Cumulative

No. of
Units No. of Units
Tier USP <711>
Tested Tested
1 6 6 All units > Q+5%
-
2 6 12 X2>0

All units > Q-15%

-
3 12 24 X3 >0

All units > Q-25%

At least 22 units > Q-15°1c:
USP criterion has the form of a three-stage
sequential design, with possibility of stopping
at each stage

So, can evaluate as a statistical hypothesis

test
Null hypothesis would be unacceptable
dissolution
Alternative hypothesis would be acceptable
dissolution
 Regulatory Negotiation
~ New Approach for Pioneer
Pick a time, To, at which to assess dissolution
Determine distribution of dissolution values in
relevant batches; preferably ones that
demonstrate acceptable clinical safety and
efficacy
Choose a minimum proportion of dissolution
values to target, R; this number should be
large, but not too large; suggest 80% or 90%
Q is then the value of percent dissolved at To,
that is exceeded by a proportion R of values
 .j::::..
a
C
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enr+
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a =:!.
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c
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r+
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:::s
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0

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~
c
~
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0 -......J C
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-
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~
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a en
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-
-h
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-
o C.
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;0
_.
-f
03 3
a CD
~
0 --I
'- 0
-.l..
a
a
• In a new batch, what proportion should
dissolve more than Q?
• This value, say P, needs to be smaller than
R, else very high producer risk
If P not near R, then at least perception of a
relaxation of a quality standard
Suggest P = R-5°10; e.g., 75°10 if R = 80°10
 _.
c
,...
tA
(J1
o ~.
C'"
_.
e
,...
o
::l
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o
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o..., -<
r CD

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Q)

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-I
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CD
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 Pass batch if one-sided lower tolerance limit
exceeds Q;
i.e., X - kS > Q
• The constant, k, is chosen so as to limit the
probability, a, of a batch passing if the
proportion exceeding Q falls to P
• k will also depend on design; will vary with
tier for multi-tier designs
This approach lends itself to flexible sample
.
sizes
 USP <711> JP Proposal New Proposal
-
~ -2.01~/F6 >0* ~-1.91~>Q**
All units > Q+5% All units > Q*-lO%
-
X2>Q X2 -1.7~/f12 >0*
All units > Q-15% All units > Q*-lO%
-
X3>Q

All units > Q-25%

At least 22 units > Q-15%
 INTERPRETA TION

Immediate-Release Dosage Forms

Unless otherwise specified +in the individual monograph ,the requirements are met if the quantities
+
of active ingredient dissolved from the dosage units tested conform to Acceptance Table 1. Continue
testing through the three stages unless the results conform at either S1 or S2. The quantity, Q, is the

amount of dissolved active ingredient + specified in the individual monograph ,expressed as a

+
percentage of the labeled content of the dosage unit; the 5%, 15%, and 25% values in Acceptance
Table 1 are percentages of the labeled content so that these values and Q are in the same terms.

Acceptance Table 1
INumberl'
I
Stage Tested Acceptance Criteria
~S1 I 6 IEach unit is not less than Q + 5%.
~-S;-1-6~lAv~-rage of 12-units (S1 ~ S2) is eq-ua-I-to-or~
greater than Q, and no unit is less than
I
j Q- 15%.
S3 I 12 Average of 24 units (S1 + S2 + S3) is equal to
I or greater than Q, not more than 2 units
are less than Q - 15%, and no unit is less
,than Q - 25%.

+ Immediate-Release Dosage Forms Pooled Sample- Unless otherwise specified in the individual
monograph, the requirements are met if the quantities of active ingredient dissolved from the pooled
sample conform to the accompanying Acceptance Table for a Pooled Sample. Continue testing through
the three stages unless the results conform at either S1 or S2. The quantity, Q, is the amount of
dissolved active ingredient specified in the individual monograph, expressed as a percentage of the
labeled content.

Acceptance Table for a Pooled Sample

[Number
Stagel Tested Acceptance Criteria
S1 6 jrAVerage amount dissolved is not less
than Q + 10%.
52 6 Average amount dissolved (51 + S2) is
equal to or greater than Q + 5%.
S3 12 Average amount dissolved (51 + 52 +
S3) is equal to or greater than Q.

+
© 2009 USPC Official 5/1/08 - 7/31/08 General Chapters: <711> DISSOLUTION Page 1 of3
 Extended-Release Dosage Forms

Unless otherwise specified -+-inthe individual monograph ,the requirements are met if the quantities
-+-
of active ingredient dissolved from the dosage units tested conform to Acceptance Table 2. Continue
testing through the three levels unless the results conform at either L1 or L2. Limits on the amounts of
active ingredient dissolved are expressed in terms of the percentage of labeled content. The limits
embrace each value of Qi' the amount dissolved at each specified fractional dosing interval. Where

more than one range is specified -+-inthe individual monograph ,the acceptance criteria apply
-+-
individually to each range.

Acceptance Table 2
Number
Level Tested Criteria
L1 6 No individual value lies outside each of the
stated ranges and no individual value is
less than the stated amount at the final test
time.
L2 6 The average value of the 12 units (L1 + L2)
lies within each of the stated ranges and
is not less than the stated amount at the
final test time; none is more than 10% of
labeled content outside each of the stated
ranges; and none is more than 10% of
labeled content below the stated amount
at the final test time.
----

L3 -12-IThe average value of the 24 units (L1 + L2 +

L3) lies within each of the stated ranges,

and is not less than the stated amount at the
final test time; not more than 2 of the 24
units are more than 10% of labeled content
outside each of the stated ranges; not more
than 2 of the 24 units are more than 10%
of labeled content below the stated amount
at the final test time; and none of the units is

more than 20% of labeled content outside

each of the stated ranges or more than 20%

of labeled content below the stated amount

at the final test time.

Delayed-Release Dosage Forms

NOT ACCEPTED BY THE JAPANESE PHARMACOPOEIA.

© 2009 USPC Official 5/1/08 - 7/31/08 General Chapters: <711> DISSOLUTION Page 2 of3
 Acid Stage- Unless otherwise specified ·in the individual monograph ,the requirements of this
•
portion of the test are met if the quantities, based on the percentage of the labeled content, of active
ingredient dissolved from the units tested conform to Acceptance Table 3. Continue testing through all
levels unless the results of both acid and buffer stages conform at an earlier level.

Acceptance Table 3
Numberl
I
Level Tested Criteria
Ai 6 No individual value exceeds 10% dissolved.
----------------------------------------
A2 6 Average of the 12 units (Ai + A2) is not more
than 10% dissolved, and no individual
unit is greater than 25% dissolved.
--+-----
A3 12 Average of the 24 units (Ai + A2 + A3) is not
more than 10% dissolved, and no individual unit is greater than 25% dissolved.

Buffer Stage- Unless otherwise specified +in the individual monograph ,the requirements are met if
+
the quantities of active ingredient dissolved from the units tested conform to Acceptance Table 4.
Continue testing through the three levels unless the results of both stages conform at an earlier level.

The value of Q in Acceptance Table 4 is 75% dissolved unless otherwise specified ·in the individual

monograph . The quantity, Q, + specified in the individual monograph is the total amount of active
+ +
ingredient dissolved in both the Acid and Buffer Stages, expressed as a percentage of the labeled
content. The 5%, 15%, and 25% values in Acceptance Table 4 are percentages of the labeled content
so that these values and Q are in the same terms.

Acceptance Table 4
Numberl
Level Tested I Criteria
B1 I 6 rEaCh unit is not less than Q + 5%.
82 6"---rAverage of 12 units (81 + 82) is equal t~
jor greater than Q, and no unit is less than
____
r- I_Q_-__ 1_5o_~_. _
B3 12 ,Average of 24 units (B1 + B2 + B3) is equal
to or greater than Q, not more than 2 units
are less than Q - 15%, and no unit is less
than Q - 25%.

© 2009 USPC Official 5/1/08 - 7/31/08 General Chapters: <711> DISSOLUTION Page 3 of3
 1074 FJP Working Group on Dissolution

TABLE 1
Dimensions of the Paddle/Basket Apparatuses (Millimeters)

Ph.J.12 Proposal
Ph.Eur.2 USP 23 (Suppl. 1) (EFPIA)

Vessel
Height 168 ± 8 160-175 160-175 160-210
Internal Diameter 102 ±4 98-106 98-106 102 ± 4

Paddle
Shaft Diameter 9.75 ± 0.35 9.4-10.1 9.75 ± 0.35 9.75 ± 0.35
(before coating)

Blade
Upper chord 74.5 ± 0.5 74.0-75.0 74.5 ±0.5 74.5 ± 0.5
Lower chord 42.0 42.0 ± 1.0 42 ± 1 42.0 ± 1.0
Height 19.0 19.0 ± 0.5 19.0±0.5 19.0 ± 0.5

Radius of the disk of

which the blade is cut
out 41.5 41.5 ± 1.0 41.5 41.5 ± 1.0
Radius upper corners 1.2' 1.2* 1.2** 1.2

Thickness 4.0± 1 4.0 ± 1.0 3-5 4.0 ± 1.0

Positioning the stirring

device
Distance between
inside of the bottom of
the vessel and the
blade 25±2 25±2 25±2 25 ± 2

Distance between
shaft axis and vertical
axis of the vessel $2 $2 $2 $2

Stirring characteristic smoothly with- smoothly without smoothly

out significant significant without signifi-
wobble wobble cant wobble
(s 0.5 mm) ($ 0.5 mm)
Basket
Shaft diameter (9.75 ± 0.35) 6.3-6.5 or (9.75 ± 0.35) 9.4±10.1
6.4 ± 0.1 9.4-10.1 6.4 ± 0.1

Screen
Wire diameter 0.254 0.254 (0.01 inch) No. 36 wire 0.254t
or 0.016 inch! gauze

Openings 0.381 0.381 (0.015 0.425 0.381t

inch)
or 0.034 inch"

Height of screen 27.0 ± 1 27.0± 1.0 27.0 ± 1 27.0±1.0

Total height of basket 36.8 ± 3 36.8 ± 3.0 36.8 ± 3 36.8 ± 3.0
Internal diameter of
basket 20.2 ± 1 20.2± 1.0 20.2 ± 1 20.2 ± 1.0
External diameter of
basket 22.2 ± 1 22.2 ± 1.0 22.2 ± 1 22.2 ± 1.0
External diameter of
ring 25.4 ± 3 25.4 ± 3.0 25.4 ± 3 25.4 ± 3.0
 FIP Guidelines 1075

TABLE 1
Continued

Ph.J.12 Proposal
Ph.Eur.2 USP 23 (Suppl. 1) (EFPIA)

Vent hole diameter 2 2.0 2 2.0 ± 0.5

Height of coupling
disk 5.1 ± 0.5 5.1 ± 0.5 5.1 ± 0.5 5.1 ± 0.5

Positioning of the
stirring device:
Distance between
inside of the bottom of
the vessel and the
basket 25 ±2 25± 2 25 ±2 25±2

Distance between the

shaft axis and the
vertical axis of the
vessel $;2 $;2 $;2 $;2

Stirring characteristic smoothly with- smoothly without smoothly with-

out significant significant out significant
wobble wobble wobble

* proposals to come (Re: USP 23 Suppl. 2 and PNPH/SG(94)83, May 94)

** proposed in JP Forum Vol. 3 NO.3 (July, 1994),see Figure 1
t basket to be used is indicated in the individual monographs
:j: should correspondwith the requirementsfor standards, eg, InternationalStandard ISO 2194-1972

ternative dissolution apparatuses should be
encouraged. If an individual drug product
cannot be accommodated by one of the appa-
ratuses, described above, altemative models
or appropriate modifications have to be de-
veloped. In such a case, however, superiority
of the alternative or the modification has to
be proven in comparison to the well estab-
lished and standardized apparatuses. In the
past, many papers intended to justify an alter-
native model by proving that in vitro dissolu-
tion results were equivalent or similar to
those obtained with, for example, the paddle
method. According to the understanding of
these guidelines, the latter provides clear evi-
dence that the paddle method should be used!
Modification ofthe apparatus as described
in the Pharmacopoeias or the harmonization
proposal in Table I can be intended for auto-
mation, for example, of the sampling proce-
dure. In such cases, whether it is, for exam-
ple, sampling via the hollow shaft of paddle
or basket or permanent sampling probes in
the beaker, which could potentially influence
agitation characteristics (7), or any other
measure, that results are equivalent with and
without the modification should be validated
on a product-by-product basis.
EXPERIMENTAL TESTING
CONDITIONS
For all applications, in vitro dissolution data
should at least allow some interpretation with
regard to in vivo biophannaceutical perfor-
mance. In order to increase their predictive
value, attempts have been made to adjust in
vitro test conditions (8-11) as close as possi-
ble to physiologic conditions. Nevertheless,
several examples demonstrate that such con-
ditions can also lead to misinterpretations
and are not able to guarantee in vitro results
routinely relevant to the in vivo situation
(12).
In general, an aqueous medium should be
used. Attempting to strictly mimic the physi-
limit is specificated to ensure (almost) quantitative drug release, which is generally ranges of changes for which the sameness of in vivo product performance is assumed, based
understood as ::::80 %. The dissolution run in quality control therefore should be extended on in vitro dissolution data. In addition, the Scale-Up and Post-Approval Change (SUPAC)
for the time interval until at least 80 % of drug substance is dissolved. Shorter test intervals document 0f FDA [36] defines the level of changes with respect to components and
can be acceptable in special cases but require justification on the basis of an in vitro-in vivo composition, site of manufacturing, the scale of manufacturing, and process and equipment
comparison study and should at least cover 24 hours. changes in manufacturing for an immediate-release oral formulation. Depending on the level
of change, different levels of dissolution testing are recommended to assure continuing
The acceptance range for the dissolution pattern at the time intervals specified should be product quality and performance characteristics. Respectively, the documentation needed to
defined case-by-case on the basis of the in vitro-in vivo comparison study and taking into assure the product performance varies, depending on therapeutic range, solubility and
consideration the capability of the manufacturing process and the commonly accepted range permeability factors of the drug. For changes greater than the acceptable values in the scale-
of 95 to 105 % of stated amount for the average content of drug substance. Where both up workshop report, additional dissolution profile determinations in several media are
upper and lower limits are specified at any time point, the difference between them should recommended for inunediate-reIease products.
usually not exceed. 20 % of the labelled content of drug substance in the formulation unless
limits have been shown to provide reproducible and acceptable in vivo performance [13]. For major changes, that are likely to have a significant impact on formulation quality and
performance, an in vivo bioequivalence study is reconunended in addition to extensive
dissolution profile testing. For manufacturing site change, scale-up, equipment changes and
8. Interpretation, Acceptance Criteria minor process changes dissolution testing is deemed sufficient to assure product quality and
performance.

Dissolution test specifications should include the defmition of limits, the number of units to
be examined and respective acceptance criteria. The procedure of data interpretation should In vitro dissolution tests have also been used to try to simulate food-effects on

be hannonised internationally, the existing compendial requirements should be uniform. bioavailabilitv. So far, these different attempts [37 - 43] have had extremely limited success
in prediction [44]. Assuming that gastro-intestinal transit times are significantly contributing
As pharmacopoeial approaches are still not fully hannonised it is recommended to follow to potential food-effects on bioavailability, the value of an in vitro model for food-effects
the acceptance criteria in accordance with USP for immediate/conventional-release products, will be limited to an evaluation whether direct drug-food-interaction could be of relevance for
modified-release (extended-release) products and gastro-resistant (delayed-release) products the observed changes in bioavailability in the in vivo study.

(Table 5). The approach with a maximum of these stages and individual units tested for
deviation from stated ranges corresponds well to requirements for content uniformity. Test media that may reflect gastric conditions (fasted) and intestinal conditions (fasted/fed)
Although there is preference in common practice in pharmaceutical industries to decide upon and thus may give additional information for research and development purpose are
batch release not later than stage 2, the three step approach is the best solution for formal surnmarised ill Table 6 [45]. Special tests have also bee suggested for consideration of
specifications, especially when referring to end-of-shelf life specification. Reference to specific situations, such as achlorhydric elderly patients [46].
labelled content does not apply for products with intentional different content at time of
manufacturing, such as in cases of stability average.
10. Conclusions

9. Special Applications In many international discussions, mainly over the years 1988 to 1993, consensus was
reached on some essential aspects, to which these Guidelines refer. On the other hand, many
A specific value of dissolution testing is recognized in its applications in scale-up and aspects have either not yet been sufficiently explored or have not been harmonised. In these
manufacturing changes for immediate/conventional-release and modified-release oral cases, e.g. more precise specifications of dissolution media and proposals for in vitro-in vivo
products. The AAPSfFDAfUSP Scale-up workshops [34, 35] recommend certain types and comparison approaches and verification of specifications for immediate/conventional-release,

Page 8 ofl2
delayed-release and modified-release preparations, the revised Guidelines will provide device
contributions for reasonable standardisation, while acknowledging that for a number of drugs Distance from the bottom 25 ± 2 25 ± 2 25 ±2 25 ± 2
e.g. with special physico-chemical or pharmacokinetic properties, case-by case development Distance between shaft axis
is required. and vertical axis of the vessel :52 :52 :52 :52

These Guidelines should be helpful and applicable for all involved in in vitro dissolution Stirring characteristics Smoothly Smoothly No comment Smoothly
testing. However, there was special emphasis on providing reliable guidance for industrial without without without
research and development, process val idation and quality control, making the Guidelines significant significant significant
especially applicable for industry, drug authorities and control laboratories but also for wobble wobble wobble
universities, hospitals, pharmacies or others, when involved in (bio )pharmaceutical quality (:50.5 mm)
evaluation.

In general these Guidelines should be understood as recommendations based on scientific

knowledge and experience. They should be helpful in the dialogue with drug regulatory
authorities. However they are not intended to represent any official requirements in this field.

Table 1: Dissolution. Paddle and Basket Apparatus, Dimensions (mm) of the

Vessel and the Paddle Table 2: Dissolution. Paddle and Basket Apparatus, Dimensions (mm) of the
Basket.
Item
I EP III
I USP23
(Suppl. 5)
I JP XIII IProposal
Item Proposal
EP III USP23 JP XIII
Vessel (Suppl. 5)
Height 163 ± 8 160 - 175 1160 - 175 1160 - 210 Basket
Internal diameter [02±4 98 - 106 98 - 106 [02 ±4 Shaft diameter (9.75 ± 035) 63 - 6.5 or 9.75 - 035 or 9.4-10.1
(ccrrcs. to shaft dia.
6.4 ± 0.1 9.4-10.1 6.4 ± 0.1 of the paddle)
Paddle
Screen
Shaft diameter 9.75 ± 0.35 9.4 - 10.1 19.4 - 10.1 19.4 - 10.1
Wire thickness 0.245 0.254 or N° 36 sieve 0.25 t )
before coating 0.406
Openings 0.381 0.425 0.400' )
Blade 0.381 or
Heigh of screen 270± 1 27.0± I 270 ± 1.0
Upper chord 74.5 ± 0.5 74.0 - 75.0 74.0 -75.0 74.5 ± 0.5 0.864
Total height ofbasket 36.8 ± 3 36.8 ± 3 37.0 ± 3.0
Lower chord 42.0 ± [ 42.0 ± [0 42.0 42.0 + [0 270 ± 1.0
Internal dia. of basket 20.2 ± 1 20.2 ± I 20.0 ± 1.0
Height 19.0± I 19.0±0.5 19.0 ± 0.5 19.0±0.5 36.8 ± 3.0
External dia. of basket 22.2 ± 1 22.2± 1 22.0 ± 1.0
Radius (disk) 41.5 41.5 ± [0 41.5 41.5 ± [0 20.2 ± 1.0
External dia. of ring 25.4 ± 3 25.4 ± 3 25.0 ± 3.0
Radius (upper comers) 1.2 1.2 1.2 12 22.2 ± 1.0
Vent hole diarnenter 2 2 2.0 ± 0.5
Thickness 4.0± [ 4.0 ± 1.0 4.0 ± 1.0 4.0 ± 1.0 25.4 ± 3
Height of coupling disk 5.1 ± 0.5 5.1 ± 0.5 5.0 ± 0.5
2
Positioning of the stirring 5.1 + 0.5

Page 9 of 12
Positioning of the stirring Phosphate buffer solution pH 4.5:
device
Distance from the bottom 25 ± 2 25 ± 2 25 ± 2 25 ± 2 13.61 g monobasic potassium phosphate are dissolved in 750
Distance between shaft axis ml of water. After adjusting the pH to 4.5 with 0.1 N
and vertical axis of the vessel ~2 ~2 ~2 ~2 hydrochloric acid or O.IN sodium hydroxide, water is added
to make 1000 mI
Stirring characteristics Smoothly Smoothly Nocommcnt Smoothly
without without without
significant significant significant Simulated intestinailluid 250 ml of a solution containing 6.8 g monobasic potassium
wobble wobble wobble without pancreatin pH 7.5 phosphate
(max. runout (max. runout + 190 ml ofO.2N sodium hydroxide
± Imm) at the basis of + water to make 1000 rnl
the basket ± I
nun)
0.05M phosphate buffer 50 volumes of 0.2M monobasic potassium phosphate
solution of pH 5.8 to 8.0 solution
i ) Test sieve (40 mesh) according to DIN ISO-Nonn 3310 (Part I): 1990 (dimensions + specified volume of 0.1 N sodium hydroxide
relevant for the plain wire cloth) + water to 200 volumes

pH 5.8 6.0 6.2 6.4 6.6 6.8 7.0 7.2 7.4 7.6 7.8 8.0

NaOH 3.6 5.6 8.1 11.6 16.4 22.4 29.1 34.7 39.1 42.4 44.5 46.1
(volumes)

Table 3: Proposed Dissolution Media

Medium Proposed Comoosition

O.IN hydrochloric acid 3.636 g of HCl, corresponding to 8.3 ml hydrochloric acid

37% (m/m) per 1000 ml of aqueous solution Table 4: Possible reasons for poor in vivo-ill vitro correlations

Buffer solution pH 4.5
Fundamentals
Acetate buffer solution pH 4.5:
in vivo dissolution is not the rate limiting step for drug absorption
2.99 g of sodium acetate trihydrate and 1.66 g of glacial acetic no in vitro test is able to model in vivo dissolution
acid are dissolved in water to 1000 ml
or Study design

Page 10 of12
 Stage Number Tested Acceptance Criteria
• inappropriate in vitro test conditions
• inappropriate in vivo test conditions
LI 6 No individual value lies outside eaeh of
the stated ranges and no individual value
Dosage form
is less than the stated amount at the final
test time
drug release not controlled by the dosage form
• drug release strongly affected by intestinal transport kinetics
~ 6 The average value of the 12 units (LI +
Drug substance L2) lies within each of the stated ranges
and is not less than the stated amount at
• non-linear pharmacokinetics (e.g. saturable first pass effect), absorption window, the final test time; none is more than 10 %
chemical degradation in the gastrointestinal tract of labelled content outside each of the
absorption of undissolved particles stated ranges; and none is more than 10 %
• large intra individual variability of labelled content below the stated
amount at the final test time

Table 5: Acceptance Tables According to USP 23 <711> 12 The average value of the 24 units (L] +
L3
L2 + L3) lies within each of the stated
Sa: Immediate/conventional-Release Drug Products ranges, and is not less than the stated
amount at the fmal test time; not more
Stage Number Tested Acceptance Criteria than 2 of the 24 units are more than 10 %
of labelled content outside each of the
stated ranges; not more than 2 of the 24
SI 6 Each unit is not less than Q + 5 %
units are more than 10 % of labelled
content below the stated amount at the
S2 6 Average of 12 units (SI + ~) is equal to final test time; and none of the units is
or greater than Q, and no unit is less than more than 20 % of labelled content
Q -15 % outside each of the stated ranges or more
than 20 % of labelled content below the
stated amount the final test time
S3 12 Average of24 units (Sl + S2 + S3) is equal
to or greater than Q, not more than 2 units
are less than Q - 15 %, and no unit is less
than Q - 25 %

5b: Modified (Extended-Release) Drug Products

Page 11 ofl2
 B3 12 Average of the units (B I + B2 + B3) is
equal to or greater than Q, not more than 2
units are less than Q - 15 %, and no unit is
5c: Gastro Resistant (Delayed-Release) Drug Products less than Q - 25 %

Acidic stage

Stage Number Tested Acceptance Criteria

Al 6 No individual value exceeds 10 %

dissolved
Table 6: Dissolution media that may reflect gastric conditions (fasted: SGF) and
conditions in small intestine (fasted: FaSSIF; fed: FeSSIF)
A2 6 Average of 12 units (A I + A2) is not more
than 10 % dissolved, and no individual SGF FaSSIF
unit is greater than 25 % dissolved
HCI 0.01-0.05 N KH2 P04 0.029 M
Sodium lauryl sulfate 2.5 G NaOH q.s pH 6.8
A3 12 Average of the 24 units (A I + A2 + A3) is
Sodium Chloride 2.0 G NaTaurocholate 5mM
not more tban 10 % dissolved, and no
Distilled Water qs. 1000 ml Lecithin 1.5mM
individual unit is greater than 25 %
dissolved KCI 0.22 M
Distilled Water q.s. 1000 m l

Buffer stage
FeSSIF
Acetic acid 0.144 M
Stage Num ber Tested Accepta nee Cri teria
NaOH q.s. pH 5
NaTaurocholate 15 mM
B1 6 Each unit is not less than Q + 5 %
Lecithin 4mM
KCI 0.19 M
B2 6 A vcrage of 12 units (B I + B2) is equal to
Distilled Water Q.S. 1000 ml
or greater than Q, and no unit is less than
Q -15 %

Page 12 of 12