flP Guidelines for Dissolution

Testing of Solid Oral Products

Joint Report of the Section for O"icial laboratories
and Medicines Control Services and the Section of
Industrial Pharmacists of the FIP
III 1981 FrP pllblisb,d Gllidelilles }or Dissoilltioll Testing of Solid ami Prodllcts Ilf If )oilll " ' p01./ oftbe
Section for Official Lnbornwries fi nd Medicines Coutrol Services flll d tbe Section oj l11dustrifll Pbn17l1ocists.
Tllese guitldillrs were il1ft'lltled flS suggestions primflrily directed to rompendifll c01J1mittees, working 011 the
illnwluctioll oJdissollltioll/"clellsc tests for the rCJpcctive pl)(wlIlflcopoeius.
During tbe pflSt 15 years there bove befl11!1f1I1Y developmems. Biopbflrlllflcelitics bns flttrflrled 7Jlllcb scien-
tific liS well os politicnl imrrest. Dissollltioll test 1IIftbodology bos been introduced to 1I1011Y phu17llflcopoeios lind
1I1l11111ber ofregulllfions IIl1d guidelines 011 bioovnilnbiJity, bioeqllivnlt11fe and ill vitro dissolution terri11g hllve
been ismed nt IIntiOllfll lll1d ill/ernntiollal level.
The joint working group 011 dissolution of/be two PIP sections tberejore decided to eSfflb/ish (llIew dissolll -
tioll guidelille, ttlkillg rill these developments illfo cOllsitiemtion bllt addiug proposfllsJorjil1'ther bflrmoJliul-
fiol/ fllld for d('jillitiollS fllld pro(edures whieb (Ire 110t yt'f L'Ovel'ed b)1 imemntioll fll recommeudotiol1s.
PIP pI/bJis/wl tbe "jillfll d/'llft" version ill 1995 II l1d co-sponsored fll1ll1fer'l1l1fiol1nl f.Vorksbop il1
November 1996 to give collet1glles from IIniversities, drug II I1/horities, phfll1l1acopoeills find pbllrmoeellti(fll
illdustries the to contribute v.;itb tbeil' c01Jl7llellls fo1' fil11ber i1Jlprove1llem of tbe gllidelim text
prior to tbis pllbJimtio11 of tbe fi1l1l1 "officiar veniol/.
The following guideline is tbe reSlllti1lgfil1a/"ojJid(" " vtf':!;ioll and "ep,'csellfs tbe position find poliry oj
FlP all DiJ'So/miol1 flS oj December 1996.
Introductory Remarks
T
he fi rst GUIDELINES FOR DIS-
SOLUTION TESTING OF
SOLID ORAL PRODUCTS were
published in 198 1 [I] as a joi nt
report of the Section for Official Laboratori es
and Medicines Control Services and me Secti on
of Industri al Pharmacists of the F.l.P. These
Guidelines were intended as suggestions primar-
il y directed to compendial cOlllmittees, working
on the introduction of dissolution/ rel ease tests
for the respective Phannacopoeias.
Duri ng the past decade, there have been
mall }1 developments. Bi opharmaceutics has
attracted much interest scientifi call y as well 3S
regarding drug regulatory poli cies. Dissoluti on
test methodology has been introduced to many
Phannacopoeias and a number of regulati ons
and guidelines on bioavailabi lity, bioequi val ence
and in vi tro dissolmi on testing have been issued
at national and international levels.
These updated Guidel ines (second edition)
are !:he result of carefu l discussions of the joint
1V0rking group of the two F.l.P. sections and are
based on recent developments. Descripti ons of
test methodology are no longer necessary,
because they are already published elsewhere,
offi ciall y or semi-offi cially. Differences between
the regulations of differem countri es and com-
pendias were identified and proposals for har-
monisation are made.
As far as is reasonabl e for the purpose of these
Guidelines, rechni cal terllls and definitions have
been adopted from other hannonised recom-
mentions and mainly correspond to USP-renni-
nology. New tenns are "in vitro-in compar-
ison," "Verification" and "side batches." "In
vitro-in vivo comparison" means any study col-
lecting in vitro- and in vivo-data 011 the sallle set
of test specimen to obtai n information and
understandi ng about how in vitro and in vivo
performance are related to each other, A signifi-
cant in vitro-in vh'o correlation can be a result of
an in vitro-i n vivo comparison study, hm valuable
infornlatioll could also be obtained when no cor-
relation in a strict sense (e.g. USP levels) is
achieved. 'I'Verification" is used to define the in
vivo data set which provides evidence that a cho-
sen in vitro test method and the proposed limitS
are suitable for the drug fonnulation in tenns of
biophann3ceutical perfonnance. "Verification" is
proposed as a new tenllinus technicus to avoid
the extension of "validation" on in vivo investi-
gations. "Side batches') are batches of a given
dnlg fonnulation which represent the intended
upper and lower dissolution limits. The)' are pre-
ferrably to be derived from the defined manufac-
turing process by setting process parameters
within the range of maximum variability expect-
ed frolll process validation studies. The term
"di ssolution" itself is used for all dosage forms,
Tbe following guideline
'[vas elaborated by PIP '[vir/)
COIIN'ibutiol1S fi'om:
J, M, AiIC'I, C/cl7lumt Pn7"lll1t,
N. IIJ1!lI, 70kyo,
H. 111.1, Esrb/JonJ,
J. lressall, F1'tI1lkfi01,
H. I. Ll'Ve1'kusen,
l. I. GI'I_I, Rockville,
i. GI'II, Rorkville,
p. .'''11, B1'OIlSboj,
I. Nllert, Rod'Ville,
1. 11,,-lllel, Genevn,
J, lri.lr, Escbborn,
. IrislllSlI, Copenbllgell,
F. lllllll .. ler. fillSCl,
l. llISII , jV1olllVille,
l. lelll, Rockville,
J. U.'erl. Bedin,
I. McGllnraJ, Oftll7.L!fI,
N. Miller. Fnmkfllrt,
S. Ilres'i, Ottawa,
i. P.IIII, Rockville,
M. Siewert, Fmnkj;wf,
R. l illrlri' , /JOIIII,
J. I. WlllersSll, Upi'mlll,
I. Wlilel .. , Kallsfls City,
I. WirlilZkl, Frnnkjrm.
I
Disso/lltio11Tecimoiogies/NOVEM BER 1997
flP Guidelines ... cont.
i.c. imlllediate-release (such as prompt drug releasing or conventional
dosage fOfms) as well as lllodified-relc3sc products (such 35 controlled,
delayed, extended, modified, prolonged or sustained).
1. Concepts of Dissolution Testing
In vitro di ssolution testing serves as an important rool for chanlc-
rerising the biopharll1:Jccutical quality of a product at different stages
in its lifccycle. III early drug dcveloplllcm in vitro dissolution proper-
ties arc supportive for choosing between different alternative (annu-
btion candidates for further development and for evaluation of active
ingredientv'drug 5ubst:1I1CCS. In vitro dissolution data are slipporti\,c
in the evaluation and imerpretation of possibl e risks, especi;:dly in the
c,lse of controlled/modified-release dosage fonns - e.g. as regards
dose dumping, food effects on bioavailibility or interaction with other
drugs, which innuence g:lsrrointestinal environmenl;ll conditions.
Biophannaceutical aspects are as important for stability concems as
they ,Ire for batch release after production, in vitro dissolution being
of high relevance in quality control and quality assurance. Last bur
nor least, in vitro dissolution data will be of great importance when
assessing ch'lIlges in production site, manufacturing process or for-
Illulation and assist in decisions conceming the need for bioavaibbil-
ity studies.
None of these purposes can be fulfill ed by an in vitro test system
without sufficient reliability. Reliability here would be defi ned as the
system being experimentally sound, yielding precise, accurate, repeat-
able results and with sufficient knowledge of the in vivo relevance of
the dissolution data obt:lined.
telll design was adopted as firs( official method in USP XVIII in
1970, described as rhe rotating basket (apparanlS I, USP).
The rotating basket and the paddl e (apparatus 2, USP) devices
arc simple, robust and adequately standardised apparatuses which are
used all around the world and thus arc supported by the widest expe-
ri ence of experilllemaluse. Jt is because of these advantages that rhe
paddle and rotating hasket app:lranlses are recommended in various
guidelines as first choice for the in vitro dissolution testing of imme-
diate as well as controlled/modified-release preparations.
I lowever, because of the "si ngle container" nature of the pad-
dle/hasket apparatus experimental diffi culties may ilrisc in tenns of
rhe nced of a change in pH or of any other (p,lrtial) change in the test
mcdium during an investigation. Furthermore, difficulties arise for a
number of sparingly soluble dmgs and for some dosage fonns, par-
ticuhuly aerophilic multiple unit dosage fonns that, tend to float ini-
tiall y. Proposal s h:lVe been made to increase solubility by addition of
.1Il ;lppropri:ltc amount of surfactant.
lVith the flow-through cell (a pparatus 4, USP) the specimen is
placed in a small column which is continuously flushed with a stream
of fluid, si multaneously providing the medium and the mechanical
agit<n-ion for dissolution of the drug substance. It can be nm as an
open as well as a closed system. The open system design especially
providcs several advantages in some of the difficult cases mentioned
abm'e :md was adopted first by the Deutscher Arl.neimittelcodex
(German Pharmaceutical Codex, DAC) in 198 I.
The now-through apparatus is currentl y monogf<lphed in USP,
Ph.ElIr . md Ph.J ap. Description of thc system is concordant world-
wide. The paddl e/basket system is described in U S ~ rhe European,
the.l 'lp'lnese ,Ind many other Pharmacopoeias. Some minor discrep-
ancies are still found in details of the respective monographs. Full
Requirements for dissolution testing have been reviewed in the lit-
erature 12 - 61. Since in vitro dissol ution is a physical test, defined by
convention ;md is of a destnlcti\,C nanlrc, proving reliabi li ty requires
special attcntion. It therefore is within the scope of these
Table 1: Dissolution. Paddle and Basket Apparatus, Dimensions [mm) of
the Vessel and the Paddle
Guidelines to define suitable testing equipment and
experimental design as well as to suggest the background
for adequate physical and allalytical validatioll, together Item EP III U5P23 IP XIII Proposal
with verification procedures according to the state of bio- ,---,---------------"'=="----------
Vessel
(5uppl.5)
pharmaceutic]! science. Height
The Guidelines arc primarily dedicated to solid or,,1 Int ernal diameter
16H 8 160 175 160 175 160 210
102 4 98 106 98 106 102 4
products. Il owever, the general concepts Ill,ly be adapt- "' P"ad""d"I. ,---------------------------
ed to in vitro dissolution testing of dmg substances/po\\'- Shaft diameter
ders, semi-solid oral products, suppositories and, with ~
distinct restrictions, to other non-oral products. Upper chord
2. A p/JfWatliS
Large Ilumbers of different dissolution ,lpp,lranlses
<Ire described in the litenuure, but only some of them
withstand critical methodological examination.
1\\'0 basic technical principles are ilpplied for in vitro
dissolution resting: the "stirred heaker
method" and the "flow through procedure,"
The "stirred beaker method" places the test
specimen :lI1d a fixed volume of fluid in a
large vessel, and stirring provides mechanical
(hydrodynamic) agitation. This closed sys- II
Disso/lllioI7Tecbll% giesINOVEM BER 1997
lower chord
Height
Radius (disk)
RadiUS (upper corners)
Thickness
Positioning of the stirring device
Distance from the bottom
Distance between shaft ax.is
and vertical ax.is of the vessel
Stirring characteristics
9.75 0.35
74.0 0.5
42.0 1
19.0 1
41.5
1.2
4.0 1
25 2
< 2
Smoothly
wllhout
significant
wobble
9-1 ' 10.1 9.410.1
be are coating
9.4 10.1
74.0 75.0 74.0 75.0 74.0 0.5
42.0 1.0 42.0 42.0 + 1.0
19.0 0.5 19.0 0.5 19.0 0.5
41.5 1.0 41.5 41.5 1.0
1.2 1.2 1.2
4.0 1.0 4.0 1.0 4.0 1.0
25 2 25 2 25 2
<2 < 2 < 2
Smoothly No comment Smoothly
without without
significant Significant
wobble wobble
0.5 mm)
Table 2: Dissolution. Paddle and Basket Apparatus, Dimensions (mm) of the Basket.
Item
Basket
Shaft diameter

Wire thickness
Openings
Height of screen
Total height of basket
Internal dia. of basket
External dia. of basket
External dia. of ring
Vent hole diamenter
Height of coupling disk
Positioning of the stjrring

Distance from the bottom
Distance between shaft axis
and vertical axis of the vessel
Stirring characteristics
EP III
(9.75 0.35)
6A 0.1
0.245
0.381
27.0 1
36.8 3
20.2 1
22.2 1
25.4 3
2
5.1 0.5
25 2
52
Smoothly
without
significant
wobble
USP23
(Suppl. 5)
6.36.5 or
9.4. 10.1
0.254 or OA06
0.381 or 0.864
27.0 1.0
36.8 3.0
20.2 1.0
22.2 1.0
25.4 3
2
5.1 0.5
25 2
5 2
Smoothly
without
significant
wobble
(max. runout
1 mm)
JP XIII Proposal
9.750.35 or 9.4.10.1
6.4 0.1 (corres. to shaft dia.
of the paddle)
W 36 sieve 0.25
11
OA25
O.4001i
27.0 1 27.0 1.0
36.8 3 37.0 3.0
20.2 1 20.0 1.0
22.2 1 22.0 1.0
25.4 3 25.0 3.0
2 2.0 0.5
5.1 0.5 5.0 0.5
25 2 25 2
52 5 2
No comment Smoothly
without
significant
wobble
(max. runout
at the basis of
the basket
lmm)
I I Test sieve (40 mesh) according to DIN ISONorm 3310 (Part 1): 1990 (dimensions relevant for the plain wire cloth)
intern,ltional hannonisation is
strongly recolllmended 3S proposed
in lilbles I and 2.
Another system (apparatus J) USP
describes the reciprocating qrlinder.
vVith these four apparatuses, dissolu-
tion testing of most oral dmg prod-
ucts should be possible on a reasoll-
able basis. Neither too tight restric
tions nor unnecessary proliferation of
alternative dissolution apparatuses
should be encouraged. If an individ-
ual drug product cannot be accomo-
dated by one of the apparatuses,
described above, alternative models
or appropriate modifications have to
be developed. However, in such a case
superiority of the alternative or the
modification has to be proven in
comparison to the well established
and standardised ilpparatuses. In the
past, many papers intended to justity
an alternative model by proving that
in vitro dissolution results
were equivalent or simi lar
to those obtained with
e.g. the paddle method.
According to the under-
standing of these II
Dis.fOlutionTechn%giesINOVEMBER 1997
FIP Guidelines ... conI.
Guidelines, the latter provides clear evidence that the paddle method
should be used'
Modification of the apparatus as described in the Ph;mnacopoeias
or the harmonisation proposals in T.1bles I and 2 can be intended for
automation e.g. of sampling procedure. in such cases, which could
potentiall y have an influence on agitation characteristics [7], or any
other measure, it should be validated on a product-by-product basis
that results are equivalent with and without the modification.
The pH of the test medium should be set within pH I and 6.8. A
higher pH needs to be justified on a case-by-case basis and in gener-
al shuuld not exceed pH 8. For low pH in the acidic ra nge Hel
should be used (0.1 N I-)el for pl-l I). If, in a certain case, artificial gas-
tric juice without enzymes (pH 1.2) is advantageous, this should be
dcmollstT<lted. The use of simulated gastric juice (with pepsin) may be
appropri'ltc for gelatine capsules.
In the pH-range of 4.5 to 8.0 USP buffer solutions are recom-
mended, as sUlllmarized in T.1ble 3. A change of pH of dissolution
3. Experimental Testing
Conditions
Table 3: Proposed Dissolution Media
For all applications, in vitro dissolu-
tion data should at least allow some inter-
pretation with regard to in vivo biophar-
maceutical performance. In order to
increase their predictive va lue, attempts
have been made to adjust in vitro test con-
ditions [8 - II [ as close as possible to
physiologic conditions. Nevenheless, sev-
eral examples demonstrate that such con-
ditions can also lead to misinterpretations
and are not able to guamntee in vitro
results routinely relevant to the in vivo sit-
uation [12].
In general, an aqueous medium
should be used. It is not recommended to
Medium
O.lN hydrochloric acid
Buffer solution pH 4.5
Simulated intestinal fluid
without pancreatin pH 7.5
0.05M phosphate buffer
solution of pH 5.8 to 8.0
Proposed Composition
3.636 g of Hel. corresponding to 8.3 ml hydrochloric acid 37% (m/m) per
1000 ml of aqueous solution
Acetate buffer solution pH 4.5:
2.99 g of sodium acetate trihydrate and 1.66 g of glacial acetic acid are
dissolved in water to 1000 ml
or
Phosphate buffer solution pH 4.5:
13.61 g monobasic potassium phosphate are dissolved in 750 ml of water.
After adjusting the pH to 4.5 with 0.1 N hydrochloric acid or O.lN sodium
hydroxide. water is added to make 1000 ml
250 ml of a solution containing 6.8 g monobasic potassium phosphate
+ 190 ml of 0.2N sodium hydroxide
+ water to make 1000 ml
50 volumes of 0.2M monobasic potassium phosphate solution
+ specified volume of O.lN sodium hydroxide
+ water to 200 volumes
attempt to strictly mimic the physiologic
gastroi n testi n a I en vi ronm ent (e.g. com _ .:.P,..H=_--,5:-.8::-----:6
cc
0:---:-6 . ..,2_-,-6.:-4::---:6-::. 6-,-_6".,..8 -:---:-7 .:-0-:---,7". 2:-::-_-::7".4-,-_7::.6:-:-_7,.-.:-8::--:-8 .:-0_
position of gastric or intestinal fluid) but 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
to choose the testing conditions as far as
(volumes)
is reasonable, based on the physico-chemical characteristics of drug
substance, within the range which a drug or dosage form could expe-
rience after oral administration. These following ranges were estab-
lished based on several conferences and recommendations [e. g. 13 -
LSI- There might be specific products for which no dissolution test
can be established without exceeding the recommended ranges of test-
ing conditions. In these cases, it should be clearly demonstrated that
dissolution r s u l t ~ obtained with other, more extreme testing condi-
tions (e.g. pH > 8.0) allow for appropriate biophannaceutical inter-
pretation.
For basket/paddle mecllOds the volume should be 500 to 1000 ml.
900 ml had been introduced historically; 1000 ml should be easier to
handle in a metric system, this vol ume being practicable with all
equipment commercially available today. 1000 ml therefore should be
considered for new drug products or in case of a revision of existing
test procedures. This recommendation does not mean that 1000 Illi
should be adopted to all existing test procedures and specifications.
Although larger vessels, such as up to 4,000 ml, could be
8
advantageous fo r poorly soluble dmgs, they are not
described in compendia, and thus are not as well stan-
dardised and therefore should be regarded as modification
of a compendial method (see section 2.)
DisrollltiollTecim%gieslNOVEMBER 1997
medium during the test or a pH gradient may be appropriate for gas-
troresistcnt formulations and products for which dissolution testing
at one pH-levd or at different pH-levels in parallel does not give bio-
pharmaceutically relevant results.
The use of water as dissolution medium bears the disadvantage
that test condition details, such as pH and surface tension, can vary
depending on the source of water and may be changed during the
dissolution test itself, due to the influence of the dmg product and to
the (re)absorption of carbon dioxide frolll air. \Nater therefore is
recommended as dissolution medium only when it is proven, that the
variations mentioned do not have influence on tl,e dissolution char-
acteristics.
Further additives e.g. enzymes, salts or surfactants, could be con-
sidered in specific cases. Their use should be justified as regards
nature and concentration of additive [16J. Addition of organic sol-
vents should be avoided.
Agitation typically should be obtained in the basket/paddle appa-
ratus by stirring at 50 to 100 rpm and in general should not exceed 150
rpm. Although maximum discriminatory power should be obtained
with lowest stirring rate, in Illilny cases experience with 75 rpm was
feltto represent a reliable agitation for paddle equipment [17].
Regarding media temperature, 37 O.5'e should generally be
used for oral dosage fonns. Slightly increased test temperatures (e.g.
(e.g.J8 0.5'C) are under consideration for special applications e.g.
for rectal dosage forms, lower temperatures (e.g. 32 O.5'C) for
transdermal systems.
Relevant parameters to be considered for the detinition of test
conditions are solubility and deaeration. In fonner Guidelines f1 L
"sink" conditions were requested. "Sink" was defined in different
ways e.g. as 10 to 20% [II or approximately 30% [18J of sol ubility
concentration to assure tl1<1t dissolution is not significantly influenced
by solubility characteristics. Since "sink" conditions per se do
not guarantee in vivo-in vitro associations and since reliabl e and pre-
dictive in vitro profiles in certain cases can be obtained by violating
"sink" conditions, solubility and drug substance concentrations
during the test should be matter of verification studi es to demonstrate
that a chosen in vitro test metllOd yields biopharm3ceutically
relevant results.
Case-by-case validation is also required regarding deaer,ltion since
some formulations will be sensitive whereas others are robust in this
concern, thus making deaeT<ltion unnecessary. 'fhe deaeration
method has to be dearly characterised, since the method chosen can
have impact on dissolution profiles [19J. It is noted that the flow rate
in the flow-tluough cell (open circuit) is particularly sensitive to the
presence of air in the medium.
Ph.jap. is currently the only Phannacopoei,l that requi res a spe-
cific (very solid) sinker device for all capsule fonnulations. USP rec-
ommends a few turns of wire helix when specimen tend to float.
EFPIA harmonisation proposal suggests a similar one. Sinkers can
significantly influence the in vitro dissolution protlle of a drug 120J.
Since they are used especially with fonnulations causing problems
during test performance, e.g. flmation, tlley will alter the dissolution
profile, so that other recommendations liS] are not applicable.
The lise of sinkers therefore has to be part of case-by-case disso-
luti on validation as well as of in vi tro-Ln vivo comparison shldies. Any
strict requirement on use of si nkers or specifi c sinker types lacks sci-
cntific justification.
4. Qualification and Validation
Due to the nature of the test method, quality by design is an
important qualification aspect for ill vitro dissolution test equi pment.
Besides the geometrical and dimensional accuracy and precision as
described and commented in section 2 (including Tables I and 2), any
irregularities such as vibration or undesired agitation by mechankal
imperfection are to be avoided.
Besides the specification of the apparatus, qualification of dissolu-
tion equipment has to consider critical parameters, e.g. temperature
of test medi um, rotation speed/flow rate, volume, sampling
probes and procedures, to be monitored periodically during the
periods of use.
Apparatus suitability test is a further important aspect of qualifica-
tion and validation. The use of USP calibrator tablets (disintegrating
as well as non-disintegrating) has been controversial for some time.
However, it is the only standardised approach and has been helpful to
identify system or operator fililurcs. Since some individual drug prod-
ucts might reveal similar or even higher sensitivi ty against technical
variance in comparison to USP calibrator tablets, "in-house" stan-
dards are judged acceptable as additional, or, if validated, equivalent
for calibrator tablets.
The suitability test has to cover each individual apparatus. Paddl e
lind basket equi pment, as well as 12 mm and 22.6 mill flow-tllrougb
cells have to be qualified, unless only paddle or basket, or in the case
of flow-through cells only small 0,. large cell is used in one specific
piece of equipment. The system su itability test of USP Apparatus
must be performed with both a multiparticubue and a monoparticu-
late standard formulation. A system suitability test for flow-tllrough
cells has just been established and will be soon published 1221.
Apparallls suitability tests are recolllmended to be performcd not
less than twice per year per equipment and after any equipment
change, significant repair or movement. However, a switching
between paddle and basket, when the apparatus has been calibrated
for both, should not require recalibration.
Additional validation aspects are precise product related operation
instructions (e.g. deacration procedure). Dissolution results may be
influcnced by the physical behaviour of the specimen stich as floating,
adherence to the walls, etc. Thus, critical inspection and observation
of test performance during thc test procedure is required. This
approach is especiall y important to explain any "out-lying" results
and it dearly limits the extent of automation for a number of drug
formulations.
Validation of automated systems, either conceming the sampling
and analytical part or also including media preparation and test per-
formance, has to consider accuracy, precision and avoid com3lllina-
ion by any dilutions, transfers, cleaning or sample or solvent prepa-
ration procedures. There should be proof thar there is no interfer-
ence. This shall be evidence of no significant differences between
data obtained with the lllanual dissolution equipment (see section 2)
and the automated system, including manipulations sllch as pemla-
nent sampling probes, additional valves, hollow shafts, etc. Since sen-
sitivity to such modification may be fonnulation related, qualification
and validation of automated dissolution equipment and testing has to
be established on a case-by-case basis.
Validation of the analytica l procedures applied in dissolution test-
ing, either automa ted or conventional, has to comply with
"Va lidation of Analytical Procedures" (lCH) and "Y.1Iidation of
Compendial Methods" (<1225>, USP). Validation aspects UlUS are
accuracy, precision (repeatability, reproducibility), specificity, lineari-
ty, range. Special care has to be taken regarding stability of the drug
in test medium and sampl e sol utions, since the test procedure often
includes exposure to hydrolytic media at 37C over significant
time spans.
5. Formulation Cbamcte>"isation
During development of the drug formulation, as a
basis for any in vitro-in vivo comparison srudy as well as
for the final choice of test conditions for quality control
DissolutionTechnologieslNOVEMBER 1997
flP Guidelines ... cont.
purposes, the respective dos.lge form h,15 to be thorough1r char<H:-
tcri'ied in vitro widl respect to its biopharm:lcclltical performance.
Special ancmion has ro be paid to controlled/modified-release prepa-
rations, since sufficient information has to be gai ned about hO\\ Illllch
the dosage form nlther than variations in test conditi ons,
trol" the rate of dntg release.
Therefore, exrensivc dissolution tests ,lre necessary to l1nderst;lIld
the delivery system and to have a rationale for the design of e,g. an in
vitro-in vi \,o comparison study. The in vitro test profil e will prefer-
ahly consist of numerous indi vidual di ssolut:i oll test>; under many dif-
ferent rest conditiolls, involving the pH of test media and agimrion
wi thin the ranges given in seerion 3. \ /a riarion of ionic strcngth, sur-
fact:lnts, enzymes or apparatus should be e\',llu,lted, if an influence 0 11
dissolution is expected for the individual fonnulation.
For formulation characterisation, dissolution tests should bc per-
formed under the di ffere nt test conditions until actual di ssolution
(e.g. mcan of six specimen) exceeds 80% of labelled amounl. \ \'hen,
even with test prol onbration, results remain significantly below 80%
and solubility is not the limiting parameter, recovery control should
be performed to prevent mi sinterpretation of di ssoluLion dar;l.
J\llost in vitro characteristics can be rehlted to physiologic,l l p;u'a-
meters, such as pi I-profi le of test medi,l (gastric ,mel intestinal pi I),
stirring or flow r:lt'e (gastfointestinallllotility, she:l ring forces), :lddi-
tion of lipids, enzymes, surfacta nts (to si mulate the physioiogicil cnvi-
ronment). Thus, the information from formulation ch:lracrcri sarion
in vitro can hc used later ;IS a tool to dcmonstnl te the rcliabiliry of;lJl
in vi[ro-in vivo compari son, based on a di stinct in vi tro model, as \\ell
as for int erpretation of all those exampl es where no or onl y a poor
correlation of in vitro and in vivo data can be achi eved. Il o\\e\'er, it is
obvious thil t ;1 meaningful in virro*in vivo col11l);}risoll (sec section 6)
is [he more probabl e. the less affected in vitro dissol ution of a given
drug formulati on is by changes in the environmcntal tcst conditions.
6. In vitro-in vivo Comparison
An in vitro test system for a given dmg fonnuhttion sen'es as the
tool as which it is dcsignated only, if it can disrjnguish hetween
"good" and "bad" batches. "Good" here means "of accept<lbl e and
reproducibl e hioph;lI'Inaccutical performance in vivo". Thus ill vivo
rele\',l1l ce of;1ll in vitro test system is sought. The purpose of in vi tro-
in vivo comparison studies in ulis sense is the scientiti c verific1tion of
the in vitro tcst system and the respective specifi carion limits for a
given drug formulation.
Regarding extended-release dosage fonns the US!' /lSI has cate-
gorised correlative methods, harmonised in a wide international con-
sensus, as correlation b 'el A (I: I relationship between in vitro and in
vivo dissolution, calculated by numeri cal deconvolution [13, 141,
according to method 1251 or to Loo-Riegelmann
method [26]), correlation level B (statistical momenr
I
an,l)'sis 117, 281) and correlation level C (single-point cor-
I
relation of a dissolution time \'s. a phannacokinetic para-
meter). Dcpending on the correlat:ion level finally
obtained, in vitro di ssolution propcrties will be decisive
Disso/llliollTecim%gi('sINOVEM I3ER 1997
for the nccessiry of how Ill ,my batches should be included for a cor-
re/ation shldy, c.g. for establishment of in vitro dissolution
lion limi ts. According to recent recommendations, one single batch
Ill;l)' be suffi cient for il scientific111r ,md fonllally accepr'lble correla-
ti on 115, [8], only in (,ISC of a correlation level A ,mel a product with
a drug rel ease, compl etely independent from environmental condi-
t-ions, which then is represented hy only one di ssolution curve.
Scientific ,md appro;lches for level A correlations have
heen proposed [19). '-11 case of:l le\'el A correlation, lll:lnUf<lChlrillg
sit e changes, process and equipment changes, minor fonnulation
l11odifi c;ltions, scal e-up considerations and specific;ltion of dissolu-
tion limi ts can he hased and justi fi ed without further in
In all other cases at Icast two or three different batches ha\'e to be
used, offering differences ill their biopharmaccutical propelties, suf-
fici ent for correlation purposes. Nevertheless, these differences have
to he 'effected' by only slllali modifications of manufacUJring \'ari-
;l bles within the r;1I1ges of the given process. In cases where differ-
ences Clllllot be achi eved by these va ri ations of the production
process, major changes will he required to ohtain samples for in
vi tro-i n vivo compari son. Il owever, ;lIlY correlation rccei\tcd for dif-
ferent forrnubtions bears the risk of being somewhat arbitrary. A
tinal eva luatioll of type and influence of the changes in the lllanUE1C-
turing processes requires thorough in \'jtro dissolution tests (' bio-
pharrnaccutical protllc'; see section 5) prior to an administration to
human volunteers in a clinical srudy.
Concerning modified-releosl' prodll(f,f there is international consen-
sus that levels A to C, \\ ilh ,1 quality ranking A > B > C, are accept-
able for correlation e.g. for speci fi cations of dissol ution limits. A
Table 4: Possible reasons lor poor In vlvoln vitro correlations
Fundamentals
in vivo dissolution IS not the rate limiting step for drug absorption
no In vitro test is able to model In vivo dissolution
Study design
inappropriate in vitro test conditions
inappropriate in vivo test conditions
Dosage form
drug release not controll ed by the dosage form
drug release strongly affected by intestinal transport kinetics
Drug substance
nonlinear pharmacokmetics (e.g. saturable fi rst pass effect). absorption
wmdow. chemical degradation in the gastrointestinal tract
absorption of undissolved particles
large intralndivldual variability
Ilumber of different reasons (see "11lhle 4) could be responsible for
"poor" or no correlation.
Even with highly sophisric:l(ed techniques it is oftcn difficult to
ohtain meaningful in vitro-in vivo compari sons, especiall y for bio-
pharmaceutically very similar (hioequivalcnr?) products, such as
b:ltches of one drug formulation, representing the upper and the
lower di ssolution limits.
Recellri}" proposals have been
Illl1de [301 which in virro-in vi\'o
compari son results scientific:1l1y
:1lld formally could suffice as vcri-
fic.ltion of dissolution specification
of controlled/modified-release
products. In C;lse of :1 signi llcant
quantitative correlation, dissolu-
tion limit<; can be derived hr inter-
polation, when batches outside the
specified biopharmaccutic:11 range
are tested for in vitro- in vivo COI11-
parison. Thcll, at Ic,lst three
hatches should be tested in vitro
and in vivo. A qUi1litativc, i. e.
rank-order correlati on verifies
ranges, whcn at least three batches
arc tested in vivo flnd ill vitro and
the dissolution dflt3 of two of the
experimental ly investi g;lted I)fltch-
cs are concluded bioequiralent
and their dissolurion chari1cteris-
tics are speci/1ed as upper and
lower dissolution limi ts (Fig. I).
\-\Th ere no correlation IS
obtained from an in vitro-in vivo
comparison study, an alternative
approach (Fig. 2) could consist of
demonstrating bioequi\ralencc of
the proposed formulation to for-
mulations with dissolution profiles
at the upper and lower limits of
the specification [13 [.
The number of volunteers to
be included in such compara tive
bioavailability snldies or in an in
vitro-in vivo comparison stlJdy is
to be defined on a case-by-case
basis but in general should not be
less than twelve.
The batch size of a fonnulation
for in vi tro-in vivo comparison
srudies need not be of full produc-
tion scale. Parameters for manu-
facrure of these batches, especia lly
of formulations representing the
intended dissolution limits, should
be defined frolll process validati on
In -Vivo Verifi cation of
In-Vitro Test System and Dissolution Limits
Dissolution
'00
r upper ' slde" batch
7S l[
I
target I .
profile
50
25
o
?I' I
j iower"slde" batch 1
I
2
SMOEIT 2 E
6
TImelhJ
Figure I
r
12
T,ma [hI
B
Dissolution Limits Verification
low Correlation level Approach
In Vilro D,ssoiullOn
Figure 2
I)
T
Examples for Verifi cation of Di ssolution limits for
Immediate Rel ease Dosage Forms with Di ssolution Times
of >30 (left) or >45 min (right )
Dissolution 1%) In VIVO
i 1 1
i, /"1
..
-----=r l-poln1 e.g 2- pomt
:: rJ d j="oo
o 30 60 90 120 0 30 60 90 120
TIme [min] TIme [min]
Figure 3
two-way crossover between an
oral solution and a fonnulation
representing the (lower) specifi ed
dissolution limit. (Fig. J).
7. Dissol1ltiol1 Limits
The purpose of specifying dis-
solution limits is to ensure b;ltch-
to-batch consistency within a
range which !,'1Iarantecs acceptable
biophal'lll:lceutical perfonmnce in
vivo. Limits therefore have to be
defined based on experience
g;lined during the dmg develop-
mcnt stage regarding
clinical de"elopmelll and/or bioe-
quivalence snldies. In Illost cases
deduction of limits requires thor-
ough in vitro-in vivo comparison
studies as described in section 6.
For illllllcdiate/conventional-
rcie,lse formulations typically one
limit is to ensllJ'e thin
most of the acti ve ingredient is
released within the present time
period. Regarding the deduction
of limits, diffe rent procedures are
recommended, depending on the
individual dissolution characteris-
tics. However, it is dearl}1 stated,
that the following categorisation
only concerns the specification
verification process. It docs not
qualify or disqualify dmg formula -
tions with dissolution properties,
characterised by a specified time of
> 15 minutes.
In case of velY fast drug releasc,
si ngle point dissolution data during
cl,e de,'elopment period and a sin-
gle point specifia1tion, consisti ng
of ,1 pan1llletcr quantitati ng the
extent and a parameter to define
cl,e time, are judged sufficient. A
formulation is in this concern
understood as very fast releasing,
when at least 80% of the drug sub-
stance, corresponding
shldies according to the expected maxlInum variability of process
parameters ("side batches").
to "Q" = 75% (see 5 a in section 8), is dissolved in
about 20 - 30 minutes (includi ng any lag times due to dis-
solution of a tablet coati ng or capsules) under reasonable
and justified test conditions. In this case dissolution limits
Concerni ng immediate/conventional-release dosage fonns a suit-
able design for an in vitro-in vivo comparison study could consist of a
Disso/litiollTecim%giesINOVEMBER 1997
flP Guidelines ... cont.
call be defined based on in data, obtained during dmg develop- an in vitro-in vivo comparison study and should at least cover
menr without an in vitro-in comparison study. 14 hours.
Although in vitro- and in vivo-time a.xes need not he related in a The acceptance range for the dissolution p:ltfcm at the time
I: I ratio, the suggested dissolution time window corresponds w typ- intcn'als specined should he defined case-by-casc 011 the basis of the
ical gastric emptying times [31-331. in vitro-in vivo comparison study and taking into considerati on the
Immediare!convent ion- Table 5: Acceptance Tables According to DSP 23 < 111 > < 124> c:lp:lbi lity of the lll"'lUfac-
ai-release fonnul:mons WIth ruring process ,mel the com-
a speciRed dissoluti on time Sa: Immediate/ conventional-Release Drug Products manly accepted range of 95
of more than 30 minutes will 5tage Number Tested Acceptance Criteria to 105% of stated amoum
requi re an III VitrO- in VIVO 51 6 Each unit is not less than Q + 5 % for the average conrenr of
comparison srudy and disso- 52 6 Average of 12 units (S1 + S2) is equal to or greater than Q. drug subsmnce. \,\'here
and no umt is less than Q - 15 %
lurion profiles with several both upper and lower limi ts
53 12 Average of 24 units (S1 + 52 + 53) is equal to or greater
(e. g. 3) poi nrs, obtained than Q. not more than 2 units are less than Q _ 15 %, are specified at ,lI1y time
duri ng development, to and no unit is less than Q - 25 % point, the difference
speci fy single point limits. 5b: Modified (Extended-Release) Drug Products between them should usmll -
Formulations with a speci- Stage Number Tested Acceptance Cnteria Iy not exceed 20% of the
fi ed dissolution time of> 45 l1 6 No individual value lies outside each of the stated ranges labell ed content of drug
minutes may require two and no individual value is less than the stated amount at substance ill the fonnula-
the final test tllne
specifi ed dissolution times
L2 6 The average value of the 12 umts (L
1
+ L
2
) lies within
for quali ty control purposes. each of the stated ranges and is not less than the stated
Gastro-resisralll drug amount at the final test time; none is more than 10 % of
labelled content outside each of the stated ranges; and
products should be treated none is more than 10 % of labelled content below the
like immediate- release prod- staled amount at the final test time
ucts for the purpose of spec- L3 12 The average value of the 24 units (L
1
+ L2 + L
3
) lies within
each 01 the stated ranges, and is not less than the stated
ifying limi ts for the second amount at the final test time; not more than 2 of the 24
dissolution test period, fol- units are more than 10 % of labelled content outside each of
the stated ranges; not more than 2 of the 24 units are more
lowi ng the initial aci dic test than 10 % of labelled content below the stated amount at the
phase. final test lime; and none of the umts IS more than 20 % of
labelled content outside each of the stated ranges or more
For modifi ed-release for- than 20 % of labelled content below the stated amount the
lTlulations (except debycd- final test time
release) dissolution require- 5c: Gastro Resistant (Delayed-Release) Drug Products
Illcnts should consist of at Acidic stage
least three points. The first
limit is specified to prevent
"dose dumping" and there-
fore should be set after a
testing interval of one to t\vo
hours or corresponding to ,}
dissolved aillounr of 20 -
30% of labell ed dmg sub-
stance. The second limit
should defi ne thc dissolution
pattern and thus be set
around 50% release of
labell ed drug substance. The
final limit is specificated to
ensure (almost) quantitative
Stage Number Tested
6
6
12
Buffer stage
Stage
8
3
Number Tested
6
6
12
Acceptance Criteria
No individual value exceeds 10 % dissolved
Average of 12 units (Al, + A
2
) is not more than 10 %
dissolved. and no indiVidual unit is greater than 25 %
dissolved
Average of the 24 units (Al + A2 + A;l) is not more
than 10% dissolved. and no individual unit is greater
than 25 % dissolved
Acceptance Criteria
Each unit is not less than Q + 5 %
Average of 12 units (B
1
+ Bll is equal to or greater than
Q, and no unit IS less than Q 15 %
Average of the units (B
t
+ 8
2
+ 8
3
) 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 %
don unless limits have been
shown to provide repro-
ducible and acceptable m
vivo performance [13 [.
8. Interpretation,
Acceptllnce Criteria
Dissolution test speci6-
C'J tions should include the
definition of limits, the
number of units to be
exa mined and respective
acceptance criteria . The
procedure of data interpre-
tation should be har-
monised inrernationally,
the existing compendial
requirements should be
uniform.
As pharmacopoeial
approaches are sti ll not full y
hllrmonised it is recom-
mended to follow Ul e accep-
tance criteria in accordance
with USP for immediate!
conventi onal-release prod-
ucts, modi fi ed-release
(extended-release) products
and gastro- resistant
drug release, which is gene"lil y understood as The
dissolution run in quali ty comrol therefore should be
extended for the tillle interval until ;It least 80% of drug
substance is dissolved. Shoner test imerv.lls can be ,lccept-
able in special cases but require justification on the basis of
(delayed-release) products Crable 5). The approach with a maximum
of three stages and individual units tested for deviation from stated
ranges corresponds well to requirements for coment uni fomlity.
Although there is preference ill common pnlctice in pharmaceutical
industries {Q decide upon batch release not later than stage 2, the three
Disso/Illio7l7ecim%giesINOVEMBER 1997
step approach is the best solution for formal specifications, especially
when referring to end-of-shelf life specificati on. Reference to labelled
content docs not apply for products with intenti onal di fferent content
at time of manufacrurillg, Sti ch as in cases of stability overage.
9. Special Applications
A value of di ssoluti on testing is recognized in its applica-
ti ons in scale-up and manufacturing changes for immediate/conven-
tional -rel ease and oral products. The
AAPS/FDA/USP Seale-up workshops 134, 151 recommend cCitain
types and ranges of changes for whi ch the sameness of in vivo prod-
uct performance is assulll ed, based on in vitro di ssolurion dam. In
addition, the Scale-Up and Post-Approval Change (SUPAC) docu-
ment of FDA IJ6] defines the level of changes widl respcct to com
1451. Spccial test, h, ve ,Iso been suggested for consideration of spe-
cifi c situations, such as ilchlorhydri c elderl y patients 146].
J O. COllclusiolls
In many international discussions, Ill'lill ly over the years 1988 to
1993, consensus was reached on some essenti al aspects, to which
these Guidelines refer. On the other hand, many aspects have either
not yet been sufficientl y explored or have not been harlll onised. In
these cases, e.g. morc precise specifications of dissolution media and
proposals for in vitro- in vivo comparison approaches and verification
of specifi cations for illlll1edi<lte/conventi onal -releasc, delayed-release
and modifi ed-rel ease preparations, the revi sed Guidelines will pro-
vide contributions for reasonable standardization, whil e acknowledg-
ing that for a numher of dnlgs e.g. wi th special physico-chemical or
ponenrs and composition,
site of manufacturing, the
sc,ll e of ll1 ,lI1ufaculring, and
process and equipment
Table G: Dissolution media that may reflect gastric conditions ,fasted:
phann,lcokilleti c proper-
ti es, case-by case develop-
lTl ent is required.
SGf) and conditions in small intestine ,fasted: faSSlf; fed: feSSlf)
changes in manufacturi ng 0.01 -0.05 N
for an immediate- release
oral fo rmulari on.
Depending on the level of
change, different Icvels of
dissolution testing are rec-
ommended to assure con-
tinuing product qual ity and
performance characteri s-
ti cs. Respectively, the docu-
mentati on needed to assure
the product performance
vari es, depending on thera-
Sodium lauryl sulfate
Sodium Chloride
Distilled Water
2.5 G
2.0 G
qs. 1000 ml
peuti c range, solubility and peml eabili ty fa ctors of the drug. For
changes greater than the acceptabl e values in the scal e- up workshop
report, addi tional dissolution profile determinations in se\'eralmcdia
are recommended for immedi ate- release products.
For major changes, that are likely to have a significant impact on
formulati on quality and performance, an in vivo bioequi v,llence study
is recommended in additi on to extensive dissolution profil e resting.
For manufacturing site change, scal e- up, equipment changes <lnd
minor process changes dissolution testing is deemed suffi cient to
assure product quality and performance.
[n vitro dissolution tests have al so been used to try to simulate
food-effects on bioavailability. So far, these different attempts 117 -
41] have had extremely limited success in predi ction 1441. Assuming
that gastro-intestinal transit times are sif,rnificanrl y contributing to
potenti al food-effects on bioavailabil ity, the value of an in vitro model
for food-effects will be limited to an evaluati on whether direct drug-
food-interaction could be of relevance for the observed changes in
bioavailability in the in vi vo srudy.
Test media that may refl ect gastric condi tions (fasted) and intesti-
nal conditions (fastedlfed) and thus may give additional infonnation
for research and development purpose are summarised in Table 6
FaSSIF
KH2 P04
NaOH
NaTaurocholate
Lecithin
KCI
Distilled Water
FeSSIF
AcetiC acid
NaOH
NaTaurocholate
lecithin
KCI
Distilled Water
0.029 M
q.s pH 6.8
5mM
1.5mM
0.22 M
q.s. 1000 ml
0. 144 M
q.s. pH 5
15 mM
4 mM
0.19 M
Q.S. 1000 ml
These Guidelines
should be helpful and
il ppl icable for all involved
in in vitro dissolution test-
ing. However, there was
special emphasis 011 pro-
viding reliabl e guidance
for industrial rese,nch and
development, process vali -
dati on .mel quality control ,
making the Guidelines
especially appli cabl e fo r
industry, dmg authorities
and control laboratori es
but al so for uni versiti es, hospitals, phannil cies or others, when
involved in (bi o)pharmil ceuti cal qll aliry evaluation.
til general these Guidelines should be understood as recommenda-
ti ons based on scientific knowledge and experience. They should be
helphll in the with drug regulatory authorities. However they
arc not intended to represent any offI cial requirements in this neld.
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10. So/tm RA, lloover ],11, .lOll" IT. Stllildisb ,II (/989) EjjictsofSillker
Sbllpes 01/ Dissollllioll Plvjilrs. J Pblll'lJl Sri 78. 35 - J9
21. U.S. Pb(fl'1llflrOpdlf 23, SlIpplmullt I (1995): Dmg Reler/sl' <72-1-> 2535
22. FIP H'orkillg Grollp: -I OhSO/lllioll tlild DisJolllfioll Spl'cij/mlion. !lPPtl/"{ftw'
Sflitllbility 7,'.11 JOI' Ibe fiJeraHbroltgb Cell (pIIN. ill prep.)
13. LnllgrlllJllcbrr F (1982): NIIIIII'rim/ com:ollltioll/decollvolllfirJIIIIJ (/ tool jar rOl'-
re/millg ill vit1"O 7:.'itb ill t'ivo drug (lr.mlttbiliry. Pblmll. 11111., -1-1- , 11 66 - I 1-:2
]-1. 1..IlJIgellll1lrber P (1981): /Jllp,vt'ed Iligorilb1lls rom-llI1mg /1(){/y respollsr 7l'irb
drug il1plll, Pb(l1'Ili. Illd . -1-1, 1275 - 117S.
15. /11lgller J IV, Nelsoll F (1963): PI'I1r1ll ,,"sorbrd limr plots dn'iVt',1 fivm blood
it'Vt'I or urillilry I'X(1"elioll tilltll.]' Pb(mJl. Sci., 57, 918 928
26. 1.00 ]CK, Riegellllllllll S (1 968): l"/t7J.1 metbod jar /"/I/cllilllillg tbe illf1'illsir
ahsorptioll mtl' of drug]. PbIlI"lJl. Sci., 57. 918 - 928.
27. iJrocklllt'ier D, l'oegele D, V()II IIl1ltillgbetX IIJI (1983): 11l 1.}if1v-ill Vi'1'O cor-
,e/lltioll. II time smJillg prob/I'II!? AI"":'lIeimittrljorsdJIIlIg n, 598 - 601
28. 1.'011 1IIlftlllgbrrg 11,\ I (198-1): Il/olIIl'lltell-Alllllysr 111111111 7.' itrolill1.'i1.'o
Korrrill1iol1, ACM Pblll7l1. Terimol .. 30, 93 - 101
29. Cllrdot J.\I, IJeyss(fr F. (1993): III vit/vlill vivo C'om'llItiolls: Scil'lllijic
ImplirtftioJlJ (fll" Stlllulllrdis(ltioli. EIII} Drug .\/t>ftI{, Pb(I17IJ1ICokillet 18 (I)
113- /20
30. SiCiliC11 M (I99';): /" Vivo V"lid(ltiulI of 111 Vitro Dissolutioll Jrsts fllld
SpI'Cijimfiolls: rlpplimtioll fur COIlf1v/ledl.\ lodifirt! Rell'IIse Prodlll1S.
iJioillfernmiol1ld 2 (293 - 299)
31. Obrrle RL, Cben T-S, UOJ'd C, /Jtl17tett JL, C (f1L)'(lIIg . .lIry'rr
I
J. Amit/oll GL (1990): The illjlllenrr of tbe mterdigestfl.'e 1111grtltmg
mOlility romp/I'x all tbe gflstrir emptyillg oflilJlllds. GlIstroellterolog;y
I 99, / 275 - 1181
/Jism//ltiollTedJll%giesfNOVEMBER 1997
n. IJrellfr W /-Ielldrix TR. ,\Ir1ll1gb PR (1981): Regulatioll oftbe gum-ir rmp-
f)'illg of glllmre. GlIst7"Ol'IItrr%gJ' S5, :-6 - 81
33. ,\1111(1111111 II. JlrCidlll1ll R.W, (1998-1): Tbr Pb)'siology 111111 Phfllopbysiology
of GIISf1'ir Emptylllg ill I hmllllls. GIISf1"Or1lferologl,8616, 1592- 1610
H. IVorkshop Repol1 (1993): Sm/I'-L"p oj IlI/lIIl'dillte Rrifllse 01"111 Solid Dos(lge
Forms. Pbllrm. Rt's. l(j. 313 - 316 IIl1d EII1: J. Pbarm. IJiopblll7J1.
39 (I). 40 - 43
J5. If'or/.:J/Jop II Rrport (1993): SCl/it'-Up of Om I Ertell/led Rdetl.ff Dosage
FOI'IlIs. PbIlI7Jf. Res. 10, I SOO - I S05 IIl1d Em: J. PI}(m". /Jiopbll17l1. 39 W'
/61- /67
J6. FDA 11IIlIIedillle Rdl'llse Smlr-up rllld Porr APP,vt'(f1 Change (SUP..4C)
Expert /I arkil1g GIVUp of tbe Chemistl)' .\[allufartlll7l1g COIlf1VIs
Coonlhultillg COlllmittel' of tbl! CrII/trfar Dmg Evaillmioll (lIId Resf(frr/J
(199-1) IlIferim GllidllllU IlIlIImlill'l' Release Solid Om/Dosage Ponl1s - Pre-
fllld Pos,-Appl"01.,"1 Cb(lIIgl'S.
17. ,\I({lIml PK. PnmulllK, II'onlt)' IV, Sbiu GK, JP (1986) IlIfllleliu of
II high Pit bretlkji/J! 01/ tbt' bio(/"1.wilflbi/ity COIl f7'oJ//'d-rr!etlse )01'-
JIIulmiolls: 1111 ill vitro dt'mollstrtltioll Ofllll illl,il'O ubsm.'IItioll. III:]. Pbll17l1.
Sci. 75. /105 - /]06
JS. It L. KJllilll. /, PI/gone I: Strrirbt'rJ, Il'irklllllllil (1988) Pood- III/luud
TbeopbJ'"mr ReI('IfselAbsOlptioli OJIIl/gfS fiwl/ COlltrollel/-Rr/l'llse FOl7llflllltions:
, I Propoml in I'itlv .\I{)(M. Drug D(1.:I. IIItI. Pb"rlll. 1-1, 13 - 28
19. Karim II: Imp0l11111Ct' ofAsJt'ssiJlg Food Effects in Et'll/l1l/tlllg COIlf1vllrd-
Rdl'llsr Furlllll/tlfiolls. (1988) I,,: )iltobi A /I/lt! fllI/perin-Wfllegll E: Oml
Siml/illcd Rel('llsl' Formllllllioll.!: I)r.l"igllll1/{/ Ev(dlllllioll. Pr1'gtlllloll Preofs, ,
157- JNJ
-10. EI-A1'llli K. Shill GK. JP (1990) Rr/ellse
PrepllrtltiollJ lifxul: ;/11 ill 6f1v SIIUiy Usillg the Rowillg Di(Ii)'sis
Cell. Ph(ll111. Res. :-, 11 3-1- 11-1-0
-II .. \Il1cbenfS P. Kouppafis ,lI. Jjllprollllis C (1986) Dmg dissoluti01l stflllirs i1l
lIIi//': Ifsmg tbl' IIIIfQIlIfltt'lJ }lerll' illjmjoll m'i,,/ dialysis tuhf/iqlfr. 1m.
]. Pbllrm. 33 , 1]5 - /36
-1 2. JIIlIgillgl'r I fE, VerbofvI' 1I J, Pt'scbi('r L]C (1990) Eille II/'/ICS ill 'vinv-/Hot/rJl
:lIr 7.'011 Wrdmltl'irkllllgm z,i.l'iscben RrftmJl/rzneilllitte/1I :wr
om/l'lu/pplik"tiol/ IlIId NlIlmmgsntittelll. Pb(wm. Ztg Wiss. 2, 53 - 58
-1- 3. I\riimrrJ, Lilltitlllt'1" Re Sirv.'ert ,\/, St,.irkt', /-I , /JIume II (/991) \tl'1ulrd-
Relel/se Tbt'opbJllillf Altfl1l1lffl.'e /11 /'itro Dissollltio1l ,\Iethotis. Elfr. J. Drug.
.\Ielllb. Pbl/l7Jlflrakill. IN, r
-1-1. Sira't'11 .1I (1989): /11 t'itlV- OlSSollllioll Jerrillg of Oml COIlf1v/led Release
Pr{)(llIm. III: Glllllim-Rnn] U 1111(1 ,\/"IJel" II: Oml COllflvlled Rde(lse
Prodllm 7])cmp('lltic IIl1d Biopblll'l)/(Iwitir Assrss-mem. Wissellsrb(iftfirbe
1't.'r/IlgsgeseJI.Kbtlfi, 139 - 1 H
-15. Gali" E, Nitoillides I';, Repplls C. DmS-III(f1l J/J (1 996): M."'JJ medill discrimi-
Illite dissolmioll propmirs oIpoor(y soillble drugs. P/)III7I1. RcSetllr/) 13, 262
-16. Ogllt/l /-I et III, (198-1): DrvelopmclII oJlwd tn'll/lIl11ioll ofa 1Il'il' perorfll test
(lgml G/ /-Test jor IISSfS'lIIell1 ofgas/1"lr lIrit/if]. J. Pbnl7llUroblO-DyIl 7, 656-
664
For COI7"I'Spol/(/fllce:
PIP JI 'orkillg Group -I: Disso/litioIlIllU/ Dissolutioll SprcijimtiollS
D/: {\ Itmill Sil7!'l'rt
do Iloabst Mllrion ROIISS{'/, Building K 607, D-65926 Fmnklim
7],is jilllll "offici,,/", versioll of tbl' PIP Gllidelillfs fOl' Dissollltioll 'Terring oj
So/i,1 Oml Protillrts i!."llll/iso be pllblis/m/ ill 11Itfl7lf1tiol/(t/ Pb(ll7)l(lry,
Pb(ll'lJUlcoporinl Forum, Die Pblll7J1f1':lItisrhe Im/llmie IIIUJ PbUl7llllfflltiat/
7frbJlology.