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medium with early points of analysis (e.g.≤ 5 min) may be surface is exposed to the medium.
recommended.It has to be noted that this early time point The pH of the medium ideally should be adjusted to pH 5
in the profile is intended to address the taste-masking prop- – 6,reflecting physiological skin conditions.For the same
erties of the formulation and may not have any relevance in reason, test temperature is typically set at 32°C (even
terms of the product’s biopharmaceutical properties.Such a though temperature may be higher when skin is covered).
dissolution criterion (typical example:≤ 10 % dissolved in 5 100 rpm is considered a typical agitation rate by Ph.Eur.,
min) would largely depend on the taste intensity of the drug which also allows for testing an aliquot patch section.The
and may enable the in vitro evaluation of the taste masking latter may be an appropriate means of attaining sink condi-
properties whilst avoiding organoleptic measurements. tions,provided that cutting a piece of the patch is validated
to have no impact on the release mechanism.
Chewable Tablets
In principle,the test procedure employed for chewable Semi-solid Topical Dosage Forms
tablets should be the same as that for regular tablets.This Semi-solid topical dosage forms include creams,oint-
concept is based on the possibility that a patient might ments and gels.In vitro drug release from semi-solid topical
swallow the dosage form without proper chewing,in which dosage forms has been extensively investigated using the
case the drug will still need to be released to ensure the Franz cell diffusion system (6) with a synthetic membrane
desired pharmacological action (4).Where applicable,test and to some extent using the Enhancer cell (7).Comparative
conditions would preferably be the same as used for studies indicate that the two types of apparatus generate
conventional tablets of the same active pharmaceutical similar data.
ingredient,but because of the non-disintegrating nature of Depending on the solubility of the drug substance,the
the dosage form,there may be a necessity to alter test receptor medium may need to contain alcohol and/or
conditions (e.g.increase the agitation rate) and specifica- surfactant.De-aeration is critical to avoid bubble formation
tions (e.g.increase the test duration).The reciprocating at the interface with the membrane.A synthetic membrane
cylinder (USP Apparatus 3) with the addition of glass beads is often used to serve as an inert support membrane.
may also provide more “intensive”agitation for in vitro disso- Depending on the characteristics of the drug product,it
lution testing of chewable tablets.As another option, may also be possible to conduct the in vitro test without a
mechanical breaking of chewable tablets prior to exposing synthetic support membrane (8).For some ointments,the
the specimen to dissolution testing could be considered. Franz cell has been used with and without membranes,
Whilst this option would more closely reflect the administra- resulting in no differences in release rate results.The drug
tion of the product and the corresponding formulation and release characteristics usually follow the Higuchi model (9).
manufacturing features,no approach for validating such a As with transdermal products,the test temperature is typi-
method has been reported in the literature or presented cally set at 32°C to reflect the usual skin temperature.Devia-
during the workshops. tions might be justified in case of products for specific sites
of action,e.g.vaginal creams may be tested at 37°C.
Transdermal Patches
Ideally,sample weight/volume should reflect a typical
Although several apparatus and procedures have been
dose of the product.However,it is preferable to use a partial
utilized to study in vitro release characteristics of trans-
dose rather than adding a surfactant or alcohol to the
dermal patches,it is desirable to avoid unnecessary prolifer-
receptor medium in order to obtain sink conditions.
ation of dissolution test equipment.Current compendial
No compendial apparatus,procedures or requirements
apparatus include the paddle over disk/disk assembly
for in vitro release testing of semi-solid topical dosage forms
method (USP apparatus 5/Ph.Eur.2.9.4.1),the rotating
have been described in relevant Pharmacopoeias to date.
cylinder (USP apparatus 6/Ph.Eur.2.9.4.3),the reciprocating
However,FDA’s Guidance for Industry on Scale Up and Post
disk (USP apparatus 7),and a paddle over extraction cell
Approval Changes for Semisolid (SUPAC-SS) dosage forms
method (Ph.Eur.2.9.4.2).
describes the release rate studies using the vertical diffusion
The paddle over disk procedure with a watch glass-patch-
cell (Franz cell) procedure and requires in vitro release rate
screen sandwich assembly is considered to be the method
comparison between pre-change and post-change prod-
of choice as it has been shown experimentally that this
ucts for approval of SUPAC related changes (10).
procedure results in almost the same release profile as other,
Because of the value and importance of release rate,it is
more complicated apparatus for all US marketed trans-
highly desirable to determine the release data of semisolid
dermal patches (5).The configuration of this assembly
dosage forms (11).There is also a need to develop compen-
ensures that the patch is prevented from floating during the
dial test method(s).It is expected that given the variety of
entire testing period.Special attention needs to be given to
the proper positioning of the patch so that the drug-loaded
See Dissolution In Vitro Release Testing… continued page 10
formulations,sites of applications,and the variety of release able methods described above it should be possible to
rates for semi-solid topical dosage forms,no single test select an adequate in vitro release test in most cases.
procedure would be suitable for the development,biophar- Recommendation of a method of first choice is inappro-
maceutical characterization and quality control of all semi- priate,based on the variety of formulation characteristics
solid topical dosage forms.Based on the foregoing of suppositories.However, when starting development of
statement,the inclusion of a single apparatus in pharma- an in vitro dissolution/release test, it might be advanta-
copoeias may not be the desired solution.However,the geous to begin with the basket or paddle in case of
Franz cell (7) is considered the most promising apparatus for hydrophilic and with the modified flow-through cell in
investigation of post approval changes. case of lipophilic suppositories.
Vaginal dosage forms are often designed for local thera-
Suppositories
peutic effects.Nevertheless, if an in vitro release test is to
In principle, for hydrophilic suppositories that release
be designed, the recommendations for suppositories may
the drug by dissolving in the rectal fluids, the basket,
be followed.
paddle, or flow-through cell can all be used.
Lipophilic suppositories release the drug after melting Liquid Filled Capsules
in the rectal cavity,and are significantly affected by the Liquid filled capsules can consist of either,hydrophilic or
rectal temperature, reported as typically 36 – 37.5 °C (12). lipophilic formulations.In the case of lipophilic formula-
In vitro release testing also requires knowledge of the tions,they may or may not include a surfactant for self-
melting point/range of the product being tested.The test emulsifying purposes.The USP recommends a dissolution
temperature should take into consideration physiolog- test procedure using the rotating paddle method (Appa-
ical conditions but may also be at or slightly above the ratus 2) with minimum amount of surfactant,if needed (e.g.,
melting point,e.g. at 37 – 38.5 °C (which can be justified dissolution of valproic acid capsules,methoxsalen capsules).
e.g.for suppositories, used for patients with fever). If the liquid filled capsule contains a water soluble base,
After melting,drug will have to partition between the then addition of surfactant is generally not needed,
lipophilic base and the receptor fluid.This may lead to a however,this is a function of solubility of the active pharma-
distribution equilibrium between the two phases rather ceutical ingredient as well as the formulation itself.The
than complete dissolution.For this reason, sink condi- rotating paddle can have disadvantages for some liquid
tions during the test are essential in order to simulate filled capsule formulations,as it might be difficult to keep
the in vivo situat i o n ,w h e re absorption across the rectal the formulation immersed.Also,emulsified formulations
membrane is continuously reducing the concentration might separate at the liquid-vessel-air interface and/or
of the drug in the rectal fluids. formulations could adhere to paddle or beaker walls.
The use of membranes in the test is in principle The modified dual chamber flow through cell,as recom-
at t ra ct i ve since it is the most elegant way to obtain a mended for lipophilic suppositories (Ph.Eur.2.9.3.-6.) is
filtered clear solution for immediate assay. However, it considered an appropriate test apparatus for liquid filled
i nt roduces an artificial process of tra n s po rt and is thus, capsules.It can be run as an open or a closed (this may be
in general, not recommended. important for self-emulsifying formulations) system.One
For lipophilic suppo s i to ri e s, a modified basket potential disadvantage is that screens might be blocked
method, a paddle method with a wired screen and a during the test.
sinker (13) and, a modified flow-through cell with a Other apparatus have also been successfully used,such as
specific dual chamber suppo s i to ry cell (Ph . Eu r. 2.9.3.-6.) the rotating basket (which keeps the formulation immersed,
have all been recommended. In order to achieve the however might result in blocked meshes) or the recipro-
specified te m pe rature in the test cell, the te m pe rature cating cylinder (which offers good mechanical agitation but a
in the water bath may have to be set up to 5 °C higher. limited media volume).
E x pe ri e n ce with the compendial flow through cell Especially during the development phase,a range of test
has shown that it may generate highly variable data media should be used to characterize and understand the
due to the behavior of the suppo s i to ry in the cell (14), formulation characteristics.In the case of lipid filled capsules,
in particular for fo rm u l ations containing spreading enzymes in addition to surfactants may be necessary to simu-
a g e nt s. Deviating from the general recommendation, late digestion if this is a rate-limiting step for dissolution and
i.e. use of membrane-based physico-chemical test absorption in vivo.The advantage of using lipases is that it
methods (15) may be considered for lipophilic supposi- more closely reflects physiological conditions.The disadvan-
tory fo rm u l ations exhibiting this kind of behavior. tages are that it can be expensive and labor intensive when
No one single test method will be suitable for all used as a routine test,and typically leads to higher variability.
suppository formulations. However, from the set of avail- No one single test method will be suitable for all liquid
possible,the method of “first choice”.Specifically,this means vitro release testing and in vivo bioequivalence docu-
that in developing a new product in the given formulation mentation, May 1997.
category,the recommended method should be tried first. 11. GL Flynn et al. Assessment of value and applications
Only if this method does not result in meaningful dissolu- of in vitro testing of topical dermatological drug
tion/release data,should an alternative method be applied
products. Pharm Res 16,1325-1330,1999
or developed.In such cases,other compendial or modified
compendial methods should be assessed first,as described 12. K Honma, Am J Physiol,31,R885,1992
in the relevant section of this document. 13. K Gjellan and C Graffner, Comparative dissolution
The in vitro drug release test for some novel/special studies of rectal formulations using the basket, the
dosage forms such as semi-solid dosage forms and trans- paddle and the flow-through methods. I.
dermal drug delivery systems has proven to be equally valu- Paracetamol in suppositories and soft gelatin cap-
able as the dissolution test for solid oral dosage forms.The in sules of both hydrophilic and lipophilic types. Acta
vitro drug release test also shows promise for other dosage Pharm Nord:343-354 (1989).
forms,such as chewable tablets,suspensions and supposito-
14. K Gjellan and C Graffner, Comparative dissolution
ries.For yet other dosage forms,such as chewing gums,
powders,and parenterals,further method development and studies of rectal formulations using the basket, the
refinement will be needed to make the drug release test a paddle and the flow-through methods. II.Ibuprofen
generally applicable,robust and valuable tool. in suppositories of both hydrophilic and lipophilic
types. Int J Pharm 112:233-240 (1994).
References:
15. Setnikar,I., Fantelli,S., Liquefaction time of rectal sup-
1. FIP Guidelines for Dissolution Testing of Solid Oral
positories, J Pharm Sci,52:566-571 (1981).
Products, Die Pharmazeutische Industrie 59:760 –
766 (1997) and Dissolution Technologies 4:5-14 16. European Pharmacopoeia 4th Edition - 2002, General
November (1997). Chapter 2.9.25,“Chewing Gum, Medicated, Drug
2. FDA Guidance for Industry: Dissolution Testing of Release From”, pp 227-228, Directorate for the Quality
Immediate Release Solid Oral Dosage Forms, August of Medicines of the Council of Europe, Strasbourg,
1997,Extended Release Solid Oral Dosage Forms: France, 2001.
Development, Evaluation and Application of In 17. K Diem and C Leutner (Editors), Documenta Geigy,
Vitro/In Vivo correlations, September 1997;and
Scientific Tables, 7th edition, Geigy Pharmaceuticals,
Dissolution Technologies 4:15-22 and 23-32,
643,1975.
November 1997.
3. USP 24 / NF 19,<1088> page 2051,2000. 18. M Shameem,H Lee and PP DeLuca,A short term
4. FDA Guidance for Industry: Bioavailability and (accelerated release) approach to evaluate peptide
Bioequivalence Studies for orally administered drug release from PLGA depot formulations, AAPS
products - General Considerations, October 2000. PharmSci 1 (3):article 7,1999. Available at
5. VP Shah,NW Tymes and JP Skelly, In vitro release pro- www.pharmsci.org/scientificjournals/pharmsci/jour-
file of clonidine transdermal therapeutic systems and nal/99_7.html
scopolamine patches, Pharm Res 6:346-351 (1989).
19. P Sathe, Y Tsong, VP Shah,In vitro dissolution profile
6. VP Shah,JS Elkins and RL Williams, Evaluation of the
comparison:statistics and analysis, model dependent
test system used for in vitro release of drugs from
topical dermatological drug products. Pharm approach. Pharm Res, 13:1799-1803,1996.
Develop Technology; 4:377-385 (1999). 20. K Makino, M Arakaw and T Kondo, Preparation and in
7. HM Fares and JL Zatz, Measurement of drug release vitro degradation properties of Polylactide microcap-
from topical gels using two types of apparatus. sules, Chem Phar. Bull.33 (3):1195-1201,1985.
Pharm Tech 19(1):52-58 (1995). 21. DJ Burgess, AS Hussain, TS Ingallinera,M Chen,
8. VP Shah and JS Elkins, In vitro release from corticos - Assuring Quality and Performance of Sustained and
teroid ointments. J Pharm Sci,84:1139-1140,1995.
Controlled Release Parenterals: Workshop Report,
9. WI Higuchi, Analysis of data on medicament release
from ointments. J Pharm Sci,51:802-804,1962. AAPS PharmSci 2002,4 (2) article 7.
10. FDA Guidance for Industry: SUPAC-SS Nonsterile 22. G Van Buskirk et.al.,Scale-up of adhesive transdermal
semisolid dosage forms. Scale-Up and Post Approval drug delivery systems. Pharm Res 14:848-852 (1997).
Changes: Chemistry, manufacturing, and controls;in