1 tg dekker – who, malaysia feb 2005 comparative dissolution testing and applications world health...

1 TG Dekker – WHO, MalaysiaFeb 2005

Comparative dissolution testingand applications

World Health OrganizationTraining Workshop on Pharmaceutical

Quality, GMP and BioequivalenceKiev - Ukraine

3 to 7 October 2005

Theo Dekker, D.Sc., consultant to WHOResearch Institute for Industrial Pharmacy

North-West University, Potchefstroom, South [email protected]


What is dissolution testing?tablets and capsules (conventional)

It measures the portion (%) of the API that (1) has been released from tablets/capsules and (2) 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

Dissolution testing is also applicable to suspensions and suppositories


GlossarySolid oral dosage forms

Immediate release 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

Not part of presentationModified-release dosage forms (consult Int.Ph., BP, USP) Formulation deliberately changes release (slows down)

• Extended-release (prolonged-release)Slower release throughout the GI tract

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


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In multipoint dissolution multiple (≥ 3) samples are withdrawn from the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

tio

n (

%)

Clarithromycin 250 mg tablets


Comparative dissolution testingThe principle

Two or more products or batches containing the same API are compared

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 & temp.• 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 testingProfile similarity determination

Two conditions to determine if the dissolution profiles of two products/batches in a particular dissolution medium are similar: 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 22. Calculate the f2 value (similarity factor):

• If f2 ≥ 50, the profiles are normally regarded similar


Comparative dissolution testingSimilarity factor f2

n = number of time pointsR(t) = mean % API dissolved of reference product at time point xT(t) = mean % API dissolved of test product at time point x Minimum of 3 time points (zero excluded) 12 units (each in own dissolution vessel) for each product (for

“official” purposes) Only one measurement should be considered after both

products have reached 85 % dissolution RSD at higher time points ≤ 10%


Comparative dissolution testingDissolution conditions (study design)

Apparatus

(choice)

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

Dissolution media

All three media for full comparison

1. Buffer pH 6.8 or simulated intestinal fluid without enzymes

2. Buffer pH 4.5

3. 0.1 M HCl or buffer pH 1.2 or simulated gastric fluid without enzymes

Volume of media 900 ml or less

Temperature 37°C ± 0.5°C

Sampling points 10, 15, 20, 30, 45, (60, 120) min. (typical)

Units (individual) 12 for “official” studies


Typical time pointsImmediate release tablets (capsules)

Rationale:1. Condition 1

≥ 85% dissolution of both products within 15 minutes

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 (both tablets)

20 minute time point thus first possible one (if 15 minute fails 1st condition)

Point Time

1 10

2 15

3 20

4 30

5 45


Comparative dissolution testingComparison of products

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

The profiles should be similar in all three media

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


Example 1Determination of similarity of profiles

Example 1-B

% API dissolved

Time(min)

Tablet D (Ref)

Tablet E (Test)

10 55 57

15 72 78

20 85 91

30 97 100

45 102 100

60 103 101

f2 required? Yes

f2 (n = 3 ?) 64 (similar)

Example 1-A

% API dissolved

Time(min)

Tablet A (Ref)

Tablet B (Test)

10 87 94

15 96 99

20 99 99

30 100 99

45 101 99

60 101 99

f2 required? No, ≥ 85% in 15 min

f2 (n = N/A ?) profiles similar


Example 1 Determination of similarity of profiles (cont.)

Example 1-D

% API dissolved

Time(min)

Tablet A(Ref)

Tablet Y (Test)

10 87 55

15 96 72

20 99 85

30 100 97

45 101 102

60 101 103

f2 required? Yes

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

Example 1-C

% API dissolved

Time(min)

Tablet X(Ref)

Tablet Y(Test)

10 29 34

15 38 41

20 47 50

30 63 64

45 80 79

60 95 91

f2 required? Yes

f2 (n = 6 ?) 74 (similar)


Example 2Ciprofloxacin: two batches of same product

Apparatus paddle at 50 rpmMedium 1: simulated gastric fluid without pepsin (SGF) (900

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

at 10, 15, 20, 30 and 45 minutesAnalysis: HPLC analysis for ciprofloxacin

Product Manufacturer Batch Nr Expiry date Status

Cipro 500 ABC Ltd xxx 06/2007 Test

Cipro 500 ABC Ltd zzz 07/2007 Reference


Example 2Ciprofloxacin: two batches (cont.)

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

Medium► SGF, pH 1.16 Buffer pH 4.5 Buffer pH 6.8

% dissolved % dissolved % dissolved

Time (min) b/n xxx b/n zzz b/n xxx b/n zzz b/n xxx b/n zzz

10 83 80 93 96 28 31

15 95 92 97 99 34 36

20 99 97 99 100 38 39

30 102 101 100 100 39 40

45 102 102 102 101 39 41

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

80

100

120

0 5 10 15 20 25 30 35 40 45 50


Dis

so

luti

on

(%

)BATCH NO: zzz

BATCH NO: xxx

ACTIVE INGREDIENT: CIPROFLOXACINMEDIUM: SGF WITHOUT PEPSIN pH 1.16

0

20

40

60

80

100

120

0 5 10 15 20 25 30 35 40 45 50


Dis

so

luti

on

(%

)

BATCH NO: zzz

BATCH NO: xxx

SGF without pepsin, pH 1.16 Acetate buffer pH6.8



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

so

luti

on

(%

)

BATCH NO: zzz

BATCH NO: xxx

Phosphate buffer pH 6.8


Questions:1. What dissolution level should ciprofloxacin 250 mg tablets be

able to reach in pH 6.8 medium?2. Should a change in particle size affect the dissolution

rate?

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 Explains 40% dissolution for

500 mg dose !!

40°C ▼


Example 3Lamivudine 150 mg & zidovudine 300 mg tablets

Source, WHO publication: Ongoing Monitoring of Antiretroviral Products as Part of

WHO’s Prequalification Project. Journal of Generic Medicines (accepted for publication, January 2006 edition)

Samples from PQ project or bought/requested

Apparatus: paddle at 75 rpm Medium: 900 ml 0.1 M hydrochloric acid, 37°C Sample times: 5, 10, 15, 20, 30 and 45 minutes Analysis: HPLC

Data presented for individual APIs in next tables


Example 3Lamivudine 150 mg & zidovudine 300 mg tablets (2)

Time (min)

% Lamivudine of label claim dissolved

Combivir® Gen-1 Gen-2 Gen-3 Gen-4

5 85 25 92 65 45

10 96 46 96 85 81

15 97 65 98 95 92

20 97 80 98 98 95

30 97 97 98 98 96

45 97 97 98 98 97

≥ 85 in15 min ?

✔Referenc

e

no ✔ ✔ ✔

f2 21



Time (min)

% Zidovudine of label claim dissolved

Combivir® Gen-1 Gen-2 Gen-3 Gen-4

5 85 22 74 68 45

10 97 44 90 88 83

15 98 64 97 96 95

20 98 81 99 100 98

30 98 100 101 99 99

45 99 100 100 99 100

≥ 85 in15 min ?

✔Referenc

e

no ✔ ✔ ✔

f2 20



Conclusion (considering only 0.1 M HCl as medium)

1. 3 products show profile similarity with Combivir®(≥ 85% in 15 minutes)

2. The profiles of Combivir® and Gen-1 are not similar• The products may still show bio-equivalency

The dissolution profiles of the APIs in a particular

product are similar (true for all 5 products) Examples: see profiles of Combivir® and Gen-1



Combivir ® dissolution profile Gen-1 dissolution profile0.1 M hydrochloric acid 0.1 M hydrochloric acid

Note the similarity of the API profiles of each productAPIs highly soluble = dissolution controlled by disintegration time

Is particle size of APIs expected to be critical ?


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?

ACTIVE INGREDIENT: CLARITHROMYCINMEDIUM: PHOSPHATE BUFFER pH 6.8

0

20

40

60

80

100

120

0 10 20 30 40 50


Dis

so

luti

on

(%

)

PRODUCT B 500 mgPRODUCT B 250 mg


USP Type II / 0.01N HCl 50 RPM / 900 ml

0

20

40

60

80

100

120

Time (Min)Nevipan MGS(1024)05 (90%LT81.12)Nevipan MGS(1024)60B (90%LT30.89)Viramune 992633B

0 10 20 300.00 50.80 73.80 83.980.00 80.00 92.00 96.000.00 83.30 96.60 97.70

% D

rug

Dis

solv

ed

Effect of Particle Size on Dissolution of Nevirapine Tablets (Source: Ranbaxy)

http://www.who.int/medicines/organization/par/FDC/VKAroraWHOGenevaDec.ppt

1 Viramune

2 Nevipan 90% < 31

3 Nevipan 90% < 81

f2 : 1 vs 2 = 72 ✔

f2 : 1 vs 3 = 31 X

f2 : 2 vs 3 = 34 X

1

2

3


Applications

1. For selection of the formulation in the development phase By comparison of the dissolution profiles of

innovator product with those of formulations Hint: start with comparator product to see:

• Immediate release?• Rapidly dissolving?• Very rapidly dissolving?• Disintegration testing can aid in the early phases

This should be a basic strategy in R&D to maximize the chances of bioequivalence


Applications (cont.)

2. It is a requirement of the prequalification programme to submit comparative dissolution data for the bio-batch and innovator batch Same batches as used in bioequivalence study ! Submit report with data, profile comparison &

discussion (see report requirements) This report form part of pharmaceutical

development report• Inclusion of the same report in the bioequivalence

study report is recommended



3. 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 product

2. demonstration of similarity of dissolution profiles,

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

4. if all pharmacokinetic requirements are met• Consult the bio-guideline, also for reverse situation



4. Comparison of the release properties of pivotal batches To demonstrate in vitro similarity of such batches

• This is considered essential for retention of efficacy and safety

• 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



5. 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: Combivir ® (from limited data in Example 3)• 80% (Q) within 20 (15?) minutes for both APIs under

conditions described in Example 3



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


Guidelines

WHO Prequalification1. Supplement 1 [for use from July 2005 (CPH25)] 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

Dissolution testingOthers Guidance for Industry. Waiver of In-Vivo Bioavailability and

Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), August 2000.

CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence. The European Agency for the Evaluation of Medicinal Products CPMP/EWP/QWP/1401/98, July 2001


Some conclusions

Comparative dissolution should form an essential part of R&D of solid oral dosage

forms (including suspensions), supports bio-studies, is required for comparison of pharmaceutical release

properties of pivotal batches, is used to set dissolution specifications, and assists in post-approval changes

It is thus important to conduct the studies under controlled conditions in the 3

media, all as required by the guidelines, to take samples for analysis at meaningful intervals and to be able to determine similarity of profiles

1 tg dekker – who, malaysia feb 2005 comparative dissolution testing and applications world health...

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