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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.
Enteric coated
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
coated films
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 VI. References
• 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- acid-sensitive medicaments
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 Polymethacrylate
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.
Cellulose derivatives
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.
Hydroxypropyimethylcellulose
Reference: DAB 9, USP XXII-NF XVII, Drug Mas- acetate succinate
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.
Carboxymethylethyl cellulose
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 Hydroxypropyimethylcellulose phthalate
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).
Polyvinyl derivatives
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 Other copolymers
– 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,
d. Plasticizers
colourants
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 Eudragit films
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 Hydroxypropyimethyl cellulose
of water present. The addition of water causes the phthalate films
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
succinate films
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 Protective coatings
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 capsules
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
gelatin capsules
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 Dipping processes, 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 VI. References
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