Date post: | 26-Aug-2014 |
Category: |
Documents |
Upload: | veena-reddy-singam |
View: | 251 times |
Download: | 18 times |
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]
2 TG Dekker – WHO, MalaysiaFeb 2005
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
3 TG Dekker – WHO, MalaysiaFeb 2005
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
4 TG Dekker – WHO, MalaysiaFeb 2005
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In multipoint dissolution multiple (≥ 3) samples are withdrawn from the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
5 TG Dekker – WHO, MalaysiaFeb 2005
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
6 TG Dekker – WHO, MalaysiaFeb 2005
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
7 TG Dekker – WHO, MalaysiaFeb 2005
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
8 TG Dekker – WHO, MalaysiaFeb 2005
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%
9 TG Dekker – WHO, MalaysiaFeb 2005
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 4.53. 0.1 M HCl or buffer pH 1.2 or simulated
gastric fluid without enzymesVolume 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
10 TG Dekker – WHO, MalaysiaFeb 2005
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
11 TG Dekker – WHO, MalaysiaFeb 2005
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
12 TG Dekker – WHO, MalaysiaFeb 2005
Example 1Determination of similarity of profiles
Example 1-B% API dissolved
Time(min)
Tablet D (Ref)
Tablet E (Test)
10 55 5715 72 7820 85 9130 97 10045 102 10060 103 101
f2 required? Yesf2 (n = 3 ?) 64 (similar)
Example 1-A% API dissolved
Time(min)
Tablet A (Ref)
Tablet B (Test)
10 87 9415 96 9920 99 9930 100 9945 101 9960 101 99
f2 required? No, ≥ 85% in 15 min
f2 (n = N/A ?) profiles similar
13 TG Dekker – WHO, MalaysiaFeb 2005
Example 1 Determination of similarity of profiles (cont.)
Example 1-D% API dissolved
Time(min)
Tablet A(Ref)
Tablet Y (Test)
10 87 5515 96 7220 99 8530 100 9745 101 10260 101 103
f2 required? Yesf2 (n = 3 ?) 31 (not similar)
Example 1-C% API dissolved
Time(min)
Tablet X(Ref)
Tablet Y(Test)
10 29 3415 38 4120 47 5030 63 6445 80 7960 95 91
f2 required? Yesf2 (n = 6 ?) 74 (similar)
14 TG Dekker – WHO, MalaysiaFeb 2005
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 StatusCipro 500 ABC Ltd xxx 06/2007 TestCipro 500 ABC Ltd zzz 07/2007 Reference
15 TG Dekker – WHO, MalaysiaFeb 2005
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 zzz10 83 80 93 96 28 3115 95 92 97 99 34 3620 99 97 99 100 38 3930 102 101 100 100 39 4045 102 102 102 101 39 41
similarity ?n = 5 ?
≥ 85% in 15 min.
≥ 85% in 15 min.
f2 = 83(≥ 50)
16 TG Dekker – WHO, MalaysiaFeb 2005
Example 2Ciprofloxacin: two batches (cont.)
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
WITHDRAWAL TIME IN MINUTES
Dis
solu
tion
(%)
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
WITHDRAWAL TIME IN MINUTES
Dis
solu
tion
(%)
BATCH NO: zzz
BATCH NO: xxx
SGF without pepsin, pH 1.16 Acetate buffer pH6.8
17 TG Dekker – WHO, MalaysiaFeb 2005
Example 2Ciprofloxacin: two batches (cont.)
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
WITHDRAWAL TIME IN MINUTES
Dis
solu
tion
(%)
BATCH NO: zzz
BATCH NO: xxx
Phosphate buffer pH 6.8
18 TG Dekker – WHO, MalaysiaFeb 2005
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 ▼
19 TG Dekker – WHO, MalaysiaFeb 2005
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
20 TG Dekker – WHO, MalaysiaFeb 2005
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 4510 96 46 96 85 8115 97 65 98 95 9220 97 80 98 98 9530 97 97 98 98 9645 97 97 98 98 97
≥ 85 in15 min ?
✔Referenc
e
no ✔ ✔ ✔
f2 21
21 TG Dekker – WHO, MalaysiaFeb 2005
Example 3Lamivudine 150 mg & zidovudine 300 mg tablets (3)
Time (min)% Zidovudine of label claim dissolved
Combivir® Gen-1 Gen-2 Gen-3 Gen-4
5 85 22 74 68 4510 97 44 90 88 8315 98 64 97 96 9520 98 81 99 100 9830 98 100 101 99 9945 99 100 100 99 100
≥ 85 in15 min ?
✔Referenc
e
no ✔ ✔ ✔
f2 20
22 TG Dekker – WHO, MalaysiaFeb 2005
Example 3Lamivudine 150 mg & zidovudine 300 mg tablets (4)
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
23 TG Dekker – WHO, MalaysiaFeb 2005
Example 3Lamivudine 150 mg & zidovudine 300 mg tablets (5)
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 ?
24 TG Dekker – WHO, MalaysiaFeb 2005
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
WITHDRAWAL TIME IN MINUTES
Dis
solu
tion
(%)
PRODUCT B 500 mgPRODUCT B 250 mg
25 TG Dekker – WHO, MalaysiaFeb 2005
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 Viramune2 Nevipan 90% < 313 Nevipan 90% < 81
f2 : 1 vs 2 = 72 ✔f2 : 1 vs 3 = 31 X
f2 : 2 vs 3 = 34 X
12
3
26 TG Dekker – WHO, MalaysiaFeb 2005
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
27 TG Dekker – WHO, MalaysiaFeb 2005
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
28 TG Dekker – WHO, MalaysiaFeb 2005
Applications (cont.)
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 product2. demonstration of similarity of dissolution profiles,3. if the lower strength is proportionally similar in
formula to the higher strength (bio-batch) and4. if all pharmacokinetic requirements are met
• Consult the bio-guideline, also for reverse situation
29 TG Dekker – WHO, MalaysiaFeb 2005
Applications (cont.)
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
30 TG Dekker – WHO, MalaysiaFeb 2005
Applications (cont.)
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
31 TG Dekker – WHO, MalaysiaFeb 2005
Applications (cont.)
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
32 TG Dekker – WHO, MalaysiaFeb 2005
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
33 TG Dekker – WHO, MalaysiaFeb 2005
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
34 TG Dekker – WHO, MalaysiaFeb 2005
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