1. Enteric Coating of Tablets 1.1. Introduction 1.1.1 Controlled Drug Release through Film Coatings Even very thin film coats of only about one hundredth of a millimetre prevent attrition and dust formation when tablets are handled or packaged in pharmaceutical factories. Impregnation with EUDRAGIT ® immediately after compression avoids dust formation from hormonal preparations or antibiotics, for example, which is harmful to people, and ensures the smooth running of dust-sensitive filling machines. Combining acrylic polymers with pigments permits evenly colored, perfectly opaque film coats to be obtained on mottled or unattractively colored cores. The active ingredients contained in these are then better protected against heat, light, moisture and other harmful influences during transport and storage, right up to their consumption by the patient. What is more, film coatings may facilitate swallowing of a drug, prevent undesirable side effects and even improve its therapeutic efficacy. This is made possible by controlled dissolution in the gastrointestinal tract, both as far as time and site are concerned, or else by a film coating of graded permeability which ensures controlled release of the active ingredient in specific regions of the digestive tract. The special solubility properties of the film formers, which are adjustable to the medication and the function it serves in the body, are caused by functional groups attached to the polymer chains. The basic difference is between water-soluble films tha t dissolve with salt formation and insoluble, but permeable film coats. The polymers dissolving by salt formation in specific pH ranges may be anionic or cationic. Table 3 on page 15 presents a survey of the chemical structure and function of EUDRAGIT ® films. The following diagram illustrates the characteristic behavior of film coatings in the digestive tract.
Transcript
1. Enteric Coating of Tablets
1.1. Introduction
1.1.1 Controlled Drug Release through Film Coatings
Even very thin film coats of only about one hundredth of a millimetre prevent attrition
and dust formation when tablets are handled or packaged in pharmaceutical
factories. Impregnation with EUDRAGIT® immediately after compression avoids dust
formation from hormonal preparations or antibiotics, for example, which is harmful to
people, and ensures the smooth running of dust-sensitive filling machines.
Combining acrylic polymers with pigments permits evenly colored, perfectly opaque
film coats to be obtained on mottled or unattractively colored cores. The active
ingredients contained in these are then better protected against heat, light, moisture
and other harmful influences during transport and storage, right up to their
consumption by the patient.
What is more, film coatings may facilitate swallowing of a drug, prevent undesirable
side effects and even improve its therapeutic efficacy. This is made possible by
controlled dissolution in the gastrointestinal tract, both as far as time and site are
concerned, or else by a film coating of graded permeability which ensures controlled
release of the active ingredient in specific regions of the digestive tract. The special
solubility properties of the film formers, which are adjustable to the medication and
the function it serves in the body, are caused by functional groups attached to the
polymer chains. The basic difference is between water-soluble films tha t dissolve with
salt formation and insoluble, but permeable film coats. The polymers dissolving by
salt formation in specific pH ranges may be anionic or cationic. Table 3 on page 15
presents a survey of the chemical structure and function of EUDRAGIT® films. The
following diagram illustrates the characteristic behavior of film coatings in the
digestive tract.
Figure 1 Behavior of films in the digestive tract
pH < 5 E 100
pH >5.5 L 100-55
pH > 6.0 L 100
pH> 7.0 S 100
perm. RL 100
perm. RS 100
Mouth 1 min.pH 5 - 8.5
Stomach 1-2 hpH 2 - 5
Duodenum 0.5 hpH 6
Jejunum 2 - 4 hpH 6.5
Ileum 2 - 4 hpH 7
Colon 10 hpH 6.5 - 7
Drug release by diffusion
Drug release by dissolution
The cationic polymer EUDRAGIT® E 100 carries amino groups. Its films are,
therefore, insoluble in the neutral medium of saliva, but dissolve by salt formation in
the acid environment of gastric fluid. Such film coatings with a thickness of
approximately 10 µm prevent medication with a bitter or revolting taste from
dissolving in the mouth upon ingestion or during swallowing. Subsequently, the
protective film dissolves quickly in the stomach and releases the active ingredient.
Thus, the drug can be administered with ease and unfolds its effect without any
major delay. A sugar coating with the same taste-masking effect must be over 100
times thicker, requiring a correspondingly larger amount of substance.
Anionic acrylic polymers such as EUDRAGIT® L and EUDRAGIT® S carry carboxyl
groups. They are insoluble in acid medium, i.e. resistant to gastric fluid, and dissolve
only in the neutral to weakly alkaline medium of the small intestine. Medication that
causes incompatibilities in the stomach, i.e. irritates the gastric mucosa or provokes
nausea and sickness, can be coated with these enteric films to pass the acid
environment of the stomach unchanged and release the active only after entering the
small intestine. Contact between the drug and the gastric mucosa is then avoided,
but the active ingredient is later easily absorbed in the intestine. No side effects occur
and the therapeutic effect is unfolded in full. Such coatings should also be used to
protect acid-sensitive drugs against aggressive gastric fluid.
By contrast, permeable acrylic polymers such as EUDRAGIT® RL and EUDRAGIT®
RS are water-insoluble over the entire pH range, but swell in digestive fluids
independently of pH. In the swollen state they are then permeable to water and
dissolved actives. The hydrophilic groups within the polymer control the water
absorption, the degree of swelling and the permeability of the films. The active
ingredients thus enveloped are gradually dissolved by penetrating water and diffuse
outwards through the intact polymer membrane at the same pace, thereby ensuring a
regular delayed-release profile. The versatility of EUDRAGIT® acrylic polymers for
the manufacture of prolonged-action dosage forms is discussed in detail in Chapter 3
"Sustained-release dosage forms."
At this point, let us have a closer look at some of the problems associated with
enteric coating formulations. What matters first of all is that the coating materials
used swell as little as possible in the acid environment of the stomach at pH 1 to 4
and remain largely impermeable for several hours, as large cores may take longer to
pass the stomach. These requirements are met by anionic polymethacrylates in layer
thicknesses of 20 to 40 µm which have been skillfully applied to form impeccable
coatings. This latter point has to be verified from case to case.
The pharmacopeial specifications allow some softening of enteric-coated cores.
Testing for gastroresistance must confirm that the films remain intact and that the
diffusion of active ingredient in gastric fluid, if at all permissible, remains within
tolerable limits. A USP test specification allows maximally 5% drug release after 1
hour. Film coatings with a dissolution pH around or below pH 5 are only conditionally
gastroresistant, since the pH of the stomach contents often rises to values around pH
5 after an opulent meal or in patients with reduced secretion of gastric fluid.
After leaving the stomach, the chyme is approximately neutralized by the addition of
pancreatic fluid, resulting in a pH of 5 to 6 in the duodenum. In the lower sections of
the small intestine, the pH continues to increase gradually, sometimes up to a value
of 7. In the colon, pH values of approximately 6.5 to 7 are found.
Enteric polymer films are normally expected to dissolve between pH 5.5 and 6.5, on
the one hand to avoid premature disintegration in the stomach and, on the other
hand, to ensure rapid release of the active ingredients in the intestinal tract. Coatings
with EUDRAGIT® L 30 D-55 applied from aqueous dispersion, or of the solid
substance EUDRAGIT® L 100-55 in the form of an organic solution, dissolve from pH
5.5 upwards. Films of EUDRAGIT® L 100 start to dissolve at pH 6.0 (see Figure 2 on
page 16).
Using EUDRAGIT® S, dissolution of enteric film coatings only sets in above pH 7
and thus occurs in vivo in the lower sections of the intestines. This, therefore, is the
principle according to which pH-dependent sustained-release dosage forms are
developed. However, since a pH of 7 is frequently only just reached and not
noticeably exceeded, excretion of active ingredients with the feces must be avoided
by mixing EUDRAGIT® S with EUDRAGIT® L or otherwise.
Surprisingly, films formed from aqueous dispersions show a somewhat lower
permeability than similar films from organic solutions. This is attributed to the
increased density of the dispersion films [9,10], but excipients like plasticizers and
pigments, for example, also play a part. The very hard dispersions of EUDRAGIT® L
100 and EUDRAGIT® S 100 have very high film-forming temperatures of over 85 °C
and therefore require additions of as much as 40 to 50% plasticizer [15], or mixing
with the relatively soft types EUDRAGIT® L 30 D-55 and EUDRAGIT® NE 30 D to
allow film formation at acceptable processing temperatures. Mixing with
EUDRAGIT® NE 30 D increases the permeability slightly in the acid pH range of the
stomach and slows down dissolution in the intestinal tract at pH 6 to 7 [12]. Films
containing carboxyl groups are normally highly water-resistant and less permeable to
water vapor than hydrophilic polymers with amino or hydroxyl groups. Therefore,
enteric coating formulations in thin layers are often also recommended to protect
moisture-sensitive cores for which gastroresistance is not specified. Up to a thickness
of approx. 10 µm such coatings are not resistant to gastric fluid and delay the drug
release only slightly - both in the stomach and the intestines - if disintegrants are
additionally incorporated into the cores. This is why they are also suitable for rapidly
disintegrating coatings intended for tropical climates.
For in vitro testing, the European Pharmacopoeia, in unison with the BP and USP,
specifies the use of simulated intestinal fluid pH 6.8, which is very close to in vivo
conditions. The required dissolution time is 45 min. Within this period the cores must
disintegrate and 80% of the active ingredient be dissolved. The disintegration times
of the polymer films are somewhat longer in vivo than in vitro.
1.1.2 Technical Aspects of the Manufacture of Enteric Sugar-Coated
Products
The following examples are meant to show a simple approach to enteric sugar
coating which allows you to verify the successful performance of the most important
processing steps or to detect possible faults immediately. For the same reason, the
formulations stated contain only the minimum number of excipients, so that enteric
property is given priority over appearance.
Figure 4 (page 18) shows the layer buildup of enteric coatings applied by ladling in
comparison with those applied by spraying. The ladling process can be used where
an additional sugar coat will be applied. The irregularities of the surface which are
inevitable with portionwise application, because of moist cores sticking together
during drying, are irrelevant in this case. Even the most skillfully performed ladling
process usually does not produce optically appealing final coats. Where these are
required, polymer solutions or dispersions containing the corresponding amounts of
talc, titanium dioxide and possibly pigments must be applied by spraying. For
gastroresistance, approx. 3 to 5 mg dry polymer substance per cm² are needed.
The aqueous acrylic dispersion EUDRAGIT® L 30 D-55 is less sticky and thus
permits an acceptable surface quality to be achieved even by portionwise application.
The cores must, however, first be sealed with organic polymer solution. This is
normally not required in a spraying process, which itself produces surfaces of
impeccable quality.
Table 2 Cellulose derivatives for film coatings
Chemical structure
H
O OOR
OR
OR
H
H H
H
HH
H
H
H
O
CH OR2
CH OR2
OR
O
O
Products
R Substitution
[mole] Substituents (%)
Methylcellulose
Hydroxypropyl
methylcellulose
(Pharmacoat®
Methocel®)
Cellulose acetate
phthalate (CAP)
Hydroxypropyl
methylcellulose
phthalate
(HPMCP)
-CH3
-CH3
-CH2-CH(OH)-CH3
-CO-C6H4-COOH -CO-CH3
-CO-C6H4-COOH
-CH3 -CH2-CH(OH)-CH3
1.5-2.0
1.80
0.25
0.50
1.20
HP 50
0.50
1.60
0.20
HP 55
0.30
1.60
0.20
high
medium
double
HP 50
27-35
18-22
4-9
28-32
23-28
22-26
7-12
30-36
19-23.5
HP 55
20-24
20-25
5-10 Specifications Methyl
cellulose Hydroxypropyl methylcellulose
USP XX
Cellulose acetate phthalate
USP XX/NF XV
Hydroxypropyl methylcellulose
phthalate
Methoxy %
Hydroxypropoxy %
Acetyl %
Phthalyl %
Drying loss %
Sulfate ash %
Arsenic ppm
Heavy metals ppm
Free phthalicacid%
22-26
23-28
28-32
-
-
max. 10
max. 1.5
16.5-20.0
19.0-24.0
27.0-30.0
4.0-7.5
7.0-12.0
23.0-32.0
-
-
max. 5
max. 3
max. 3
max. 10
-
-
-
19.0-23.59
30.0-36.0
max. 5
max. 1.0
-
-
max. 6
18.0-22.0
20.0-25.0
4.0-9.0
5.0-10.0
-
27.0-35.0
20.0-24.0
max. 5
max. 0.1
max. 3
max. 10
max. 1
Table 3 Acrylic polymers for film coatings
Chemical structure
CH3 3
C=O
O - Alkyl
CH 2 C CH 2 C
(H) CH (H)
R
Products R Substitution
[mole] Function
Methacrylic acid copolymersa
EUDRAGIT® L 100-55/L100/S 100
Aminoalkyl methacylate copolymersb
EUDRAGIT® E 100
Ammonio methacrylate copolymersb
EUDRAGIT® RL 100 / RS 100
Methacrylic ester copolymersa
EUDRAGIT® NE 30 D
-COOH
-COO-CH2CH2N(CH3)2
-COO-
CH2CH2N+(CH3)3
Cl- -COO-CH3
0.3-0.5
0.5
0.05-0.1
0.3
gastroresistant enterosoluble
gastrosoluble permeable pH > 5
permeable
independent
a = polymerization in emulsion b = polymerization in bulk
Specification L 100-55/
L 100 S 100 E 100 RL 100 RS 100
USP/NF DAB USP/NF
Methacrylic acid groups
(acid value mg KOH/g)
Dimethylaminoethyl groups %
(alkali number mg KOH/g)
Ammoniomethacrylate groups%
(alkali number mg KOH/g)
Loss on drying %
Sulfate ash %
Arsenic ppm
Heavy metals ppm
46.0-50.6
(300-330)
max. 5
max. 4
max. 2
max. 20
27.6-30.7
(180-200)
max. 5,0
max. 0.1
max. 2,0
max. 20
20.8-25.5
(162-198)
max. 2
max. 0.1
max. 2
max 20
8.85-11.95
(23.9-32.3)
max. 3
max. 0.1
max. 2
max. 20
4.48-6.77
(12.1-8.3)
max. 3
max. 0.1
max. 2
max. 20
Figure 2 Dissolution behavior of enteric films with EUDRAGIT® L/S
Portionwise application is normally part of a sugar-coating process. A dusting phase
consisting of sugar syrup and binder (acacia gum) as well as dusting powder (talc)
serves to reduce tablet attrition and seal the cores against penetrating solvent. If
highly volatile solvents are used in the subsequent film coat, dusting can be
dispensed with. Alternatively, aqueous or alcoholic solutions of PVP can be used
together with confectioner's sugar, calcium carbonate, calcium sulfate, starch or
Aerosil® as dusting agents.
The enteric layer can be applied as either an organic polymer solution or an aqueous
dispersion. The use of EUDRAGIT® L, dissolved in isopropyl alcohol and acetone,
together with a plasticizer and dusting agent is described in exercise 1.3.1.
The aqueous dispersion EUDRAGIT® L 30 D-55, which also requires the addition of
a plasticizer and is applied on top of a sealing coat, is described in exercise 1.3.2
Given adequate warm air supply, dusting may no longer be necessary.
The film coat should form a coherent layer that is largely impermeable to penetrating
gastric fluid and emerging active, as well as resistant to mechanical stress during
further processing. A mixture of EUDRAGIT® L dispersion, sugar and talc is
suggested for the subsequent transition phase, which is to provide good adhesion to
the following sugar coat and protect the enteric film coat during the sugar coating
process. The final sugar coat for rounding and finishing is prepared from
conventional sugar syrups with adjuvants. All well-known sugar coating formulations
can be used for the purpose, as can sugar-free formulations in the appropriate layer
thickness.
The layer buildup of an enteric sugar-coated product manufactured by portionwise
application starts in exercise 1.3.1 and may be continued as described in exercise
1.3.3.
Layer buildup by spraying
Organic polymer solutions can be sprayed directly on tablet cores and do not require
a transition phase. Combined with pigments, the enteric layer can also be the final
coat. A layer thickness of approx. 10 µm is sufficient for coloring, so that the approx.
20 µm thick base coat can be made of plasticizer and glidant (talc) only, in order to
save on pigments (1.3.4 and 1.3.5). Where pigments play a subordinate role (white
or light-colored coatings), a single homogeneous film coat will do (1.3.4 with
EUDRAGIT® L 100 and 1.3.6 with EUDRAGIT® L 30 D-55).
Application of a sealing coat and water barrier made of EUDRAGIT® L solution in
isopropyl alcohol is recommended. If the aqueous dispersion EUDRAGIT®
L 30 D-55 is used for spraying, the decision for or against a sealing coat depends on
the sensitivity of the cores. If drying is effected rapidly, no such coating may be
required. On the other hand, sealing is necessary to prevent interactions triggered by
direct contact between the active ingredient and the film coat.
Exercises 1.3.4 to 1.3.8 describe spraying processes and formulations which can
also be used for the large-scale production of enteric sugar-coated products.
Figure 4 Layer buildup of enteric coatings
1.1.3 Calculation of Polymer Quantities
Since a certain layer thickness has to be achieved in film coating, the amount of
coating material must be related to the surface area of the substrate. For this reason
it is expressed in mg of dry polymer substance per cm² of surface area. The surface
areas of some pharmaceutical dosage forms can be calculated according to the
following formula, for which it is assumed that tablets have approximately the shape
of a circumscribed cylinder:
S = surface (mm²), d = diameter (mm), h = overall height (mm)
Tablets: S = π ⋅ (d ⋅ h + 0.5 ⋅ d²) = mm²
Capsules, oblongs: S = π ⋅ d ⋅ h = mm²
Spherical shapes
(microtablets, pellets, granules): S = π ⋅ d² = mm²
pigmented final coat approx. 10 µ m
enteric layer approx. 15 µ m sealing coat approx. 5 µ m
through-colored enteric layer, approx. 25 µ m
Dusting phase approx.10 µ m
Enteric layer approx. 15 µ m
Transition phase approx. 10 µ m
Sugar layer up to several mm
Ladling: aqueous or organic formulations Spraying, aqueous or organic formulations
through-colored polymer layer pigmented final coat
If we divide the surface area of a substrate S (mm²) by its weight w (mg), we
immediately obtain the requisite coating quantity in %, i.e. the polymer consumption
in kg of dry polymer substance per 100 kg of substrate for a coating of 1 mg of dry
polymer substance per cm². If lower or higher coating weights are specified for
certain dosage forms, we must multiply by this additional amount A = mg polymer per
cm². S (mm²) · A (mg/cm²)
Coating weight (%) = ___________________ w (mg)
Note that mm² in this formula refers to the surface area and mg per cm² to the
amount of film former. Both quantities are linked by the factor 100, which leads to the
result in percent.
The formula according to P. H. List (Arzneiformenlehre) may be used for exact
calculation of the tablet surface area:
S = 2 π (R ⋅ Bw + R² + Ch²) =mm² R = radius, Bw = band width, Ch = cup height If we introduce the overall height H = Bw + Ch for the band width plus cup height, both of which are difficult to measure, and calculate the cup height from the convex
radius (Cr) according to Ch Cr Cr R= − −² ² , we arrive at
S = 2 π (R ⋅ H + (R · Cr - √Cr² - R²))² = mm²
This formula may look rather complicated, but it can easily be stored in a modern
pocket calculator to be at hand when needed.
Presentation of formulations and conversion of batch size and polymer requirement
Our examples are up-to-date formulations for the batch sizes stated. If ready-to-use
preparations and premixes are processed rather than the pure raw materials, the
concentration and solvent are stated. All other solvents and diluents are summarized
at the end, even if they are used at the very beginning or added in portions according
to our instructions. As a general rule, EUDRAGIT® polymer solutions or dispersions
are combined with premixes and other components of the formulation just before
use. If a pigment suspension is separately prepared, the entire amount goes directly
into the formulation.
Besides the sample formulation, a standard formulation is given which contains all
components in % by weight, based on their sum total = 100 parts by weight. The
solids or pure substances contained in ready-to-use preparations or premixes as well
as the solvents and diluents are stated as one amount each.
For conversion of a formulation to a different batch size with an equivalent amount of
EUDRAGIT® and cores of approximately the same size, use the following batch
factor: desired batch size (kg)
F = ______________________
example of batch size (kg)
In this case, multiply all quantities stated in the sample formulation by this factor F.
The standard formulation remains unchanged.
Example 1: formulation for exercise 2.3.7
The stated batch size of 7 kg is to be increased to 50 kg: 50
batch conversion factor F = ____ = 7.14 7
Formulation converted to 50 kg: EUDRAGIT® L 30 D-55 (30% aqueous dispersion) 260 g ⋅ 7.14 = 1,856 g Talc 39 g ⋅ 7.14 = 278 g Polyethylene glycol 6000 16 g ⋅ 7.14 = 114 g Water 345 g ⋅ 7.14 = 2,464 g 660 g 4,712 g
If the amount of EUDRAGIT® has to be varied because the size or structure of the
cores or the function of the film coat has changed, use the EUDRAGIT® factor to
convert the formulation while maintaining the quantity ratio to the other excipients: required amount of EUDRAGIT® (kg)
EUDRAGIT® factor EF = _______________________________________ amount of EUDRAGIT® in sample formulation (kg)
Multiply all quantities stated in the sample formulation by EF. The standard
formulation remains unchanged.
Example 2: formulation for exercise 3.3.7
Batch size 150 kg coated with 50 kg of EUDRAGIT® L 30 D-55 (30% aqueous
dispersion), application of dry coating substance 15 kg = 10%.
For improved gastroresistance, you now want to change the amount of dry coating
substance to 12% at a reduced batch size of 50 kg. You require 6 kg of EUDRAGIT®
solids equivalent to 20 kg of 30% aqueous dispersion. 20 (kg)
EUDRAGIT® factor EF = _______ = 0.4 50 (kg)
Converted formulation:
EUDRAGIT® L 30 D-55
(30% aqueous dispersion) 50,000 g ⋅ 0.4 = 20,000 g
Acetyl triethyl citrate 1,500 g ⋅ 0.4 = 600 g
Talc 7,500 g ⋅ 0.4 = 3,000 g
Silicone antifoam emulsion 150 g ⋅ 0.4 = 60 g
Water 36,850 g ⋅ 0.4 = 14,740 g
96,000 g 38,400 g
Should you want to modify the quantity ratios of individual constituents in a controlled
manner, the formulations remain clear and comparable if an increase in one
constituent is balanced by a corresponding reduction in others, so that the sum total
remains the same.
Example 3: formulation for exercise 2.3.8
You now want to increase the amount of talc in relation to the solid substance
EUDRAGIT® to a ratio of 1:1. 260 g of the 30% dispersion contain
260 g ⋅ 0.3 = 78 g EUDRAGIT® solid substance. So you increase the amount of talc
to 78 g and reduce the water quantity accordingly by 78 g - 39 g = 39 g: 345 g - 39 g
= 306 g.
Alternatively, you may use the standard formulation for conversion:
talc 5.9 + 5.9 = 11.8%, water 79.9 - 5.9 = 74.0%.
Hence the amounts for the sample formulation: talc 11.8 ⋅ 660 g : 100 = 77.9; water
74.0 ⋅ 660 g : 100 = 488.4 g minus 260 g ⋅ 0.7 = 182 g water contained in 260 g of the
30% EUDRAGIT® dispersion gives 306 g water as a diluent.
converted standard
EUDRAGIT® L 30 D-55 ↓ ↓
(30% aqueous dispersion) 260 g 11.8% 260 g 11.8%
Talc 39 g 5.9% 78 g 11.8%
Polyethylene glycol 6000 16 g 2.5% 16 g 2.4%
Water 345 g 79.9% 306 g 74.0%
660 g 100.0% 660 g 100.0%
The standard formulation shows very clearly that the parts by weight of EUDRAGIT®
solid substance and talc are the same and that the total solids concentration is 26%.
1.1.4 Solvents
When working with organic solvents, you should test in each case whether traces of
a particular solvent may cause incompatibilities in the core, or which solvent residues
will be found in the end product and whether these quantities are acceptable. Owing
to the flammability and toxicity of the solvents, the explosive limits and TLVs must be
observed and adequate ventilation provided for. The compilation of physical data in
Table 4 on page 16 is meant for your guidance in selecting organic solvents and
assessing the technical problems involved. In view of the increasing air pollution,
their use will generally be reduced to a minimum and preference be given to acrylic
polymers in the form of aqueous dispersions wherever possible. Our technical advice on the applications of our products is given without obligation. The buyer is responsible for the use and processing of our products and is also liable for observing any third-party rights. Technical data concerning our products are typical values. Subject to alteration. ® = registered trademark EUDRAGIT = reg. Trademark of Röhm GmbH & Co. KG, Darmstadt, Germany
