product D

0

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60

80

100

120

0 10 20 30 40 50 60 70


isso

lutio

n (%

)

Ethambutol HCl

Isoniazid

fails requirement: <85%



All 4 productsAPI: Isoniazid

0

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40

60

80

100

120

0 10 20 30 40 50 60 70


Dis

solu

tion

(%)

All 4 productsAPI: Ethambutol

0

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100

120

0 10 20 30 40 50 60 70


isso

lutio

n (%

)

A

C

D

B


Isoniazid/Ethambutol tablets (4)Discussion of results

The dissolution profiles of the 2 APIs in a particular product are similar (this is true for all 4 products)– Both APIs are highly soluble (BCS definition)

The products show different dissolution rates– Dissolution rate A > B ≈ C >> D– Disintegration (min) 7 11 11 21– Dissolution rate related to disintegration time– f2 values show that B & C have similar profiles– Dissolution method discriminating

Typical type of results during pharmaceutical R&D


Example 54FDC TB tablets

Rifampicin/Isoniazid/Pyrazinamide/Ethambutol 150mg/75mg/400mg/275mg

Dissolution conditions (USP)– 900 ml pH 6.8 phosphate buffer (not degassed)– paddle, 100 rpm– 37°C ± 0.5°C– Sampling points: 10, 15, 20, 30 and 45 minutes– USP requirement: 75% (Q) in 45 minutes (all APIs)

Rifampicin stability– Good in pH 6.8 buffer (reason for choice)– Poor at lower pH


Example 54FDC TB tablets (2)

Similar dissolution profiles Isoniazid, pyrazinamide &

ethambutol hydrochloride– high solubility (BCS) –

expected to be similar

Rifampicin shows slower dissolution rate

– Low solubility (BCS)

DISSOLUTION OF 4FDC TB TABLETSMEDIUM: pH 6.8 phosphate buffer

0

20

40

60

80

100

120

0 7.5 15 22.5 30 37.5 45


Dis

solu

tion

(%)

Rifampicin

Isoniazid

Pyrazinamide

Ethambutol


Example 54FDC TB tablets (3)

WHO Technical Report Series 937, page 8:– The Expert Committee “agreed that rifampicin should serve as

the marker for dissolution testing in the relevant FDCs, as it was the least soluble substance.”

– This data supports the decision


Example 6Rifamicin powder

Rifampicin exist in 3 solid state forms:– Polymorph I– Polymorph II– Amorphous form

Commercial material contains:– Polymorph II (predominantly) or– Mixture of polymorph II and amorphous form

Five commercial samples (A to E) testedSamples A, B & E: Form II Samples C & D: Form II + amorphous form


Example 6Rifamicin powder (2)

Medium: Water

– Profiles A, B & E are similar (f2 ≥ 50)– Profiles C & D are similar (f2 ≥ 50) - dissolution incomplete– Profiles A, B, E dissimilar from profiles C,D (f2 < 50)

A, B, E(form II)

C, D(form II + amorph)


Example 6Rifamicin powder (3)

1. Presence of amorphous form slows down dissolution of raw material powder at higher pH (f2 test)– Reason: Agglomeration / wettability

2. Comparative powder dissolution powerful tool for– selection of API manufacturer and– even in-house specification ?

Dissolution method for API powders– overcome floating on medium

see reference below

Reference: S.Q Henwood et al. Drug Dev. & Ind. Pharm. 26, 403-408 (2000) (RIIP)

amorphous form


Applications

1. Comparative dissolution: basic tool for selection of the formulation during product development– By comparison of the dissolution profiles of comparator

product with those of development batches• Optimise, to get similar profiles

– Hint: start with comparator product before development• To get dissolution profiles required for the generic product• Disintegration testing can aid in the early phases

– Maximize the chances of bioequivalence– Integral part of development report

• dossier and PQIF


Applications (cont.)

2. Scale up from development (pivotal) to production batches– To demonstrate in vitro similarity of such batches

• This is considered essential for retention of efficacy and quality• Note that bioequivalence studies are done normally only once on a bio-

batch during development• It must be demonstrated that the product retains the dissolution

characteristics up to production scale– The studies should be submitted in dossier as part of the FPP

development report



3. Selection of the dissolution specifications for product release & stability purposes1. Conditions and acceptance criteria to be set2. The dissolution profiles of the bio-batch should be used for this

purpose3. A dissolution specification should be able to detect inadequate

release properties of the commercial batches• A “generous” dissolution limit has no quality selectivity

4. Example: Isoniazid/Ethambutol hydrochloride tablets



4. Demonstration of in vivo bioequivalence of one or more of the lower strength(s) of an FPP may be waived based on1. an acceptable in vivo BE study of the highest strength against

the comparator product2. demonstration of similarity of dissolution profiles between the

higher (bio-batch) and lower strength 3. if the lower strength is proportionally similar in formula to the

higher strength (bio-batch)4. if all pharmacokinetic requirements are met

• Consult the bio-guideline, also for reverse situation



6. Post-approval amendment application– A requirement of a particular change may be to demonstrate

that the profiles of the amendment batch and the current batch are similar• Consult guideline on variations


Reporting Comparative dissolution data

Full report, including1. Purpose of study2. Products / batches information

• Batch number, manufacturing/expiry date, packaging, etc.• CoA & size for “own” batches (and BMR for bio-studies report)

3. Dissolution conditions and method4. Analytical method or reference to part of dossier5. Results (% API dissolved)

• Tabulated• Graphically• Similarity determination / calculation

6. Conclusion


Comparative dissolution testingGuidelines

Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability– Paragraph 9: In vitro testing (dissolution)– WHO Technical Report Series 937, Annex 7 (2006)

Dissolution testing. Supplement 1 to– Guideline on Submission of Documentation for Prequalification

of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis• (Generic guideline)


Comparative dissolution testingRelevant training material

WHO/FIP Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceuticals Classification System (BCS)– Kiev, Ukraine, 25 - 27 June 2007– On WHO Prequalification website

Strongly recommended


Closing remarks Comparative dissolution plays an important role in:

– product development– up-scaling from development to production – setting of quality dissolution specifications– waiving of BE studies in proportionally similar formulations– post-approval changes (variations)

Manufacturers should– understand the basic requirements of conducting comparative

dissolution testing– know how and where to apply it– be able to determine similarity of profiles

All data in presentation generated at the RIIP


Multipoint dissolutionExample of (fast) manual sample pulling

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