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Examples of enteric Coating Process for Tablets

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					1.3.    Examples of Enteric Coating Processes for Tablets
1.3.1   Enteric Coatings with Organic Solvents Applied by Ladling


1. Principle


Simplest method for film coating.
The coating solution is ladled on the rotating tablets in small portions.
Glidant i n powder form prevents the tablets from sticking together.
Manual intervention required!
Functionality of skillfully operated equipment is guaranteed.
Surface quality moderate to unsatisfactory.
Absolutely adequate for subsequent sugar coating.
Subcoating of porous tablets recommended.
Smooth sharp tablet edges before coating.

2. Important Hints


Caution with flammable solvents! No smoking, no fire!
Prevent containers holding coating solution from tipping over or spilling.
Switch on laboratory hood before starting to work; make sure it is functioning.
Apply the shots quickly in a thin stream; use your hand for better distribution.
If the moist tablets agglomerate, sprinkle with talc and magnesium stearate.
Use dusting powder sparingly, but also on pan wall and in the center of tablet motion.
In case of pronounced sticking, reduce the quantity per shot and allow more time for
drying.
Promote tablet movement and separation of cores manually, using a spatula.
Dry thoroughly at intervals of about 5 shots.
Analyze for residual moisture and solvent during final drying phase.

3. Material / Polymer Requirement

2 kg of tablets (placebos with methylene blue), slightly convex, 7.0 mm in diameter,
3.6 mm in height, 140 mg in weight.
150 g each of talc and magnesium stearate for dusting.

Sealing the tablets with a dusting phase may be of advantage, e.g. two portions
of a solution of acacia gum and sugar with talc, 14 mg/cm² in all, according to
G. Rothgang: APV-Informationsdienst 14 (4), 221 (1961).
Polymer requirement:             P = 3 mg polymer per cm²
Tablet size:                     d = 7 mm, h = 3.6 mm

                                 S = π · (d· h + 0.5 · d²)
                                 S= 3.14 · (7 mm· 3.6 mm + 0.5 · 7² mm²) = 156 mm²



                                   156 mm² ⋅ 3.0 mg/cm²
                                 _____________________
          Coating weight (%) =                               = 3.35% polymer
                                              140 mg

This corresponds to 67 g of polymer (EUDRAGIT® L 100) for 2 kg of tablets.

4. Equipment


Coating pan with warm air supply; possibly hairdryer, explosion-proof or at a safe
distance.
Accessories: hand sieve, graduated cylinder (50 ml), stainless-steel spatula and
ladle.


See pictures on page 45 (Fig. 8)

5. Formulation for 2 kg of tablets

EUDRAGIT® L 100                70 g          8.2%
Triethyl citrate               14 g          1.7%
Isopropyl alcohol             483 g         56.8%
Acetone                       283 g         33.3%
Coating solution              850 g        100.0%

Polymer quantity:             70 g
Excipients (plasticizer):     14 g
Solids content:             9.9%
Coating weight:             3.5% polymer, corresponding to 3.1 mg/cm²(slightly
                                   more than the quantity calculated above).

6. Preparation

Dissolve the EUDRAGIT ® L 100 powder as described under 1.2.1 on page 24 by
slowly stirring 70 g into a mixture of 483 g isopropyl alcohol and 283 g acetone,
avoiding lump formation. The recommended temperature is 20 °C. Then add 14 g of
triethyl citrate as a plasticizer. After about 30 minutes you have a clear to slightly
cloudy solution, which you pass through a fine-meshed sieve.
7. Working Instructions


Adjust the pan angle to approximately 75° and the speed to 25 to 35 rpm. Note these
conditions in the journal.


Prewarm the tablets to about 40 °C, pour on the film coating solution in 40 mL
portions in a thin stream and move the moist cores immediately with a spatula. If you
notice a tendency to sticking, dust the cores and the pan wall with approx. 15 mg
portions     each     of   a   mixture     of    talc   and    magnesium   stearate.
Use a hand sieve for better distribution. Divide remaining agglomerations with a
spatula. When the cores rotate freely, blow in warm air for about 1 minute.
The total time required for one coating layer is about 5 minutes.


Perform this processing step always in exactly the same way, with more intensive
intermediate drying after five portions, so that any smell of solvent is eliminated. Take
samples of 10 to 20 tablets in each case.


Upon completion of the film coating process, rotate the pan ve ry slowly while
introducing warm air to heat the cores to 40 °C. Dry them at the same temperature
for another 2 hours in the oven and finally on trays at room temperature and normal
humidity overnight.

Journal entries:


Work step                   Time/Temp.           Quantities applied/Remarks
Prewarming                 ......./40 °C
Amount of coating solution                       40 mL + 15 g talc + Mg stearate
........
Drying
Post-treatment

8. Validation of Results and a Assessment

Test the tablet samples taken with increasing coating thickness for disintegration in
simulated gastric and intestinal fluid according to exercise 1.2.3 and enter the results
in a diagram as shown on page 29 (Figure 6).
When the disintegration time in gastric fluid rises to over 2 hours, you know that
gastroresistance has been achieved and at which coating weight. You can also see
the extent to which the intestinal disintegration time is further increased with the
coating quantity.

The steeper the rise of the disintegration times in gastric fluid and the less
pronounced the increase in intestinal disintegration times, the better the quality of the
film coating.
The coating may be uneven, but there must not be any particles on top of it, no edge
chipping or cracking. At tablet bands the coating is usually somewhat thinner.

9. Modifications and Scale-up

Exercise 1.2.1 can also be performed using a 6:4 ethanol/water mixture as the
solvent. The fire risk and load on the environment are then considerably reduced.
Moreover, this solvent mixture is easier to condense in offgas purification plants. In
this case, however, the drying times for the tablets at the beginning and end of the
coating process must be somewhat longer.
In production plants, the ladling process can be performed semi-automatically with
the aid of a peristaltic pump and distribution enhanced by means of a rake. Baffles
reduce the tendency to twinning. Talc and magnesium stearate as glidants can also
be suspended in the polymer solution.

1.3.2   Enteric Coating with Aqueous Polymer Dispersions Applied by
        Ladling

1. Principle

Aqueous polymer dispersions are emulsion polymers which contain the film former as
submicroscopic latex particles.
Dispersions tend to coagulate under the influence of heat, frost or high shear, or
when    electrolytes   or    finely  divided      solids   (pigments)  are  added.
Therefore you are advised to adhere strictly to the formulation given.


Bear in mind the water sensitivity of the cores. At the beginning of the film coating
process dry as quickly as possible. Spray at a bed temperature which is about 10 to
20 °C higher than the minimum film-forming temperature. Use coating equipment
with         the         highest         possible        air-handling         capacity.
The first few film coats close pores in the core and form a sealing coat that prevents
further water penetration.

2. Important Hints

Caution when handling flammable organic solvents for application of a sealing coat.
Prewarm tablets to 40 °C and apply the EUDRAGIT® sealing solution in one shot.
Prewarm the tablets also to about 40 °C before applying the film-coating dispersion
and after each such coating step.
Dusting is not required.
Post-drying at the end of the coating operation for at least 2 hours at 40 °C or 16
hours at room temperature and normal humidity.
Preparatory work:

For the sealing coat, dissolve 12 g of EUDRAGIT ® L 100 powder according to
exercise 1.2.1 in 84 g of isopropyl alcohol. Add 1 g of triethyl citrate as a plasticizer
and 3 g of water and apply in this form.

3. Material / Polymer Requirement


2 kg of tablets, slightly convex (placebos with methylene blue), 7 mm in diameter, 3.6
mm in height, 140 mg in weight.

Polymer requirement:
for sealing coat:          Ps = 0.5 mg polymer per cm²
for enteric coating:       Pe = 3 mg polymer per cm²

Calculation according to exercise 1.1.2.

Coating weight in %
for sealing coat:          0.56% polymer = 11.2 g of polymer for 2 kg of tablets

Coating weight in %
for enteric coating:       3.30% polymer = 66.0 g of polymer for 2 kg of tablets

4. Equipment

Coating pan measuring 35 cm across, with heated-air supply.

Accessories: adhesive foam strips, to be stuck in the pan as baffles; graduated
cylinder, stainless-steel spatula and ladle.

5. Formulation for 2 kg of Tablets

Enteric coating

EUDRAGIT® L 100              66.0 g         29.1%
Water                       154.0 g         67.8%
Triethyl citrate              7.0 g          3.1%
Coating dispersion:         227.0 g        100.0%


Polymer quantity:            66.0 g
Plasticizer:                  7.0 g
Solids content:              32.2%
Coating weight:                    3.9% polymer = 3.5 mg/cm² (including sealing
coat)
6. Preparation


Suspend EUDRAGIT® L 100-55 (powder) according to exercise 1.2.2 in the water
quantity stated and redisperse with continuous stirring while adding the calculated
amount of caustic soda solution.


A latex-like dispersion has formed if virtually no particles are visible in a milky liquid
without any sediment formation.
The plasticizer is stirred in last.
The pH of the dispersion thus obtained should be 5.0 to 5.2.

7. Coating Procedure


Adjust pan angle to 75°.
Pan speed 30 to 35 rpm.
Apply a first shot of 50 g of the EUDRAGIT® solution, distribute with spatula and
separate agglomerates.
Blow in warm air for one minute and apply remaining solution in two portions of 20 g
each.
Prewarm cores to 40 °C for enteric coating.
Smell of organic solvents no longer perceptible.
Pour on 10mL portions of dispersion and distribute by means of spatula.
Blow in warm air until cores rotate freely.
Maintain core temperature at approx. 30 to 35 °C
Dry after every 3 rd to 5 th shot at up to 40 °C.
Upon completion of the coating operation, dry for at least 2 hours at 40 °C.

Journal entries:

Work step             Time/Temp.                  Quantities applied/Remarks
Prewarming            ......../40 °C
Coating solution                                  10 mL
...
Drying
Post-treatment

8. Validation of Results and Assessment


After applying 3 to 5 film coats, take 10 tablet samples and test their disintegration in
0.1 M HCl. Note the time for each tablet and enter the values in the diagram for
exercise 1.2.3 on page 29.
Test tablets which remained intact for more than 60 minutes subsequently in
simulated intestinal fluid pH 6.8. Enter the dissolution times of the gastroresistant
tablets in the same diagram.
For more accurate testing, see the individual monographs of the USP or Ph.Eur.
Given skillful operation, the tablets with a polymer weight of approx. 3 mg/cm² are
gastroresistant for at least 60 minutes and disintegrate within 30 minutes at pH 6.8.
Analyze the water content of the cores and enteric-coated tablets. It should increase
only slightly in the initial phase of the coating operation and revert to its original value
after drying.
If the water absorption is more pronounced, increase the thickness of the sealing
coat, reduce the individual shots and dry more intensively in between.

9. Modification and Scale-up


Product delivery by means of a time-controlled valve can be automated and used
with larger pans.
Spraying is, howe ver, the more effective and safer coating process (see exercise
1.3.6 on page 52 ff).

1.3.3   Sugar Coating of Film-Coated Cores
        Transition from Enteric-Coated Cores to Sugar-Coated                  Products


1. Principle


Good adhesion of the sugar coating to the polymer film must be ensured.
To this end you can dust the final film coat with acacia gum or incorporate the latter
in the first few sugar coats.
Addition of the aqueous polymer dispersion EUDRAGIT® L 30 D-55 to a conventional
sugar syrup containing acacia gum provides a good transition phase.

2. Important Hints


Since exclusively water-based formulations are used, there is no need to take any of
the precautionary measures associated with organic solvents because of their
flammability, toxicity and environmental hazard.
The sugar syrup should be mixed with the polymer dispersion while cold in order to
avoid coagulation.

3. Material / Polymer Requirement


2 kg of enteric-coated cores prepared according to exercise 1.3.1 or 1.3.2.
In the adhesive layer, the ratio of dry coating substance to sugar should be about 1:2.
The adhesive layer adds approx. 2.5%, the sugar coating approx. 35% to the weight
of the enteric-coated cores.
4. Equipment


Coating pan measuring 35 cm in diameter, with heated-air supply.
Accessories: hand sieve, stainless-steel spatula


See pictures on page 45 (Fig. 8)
5. Formulation for 2 kg of Tablets
Dispersion syrup

EUDRAGIT® L 30 D-55                     15.0 g
Water                                   35.0 g
Sugar syrup, 67%                        50.0 g
Coating dispersion                     100.0 g


Pigment suspension

Sugar syrup, 67%                       935.0 g
Acacia gum, 36% solution                30.0 g
Iron oxide yellow E 127                 35.0 g
Coating syrup                         1000.0 g


6. Preparation


Stir the EUDRAGIT ® dispersion into the cold sugar syrup until a homogeneous, milky
liquid is obtained.
Suspend 11 g of acacia gum in 19 ml of water and stir to complete dissolution. Add
the yellow pigment to the cold syrup and homogenize in a ball mill or Ultra-Turrax.
Take care to entrap as little air as possible while homogenizing.
Stir the acacia gum solution into the air-bubble -free pigmented sugar syrup.

7. Coating Procedure


Prewarm tablets to 40 °C. Adjust pan to a steep angle of approx. 75°.
Rotate tablets at high speed (35 rpm).
Ladle on 50 g (44 ml) of dispersion syrup and distribute with the spatula.
Dust with 100 g of talc through the sieve.
Adjust pan angle to 45° and reduce the pan speed (20 rpm).
Introduce warm air for drying.
Repeat procedure with a second portion of 50 g of dispersion syrup.
Add pigment suspension at the steep angle of 75° and the higher speed. Pour on 15
g (11 ml) at a time and distribute with the spatula.
Lower pan (45°) and reduce its speed again (20 rpm). Blow in warm air.
Pour on second portion of pigment suspension as above and dry.
Apply further coats as in conventional sugar coating. Maintain pan angle at 45° and
speed at 20 rpm for the remainder of the process.
Continue with 15g portions of pigment suspension.
Maintain the bed temperature at approx. 35 °C.
Journal entries:


Work step              Time/Temp.             Coating quantities/speed/inclination
Prewarming         ......./40 °C
Dispersion syrup                                               44 mL        3575°
Pigment suspension                            11 mL            ...          ....
...
Drying
Post-treatment

8. Validation of Results and Assessment


The pigmented sugar coat should come off in simulated gastric fluid within less than
15 minutes. The enteric coating beneath it must be undamaged and resist
disintegration in simulated gastric fluid for 2 hours. The disintegration times of the
cores in simulated intestinal fluid pH 6.8 are the same as in exercises 1.3.1 and
1.3.2.

9. Modification and Scale-up


If dusting with talc proves to be difficult on a production scale, stir the additive into the
dispersion syrup. In this case a quantity of 50 g per 100 g of syrup is sufficient.

1.3.4   Enteric Spray Coating with Organic Solvents


1. Principle


Use a simple air gun for spraying that allows adjustment of the spray rate and the
droplet size.
Batch sizes of over 80 kg are required for continuous airless spraying.
Whenever possible, spraying should be done continuously.
The finely dispersed film former must dry quickly on the tablet surface.
There should be a minimum of twinning or sticking of tablets.
Tablets should not become too dry in order to avoid attrition and dust formation. Dust
and too rapid spraying may cause surface roughness.
Prewarm cores to about 25 °C.
A generous supply of drying air ensures rapid evaporation of the organic solvents.
During the spraying process the tablets should have a temperature of 20 to 25 °C.
2. Important Hints


The flammability and toxicity of organic solvents call for protection against explosion
and adequate ventilation.
Post-dry coated tablets carefully to remove residual solvents, i.e. for a minimum of 2
hours at 40 °C or 6 hours at room temperature (20 - 25 °C).

3. Material / Polymer Requirement

2 kg of tablets, slightly convex, 7 mm in diameter, 3.6 mm in height, 140 mg in
weight; placebos with methylene blue.


Calculation of polymer quantity:


Polymer requirement:            P = 4 mg/cm²
Tablet surface area calculated according to exercise 1.3.1: 156 mm².


             Coating weight (%) 156 mm²· 4.0 mg/cm² = 4.45% polymer
                                       140 mg


This corresponds to 111 g of polymer (EUDRAGIT® L 100) for 2.5 kg of tablets.

4. Equipment

Stainless-steel coating pan (Erweka), 35 cm in diameter;
Walther "Bingo" air spray gun, nozzle diameter 1 mm;
drip funnel or peristaltic pump, hot-air fan.
Figure 8




1 = inlet air                                   5 = pneumatic spray
2 = inlet air filter and air heater             6 = outlet air
3 = coating pan                                 7 = container with pneumatic stirrer
4 = compressed air                              8 = peristaltic pump
    (control pressure 5-6 bar,
    atomizing air pressure 1-2 bar)

5. Formulation for 2.5 kg of Tablets

EUDRAGIT® L 100                        110 g          7.3%
Isopropyl alcohol                      770 g
Diethyl citrate                         22 g          1.5%
Talc                                    27 g          1.8%
Isopropyl alcohol (diluent)            571 g         89.4%
Coating solution                      1500 g        100.0%

Polymer quantity:                                     110 g
Excipients:                                            49 g
Total solids content of spray solution:              10.6%
Application of total dry substance:                   4.6%

6. Preparation


Dissolve EUDRAGIT® L 100 in isopropyl alcohol according to exercise 1.2.1. Stir
triethyl citrate directly into the polymer solution until no more striation is visible.
Stir talc into remaining isopropyl alcohol (diluent) and disperse in an Ultra-Turrax
within 5 minutes.
Pour the talc suspension into the EUDRAGIT® solution with stirring.
7. Coating Procedure

Stick 3 to 4 adhesive foam strips into the coating pan at right angles to the direction
of rotation.
Remove tablet dust with air.
Direct spray gun at the upper portion of the cascading cores. Adjust a fine spray with
compressed air at 0.5 bar. Test by first spraying against a sheet of blotting paper.
Adjust spray rate to about 20 mL per minute.
Control rate via the decreasing liquid level in the drip funnel.
Stir coating solution from time to time to prevent sedimentation of talc.
Introduce a gentle stream of warm air at 40 °C into the lower part of the pan while
spraying.
Keep the cores at about room temperature while spraying.
Interrupt the process when the cores are too moist or sticky. Dry until they once more
tumble freely. Spraying should not take longer than 60 to 80 minutes altogether. At
the very end, dry with warm air for 5 minutes at reduced pan speed. Spread tablets
on filter paper and air overnight.

Journal entries:


Work step            Time/Temp.               Spray rate/Remarks
Dedusting                      ...../......
Spraying                      ....../......          20 mL/min
Drying         ...../......

8. Validation of Results and Assessment


The coating should be smooth and glossy.
Tablet bands and edges must be equally well coated.
The tablets should be harder than the uncoated cores.
Testing for gastroresistance: in the USP/EP disintegration tester, film-coated tablet
samples should resist disintegration or softening in simulated gastric fluid for a
minimum of 2 hours.
Weak points in the film coating can be detected by blueing, which reveals small
pores or crazes.
Disintegration in simulated intestinal fluid pH 6.8 is to occur within 30 to 45 minutes.
For a more accurate assessment, the dissolution of the active has to be examined
analytically.
9. Modification and Scale-up


Suitable plasticizers besides triethyl citrate are polyethylene glycol, triacetin or dibutyl
sebacate in the same quantities.
EUDRAGIT® L 100 can also be replaced with EUDRAGIT® L 100-55 (soluble above
pH 5.5).
In the lower intestinal regions, coatings with EUDRAGIT® S start to dissolve gradually
above pH 7.

1.3.5 Spray Application of Colored Final Coats from Organic Polymer
Solutions to Enteric -Coated Cores


1. Principle


Combination of an unpigmented enteric base coat with a pigmented top coat.
The final coat serves to protect and stabilize against mechanical stress.
Food color lakes or iron oxides together with titanium dioxide are used as pigments.
The pigment quantity must be adequate for covering the base coat evenly.
The characteristic solubility properties of the polymer are not affected.
The combined layer buildup ensures gastroresistance at a minimum of pigments.
Alternatively, a through-colored film may be sprayed on.


EUDRAGIT® L with or without pigments can be applied as a thin (approx.
1 mg/cm²) protective film against moisture, light and air as well as tropical climates,
and for sealing hygroscopic cores. Cores containing disintegrants usually already fall
apart in the stomach with only slight delay, but in any case after dissolution of the film
coating in the intestinal region above pH 6.0.


The usual polymer requirement for enteric coatings is 3 to 5 mg per cm², the weight
gain with pigments about 6 to 9%.
Polishing with an aqueous solution of polyethylene glycol provides high-gloss
coatings.

2. Important Hints


Spraying should be done continuously with simultaneous introduction of warm air.
The finely distributed film former on the tablet surface should dry very quickly. There
must be no twinning or sticking together of tablets.
Owing to the organic solvents used, protection against explosion is required.
Preparatory work:


Prepare the pigment suspension according to exercise 2.2.1 the day before and
homogenize it overnight in a ball mill. Prepare a 12.5% polymer solution according to
exercise 1.2.1.

3. Material / Polymer Requirement


2.5 kg of tablets with methylene blue, provided with an enteric base coat of at least 2
mg of polymer/cm² according to exercise 1.3.4.
The polymer requirement for enteric coatings is 3 to 5 mg/cm².
Two thirds thereof, i.e. 2.0 to 3.3 mg of dry polymer substance per cm², should be
applied for the base coat according to exercise 1.3.1 and 1 to 1.7 mg of polymer per
cm² combined with pigments.
Tablet surface area 156 mm².
Pigmented film coat 1.1 mg/cm²:
(156 mm² · 1.1 mg/cm²) : 140 mg = 1.2% dry polymer substance

4. Equipment

Erweka coating pan (stainless steel), 35 cm in diameter, angle of inclination
30 - 45°;
Walther "Bingo" air spray gun, nozzle diameter 1.0 mm;
250 mL drip funnel or peristaltic pump;
Compressed-air system with reducing valve, hot-air fan.

See pictures on page 45 (Fig. 8).
5. Formulation for 2.5 kg of Tablets

30% pigment suspension                     Polymer/pigment suspension
                   [g]        [%]                                             [g]     [%]
                                                       ®
Talc               42          14          EUDRAGIT L 100                     30      2.0
Mg stearate          6          2          Isopropyl alcohol                 195         -
Ti02               18           6          Water                              15      0.8
Quinoline yellow   18           6          Triethyl citrate                     3     0.2
PEG 6000            6           2          30% pigment suspension            300      6.0
Water              12           4          Acetone                           480     32.0
Isopropyl alcohol 198          66          Isopropyl alcohol                 480     59.0
                  300         100                                           1500    100.0

Content in dry polymer substance: 30 g, other solids: 93 g
Total solids content:           123 g = 8.2%, polymer application 1.1 mg/cm²
Total dry coating weight:       4.4 mg/cm² = 4.8%


Together with the enteric base coat from exercise 1.3.4, the total dry polymer
substance sprayed on is 5.1 mg/cm² = 5.6%
Quinoline yellow = FD&C Yellow No. 10

6. Preparation


Add triethyl citrate to the EUDRAGIT® solution, stir, and pour this mixture into the
pigment suspension with stirring.

7. Coating Procedure


Stick 3 or 4 adhesive foam strips into the coating pan at right angles to the direction
of rotation. Blow in air to dedust the tablets. Direct spray gun at the upper portion of
the cascading cores.
Adjust a fine spray at 0.5 bar and a spray rate of 20 mL per minute.
Stir polymer/pigment suspension in the funnel and reservoir at frequent intervals.
Introduce hot air at 40 to 50°C into the lower section of the pan.
Keep the core bed at approximately room temperature.
If the tablets become too moist or sticky, interrupt the spraying process briefly until
they are dry again.
The total spraying process should be completed within 60 to 80 minutes.
Post-dry with warm air for another 5 minutes.
Pour on solution of 1.0 g of polyethylene glycol 6000 in a mixture of 4.5 g of acetone
and 4.5 g of water and polish for 15 minutes without air supply.


Finally blow in more warm air.
Spread the tablets on filter paper and air overnight.

8. Validation of Results and Assessment

Appearance: the coating should be smooth and glossy, also along bands and in
break lines.
The coated tablets are somewha t harder than the uncoated cores.
Testing for gastroresistance: the tablets should resist gastric fluid for a minimum of 2
hours and disintegrate in intestinal fluid pH 6.8 within 30 minutes as described in
exercise 1.2.3.
Gastroresistance must also be given under mechanical stress, e.g. in the friabilator
(100 rev./4 min).

9. Possible Modifications


As an alternative to EUDRAGIT® L 100, the film formers EUDRAGIT® L 100-55
(soluble above pH 5.5) or EUDRAGIT® S 100 (soluble above pH 7.0) may be used.


The application of a pigmented final coat from aqueous dispersions is described in
exercise 1.3.7.
1.3.6   Enteric Spray Coating with Aqueous Polymer Dispersions


1. Principle


Aqueous polymer dispersions contain the film former as minute latex particles of less
than ∅ 1 µm.
These particles coalesce to a water-insoluble film.
Aqueous dispersions are environment-friendly and avoid the risks associated with
organic solvents, i.e. flammability and toxicity.
Their minimum film-forming temperature (MFT) has to be observed, however.
Aqueous dispersions are easily atomized by means of pneumatic nozzles.
For details see exercise 2.1.2 "Technical Aspects of the Manufacture of Rapidly
Disintegrating Coatings."
Dispersions are sensitive to electrolytes, frost, heat, changes in pH, organic solvents
and high shear, and they tend to foam formation.
Coagulated dispersions cannot be redispersed and must be discarded.

2. Important Hints


Ensure rapid evaporation of the water by introducing a copious amount of drying air.
Spraying should be performed continuously with simultaneous drying.
Preheat the cores to about 40 °C. Maintain the core bed at a temperature around
30 °C.
Use talc as a glidant, polyethylene glycol 6000 as a plasticizer and silicone emulsion
as an antifoam agent.
Dry coated cores carefully before further processing.

3. Product / Polymer Requirement


2.5 kg of placebos with methylene blue, ∅ 7 mm, 3.6 mm in height,
140 mg in weight.
Tablet surface area S = 156 mm².
The polymer quantity used for enteric coating from aqueous dispersions is also 3 to 5
mg/cm².
Coating weight (156 mm² · 4.0 mg/cm²) : 100 = 4.45% dry polymer substance.


For 2.5 kg of cores, this adds up to 111 g of dry polymer substance contained in 111
g · 100 : 30 = 370 g EUDRAGIT® L 30 D-55.
4. Equipment

Coating pan, ∅ 30 - 35 cm, angle of inclination 30 - 45°;
Walther "Bingo" spray gun, nozzle ∅ 1.0 mm;
250 mL drip funnel or peristaltic pump;
Compressed-air system with reducing valve, hot-air fan.
See picture on page 45 (Fig. 8).

5. Formulation for 2.5 kg of Tablets

EUDRAGIT® L 30 D-55                                370.0 g         16.6%1
(30% dispersion)
Talc                                              27.0 g             4.0%
PEG 6000
(10% aqueous solution)                            107.0 g           1.6%2
Antifoam emulsion SE 2                             1.5 g            0.2%
Water                                            164.5 g           77.6%
                                                 670.0 g           100.0%


Solids content of the spray suspension:                     150 g = 22.4%
thereof dry polymer substance:                              111 g = 16.6%
coating weight of dry polymer:                         3.95 mg/cm² = 4.4%
coating weight of total dry solids:                    5.30 mg/cm² = 5.9%

1 dry polymer substance    2 solids

6. Preparation

Start by finely homogenizing talc, polyethylene glycol 6000 (as a 10% aqueous
solution), antifoam emulsion and water (Ultra-Turrax, 5 to 15 minutes) and stir this
mixture rapidly into the available dispersion.
Adhere strictly to the order and procedure of adding the excipients.

7. Coating Procedure

Stick 3 to 4 adhesive foam strips into the coating pan at right angles to the direction
of rotation. Prewarm the tablets at reduced pan speed (approx. 20 rpm) to 40 °C.

Maintain the core bed at about 30 °C throughout the coating operation.
Direct the spray gun at the upper third of the cascading cores while continuously
introducing warm air (60 to 80 °C).
Adjust atomizing air pressure to about 0.5 to 1 bar.
Deliver spray suspension from a drip funnel or by means of a peristaltic pump and
set feed to 6 to 8 mL per minute.
If the cores become too wet, interrupt the spraying process and dry for a few
minutes.
The entire coating operation should be completed within 60 to 80 minutes. Post-dry
the film-coated tablets in the coating pan for another 5 minutes, then keep them for 2
hours at 40 °C or at room temperature overnight.

8. Validation of Results and Assessment


Appearance: The coating should be smooth and glossy and cover the tablets evenly,
also along bands and edges.
Testing for gastroresistance: in the disintegration tester to DAB/USP, samples of the
film-coated tablets should resist gastric fluid for a minimum of 2 hours and then
disintegrate in intestinal fluid pH 6.8 within 20 to 40 minutes.
The dissolution of the actives can be measured additionally.
To determine the optimum polymer quantity, take an adequate amount of samples
and test these according to exercise 1.2.3.

9. Possible Modifications


Instead of working with the commercially available EUDRAGIT® L 30 D-55
dispersion, you may use the polymer powder EUDRAGIT® L 100-55, which can be
redispersed to a latex in water as described in exercise 1.2.2.

1.3.6 b Colored Enteric Coating of Tablets with EUDRAGIT® L 30 D-55


1. Principle


Enteric coatings based on EUDRAGIT® L 30 D-55 should contain plasticizer in order
to prevent crack formation. Moreover, glidants like talc, kaolin or glycerol
monostearate (Mono- and diglycerides NF) should be added to avoid sticking
tendencies during the coating processes.


Other excipients such as pigments increase the permeability of coatings. Therefore,
the amount of polymer required for protecting tablets against gastric fluid is higher in
colored enteric coatings than in colo rless formulations.
Since pigments may act as electrolytes, resulting in coagulation of the latex
dispersion, addition of stabilizing agents like Na carboxymetylcellulose to the pigment
suspension is recommended. Partial neutralization of the carboxylic groups in the
range of 6 mole % according to exercise 1.2.2 is also possible.


Pre-formulated, ready-to-use pigment suspensions or dry ble nds are also available.
Manufacturers of these products also offer color-matching service. By color matching,
optimal pigment combinations can be established during development of a product.
2. Important Hints


Sedimentation in spraying suspensions containing pigments occurs naturally.
Therefore it is necessary to stir the suspensions throughout the coating process.

Mg stearate is incompatible with EUDRAGIT® L 30 D-55 and causes coagulation.


3. Equipment


Brucks coating pan (stainless steel), ∅ 50 cm
Walter Domino spray gun, nozzle diameter 1.0 mm, flat spray
Reservoir with magnetic stirrer
Watson Marlow 505 S peristaltic pump
Mobile air-supply and an exhaust system with temperature recorder and air filters, air
feed max. 4 m³/min.

4. Product


10 kg of placebo tablets, diameter 7 mm, height 3.6 mm, weight 140 mg.
Disintegration in water and simulated gastric fluid max. 5 min.

5. Polymer Requirement


Surface area per tablet, calculated according to exercise 1.3.1.

                  72 
S = π ⋅  7 ⋅ 3.6 +  = 156. mm²
                  2

If 5.0 mg/cm² of polymer are required, the quantity to be applied is

156 ⋅ 5
        = 56% polymer , for 10 kg tablets, these are approx. 560 g.
           .
 140
6. Formulation for 10 kg of Tablets


Polymer/pigment suspension


EUDRAGIT® L 30 D-55                       1857 g    14.0%     1

                                                              2
1N NaOH                                   188 g     0.2%
Talc                                      279 g     7.0%
Triethyl citrate                          56 g      1.4%
                                                              2
Polyethylene glycol 6000, 33% aqu.        66 g      0.6%
Titanium dioxide                          56 g      1.4%
FD&C Yellow No.10*                        17 g      0.4%
Water                                     1459 g    75.0%
                                         3978 g     100.0%
* color lake based on quinoline yellow, E 172
1
   dry polymer substance
2,
   solid substance


Dry polymer:                              557.1 g
Other solids:                       437.4 g
Total content in solids:                    25 %


Quantity of dry polymer applied:         5.0 mg/cm² = 5.6 %
Total quantity of dry substance applied: 8.9 mg/cm² = 9.9 %


To prepare the final film coating suspension, the ingredients must be poured together
in this order:
Feed 1N NaOH slowly into EUDRAGIT® L 30 D-55 with gentle stirring for 5 minutes.
Suspend the other excipients in the remaining water and homogenize for 20 minutes
using a colloid mill. Then add the pigment suspension to the stabilized EUDRAGIT® L
30 D-55 with slight stirring for 5 min.
7. Working Instructions


Pan rotational speed:                          40 rpm
Distance nozzle/material:              10 cm
Atomizing air pressure:                1 bar
Inlet air capacity:                           approx. 2 m³/min
Inlet air capacity:                           0.2 m³/min/kg tablets
Outlet air capacity:                   > 2 m³/min
Inlet air temperature:                        50-60 °C
Outlet air temperature:                       - °C
Product temperature:                          30 °C
Spray method:                                 continuous
Pump speed:                            25 - 30 rpm
Spray suspension applied:              3978 g
Dry substance applied:                 994.5 g
Spraying time:                                 ≈ 160 min
Spray rate:                                   2.48 g/min/kg product
Evaporation rate of solvent:                  1.86 g/min/kg product
Drying time:                           RT, 5 min
Appearance of coating:                 smooth, even, glossy
Final drying                           2 h, 40 °C, airflow oven

8. Validation of Results and Assessment


The coating should be smooth and shiny and provide uniform cover even over edges.
Hardness is about 70 N.
Gastric resistance is given for 2 hours, followed by a disintegration in simulated
intestinal fluid BP 80, pH 6.8, within 5 minutes.

9. Possible Modifications


Insoluble plasticizers must be pre-emulsified in water with addition of 1 %
Polysorbate 80, using high shear mixers.

1.3.6 c Coating of Drug Crystals in Hüttlin Kugelcoater® HKC 5


1. Principle


The Hüttlin Kugelcoater® is a typical apparatus for bottom spray technique. It can be
used for coating tablets, pellets, granules, crystals and powders.
The spherical product container is fitted with spray guns beneath the product bed,
which allow concurrent spray application of the polymer suspension. The specially
designed spray guns produce a "microclimate" around the spray which avoids spray-
drying effects.
Owing to the high drying -air capacity, rapid and effective drying is possible, and thus
shorter processing times. All standard formulations with EUDRAGIT® polymers can
be used in this equipment without any change in composition.

2. Important Hints


During prewarming, the particles should be fluidized carefully with reduced air flow in
order to minimize mechanical stress on the particles. When the first few coating
layers have been applied, the particle surfaces are stabilized to a certain extent.
Towards the end of the coating process, intensive fluidization should be prevented so
as to avoid damage to the coating.


Compared to top spray processes with coating suspensions, bottom spray technique
provides a more uniform, homogeneous coating with fewer defects. In many cases,
the amount of polymer required for the same coating function can be reduced.

3. Equipment


Hüttlin Kugelcoater® HKC 5 with a three-way air-borne nozzle system
Peristaltic pump with silicone tubing, internal diameter 3.2 mm
Magnetic stirrer

4. Product


Acetylsalicylic acid crystals, 0.5 - 0.8 mm ∅ (Aubing, Mannheim, Germany)


5. Polymer Requirement


The surface area of the ASA crystals can be estimated according to exercise 3.2.2
and then calculated as in exercise 1.1.2. If dimensions are not available, perform a
small-scale test and take 5 to 10 samples between 5 and 25% polymer weight gain.
Make a drug release test, which will show the optimum amount of polymer.
6. Formulation for 4.0 kg of Crystals


Spray suspension:


Solids content 24%

EUDRAGIT® L 30 D-55                2000 g = 600 g polymer
Talc                                        240 g = 240 g dry substance
Triethyl citrate                             60 g = 60 g dry substance
Iron oxide red, E 172*                       12 g = 12g dry substance
Water                              1488 g
                                         3800 g = 912 g dry substance



Solids content of spray suspension:       24%
Polymer applied:                          15%
Total dry substance applied:              22.8%


* ferric oxide

7. Coating Procedure


Fill the crystals into the Kugelcoater® HKC 5 and preheat to approx. 25-30°C. Adjust
the drying air to 150m³/h and 40°C, the atomizing air pressure to 1.5 bar and the
pressure for the microclimate to 1.6 bar.


After about 3 min, start the peristaltic pump (8 rpm = ~ 26g/min.). During the coating
process the product temperature should be kept between 25 and 30°C by adjusting
drying-air volume and temperature.


Maintain a steady flow of crystals while coating. If any signs of sticking are noted,
interrupt spraying until the pellets are sufficiently dry to allow unimpeded fluidization.
Then continue spraying at a reduced rate.


The whole process takes approx.150 min. The coated crystals are then dried for 2
min. at reduced air flow and are finally discharged from the coating equipment and
spread out on trays for a final drying at 40°C within 2 hours.

8. Validation of Results and Assessment


Measure the drug release according to USP 23, apparatus 2, 50 rpm. 250 mg ASA/
800 ml 0.1N HCl. Buffering for 2 hours with 22g Na 3PO4 x 12 H2 O in 100 ml 0.1N
HCl.
Time [h]                          1            2      |       3
Drug dissolved [%]         3             5     |      96

1.3.6.d Enteric Coating of Acetylsalicylic Acid Crystals by
         Fluidized-Bed Process


1. Principle


Spray coating of small batches from 1 to 20 kg serves above all for designing useful
formulations and defining the limits of polymer consumption.


Scale-up batches of 50 to 150 kg are handled to optimize the excipient quantities
with a view to avoiding particle agglomeration and nozzle clogging, as well as to
verify the polymer requirement, which usually needs to be corrected at this stage.


When larger equipment is used, the polymer quantity can often be reduced, because
less spray is lost and the film former is more evenly distributed.


Compared with laboratory equipment, production-size coaters usually have lower
drying-air capacities per kg of product, so that the relative spray rate (quantity per
time and kg of cores) must be adapted accordingly, i.e. will normally be reduced.


In large coaters it is often easier to position the nozzle within the fluidized bed. The
spray that is carried upwards with the drying -air can then still settle on the product.
When validating the process, make sure to observe the official regulations and
recommendations.


When designing the formulations, allow adequate scope for variation of all excipient
quantities, so that you can reproduce the desired release profiles despite changes in
raw material quality and process parameters.
Even on a production scale you should take samples of coated product to check the
specified polymer quantities. This is a simple way to prove your growing experience
and the increasing effectiveness of your coating process and allows you to see what
scope you have in achieving products that meet the standards.

2. Important Hints


When working with organic solvents, make sure that your equipment and the vessels
are explosion-proof and adequately grounded. For the present exercise purely water-
based EUDRAGIT® L 30 D-55 is used.
If a polymer dispersion contains suspended pigments or other solids which need to
be evenly distributed, the storage vessel must be stirred throughout the coating
process to avoid sedimentation. For the same reason, the feed tubes to the spray
guns should be as short as possible.


If a tendency to sticking or agglomeration is observed during spraying, this can be
reduced by lowering the spray rate and possibly also by increasing the air
throughput.

3. Product / Polymer Requirement


150 kg of acetylsalicylic acid crystals, particle size 0.315 - 1.25 mm (supplier: Aubing,
Munich)


The surface area of the ASA particles can be measured according to exercise 3.2.2.
Given a weight-specific surface area of 100 cm²/g and a polymer application of 3
mg/cm² for enteric coating, the resultant dry polymer weight is 300 mg per g of ASA
or 30% of active. In practice, however, 10 to 20% polymer is usually sufficient, i.e.
approx. 1 to 2 mg/cm².


Where data for calculation of the total surface area are not available, the polymer
requirement must be determined in laboratory trials. When doing so, bear in mind
that the coating procedure on a production scale is usually more effective than the
laboratory process, so that the polymer quantities can be reduced during scale-up.
Sampling and intermediate testing for drug release is always advisable, as it permits
you to apply your findings immediately to the next batch.

4. Equipment


Fluid bed coaters WSG 30/WSG 60 with exhaust air screen (Glatt, Binzen),
peristaltic pump with silicone tube, internal diameter 8 mm;
storage vessel with pneumatic stirrer.

5. Formulation for 150.0 kg of ASA Crystals


EUDRAGIT® L 30 D-55                50,000 g          15.6%¹
(30% dispersion)
Triethyl citrate                    1,500 g           1.6%
Talc                                7,500 g           7.8%
Antifoam emulsion SE 2                750 g           0.2%
Water                              36,250 g          74.8%
                                   96,000 g        100.00%
Dry polymer substance:                            15,000 g
Additives:                                         9,150 g
Total solids content:                             25.2%
Application of dry polymer substance:             10.0%
Application of total dry substance:               16.1%


¹ dry polymer substance

6. Working Instructions


Set the exhaust air flap for slight fluidization of the active crystals and prewarm to
approx. 30 °C.


Adjust an inlet air temperature of 40 to 50 °C for spraying and a pressure of
2 bar for the air spray gun. Then spray the dispersion continuously onto the freely
floating crystals.


The nozzle aperture should be 1.8 to 2.2 mm. A spray rate of 5 to 6 g of dry polymer
substance/min/kg of crystals will be adequate in the majority of cases.


During spraying, the temperature of the outlet air decreases to approx. 25 °C. The
temperature in the product bed should not exceed 30 °C.
If agglomeration occurs, interrupt the spraying process until the crystals are dry and
once more able to float freely. If necessary, introduce more air. Then continue
spraying at a reduced rate and/or increased air supply.


The entire process takes about 2 hours. Upon its conclusion, dry for 5 to 10 minutes
at reduced fluidization, then spread the coated crystals on trays for airing. Drying in
an airflow oven within 6 hours at 40 °C is more effective.

7. Validation of Results and Assessment


Testing for drug release can be performed according to exercise 3.3.6 and in
observation of the principles described in exercise 3.2.3.


Drug release in gastric fluid should be as low as possible, but quantities below 5%
per hour are still acceptable. Given skillful operation, less than 1% release can be
achieved [17].


Owing to the acidic reaction of the embedded acetylsalicylic acid, the dissolution of
the film coating slows down in buffer solutions of pH 6 to 7.5, so that the larger part of
the active is initially set free by diffusion. The coating only dissolves towards the end
of the release test.
Since the polymer substance is insoluble below pH 6, you must check that the pH
has not dropped below this value because of liberated ASA and is actually within the
specified range.

8. Possible Modifications


An alternative film former is EUDRAGIT® L 100-55 powder, obtained by spray drying
from EUDRAGIT® L 30 D-55.


This product can be redispersed in water by pH adjustment to around 5.2. In this
case the addition of alkali corresponds to a neutralization of approx.
6 mole-% of the carboxyl groups contained in the polymer.


The dispersion thus obtained can be handled and processed just like EUDRAGIT® L
30 D-55 (see exercise 1.2.2).


For the manufacture of a so-called slow-release preparation with the same ASA
crystals, i.e. a dosage form for gradual drug release from the stomach onwards,
polymer quantities of only 1.5 to 2.5% are sufficient, with no other changes in the
formulation.
Table 7 Technical Data of Various Types of Equipment


                   Driacoater   Pellegrini   Pellegrini   Walther     Accela      Conven-
                   1200         T 300        MC 25        "Coating    Cota        tional
                                with         with         Rotamat"    150         coating
                                immersion    „Fast Dry                            pan
                                sword        Coater"                              ∅ 67 cm
Batch size [kg]    85           150          25           100         120         25
Inlet air
m³/min:            30           26.7         7            18          45.3        2.7
m³/min/kg:         0.35         0.17         0.28         0.18        0.38        0.11
°C:                56           70           72           70          60          75
Spray suspen-
sion [kg]          17.77        31.35        6.44         26.17       29.97       8.49
Solids content
of spray sus-      19.5         20.0         25.0         23.1        25.2        20.0
pension [kg]
Coating
Weight
DPS [mg/cm³]:      2.9          3.56         4.24         4.21        4.00        5.30
TDS [mg/cm³]:      4.65         5.68         6.77         6.74        6.39        8.46
Spray rate
[g/min/kg]         1.90         0.95         2.86         2.94        2.25        1.20
Spraying time
[min.]             110          20           90           89          111         283
Gastro-            given for    given for    given for    given for   given for   given for
Resistance         1 hour       2 hours      2 hours      2 hours     2 hours     2 hours
Disintegration
in intestinal fluid 10          4            4            5           5           5
[min.]


1.3.7       Spray Application of Colored Final Coats from Aqueous
            Dispersions to Enteric-Coated Cores


1. Principle


Combination of an unpigmented base coat with a pigmented top coat.
The top coat stabilizes against mechanical stress.
The combined layer buildup ensures reliable gastroresistance and reduces the
pigment consumption.
The formulation according to this exercise can also be applied as a single through-
colored film coat.
Moreover, in thin layers of approx. 10 µm, the formulation serves to protect
hygroscopic cores against moisture, light and air as well as tropical climates.
Depending on the disintegrating behavior of the cores, such coatings usually already
fall apart in the stomach, but most certainly upon dissolution of the film coating in
intestinal medium above pH 5.5.
The polymer requirement for enteric coatings of 3 to 5 mg of dry coating substance
per cm² corresponds to a weight gain of 6 to 9%, pigments included.
Ensure rapid evaporation of water by introducing a copious amount of drying-air.

2. Important Hints


Polymer dispersions may coagulate when exposed to high shear and mixing
operations. Please observe the working instructions.
Take care to prepare the pigment suspension separately one day before the polymer
dispersion.
Pigments on their own can be homogenized in high-speed dispersion equipment
(e.g. Ultra-Turrax, corundum disk mill, toothed colloid mill).
Avoid foam formation as a result of too much air entrapment.
Add some antifoam agent and wait for the air to escape.
Mix pigment suspension and EUDRAGIT® dispersion only just before use and take
care not to generate high shear.


Preparatory work:


Prepare pigment suspension the day before according to exercise 2.2.1 on page 89
(No. 6).
3. Product / Polymer Requirement


2.5 kg of tablets provided with an enteric base coat of 4 mg of dry polymer substance
per cm² according to exercise 1.3.6.
The polymer quantity for the top coat depends on the amount of pigment required for
uniform coloring, which should be about 1 mg/cm², plus the same or twice the
amount of talc. The polymer quantity needed for binding the pigments is 0.8 mg/cm².

Tablet surface area = 156 mm²

Application of dry polymer substance:
(156 mm² · 0.8 mg/cm²) : 140 mg = 0.89% or 22.25 g for 2.5 kg of cores.

Coating weight of pigments and talc: 3.0%
4. Equipment


Erweka coating pan (stainless steel), 30 - 35 cm in diameter, angle of inclination 30 -
40°; Walther "Bingo" air spray gun, nozzle diameter 1.0 mm;
250 mL drip funnel or peristaltic pump, spatula, compressed-air system with reducing
valve, hot-air fan.
See picture on page 45 (Fig. 8).

5. Formulation for 2.5 kg of Tablets


Polymer/pigment suspension
EUDRAGIT® L 30 D-55
(30% dispersion)                                 75 g              5.0%1
Pigment suspension* (30%)                       250 g             16.7%2
Water                                           125 g              78.3%
                                                450 g             100.0%


Solids content of spray suspension:                         97.5 g = 21.7%
thereof dry polymer substance:                              22.5 g = 5.0%
Application of dry polymer substance:                 0.82 mg/cm² = 0.9%


* prepared in advance according to exercise 2.2.1, no. 6.

1 dry polymer substance, 2 solids


6. Preparation


Have the finely homogenized pigment suspension ready (prepared in a ball mill the
day before according to exercise 2.2.1, no. 6). Dilute it now with the water quantity
stated and stir the mixture quickly into the EUDRAGIT ® dispersion, using the spatula.

7. Coating Procedure


Stick 3 to 4 adhesive foam strips into the coating pan at right angles to the direction
of rotation. Prewarm the tablets to approx. 40 °C.
Maintain the core bed at about 30 °C throughout the coating operation.
Direct the spray gun at the upper third of the cascading cores while continuously
introducing warm air (50 to 80 °C).
Adjust the atomizing air pressure to between 0.5 and 1 bar so as to obtain a very fine
spray.
Deliver the spray suspension from a drip funnel or by means of a peristaltic pump
and feed at a rate of 6 to 8 mL per minute.
If the cores become too wet, interrupt the spraying process and dry for a few
minutes. The entire coating operation should be completed within 60 to 80 minutes.
Post-dry the film-coated tablets in the coating pan for another 5 minutes.

8. Validation of Results and Assessment


The coating should be dry and glossy and of uniform color, also along tablet bands
and edges.


Test the tablets for gastroresistance according to exercise 1.2.3. Even after treatment
in the friabilator (100 rev./4 min), they should withstand gastric fluid for a minimum of
2 hours.

9. Possible Modifications


For the sake of convenience you may use a commercially available pigment
suspension. Manufacturers offer to develop the any desired shade with only slight
variations from batch to batch.
The compatibility of such ready-to-use preparations must be tested from case to
case. Concentrates and dry mixtures need to be diluted to 30% solids to be suitable
for use with the formulation stated under 5.
If this formulation is processed as a colored protective coating on ordinary tablets,
the delayed disintegration in gastric fluid also depends on the swelling and
disintegration behavior of the cores themselves. Owing to its low permeability, the
sealing effect of EUDRAGIT® L film is superior to that the of the rapidly disintegrating
coatings according to exercises 2.3.1 to 2.3.4.

1.3.8   Enteric Coatings with Delayed Release in the Intestinal Tract


1. Principle


The anionic polymer EUDRAGIT® S 100 contains 30% methacrylic acid units and
forms enteric films which only start to dissolve above pH 7.
The powder obtained by spray drying of the emulsion polymer can be redispersed to
a latex via partial neutralization up to about pH 6.


The addition of 50% triethyl citrate as a plasticizer is required to lower the film-
forming temperature to the processing range of 25 to 35 °C and thus to obtain less
brittle and crack-free films.
The use of talc as a glidant and of pigments for coloring is optional.
2. Important Hints


The coating formulation in the storage vessel should be permanently stirred to avoid
sedimentation of talc or pigments.


Preparatory work:


Disperse EUDRAGIT® S 100 powder according to exercise 1.2.2 one day before
starting the coating operation. The base to be employed in this case is ammonia
solution (see under '6. Preparation'). Prepare the pigment suspen-sion also the day
before.

3. Product / Polymer Requirement


10 kg of tablets, 7 mm in diameter, 3.6 mm in height, 140 mg in weight.
Disintegration time in water or simulated gastric fluid max. 5 minutes.
Tablet surface area S = 156 mm².
The dry polymer requirement for a coating weight of 6 mg/cm² is then
156 mm² · 6 mg/cm² : 140 mg = 6.7%, i.e. 670 g for 10 kg of tablets.

4. Equipment

Accela Cota 10 (pan diameter 10“ = 254 mm),
peristaltic pump with silicone tubes of diameter 2 mm;
Manesty air spray gun, nozzle diameter 1.2 mm, flat spray.

Figure 9




1 = inlet air                                  4 = spray gun
2 = coating pan with perforated wall           5 = exhaust air
3 = mixing blades                              6 = suction shoe
5. Formulation for 10 kg of Tablets

EUDRAGIT ® S 100 dispersion
EUDRAGIT® S 100                           672.0 g
1 M ammonia solution (1.7%)               342.0 g
Triethyl citrate                          336.0 g
Water                                    2010.0 g
                                         3360.0 g        = 1014 g solid substance

Pigment suspension
Talc                                      219.6 g
Titanium dioxide                           58.0 g
FD&C Yellow No. 10                         88.0 g
Antifoam emulsion                           2.0 g
Water                                     754.4 g
                                         1120.0 g        = 365.6 g solid substance

6. Preparation

Prepare the EUDRAGIT® S 100 dispersion according to exercise 1.2.2 one day in
advance. After adding the ammonia solution, continue stirring for another 60 minutes,
and the same after adding triethyl citrate. Finally pass the mixture through a 0.25 mm
sieve.

Prepare the pigment suspension separately. Start with water and talc, pour on
titanium dioxide and yellow pigment and stir gently with the spatula. Add antifoam
emulsion and disperse in an Ultra-Turrax, colloid mill or similar apparatus within 10
minutes. Leave the suspension to stand for at least one hour, but preferably
overnight, so that entrapped air can escape.

Prepare the polymer/pigment solution by pouring the pigment suspension into the
diluted EUDRAGIT® S dispersion and stirring gently by hand with the spatula or using
a broad-paddle mixer at low speed (approx. 30 rpm).

7. Coating Procedure

Set the idle equipment to the parameters stated below. After testing its functions, fill
in the tablets and prewarm to 40 °C at 50% pan speed while extracting dust. Then
spray for 5 to 10 minutes at full rotational speed until all tablets are slightly moist and
superficially sealed.

Adjust the spray rate to the air-handling capacity, so that the cores are always moist
but never wet. In the latter case, interrupt the spraying process for intermediate
drying. After applying about two thirds of the specified coating weight, take samples
for testing the enteric properties.
Rotational speed                    11 rpm
Atomizing air pressure              1.3 bar
Flat spray pressure                 0.6 bar
Relative humidity                   32%
Inlet air temperature               45 - 50 °C
Outlet air temperature              32 °C
Inlet/outlet air capacity           11.3/>12 m³/min
Bed temperature                     30 °C
Spray rate                          46 g/min (4.6 g/min per kg)
Total spraying time                 147 min
Qty. of suspension applied          6700 g = 1350 g solid substance
Final drying in pan                 3 min. at 42 °C and 5 rpm
Post-drying on trays                2 hrs in airflow oven at 40°C, 24 h at RT
                                    (50 - 60% RH)

8. Validation of Results and Assessment


The coating should be smooth and glossy. There must be no erosion along bands or
edges, with adequate coating thickness in these areas. Microscopic evaluation:
nowhere must the coating thickness be less than 10 µm.
Conduct the test for gastroresistance, also on samples previously taken to examine
the abrasion along edges.
The coated tablets should withstand simulated gastric fluid for 2 hours and buffer
solution pH 6.4 for at least 1 hour. Dissolution of the coating and disintegration of the
tablet      in      intestinal       fluid     pH        7.4      within      maximally
30 minutes.

9. Possible Modifications


If pigments are unwelcome, do use the stated quantity of talc, however, in order to
prevent sticking and to achieve a smooth coating.


If a high dissolution pH is not required, EUDRAGIT® L 30 D-55 (soluble above pH
5.5) or redispersed EUDRAGIT® L 100 (soluble above pH 6) may be used in the
same formulation.

1.3.9   Enteric Coating of Drug Capsules Using Aqueous Dispersions


1. Principle


Observe the special characteristics of drug capsules.
Capsules must be tightly locked. Inspect the coating around joints.
Coated capsules show reduced mechanical stability.
The adhesion between coating and capsule is limited and depends very much on the
environmental humidity and temperature.
Intermediate layers mitigate such problems.

2. Important Hints


Do not heat the capsules excessively or irregularly.
Carefully control the atmospheric humidity.
Avoid mechanical stress.


Preparatory work:


Condition capsules at 50 to 60% RH and room temperature (20 - 25 °C).

3. Product / Polymer Requirement


1 kg of hard gelatin capsules, size 00, 'snap-fit' (Capsugel, Basel, Switzerland), filled
with lactose; weight 986 mg, ∅ 8.5 mm, total length 23.5 mm.
Polymer quantity 17 mg/cm². (This is roughly three times the quantity for tablet
coatings!)

                      S=π ⋅d⋅l
                      S= 3.14 ⋅ 8.5 mm ⋅ 23.5 mm = 627.2 mm²


     Coating weight (%) = 627.2 mm² · 17 mg/cm²               = 10.8%
                                            986 mg


4. Equipment


Erweka coating pan (copper impregnated with EUDRAGIT® L                       30   D-55),
∅ 25 cm, angle of inclination 30°;
Walther "Bingo" air spray gun, peristaltic pump, compressed-air system with reducing
valve, hot-air fan.
See picture on page 45 (Fig. 8).

5. Formulation for 1.0 kg of Capsules

EUDRAGIT® L 30 D-55                               330 g               12.4%1
(30% dispersion)
Talc                                              50 g                 6.2%
Triethyl citrate                                  10 g                 1.2%
Silicone antifoam emulsion                         1g
Water                                            414 g                80.2%
                                                 805 g               100.0%

1 dry polymer substance
Solids content of polymer dispersion:                19.8%
thereof dry polymer substance:                       12.4%
Application of dry polymer substance:                99 g = 17 mg/cm² = 9.9%

The following formulation can be recommended as a sealing coat:

Hydroxypropyl cellulose          4.00%
PEG 400                          0.80%
Glycerol monostearate            0.10%
Polysorbate ® 80                 0.05%
Water                           95.00%

Solids content 5.0%, coating weight 3 to 5 mg solids per cm² of surface area,
corresponding to between 17.5 and 29.0 g per kg of capsules.

6. Preparation

Start by stirring talc and triethyl citrate into the water quantity stated (414 g) and
homogenize the mixture in an Ultra-Turrax for 5 minutes. Then add two drops of
silicone antifoam emulsion, allow 30 minutes for entrapped air to escape and stir this
suspension into the 30% EUDRAGIT® L 30 D-55 dispersion using the spatula.

7. Coating Procedure


Set drying-air to 50 °C. Heat capsules to 30 °C at a pan speed of approx.
10 rpm.
Spray in about 3 g/min of polymer dispersion within the first 5 minutes. Then increase
the spray rate to 6.5 to 7 g/min.
Atomizing air pressure: 1.0 bar, core bed temperature: 30 to 33 °C.
Maintain drying air at 48 to 52 °C. Total spraying time approx. 2 hours.

8. Validation of Results and Assessment


The surface tends to become rough and its gloss subdued.
Where the two halves of the capsule overlap, the coating must be free from pores or
other defects.
Testing for gastroresistance according to USP 23 method <701> "hard gelatin
capsules."
Shelf life at RT and 50 - 60% RH: min. 2 years.
Do not exceed a temperature of 37 °C.

9. Possible Modifications


Soft gelatin capsules can be coated in the same way. In this case, however, residual
oil may have to be removed.
Our technical advice on the uses of our materials is given without obligation. The buyer is responsible for the application and
processing of our products and is also liable for observing any third-party rights. Technical data concerning our products are
typical values. ® = registered trademark. EUDRAGIT = reg. Trademark of Röhm GmbH, Darmstadt

				
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posted:1/23/2013
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