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Professor Karl THOMA and Karoline BECHTOLD
About the authors
During the early stages of pharmaceutical
Karl Thoma is professor of pharmaceutical
technology at the University of Munich. He
tin capsule is often the only possibility to
administer an acid labile drug or to protect
the stomach from a potentially irritant drug
technology in 1959. After lecturing at the
applications of enteric coated pharmaceu-
of pharmaceutical technology in Frankfurt
tical dosage forms have been reviewed.
in 1967 and was director of the Institute of
The properties of the various enteric film
plasticizers and other excipients and for-
ceutical Technology Section and an alter-nate member of the European Pharmaco-
General difficulties of enteric coating do-
sage forms and those specific to hard ge-
latin capsules are discussed as well as as-
Scientific Council of the German Associa-
tion of Pharmacists. His research interests
Over 100 references have been sited.
are in the area of drug stability and newdosage form design and he is the authorof about 350 articles in scientific journalsand books.
Karoline Bechtold is research assistant inthe department of Pharmaceutical Tech-nology at the University of Munich. Shegraduated as a pharmacist in 1988 fromthe University of Munich and continued asassistant to Prof. Thoma. Her research ac-tivities at present are in the area of the de-velopment and stability of enteric coateddosage forms.
hard gelatin capsules
Department of Pharmaceutical Technology, Ludwig Maximilian University, 8000 Munich 2, Germany.
Table of contents
I. Therapeutic applications
of enteric coated films
I. Therapeutic applications of enteric
Field of application
II. Film components
of enteric coated dosage forms
Enteric coated dosage forms, such as coated ta-
blets, sugar-coated tablets, soft and hard gelatincapsules, granulates or pellets, have their firm place
in the medical arsenal (1a, 2). An investigation of
c. Characteristics of enteric coated film formers
181 ready-to-use enteric coated medicaments re-vealed that this sample comprised about 59 % su-
gar-coated tablets (106 preparations), about 27 %film-coated tablets (49 preparations) and about
e. Anti-adhesion agents, pigments, colourants
14 % soft and hard gelatin capsules (25 prepara-
tions) (1). However, this group of investigated prepa-rations covered only some of the preparations on
III. Formulations for the enteric coating
of hard gelatin capsules
The preparations most commonly provided with
IV. Technological aspects and problems
enteric coatings contain pancreatin and other pro-
in enteric coating capsules
teolytic enzymes, diclofenac, cardiac glycosides,electrolyte preparations with sodium, potassium
and magnesium salts as well as calcium, iron andmanganese preparations. Bisacodyl preparations,
preparations containing valproic acid as well as for-
c. Stability of coated hard gelatin capsules
mulations with plant extracts or terpenes are alsocommon.
V. Processes for coating hard gelatin capsules
Nowadays, enteric coatings are in particular
• protect active substances destroyed by the
• improve tolerability of medicaments irritating
the stomach by only releasing them in the smallintestine,
• making active substances available after a time
To improve stability, enteric coating is also re-
commended for bacterial preparations given when
• achieving targeted release and concentration in
the intestinal flora is impaired (17). Other examples
of medicinal substances which need to be protec-ted against stomach acid are diethyl dithiocarba-
Enteric coating to stabilise
mate (18), the anti-tumour preparation N-ethylcar-
bamidomethylisoleucine (19) as well as tibenzoniumiodide (16), an antimicrobial benzodiazepine deriva-
Medicaments which could be destroyed by gas-
tric juice include pancreatin and pancreatic lipase,which decompose at pH values of 4 and under. In
Enteric coating to improve tolerance
artificial gastric juice, lipase activity decreases toabout 10 % of the initial value within 15 minutes at
Some active substances cause irritation of the
pH 3.5. The majority of formulations containing pan-
gastric mucosa or are not tolerated for other rea-
creatin or other digestive enzymes are therefore
sons following their release in the stomach. Gastric
processed to make them resistant to gastric juice
disorders have, for example, been reported in
connection with administration of diclofenac, phe-nylbutazone, oxyphenbutazone, salicylates, iron
In the case of enzyme preparations in particular,
salts, bisacodyl, valproic acid, indomethacin, potas-
gastric-juice resistance often has to be associated
sium chloride, tolbutamide, reserpine, nitrofurazone,
with rapid degradation in the small intestine. Since
anticoagulants, levodopa, ethionamide, thiazides
food constituents are mainly absorbed in the duo-
and diphenhydramine (28, 30, 54-74, 76, 77).
denum or in the upper region of the jejunum (5, 6),
Irritation of the gastric mucosa and gastrointesti-
where their enzymatic splitting must already have
nal bleeding may occur after the peroral administra-
commenced here after passage through the sto-
tion of certain analgesics. Disturbances of this type
mach. An enteric coated dosage form should there-
are, however, in part also connected with an in-
fore degrade as quickly as possible in the small in-
fluence of prostaglandin synthesis related to a sys-
testine. This is noticeably below the upper limiting
temic effect. Although it has been shown, for
value of degradation of not more than 60 minutes
example in the case of acetylsalicylic acid and its
derivatives, that side effects (20, 21, 24) are due to
In the case of cardiac glycosides there have also
prostaglandin synthesis inhibition (23), some fin-
been reports of acid-associated hydrolysis and re-
dings suggest that gastric lesions are markedly re-
duction in the efficacy of digitoxin has also been
duced when enteric coated dosage forms are given
claimed (8, 11). In this case some findings do, ho-
wever, dispute whether enteric coatings improve ef-
Similarly, there is conflicting evidence in the case
ficacy (9). Apart from digitoxin and digoxin, the pos-
of phenylbutazone and its derivatives as to whether
sibility of hydrolytic degradation has also been
or not enteric coatings improve tolerance. Recent
reported in particular in connection with strophan-
investigations suggest, however, that local tolerance
thin (9) and proscillaridin (10), whereas the corres-
of enteric coated phenylbutazone preparations is
ponding methyl ethers such as meproscillaridin are
markedly superior to that of formulations which are
not enteric coated (27, 28). A study involving 103
With regard to antibiotics, penicillin G is known to
patients reacting to long-term phenylbutazone the-
be unstable in the presence of gastric acid (15). No-
rapy with gastrointestinal disorders also yielded po-sitive findings (28). It showed that these patients
wadays, enteric coated penicillin formulations have,
tolerated an enteric coated phenylbutazone prepa-
however, been superseded by the synthesis of
ration for six years without problems.
Enteric coating is also recommended for sub-
The activity of antibiotic formulations containing
stances such as diclofenac, indomethacin, flufena-
erythromycin is significantly improved by enteric
mic acid and azapropazone, because of gastric in-
coating (12, 13, 14). The hydrochloric acid in the
tolerance (23, 25). According to the literature,
stomach transforms erythromycin as well as ery-
enteric coated naproxen is not only better tolerated,
thromycin stearate into the hydrochloride, which is
but also displays superior biological availability (29).
30 to 70 % less active (14). In this case erythromy-cin estolate, which is stable, could be used as an
Gastrointestinal disturbances, nausea and vomi-
alternative to enteric coated formulations.
ting which may be associated with the ingestion of
iron salts (35), magnesium salts (34), cobalt chloride
Possibilities of enteric coated capsules
(32), sodium fluoride (33) and cobalt chloride (31)
in the product development phase
also often make enteric coatings desirable for medi-caments containing them. In the case of potassium
During the early stages of development of a new
chloride, however, reports of irritation in the small in-
chemical entity availability of the active substance in
testine are more frequent in this connection (36).
sufficient quantities to develop a tablet or pellet canbe a problem. In such cases on enteric coated cap-
In the case of theophylline and its derivatives, en-
sule is often the only possibility to administer an
teric coated formulations are believed to achieve a
marked reduction in irritation (37). Very pronouncedgastric side effects occur when valproic acid is in-
Enteric coatings are thus used for numerous me-
gested. Because of its liquid consistency, this anti-
convulsant also presents pharmaceutical formula-
Critical appraisal is needed in those cases in
tion problems and is generally processed in the
which there are conflicting views on their use.
form of enteric coated soft gelatin capsules (30). Inthe case of chloroquine phosphate (38), bisacodyl
In principle and provided they display adequate
(41) and levodopa (39, 40) the desire, not only to
resistance and disintegration properties, are phar-
prevent possible irritation, but also to achieve targe-
macokinetically appropriate and meet stability requi-rements, coatings of this type display important po-
ted release of the active substance or delayed acti-
vity, may necessitate enteric coating.
Enteric coating to delay onset of action
• controlling the effects of medicaments and,• avoiding side effects.
To a certain extent, enteric coated formulations
postpone onset of action via targeted release in theintestine (42, 43, 50, 52). Prolongation of effect is,for example, reported to occur with use of enteric
II. Film components
coated and non-enteric coated granulates of anti-biotics such as amoxycillin or cephalexin (44, 45).
a. General composition
Similarly, in the case of sugar-coated preparations,the active substance content in a core with an ente-
of film coating formulations*
ric coating can be released about two to three
Generally speaking, formulations for enteric film
hours later than the initial dosage coated thereon
coating contain the following main components:
In some cases, delaying the onset of action is
believed to improve the biological availability of me-
dicaments. A longer duration of action and higher
blood level values have, for example, been reported
• solubilizers or dispersion agents and
for enteric coated quinidine (48), theophylline (38),
ephedrine (51), sodium fluoride (53) and enteric
To these may be added viscosity-enhancing sus-
pension stabilizers designed to retard the sedimen-tation of undissolved excipients or dispersed film
Enteric coating for targeted release
in the small intestine
Other additives that may be mentioned include
Targeted release in the small intestine may be
surfactants used as wetting agents or to emulsify li-pophilic plasticizers in aqueous formulations. Defoa-
used to achieve higher local active substance
ming agents and hydrophobic substances are so-
concentrations. This may be desirable for laxatives
containing bisacodyl and for sulphonamides used totreat intestinal disorders (46). It d also described for
Whereas the majority of enteric coated films have
peppermint oil and terpene derivatives used in the
hitherto been applied as solutions in organic sol-
treatment of colitis (47). In the case of vermicides,
vents, there is a growing trend today to use neutrali-
an enteric coating achieves targeted release of the
zed aqueous solutions or aqueous polymer disper-
active substance in the small intestine (41).
sions. On the one hand, the aqueous base relieves
(*) Data from the literature and the quoted film formulations are given without guarantee of correctness.
the user of certain disadvantages and problems of
Shellac is also used mixed with other enteric
coating polymers and to isolate sensitive cores
• costs of exhaust air disposal or recovery for
The film formers mainly in use today are poly-
• removal of solvent residues in the film-coated
mers with carboxyl groups, which are water inso-
luble in the protonized state and pass into solution
in the weakly acid to neutral range between pH 5
• protection of the workforce against the toxic ef-
Manufacturers of film polymers offer products
• storage of substantial amounts of inflammable
displaying a variety of release profiles since the re-
lease characteristics can be directed in certain
Additional regulations regarding organic solvents
ranges through the number of carboxyl groups and
the nature of the acids in the molecule (99). It is the-refore possible to choose a lower or higher dissolu-
Aqueous dispersions have the advantage that
tion pH as required to influence the onset of degra-
they can be sprayed in a higher percentage since
dation and release in the small intestine.
viscosity is virtually independent of molecularweight. The greater heat of evaporation of water as
compared to organic solvents can therefore be lar-
– methacrylic acid ethacrylate poly (MA 1 - EA 1),
On the other hand, transfer to aqueous systems
– methacrylic acid methyl methacrylate poly
raises numerous individual questions requiring clari-
fication, and difficulties have to be solved when de-
veloping a medicinal form. In many cases, aqueous
dispersions or solutions may present instability pro-
blems. Reference is made in this connection to the
– hydroxypropylmethylcellulose phthalate HPMCP,– hydroxypropylmethylcellulose acetate succinate
b. Survey of enteric film formers
The disadvantage of the former practice of har-
dening hard gelatin capsules using formaldehyde,
which brought about cross-linking of the gelatin and
reduced gastric-juice solubility, is that post-harde-
– half esters of the copolymerisate of styrene and
ning processes take place during storage which can
cause the capsules to become increasingly inso-
– half esters of the copolymerisate of vinyl ether
luble, in intestinal juice too, over the entire physiolo-
gical pH range (82, 83, 95, 92, 93).
– copolymerisate of vinyl acetate and crotonic
Use of the following coating materials has largely
Their acid groups are either firm constituents of
the molecular skeleton or are secondarily introdu-
- esters of organic acids, fats, waxes, fatty acids,
ced through esterification of alcohol groups with di-
resins such as salol, colophonium, carnauba wax,
and poly-basic acids such as phthalic acid, trimelli-
carnauba wax mixed with n-butyl stearate, bees-
tic acid or succinic acid. The principle of manufac-
wax, acetylated fatty acid glycerides; these sub-
ture therefore has consequences for the stability of
stances are decomposed by the digestive enzymesand the rise in pH in the intestine (88, 92, 93),
the resultant films (sensitivity to hydrolysis).
- proteins such as keratin, zein and gluten; these
c. Characterization of enteric film formers
are resistant to pepsin in acid gastric juice, decom-position occurs in the intestine through the action of
The quality of natural substances such as shellac
Eudragit L 30 D (30 % aqueous dispersion),
Aqueous Eudragit dispersions are processed in
Eudragit L 100-55 (redispersable powder),
more concentrated form, generally between 15 and
30 % (101), although the upper concentration range
tends to be used for porous dosage forms. It
Eudragit L 12.5 and S 12.5 (12.5 % solutions
should be noted with regard to the spectrum of ex-
cipients that there is incompatibility between Eudra-
Eudragit L 12.5 P and S 12.5 P (12.5 % solu-
git L 30 D / L 100-55 and magnesium stearate
tions in isopropanol with 1.25 % dibutyl phtha-
(coagulation). The added plasticizer in these MA-EA
dispersions should be at least 10 % based on the
Manufacturer: Röhm Pharma, Weiterstadt, Germany.
dry polymer substance content and may if neces-
sary, be raised to 20-25 % without impairing the
specific solubility characteristics of the film (101). It
Eudragit L 30 D / L 100-55 from pH 5.5.
is possible to use various polyethylene glycols, citricacid esters (Citroflex®), triacetin, dibutyl phthalate,
Eudragit L and S are copolymerisates based on
1,2-propylene glycol (101) and clibutyl sebacate
methacrylic acid and methyl methacrylate. The ratio
(84). Eudragit acrylic resins have such a high pig-
of the free carboxyl groups to the esters is about
ment binding capacity that twice to three times the
1 : 1 for Eudragit L and ca. 1:2 for Eudragit S (101),
amount of pigments or other excipients can be ad-
resulting in enteric coatings with varying dissolution
ded relative to the dry polymer substance (101).
pH values (L = easily soluble, S = sparingly soluble).
Preferred solvents are isopropanol, acetone and
Reference: FDA Drug Master File for Eudragit,
ethanol, as well as mixtures thereof. Delivery is ei-
USP XXII / NF XVII "Methacrylic Acid Copolymer,
ther in isopropanolic solution with or without added
plasticizers or as solvent-free powder under thetrade name Eudragit L 100 or S 100 respectively.
The latter product types can be dissolved in organicsolvents and mixtures or redispersed in water.
Cellulose acetate phthalate
Eudragit L 30 D and L 10-055: acrylic resins for
use in aqueous coating formulations consisting of a
copolymerisate of methacrylic acid and ethyl acry-
CAP as ammonium salt (Eastman Kodak, USA),
late, the carboxyl ester group ratio being 1 : 1.
Eudragit L 10-055 is only the lyophilized adjunct to
Eudragit L 30 D dispersion (100). On partial neutrali-
zation with sodium hydroxide solution or organic
Aquateric: a dry powder that must be dispersed
bases the powder can be reprocessed into a redis-
in water before use (redispersion latex). Other
persion latex (degree of neutralization 3-6 %). In
constituents apart from 63-70 % cellulose acetate
contrast, Eudragit L 30 D only needs to be diluted
phthalate (98) are polyoxypropylene-polyoxyethy-
lene block copolymer and acetylated monoglyce-
Since aqueous dispersions of Eudragit L 100
rides intended to improve the physical stability and
or S 100 have high film-forming temperatures
formulation of the product and necessary for techni-
(> 85°C), mixing with the softer Eudragit L 30 D or L
100-55 makes it possible to reduce the film-forming
Suitable plasticizers: diethyl phthalate (98), tri-
temperature to < 40°C, thus reaching the conven-
acetin (81). Triethyl citrate, on the other hand, is in-
tional processing range (100, 103). Mixing makes it
possible to achieve fine differentiation in the activesubstance release profile (pH 5.5-7.0), further mo-
CAP: suitable organic solvents are acetone (85,
dulations in release profile can also be achieved by
91), mixtures of acetone and ethanol (81, 83), of
mixing in Eudragit NE 30 D (polyethylacrylate- me-
isopropanol or ethanol and methylene chloride, or
ethyl acetate (81, 93, 95), of acetone and methylenechloride (90), of isopropanol methylene chloride wa-
Organic Eudragit lacquers are often applied as 6
to 10 % spray solutions (101), 10 to 20 % plastici-zer being recommended. Suitable plasticizers are,
Suitable plasticizers: triacetin 20-30 % related to
for example, triacetin (91), PEG 6000 (81), dibutyl
the polymer (81, 91), diethyl phthalate 25-60 %
phthalate (85) and diethyl phthalate (94).
(111, 85), propylene glycol 133 % (90).
Eastman Kodak also offers a possibility of using
Suitable plasticizers: PEG 400 to 6000 (80, 86),
CAP as a neutralized aqueous solution. The poly-
films containing the higher molecular weight PEG
mer powder is not marketed in micronized form,
being mechanically more stable and less sticky, tri-
with the result that it is not possible to prepare
a dispersion in water by analogy with Aqoat®
Solvents: e.g. ethanol-water (79), acetone-water,
(HPMCAS). Instead, CAP is dissolved in a dilute
acetone- isopropanol or ethanol (86, 81), ethyl ace-
ammonia solution, the time to produce the clear
tate-ethanol, methylene chloride-ethanol (81), iso-
spray solution depending on the amount of neutrali-
propanol-ethylene glycol monoethyl ether-wa-
zation agent, excess ammonia accelerating the dis-
solution process. A disadvantage of this form of en-teric film coating is the presence of ammonium salts
Reference DAB 9, USP XXII-NF X11 type 220824
in the dry film, causing the coat to be highly hydro-
philized. In addition, the unpleasant smell of ammo-nia causes problems during formulation.
Reference: DAB 9, USP XXII-NF XVII, Drug Mas-
Aqoat LF, MF, HF (Shin Etsu, Japan), micronized
powder specially for the aqueous film coating using
Cellullose acetate trimellitate
– for organic and ammoniacal-aqueous film coating:
HPMCAS MF above pH 5.5,HPMCAS HF above pH 7.0.
The polymer is supplied in three types in each
Since CAT already begins to pass into solution at
case with a different release profile determined by
ph 5.2, the polymer is a necessary addition to CAP.
What is more, the two film formers can be mixed inany ratio, making it possible to achieve a release
Suitable plasticizers: triethyl citrate, triacetin.
Reference: Drug Master File No. 7507 (106).
Solvent: e.g. acetone-water, methylene chlori-
deethanol, acetone -ethanol, ethyl acetate-ethanol.
Plasticizers: triacetin, acetylated fatty acid glyce-
Reference: Drug Master File No. 6703, USFDA
Carboxymethylethyl cellulose is manufactured by
ethylation of carboxymethyl cellulose and, incontrast to the cellulose derivatives described
above, the hydroxyl groups of which have been par-tially reacted with di- or poly-basic acids, contain no
ester groups, but only ether groups. The mode of
HP 50, HP 55, HP 55 S (Shin Etsu, Japan),
manufacture is intended to ensure an absence of
sensitivity to hydrolysis and special storage stability
HP 50 F and HP 55 F S (Shin Etsu, Japan,
– HPMCP 50 and HPMCP 55 made by Eastman
CMEC may be dissolved to about 8 % in 70 %
Kodak may be applied as aqueous solution, both
propanol, ethanol-water mixtures, methylene chlori-
in organic solution and neutralized with ammonia
deethanol and processed to ca. 8-12 % in water as
Suitable plasticizers for organic or organica-
queous solutions are myvacet 9-40, silicone oil, tri-
The two types of film former have different substi-
acetin, diethyl phthalate, triethyl citrate and acety[tri-
tution patterns and hence different solubility profiles.
butyi citrate; glycerin monocaprylate being used for
HP-50 has a lower proportion of phthalic acid groups
aqueous dispersions (Imwitor 908 R) (110),
(21-27 %) than HP-55 (27-35 %) and therefore passes
Reference: Standards for ingredients of drugs
into solution at lower pH values than its analog.
not in the Japanese Pharmacopeia (110).
By using the appropriate plasticizer it is possible
Polyvinyl acetate phthalate
to reduce the tendency of a film to become brittleand to increase its resilience. Spray formulations
containing plasticizers often spread better over the
Opadry (Aqueous) Enteric (Colorcon, UK).
surface of the material and in the case of aqueous
dispersions, addition of a plasticizer is generally
This enteric coated film former is characterized
needed to encourage film formation by means of
thermosetting or coalescence. Plasticizers increasethe motility of the polymer chains by interposing
Suitable plasticizers for PVAP are diethyl phtha-
themselves between the molecule chains and thus
late, triethyl citrate (82), acetyltriethyl citrate, triace-
restricting the ability of the film-forming chains to in-
teract or bringing about conformative changes. A
Suitable solvents are ethanolacetone-water
dynamic equilibrium is assumed (81) to develop
21:12 (83), methanol, methanolmethylene chloride
between plasticizer and polymer segments. Use of
a plasticizer reduces the glass transition tempera-ture Tg.
The dry commercial product Coateric is a film
concentrate containing a suitable plasticizer in addi-
Because of its consistency, a coated gelatin cap-
sule is more susceptible to deformation, forexample when being removed from a blister pack,
Opadry (Aqueous) Enteric contains all formulation
and slightly more plasticizer may be needed to pre-
constituents already premixed: film formers, plastici-
zers, anti-adhesion agents, pigments. The sprayformulation no longer needs to be reconstituted by
Plasticizers that have been named are (104):
adding water or solvent, a little ammonia solution
– alkyl esters of citric, tartaric and sebacic acids;
being added to aqueous dispersions to achieve
examples: diethyl sebacate, triethyl citrate, tribu-
partial neutralization. 15 parts by weight of Opadry
tyl citrate, acetyitriethyl citrate, acetyltributyl ci-
are recommended for aqueous systems; 5 parts by
– esters of phthalic acid, such as dimethyl phtha-
late, diethyl phthalate, clibutyl phthalate, dioctylphthalate, ethylphthaloyl- and butylphthaloyl
– glycerol esters such as castor oil, sesame oil,
The copolymerisate of vinyl acetate and crotonic
acetylated fatty acid glycerides, glycerol diace-
acid is converted into the salt with ammonia and is
applied as an aqueous solution (108). Since the hy-
– higher alcohols such as glycerol, 1,2-propylene
drophilized ammonium salts do not decompose un-
der the conditions of spray application and drying,and the added amounts of ammonia are removed,
– polyethers such as polyethylene glycols and po-
the film has a marked tendency to swelling and sof-
lyoxyethyiene-polyoxypropylene block copoly-
tening, making it necessary to apply very high mini-
– surfactants such as PEG-400 stearate, PEG sor-
As far as we know, the film polymer is no longer
bitane monooleate, sorbitane monooleate.
e. Anti-adhesion agents, pigments,
Plasticizers are generally liquids or solids with a
Adhesion of coating substances during film coa-
high boiling point which are intended to distribute
ting gives rise to unwanted aggregates. In addition,
themselves evenly in film polymers and improve
the freshly applied coats may be damaged in the at-
their mechanical properties through interaction with
tempt to separate the adhered parts. This effect
may be counteracted by anti-adhesion additives in
the formulation or by applying the substances di-
Ill. Formulations for the enteric
rectly into the coating chamber. Useful separating
coating of hard gelatin capsules
agents include talcum, magnesium stearate, Syloid®(micronized amorphous silicic acid), Aerosil® and
The amount of polymer needed must be calcula-
ted before starting the film coating process. In thecase of hard gelatin capsules, the surface area of
Film coatings can be coloured with titanium
the product to be coated is calculated (82, 101) and
dioxide and pigments (foodstuff colouring lakes, iron
the amount of coating required is then given in mg
oxide pigments). Undissolved excipients should be
of dry polymer substance per cm2 . The surface
finely distributed in appropriate dispersion agents
may either be calculated using the formula A = π x d
separately from the film formers, preferably using a
x h (mm2) or any of the available tables (84, 101):
ball mill, a toothed colloid mill or an Ultraturrax ma-chine and only subsequently mixed with the remai-
ning constituents. When adding finely distributed
pigments it is desirable to add additional nonionic
emulsifiers, stabilizers, wetting agents such as PVP,Tween 60/80 and PEG, to the pigment suspensions
There are five basic types of application system,
(101). Spray suspensions generally need to be stir-
each of which has quite specific properties.
red during the spray application. Many instructions
recommend use of the smallest possible pigment
particle sizes (< 15 µm) to obtain smooth films. Care
• as an aqueous-organic coating emulsion,
must be taken when adding pigments to ensure
• as an aqueous alcoholic coating solution,
that the upper limit for the particular film is not ex-
ceeded since the films increasingly lose their com-
• as a neutralized aqueous solution.
pactness and resilience beyond this value.
In the case of neutralized aqueous solutions, the
In the case of capsules, anti-adhesion agents or
acids are only released from the salts of the film
added pigments may cause difficulties since the
polymers under the influence of the gastric acid.
opaque coatings formed cause the originally often
Formulations for the film coating of hard gelatin
brightly coloured and glossy gelatin capsules to be-
capsules quoted in the literature are set out below
come matt. It is therefore advisable either to work
to provide a summary of the practical application of
without adding insoluble substances or else to se-
the film formers presented. These formulations
lect pastel coloured hard gelatin capsules from the
should only be regarded as indications and should
be adapted to the appropriate requirements andmodified to suit the product and process in each
f. Other additives
Since aqueous dispersions can coagulate as a
reaction to foaming, foam can form in bubbles inthe finished film and pronounced foaming can im-
a. Organic solution of Eudragit L 100 (8 1)
pair processing, it is advisable, when using large
batches, to add an antifoaming agent, e.g. various
silicon emulsions or sorbitan sesquioleate (109). To
prevent suspended pigments or polymer particles
seclimenting too quickly in the spray formulation it
is possible to use suspension stabilizers such as
PVP (in the form of Kollidon 25). Emulsifiers or wet-
ting agents such as polyethylene glycol sorbitan
fatty acid ester are added to formulations to mois-
ten pigments or to distribute fat soluble sub-
Solid content of spray suspension: 15,0 %
stances (plasticizers, silicon oils) in aqueous spray
Coating of dry polymer substance: 2-4 mg/cm2
b. Aqueous dispersion of Eudragit L 30 D (78)
Celluloseacetate phthalate films
(i.e. 0.24 % surfactant in the formulation)
Solid content of spray suspension: 20.0 %
Coating of dry polymer substance: 10.0 mg/cm2 or 9.1 %
Total dry substance coating: 12.1 mg/cm2 or 11.1 %
Coating machine: coating drum 35 em cliarn. with air ato-mization (1 mm bore)
Drying temperature: 45°CProduct temperature: 27°C
Using acetone as solvent, Jones (85) obtained
capsule coatings of even smoothness. Application
Srapying rate: 4.32 g/min/kgSpraying time: 128 min
of 4-6 mg/cm2 CAP, corresponding to 25 to 35 jumfilm thickness, a 5 % solution with 1.25 % diethylphthalate as plasticizer produced an enteric coating
The already precoated capsules were sprayed
with this dispersion. The precoat was composed of46.51 parts Eudragit L 30 D, 4.65 parts glycerol
b. Aqueous formulation of Aquateric (98)
(33 % related to the DPS), 4.65 parts Tween 80 (as33 % solution, i.e. the formulation contains 1.40 %
surfactant) and 44.19 parts water. A precoat was
needed to improve adhesion of the film to the
smooth surface of the capsule. 0.22 mg/cm2 or
0.20 % polymer or 0.32 mg/cm2 or 0.29 % solid
substance was applied. Alternatively it is possible to
use an HPC precoat (78), applied as a 5 % solution
Solid content of spray suspension: 14.71 %
to obtain a coating of 4.0 to 6.0 mg dry polymer
c. Aqueous dispersion of Eudragit L 100-55 (81)
A precoat of 7.2 parts Eudragit RS 100 and 0.8
parts dibutyl phthalate in methanol (0.4 mg/cm2)
was needed to obtain gastric-juice resistance for
hard gelatin capsules filled with sodium salicylate
since this active substance adjusts to a pH of 6 in
the diffusion layer and thus causes partial solubility
Solid content of spray suspension: 20.1 %Content of dry polymer substance: 12.5 %Coating of dry polymer substance: 3-5 mg/cm2
Carboxymethylethyl cellulose films
c. Low solvent content emulsion coating of HP-55 (87
Aqueous formulation of Duodcell (81)
Plasticizer (triacetin, PEG 6000,polyethylenegiycol-
Although emulsion coatings still contain solvent,
they are no longer inflammable due to the amount
of water present. The addition of water causes the
gelatin to swell slightly when the formulation is ap-plied ' polymer penetrates the capsule shell and the
film adheres well. Tendency to brittleness is alsocounteracted (87, 88).
d. Aqueous-alcoholic solutions of HP-55 (87)
Coating amount: 47 mg polymer per capsule
A clear film is formed since ethyl glycol, which
has a high boiling point, is.a good solvent for the
Hydroxypropyl cellulose acetate
The gastric-juice resistance and appearance of
capsules film coated in a laterally ventilated drum
No published formulations for the film coating of
instead of in a fluidized air bed were inferior (so-mewhat cloudy, overlap between body and cap in-sufficiently covered).
Polyvinyl acetate phthalate films
a. Organic formulation of PVAP (81)
Coating of dry polymer substance: 8 mg/cm2
b. Aqueous formulation using Opadry Enteric (81)
shearing force in high speed stirrers, partly also tothe presence of organic solvents and finely distribu-
ted pigments. Coagulation may then occur (101,
102). Coagulated dispersions are not reclispersible
In view of their sensitivity, ready-to-use aqueous
Eudragit dispersions should be processed within 1to 2 days. Cooling is necessary in the case of some
Aggregates of polymer can block the spray jets
A special problem when film coating capsules
To prevent this, aqueous dispersions are passed
with organic polymer solutions is imperfect adhe-
through a fine sieve before the coating is applied
sion of the enteric coating onto the smooth surface
of the capsule, the so-called orange peel effect.
Dosage forms can stick together during film coa-
A precoat can be applied to prevent this. For
ting, thereby damaging films layers already applied.
example, a 5 % aqueous solution of HPC (Klucel EF,
Very soft films have also been found to stick toge-
Hercules) or HPMC (Pharmacoat, Shin Etsu) is sui-
ther during storage. The addition of anti-adhesion
table (83,84) with a coating of 3 to 6 mg/cm2 dry
agents can lead to a loss of desired film transpa-
polymer substance. A solution of PVP or HPMC in
rency in the case of hard gelatin capsules.
an ethanol-mthylene chloride mixture has also beendescribed as a precoat (87) (coating 5 to 10 % of
Spraying losses due to the spray drying of the
polymer have been observed in the case ofaqueous dispersions. The distance between the jet
The main difficulty with aqueous formulations is
and the product should be carefully adjusted, sui-
that the gelatin shell softens. This can be prevented
table plasticizers should be selected and optimum
by applying an intermediate layer of gastric-juice so-
process parameters (drying temperature, amount of
luble Eudragit E in aqueous-alcoholic solution in an
air, spraying pressure, spraying speed, batch loa-
amount of about 10 % of the total coating (87).
ding, etc.) should be determined so that the spray
Since the film polymers presented are only inso-
luble in water in the protonized state, basic capsulefill materials which form a diffusion layer with neutralto alkaline pH value may reduce gastric-juice resis-
b. Special problems relating to capsules
tance. Diffusion barriers in the form of precoatssuch as Eudragit RS should then be used (98).
Problems occuring during the coating of cap-
sules are generally due to the characteristics of the
During storage of the film coated capsules, ad-
capsule wall - gelatin. This is illustrated by the follo-
hesion which sometimes occurs can be prevented
wing list of problems and their remedies:
by an overcoat also composed of HPC or HPMC(83.84). Use of an overcoat also improves the ap-
• During coating with aqueous spray formula-
pearance of the capsules and can have a positive
tions the gelatin shell softens and becomes
effect on the stability of the product.
• The gelatin shell becomes brittle due to water
evaporation and drying, especially when coa-
IV. Technological aspects and
problems in enteric coating
This may also occur during long term storage.
The brittleness causes the capsules to lose
their mechanical stability and they break underslight pressure (87).
a. General film coating problems
Aqueous dispersions are to a greater or lesser
• Insufficient adhesion of the film with splintering
extent sensitive to electrolytes, pH shifts, foam for-
and peeling of the coat (orange peel effect), es-
mation, higher temperatures and frost, the effects of
pecially with organic spray formulations.
The capsule shell is very smooth and gives little
Remedy: no pigment with a matt effect should
be added if the bright capsule colour is to be re-
The influence of moisture causes film coats and
tained. The uniformity of the film (81), choice of
the gelatin wall to swell to a varying extent,
plasticizer and solvent also determine the trans-
which also causes the coat to become deta-
Remedy: higher plasticizer content (81), a pre-coat in the form of a two-layer film coating (PVP,
c. Stability of coated
HPMC, Eudragit E) or the use of an aqueous-al-coholic solution or a hydrated coating emulsion
hard gelatin capsules
with low solvent content (81, 87). Addition of
Regardless of which enteric coated dosage form
is used, instability does occur when films are ap-
plied. Investigations involving 181 preparations, pre-
• Increased cracking on handling the medica-
dominantly tablets, revealed a number of stability
problems depending on duration of storage, tempe-
Remedy: a higher proportion of plasticizer makes
rature, coated active substance and other factors
• Separation of the capsule halves due to move-
Particularly in the case of hard gelatin capsules
stability problems are encountered above all in ente-
Remedy: use of hard gelatin capsules having pa-
ric coats applied in the form of aqueous dispersion
tent closures or banding the capsules.
systems. A report by Murthy** (82), who has publi-shed investigations in this field of aqueous coat->
• Problem zone: contact zone between upper
ings, showed that hard gelatin capsules coated with
Aquateric displayed noticeably slower release after
Remedy: to prevent any liquid penetrating the
three-months' storage at room temperature due to
space between the cap and body when spraying
reaction of the gelatin coat with CAP or with its hy-
begins, 0.2 to 0.3 % Aerosil 200 may be added
drolysis products phthalic acid and acetic acid
to the spray formulation to achieve rapid filling of
More plasticizer and the choice of a suitable coa-
changes in the polymer, has been reported for Coa-
ting machine also improve coverage at the join
teric films 9 months after manufacture.
(79). Cracks may form at the contact site.
Good stability was reported for Eudragit L 30 D.
Another possibility to prevent such effects is to
Film characteristics and release performance remai-
apply a gelatin band to the capsule at the point
ned constant, even after somewhat more stringent
of overlap between the cap and body.
storage conditions. Enteric film formers with an es-
The stability of a moisture sensitive active filled
ter structure are liable to hydrolyse under the in-
into the capsule can be affected by aqueous
fluence of moisture; in the case of cellulose deriva-
tives, HPMCAS is considered more stable thanHPMCP and this, in turn, more stable than CAT and
This also applies to the use of not totally anhy-
drous solvents (95). The hard gelatin capsuledoes not provide a complete barrier since the
A stability study (83) compared organically ap-
contact point of the two halves of the capsule
plied films of polymethacrylic acid-methyl methacry-
and the thin gelatin film at the transition between
late Eudragit L 100, polyvinyl acetate phthalate and
the cylindrical and the curved part of the capsule
cellulose acetate phthalate with films obtained from
represent possible moisture penetration zones.
aqueous dispersions of Eudragit L 30 D, Coatericand Aquateric. The authors used diethyl phthalate
Remedy: if this occurs, anhydrous solvents
as plasticizer. Aqueous dispersions of Eudragit were
should be used (95), at least for the sealing coa-
nonetheless somewhat superior to organic poly-
acrylate solutions whereas Aquateric only matched
• Loss of the desired glossy, attractive appea-
up to organic CAP systems when an overcoat was
rance of the capsule due to a non transparent
used. Capsules film-coated with Coateric displayed
signs of instability in the form of lost gastric-juice re-
sistance. PVAP organic system coaJts needed a
against a less powerful air flow and passes back
protective coating to prevent adhesion of the pro-
Examples of this type of machine include Strea-1
In this context, reference is made to special in-
(laboratory model) and Aerocoater (Niro, Bubendorf,
vestigatory methods for testing acid permeability
Switzerland) optionally with Wurster insert and Uni-
(88) or release kinetics in vivo (89).
Glatt (laboratory model) and Glatt-WSG (Glatt, Bin-zen, Germany) also optionally with Wurster insert.
V. Processes for coating hard
More recent combined processes
In the drum process the material is mainly moved
by rotation of the container and in the fluidized air
Developments in machinery over the last few
bed process it is moved by the stream of air. Com-
years in the field of coating methods have led to fur-
bination of both principles yields new possibilities of
ther refinements, which are described briefy below:
handling the material and optimizing the stream of
used only occasionally
air as a means of drying. In this combined process
and on a small scale or in formulations made up by
the stream of drying air does not have to move the
pharmacists (80, 86, 91), call for rather more
material on its own and consequently less air is
viscous dipping media. Using tweezers or capsule
needed. The interaction of centrifugal force, stream
halves fixed to a rotating plexiglass disc (91), each
of air and gravitation causes circular movement of
capsule half is dipped into the film solution. The
process is repeated until the layer has the desired
A report by Osterwald on the coating of gelatin
capsules (87) compared the Driacoater, Wurster-WSG and Rotor-WSG with respect to HPMCP-55
Use of horizontal drums
film coatings. It was found on the basis of the pro-
The Acela Cota (Manesty Machines Limited, UK)
cess parameters that the fluidized air bed permitted
is an example of a machine with a perforated drum.
a larger batch volume but needed more energy be-
It works on the principle of a horizontally mounted,
cause of the larger amount of inlet and exhaust air.
rotating cylinder to which drying air is fed through a
There was, however, a comparative saving in
lateral lymounted shoe and then withdrawn from
energy due to the rotor technology which optimizes
another location after passing through the bed of
product to be coated. The spray device is inside the
Application of HP-55 emulsion in classic fluidized
drum and sprays the rotating capsules from above.
air bed processing in the WSG produced relatively
The Diacoater, Hi-Coater and Glatt-Coater are si-
rough coatings since drying occurred very quickly in
the strong flow of air, moreover the spraying losseswere higher than when other machines were used.
Use of fluidized air bed processes
The rotor model produced a comparatively faster
In fluidized air bed processes, air flowing through
film coating: capsules film-coated in this manner
a screen in the base of the equipment keeps the
with an aqueous- alcoh oli c HP-55 formulation
material moving and is then sprayed with the film
quickly became gastric-juice resistant and had
formulation either in a counterflow principle from
above (top spraying) or in a parallel flow principle
Other exarnples of more recent combined pro-
cesses are the Roto-Processor (Niro, Bubendorf,
Movement of the material can be controlled more
Switzerland), the Ultracoater (also Niro) and the CF-
accurately by use of guide cylinders (Wurster in-
Granulator (Freund Industrial Co. Ltd., Japan).
serts). The capsules are propelled upwards in an al-
Finally, a machine of a different type is the Hütt-
most laminar flow through the central guide tube by
linKugelcoater (Hüttlin Entwicklung und Verfahrens-
a powerful air flow, sprayed with the coating formu-
lation and simultaneously dried by the stream of air.
On discharge from the tube, the material flows freely
Practical trials are needed in each individual case
downwards outside of the cylinder towards the
to determine the best coating equipment and best
screen in the base the equipment under gravity
43. J. Sjögren, C. Bogentoft; Alfred Benzon Symposium 17, Ko-
1a. K Thoma, R. Oschmann and H. Heckenmüller; Dtsch. Apoth.
44. H. Kato, H. Maekawa, Y, Tagagishi; US-Pat. 4, 250, 166
1. K. Thoma, R, Oschmann; Publication in preparation.
45. Y. Miyauchi; Jpn. Pat. Jpn. Kokai Tokkyo Koho 79, 129, 115
2. W.G. Chambliss; Pharm. Technol. 7
3. G. Cordes; Pharm. Ind. 31
: 328 (1969).
46. H.J. Pienaszelk, D.E. Resetarits, W.K Wilferth, H. Blumenthal;
4. H. Möller; Pharm, Ztg. 125
: 2254 (1980).
J. Clin. Pharmacol. 19
: 39 (1979).
5. K.H. Grötzinger, A. Volkwein, R. Böhler; Arzneim. Forschung
47. J. Rhodes, B.K. Evans; Eur, Pat. Appl. 15
: 334 (1980).
48. C.M. Bakke, L. Anderud, A. Aslaksen; Acta Med. Scand. 207
6. L. Ehrhardt, V. Hartmann, L. Patt; Med. Welt 24
: 45 (1973).
7. L. Ehrhardt; Acta Pharm. Technol. Suppl. 1
: 125 (1976).
49. J. Franz, L. Patt; US-Pat. 4, 411, 882 (1983).
8. U. Peters, C. Funcke, T.U. Hausmann, W. Staib; Arzneim.
50. M.M. Ghorab; Bull. Fac. Pharm. Cairo Univ. 11
: 259 (1972).
51. J. Spitael, R. Kinget; Pharm. Acta Helv. 52
: 106 (1977).
9. K. Lingner, W. Küssner; Arzneim. Forsch. 12
: 835 (1962).
52. D. Steinbach, H. Möller; Pharm. Ztg. 122
: 507 (1977).
10. K.E. Andersson, A. Bestler, A. Redfoss; Eur. J. Clin. Pharma-
53. M. Lorent, J.P. Gervois, J. Sondagh; J. Pharm. Belg. 34
11. H. Einig, D. Mayer; Arzneim. Forsch. 28
: 527 (1978).
54. German Association of Pharm. Industry, Red List (1982).
12. D. Clayton, A. Leslie; J. Int. Med. Res, 9
: 470 (1981).
55. U.E. Mutter, et al.; Pharm. Incl. 35
: 815 (1973).
13. T. Hovi, K. Josefsson, O.V. Renkonen; Eur. J. Clin. Pharmacol.
56. D. Katz, J. Siegel; Progress in Gastroenterology, New York
14. B.G. Boggiano, M. Gleeson; J. pharm. Sci. 65
: 497 (1970).
57. J.R. Hoon; Incl. Med. 38
: 362 (1969).
15. Z. Zalkrzewski, E. Siedlecka, E. Kozial; Fam. Pol. 35
: 7 (1979).
58. U.M. Smith, R.R. Babb; Fortschr. Med. 87
: 1153 (1969).
16. F. Fontani, G. Targa, D. Norde; Estr. Boll. Chim. Farm. 116
59. B. Arvidson, A. Magnussen, L. Soelvell; Läkartidnigen 74
17. Gumma, AA Mirimanoff; Pharm. Acta Helv. 46
: 278 (1971).
60. G.B. Howe, et al.; Aust. N, Z. J. Mod. 7: 600 (1977).
18. B.K. Evans, V.G. Fenton-May, M.G. Lee; J. Clin. Pharm. 4
61. V. Laine; Sven. Läkartidn, 65
: 3838 (1968).
62 J.E. Rossouw, M. Clark, M. Davis, R. Williams; Rheumatol.
19. Ajinornoto, Co. Inc.; Jpn, Pat. Jpn. Kokai Tokkyo Koho 81, 65,
63. D. Birnbaum, D. Kormeli; Isr. Pharm. J. 18
: 216 (1975).
20. C. Bogentoft; Eur. J. Clin. Pharmacol, 14
: 351 (1978).
64. J.R. Leonhards, G. Levy; J. Am. Med. Assoc. 193
: 99 (1965).
21. A. Bennett, T. Clark-Wibberley, I.F. Stanford, J.E. Wright;
65. R. Clark, L. Lasagua; Clin. Pharmacol. Ther. 6: 568 (1965).
J. Pharm. Pharmacol, 32
66. G. Levy; Clin. Pharmacol. Ther. 8: 887 (1967).
22. P. Lechat, P. Ganter, MA Fontagne, B. Flouvart; Thérapie
67. W.A. Rushford, P.D. Fowler; J. Int. Med. Res. 5, suppl. 2, 67
23. K.D. Rainsford, B.M. Peskar, K. Brune; J. Pharm. Pharmacol.
68. E.H. Mauracher; Praxis 64: 1644 (1975).
24. J. Brandslund, H. Rask, N.A. Klitgaard; Scand. J. Rheumatol.
69. DA. Dropplemann; US Pal. 3, 993, 767.
70. E. Schmid; Schweiz. Med. Wochenschr. 95
: 1204 (1965).
25. F.L. Lanza, E.R. Umbenhauer, R.S. Nelson, M.F. Rack;
71. J.A. Beirne; Clin. Pharmacol. Ther. 16
: 821 (1975).
72. Anonymus; Drugs and Therapeutics Bulletin 10
: 9 (1972).
26. G.R. Silvoso, KA lvey; Ann. Intern. Med. 91
: 517 (1979).
73. 0. Lockard, et al.; Gastrointest. Endosc. 26
: 5 (1980),
27. V.A. John, Goldsborough; Biopharm. Drug Dis, 3
: 67 (1982).
74. W. Rothe, G. Groppenbächer Pharm. Ind. 35
: 723 (1973).
28. N. Cardoe, P.D. Fowler; J. Int. Med. Res. 5
: 59 (1977).
75. B. Hänselmann; Pharmazie 26: 57 (1971).
29. 0.N. Gamst, A.K. Haga, T. Holler, A.H. Farup; Nov. Pharm. Acta
76. J.P. Deporte; J. Pharm. Belg. 31
: 341 (1976),
77. J.P. Deporte; J. Pharm. Belg. 31
: 263 (1976).
30. W. Oelkers, G. Stoffels, H, Schäfer, H. Rieth; Arzneim. Forsch.
78. Röhm Pharma, Applicationsheet Eudragit L 30 D, 3191.
31. M. Payne; Pharm. J. 25
: 657 (1966).
79. Shin Etsu, Technical Information, 10/1988.
32. G. Smith, P.H. Cox; Pharm. J., 22
: 245 (1963).
80. Shin Etsu, Technical Information H-1 4 (1977).
33. M. Jacob, C. Duru, A. Puech; Sci, Tech. Pharma. 8
: 93 (1979).
81. K.H. Bauer, K. Lohmann; H.P. Osterwald, G. Rothgang, Über-
zogene Arzneiformen, Wissenschaftliche Verlagsgesellschaft
34. A Warren, W. H. Davis; Swiss Patent 620,124 (1980).
35. B. Helwig; Moderne Arzneimittel, Wissenschaftliche Verlagsge-
82. K.S. Murthy, N.A. Enders, M. Mahjour, M.B. Fawzi; Pharm.
36. H. Renker, E. Schaub, M, Bürgin; Arzneim. Forsch. 27
83. K.S. Murthy, D.A. Kulbert, M.B. Fawzi; Journal of Biomat. Appl.
37. R.A. Upton, J.R. Powell, Th. W, Guenthert, J.F. Thiercelin;
J. Pharmakokin. Biopharm. 8:151 (1980).
84. K.S. Murthy; Application-letter.
38. O.A. Gubara, A.S. Geneidi, M.S. Adel; Pharm. Ind. 42
85. B.E. Jones; Manuf. Chem. Aerosol News 53 (1970).
86. K. Thoma; Neuere Arzneiformen in der Apolhekenrezeplur,
39. Laboratories Sobio Sa; French. Pat, Fr. Demancle 2, 116, 156
Schriftenreihe der Bayer. Landesapothekerkammer Heft
40. K. Nishimura, K Sasahara, M. Arai, T. Nitanai; J. pharm.
87. H.P. Osterwald; Acta Pharm. Technol. 28: 329 (1982).
88. K. Thoma, R. Oschmann; Pharmazie 46
: 278 (1991).
41. G. Rothgang; Dtsch. Apoth. Ztg. 115
: 701 (1975).
89. K. Thoma, R. Oschmann; Pharmazie 46
: 331 (1991).
42. B., Hänselmann, R. Voigt; Pharmazie 26
: 57 (1971).
90. D. Werchan; Pharmazie 39
: 275 (1984).
91. J.P. Remon, P. Gyselinck, R. van Severen, P. Braeckman; Acta
92. J.M. Aiache, S. Aiache, A. Jeanneret, F. Cornat; Boil. Chim.
93. J.H. Aiache, J1. Vidal, S. Aiache, A. Jeanneret, F. Cornat;
94. C. Boymond, J. Chanliau, R. Minck, A. Stamm; Pharm. Act.
95. F. Dussauge: Journées Galéniques de Saint-Rémy-de-Pro-
96. K. Thoma, H. Heckenmüller, R. Oschmann; Pharmazie 42
97. K. Thoma, H. Heckenmüller, Pharmazie 42: 837 (1987).
98. 1. Cherette, J.A. Plaizier-Vercammen, Congr. Int. Pharm. Tech-
99. K. Lehmann, D. Dreher, H. Götz, EP 0152038 B1 (1989).
100. K. Lehmann, D. Dreher; Pharm. Ind. 48: 1182 (1986).
101. Röhm Pharma, Info V-7, 1990
Röhm Pharma, Info V-6Röhm Pharma, Info Eudragit L 30 DAnwendung in der Arzneirnittelherstellung Röhm Pharma,Info L/S-7 und 7a.
102. Handbook of Pharmaceutical Excipients, Joint Publication of
the Amer. Pharmaceutical Association and the Royal Phar-maceutical Society of GB (1986).
103. K. Lehmann; Acta Pharm. Technol, 31
: 96 (1985).
104. K. Thoma, H. Heckenmüller; Pharmazie 41
: 328 (1986).
105. Product information Eastman Kodak, Publication No. EFC-
106. Information from Syntapharm GmBH (Distribution of Aqoat in
107. R. Oschmann; Dissertation Munich (1985).
108. K.H. Bauer, H. Osterwald: Pharm. Ind. 41
: 1203 (1979).
109. Product information from Shin Etsu Chemical Co.; "Shin-Etsu
Aqoat, for aqueous enteric coating and aqueous sustained-release coating".
110. Product information PK 7 4093 and PK-7 4200 Lehmann &
111. Correspondence from Capsugel (1990).
Wolfgang Rihm – deR komponist und sein sendeR Zuschreibung mehr als nur voreilig war. Zu äußersten pianoregionen und die nahtlosen vielfältig, zu ausdifferenziert ist seine musi-übergänge sind bis heute die musikalischen für neue ideen und ästhetische linien, und laus, aufgeregte buhrufe: Verklungen ist kalische Weltsicht, als dass diese sich auf soeben mit „morphonie“ d
COMPETITIONS PLANNER - 2 0 1 2 February February EUROPEAN CHAMPIONSHIPS 10/4/12 - 15/4/12 OLYMPICS BRITISH NIA, 27/7/12/11 - 12/8/12 LONDON, UK OLYMPICS 27/7/12/11 - 12/8/12 LONDON, UK September September November November December December FIG A & FIG B TRI COMPETITIONS 2012 Comp Date Saturday 18th February Satu