Transcript THE TITLE COMES HERE Day Month Year

COMPARATIVE DISSOLUTION
REQUIREMENTS AND
CHALLENGES TO THE
PHARMACEUTICAL INDUSTRY
Dr Erna Swanepoel
Research Institute for Industrial Pharmacy,
incorporating CENQAM
What is dissolution testing?
Tablets and capsules (conventional
IR)
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.
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 suspension
– 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)
Glossary
Solid oral dosage forms
Immediate release (IR) dosage forms
– Not rapid/Slowly dissolving: ≥ 85% in >30 minutes
– Rapidly dissolving: ≥ 85% in ≤ 30 minutes
– Very rapidly dissolving: ≥ 85% in ≤ 15 minutes
Modified-release dosage forms (consult Ph.Int.,
Ph.Eur./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– multiple (≥ 3) samples are withdrawn from the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
– in-line filtration!
– 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 dissolution
Example of dissolution profile
ACTIVE INGREDIENT: CLARITHROMYCIN
MEDIUM: PHOSPHATE BUFFER pH 6.8
120
Dissolution (%)
100
80
60
40
20
Clarithromycin 250 mg tablets
0
0
10
20
30
WITHDRAWAL TIME IN MINUTES
40
50
Comparative dissolution testing
The 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 testing
Example
ACTIVE INGREDIENT: CLARITHROMYCIN
MEDIUM: PHOSPHATE BUFFER pH 6.8
120
Dissolution (%)
100
80
60
40
PRODUCT B 500 mg
PRODUCT B 250 mg
20
0
0
10
20
30
40
WITHDRAWAL TIME IN MINUTES
50
Comparative dissolution testing
When are dissolution profiles similar?
Comparative dissolution testing
Profile 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 testing
Similarity 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
comparator and test products have reached 85 %
dissolution (or asymptote is reached)
 RSD: ≤ 20% at early time points &
≤ 10% at higher time points
Comparative dissolution testing
f2 calculation – spread-sheet design
Comparative dissolution testing
Dissolution conditions
Apparatus
(choice)
Dissolution media
(All three media for full
comparison)
Volume of media
Temperature
Sampling points
Units (individual)
• Paddle, 75 (or 50) rpm or
• Basket, 100 rpm
1. pH 6.8 phosphate buffer
2. pH 4.5 acetate buffer
3. Buffer pH 1.2 or 0.1 M HCl
900 ml or less
37°C ± 0.5°C
10, 15, 20, 30, 45, (60, 120) min.
(short intervals)
12 for “official” studies
Typical time points
Immediate release tablets (capsules)
Point Time
1
10
2
15
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
3
20
4
30
5
45
•
•
•
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)
Comparative dissolution testing
Comparison 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 1
Determination of similarity of profiles
Example 1-A
Example 1-B
% API dissolved
% API dissolved
Time
(min)
Tablet A
(Ref)
Tablet B
(Test)
Time
(min)
Tablet A Tablet B
(Ref)
(Test)
10
87
94
10
55
57
15
20
96
99
99
99
15
20
72
85
78
91
30
45
100
101
99
99
30
45
97
102
100
100
60
101
99
60
102
101
f2 required?
No, ≥ 85% in 15 min
f2 required?
Yes
f2 (n= N/A ?)
Profiles similar
f2 (n = 3 ?)
64 (similar)
Example 1 (cont.)
Determination of similarity of profiles
Example 1-C
Example 1-D
% API dissolved
% API dissolved
Time
(min)
Tablet X
(Ref)
Tablet Y
(Test)
Time
(min)
Tablet D
(Ref)
Tablet A
(Test)
10
15
20
30
29
38
47
63
34
41
50
64
10
15
20
30
55
72
85
97
87
96
99
100
45
60
80
95
79
91
45
60
102
102
101
101
f2 required?
Yes
f2 required?
Yes
f2 (n = 6 ?)
74 (similar)
f2 (n = 3 ?)
31 (not similar)
Example 2 Ciprofloxacin:
two batches of same product
Product
Manufacturer
Batch Nr
Expiry date
Status
Cipro 500
ABC Ltd
XXX
06/2008
Test
Cipro 500
ABC Ltd
ZZZ
07/2008
Reference
Apparatus:
Media:
Temp.:
Units:
Sampling:
Analysis:
paddle at 50 rpm
1
pH 1.2 HCl solution (900 ml)
2
pH 4.5 acetate buffer (900 ml)
3
pH 6.8 phosphate buffer (900 ml)
37°C ± 0.5°C (start, middle, end)
Twelve tablets per medium, each batch
Manual, through in-line filter (0.45 μm PVDF)
at 10, 15, 20, 30 and 45 minutes
HPLC
Example 2
Ciprofloxacin: two batches (cont.)
Medium
pH 1.2
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 ?
Conclusion:
≥ 85 % in
15 min
≥ 85 % in
15 min
f2 = 83
(> 50)
The profiles in all three media can be regarded
similar / not similar, since …………
Example 2
Ciprofloxacin: two batches (cont.)
pH 1.2
Acetate buffer pH 4.5
Example 2
Ciprofloxacin: two batches (cont.)
Phosphate buffer pH 6.8
ACTIVE INGREDIENT: CIPROFLOXACIN
MEDIUM: PHOSPHATE BUFFER pH 6.8
Why is only
40% dissolution
reached in
buffer pH 6.8?
Dissolution (%)
120
100
BATCH NO: zzz
80
BATCH NO: xxx
60
40
20
0
0
5
10
15
20
25
30
35
WITHDRAWAL TIME IN MINUTES
40
45
Ciprofloxacin (cont.)
Solubility is pH dependent:

“Highly soluble” at pH < 6
 100% dissolution obtained in pH
4.5 and pH 1.2

At pH 6.8 and 40°C the solubility is
about 0.2 mg/ml
 this explains 40% dissolution for
500 mg dose !!
Questions:
1. May change in particle size affect
the dissolution at pH 6.8?
2. What dissolution level should
ciprofloxacin 250 mg tablets be
able to reach in pH 6.8 dissolution
medium?
40°C ▼
Example 3 Clarithromycin 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?
Example 4
Isoniazid/Ethambutol tablets
Purpose of study
– Part of quality testing according to Ph.Int.
monograph
Samples studied
– Note that the Product A is double strength
• (though it has fastest dissolution rate !)
Product
Isoniazid /
Ethambutol 2HCl
A
B
C
D
300mg / 800mg
150mg / 400mg
150mg / 400mg
150mg / 400mg
Example 4
Isoniazid/Ethambutol tablets
Conditions and requirement according to
– Monograph for Isoniazid and Ethambutol
hydrochloride tablets in
– International Pharmacopoeia (Ph.Int.)
Apparatus
Paddle, 75 rpm
Dissolution medium pH 6.8 phosphate buffer
Volume of medium
500 ml
Degassed?
No (undegassed)
Temperature
37°C ± 0.5°C
Sampling points
10, 15, 20, 30, 45, and 60 minutes
Requirement
≥ 85% of label claim dissolved in
30 min
Isoniazid/Ethambutol tablets (1)
Medium: pH 6.8 phosphate buffer
Product A
120
Dissolution (%)
100
80
60
40
Ethambutol HCl
20
Isoniazid
0
0
10
20
30
40
50
60
Withdrawal time in minutes
70
Isoniazid/Ethambutol tablets (2)
Medium: pH 6.8 phosphate buffer
Product D
120
120
100
100
Dissolution (%)
Dissolution (%)
Product C
80
60
40
Ethambutol HCl
80
60
40
Ethambutol HCl
20
20
Isoniazid
Isoniazid
0
0
0
10
20
30
40
50
60
Withdrawal time in minutes
70
0
10
20
30
40
50
60
Withdrawal time in minutes
70
Isoniazid/Ethambutol tablets (3)
Medium: pH 6.8 phosphate buffer
All 4 products
API: Isoniazid
Dissolution (%)
120
100
B
80
60
40
20
0
0
10
20
30
40
50
60
Withdrawal time in minutes
70
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 5
4FDC 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 5
4FDC 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)
Example 5
4FDC 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 6
Rifampicin powder
 Rifampicin exists 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) tested
Samples A, B & E: Form II
Samples C & D:
Form II + amorphous form
Example 6
Rifampicin powder (2)
– 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)
Example 6
Rifampicin powder (3)
1.
Presence of amorphous form slows down dissolution
of raw material powder at higher pH (f2 test)
– Reason: Agglomeration / wettability
Amorphous form
2.
Comparative powder dissolution powerful tool for
– selection of API manufacturer
– 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)
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 pharmaceutical development report
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
Applications (cont.)
3. Selection of the dissolution specifications
for product release & stability purposes
1. Conditions and acceptance criteria to be set
2. The dissolution profiles of the bio-batch should be
used for this purpose
3. 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
Applications (cont.)
4. Demonstration of in vivo bioequivalence of
one or more of the lower strength(s) of an
FPP may be waived based on
1. an acceptable in vivo BE study of the highest
strength against the comparator product
2. 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
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 amendments
Reporting
Comparative dissolution data
Full report on letterhead of laboratory, including
1. Purpose of study
2. Products / batches information
• Batch number, manufacturing/expiry date, packaging, etc.
• CoA & batch size for “own” batches (and BMR for biostudies report)
3. Dissolution conditions and method (in-line
filtration!)
4. Analytical method (validated) or reference to part
of dossier
5. Results (% API dissolved)
• Tabulated
• Graphically
• Similarity determination / calculation
Reporting
Comparative dissolution data (cont.)
6. Discussion/Conclusion
7. Date of analyses and date of report
8. GMP/GLP compliance declaration by laboratory –
reference to
•
•
•
Availability of validation records of test methods
Procedures for and
Records calibration and maintenance of equipment
9. CoA (P & A Guideline) for test and reference
products w.r.t.
•
•
Description, assay (NMT 5% difference),
content/mass uniformity and dissolution
Methods as per submission for test product
Guidelines
 Medicines Control Council
–
–
–
–
Dissolution (March 2011)
Biostudies (June 2011)
Amendments (March 2011)
Pharmaceutical and Analytical (June 2011)
 Other
– FDA (August 2000)
– WHO Technical Report Series, No. 937, Annex 8
(2006)
– EMEA (January 2010)
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 (amendments)

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/CENQAM
Thank you