Sei sulla pagina 1di 14

1. 1.1. 1.1.

Enteric Coating of Tablets Introduction 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

Drug release by dissolution


pH >5.5 L 100-55

pH > 6.0 L 100

pH> 7.0 S 100

perm. RL 100

Drug release by diffusion

perm. RS 100

Mouth 1 min. pH 5 - 8.5

Stomach 1-2 h Duodenum 0.5 h pH 2 - 5 pH 6

Jejunum 2 - 4 h pH 6.5

Ileum 2 - 4 h pH 7

Colon 10 h pH 6.5 - 7

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 m 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 m 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 m 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 cm 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 OR OR CH2 OR

H H H
CH2 OR

H H
OR O

H
O

H H
OR

Products Methylcellulose -CH3

Substitution [mole] 1.5-2.0

Substituents high medium double

(%) 28-32 23-28 22-26

Hydroxypropyl methylcellulose (Pharmacoat Methocel) Cellulose acetate phthalate (CAP) Hydroxypropyl methylcellulose phthalate (HPMCP) Specifications

-CH3 -CH2-CH(OH)-CH3 -CO-C6H4-COOH -CO-CH3 -CO-C6H4-COOH -CH3 -CH2-CH(OH)-CH3 Methyl cellulose 22-26

1.80 0.25 0.50 1.20 HP 50 0.50 1.60 0.20 HP 55 0.30 1.60 0.20 HP 50 27-35 18-22 4-9 7-12 30-36 19-23.5 HP 55 20-24 20-25 5-10 Hydroxypropyl methylcellulose phthalate

Hydroxypropyl methylcellulose USP XX 16.5-20.0 19.0-24.0 27.0-30.0 4.0-7.5 7.0-12.0 23.0-32.0

Cellulose acetate phthalate USP XX/NF XV

Methoxy

23-28 28-32

18.0-22.0 20.0-25.0 4.0-9.0

Hydroxypropoxy % Acetyl Phthalyl Drying loss Sulfate ash Arsenic % % % % ppm max. 10 max. 1.5

19.0-23.59 30.0-36.0 max. 5 max. 1.0 max. 6

5.0-10.0 27.0-35.0 20.0-24.0 max. 5 max. 0.1 max. 3 max. 10 max. 1

max. 5 max. 3 max. 3 max. 10 -

Heavy metals ppm Free phthalicacid%

Table 3 Acrylic polymers for film coatings Chemical structure


CH3 (H) CH 2 C CH 2 CH3 (H) C R

C=O O - Alkyl Products 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

R -COOH

Substitution [mole] 0.3-0.5

Function gastroresistant enterosoluble gastrosoluble permeable pH > 5 permeable

-COO-CH2CH2N(CH3)2

0.5

-COOCH2CH2N+(CH3)3 Cl-COO-CH3

0.05-0.1

0.3

independent

a = polymerization in emulsion b = polymerization in bulk


Specification L 100-55/ L 100 S 100 E 100 DAB RL 100 RS 100

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 Heavy metals % % ppm ppm max. 5 max. 4 max. 2 max. 20 max. 5,0 max. 0.1 max. 2,0 max. 20 46.0-50.6 (300-330) 27.6-30.7 (180-200)

USP/NF

20.8-25.5 (162-198) 8.85-11.95 (23.9-32.3) max. 2 max. 0.1 max. 2 max 20 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


Mixtures EUDRAGIT L and S mg min*g
300

EUDRAGIT L

2:1

1:1

1:2

250

Dissolution rate

200

150

EUDRAGIT S

100

50

6.0

6.5

7.0

7.5

8.0

pH

Table 4 Physical data and TLVs for some solvents Solvent Boiling point (1013 mbar) C Ethanol Methanol Isopropyl alcohol Diethyl ether Acetone Petroleum spirit Methylene chloride Chloroform Water 78.3 64.7 82.3 34.6 56.2 100140 40.2 61.2 100.0 8.3 6.3 11.0 1.0 2.0 8.0 2.0 2.5 60.0 Evapo- Heat ration of number vapori -zation Vapor TLV Odor pressur threshe 3 old (ml/m (20 C) ) mg/m3 joule/g mbar ppm 855 1102 667 374 520 300 321 247 2264 60 128 43 588 245 40 475 210 17.5 1,000 200 400 400 1,000 * 100 10 93 7800 90 n.d. 770 n.d. 550 1000 AutoFlas Explosiv ignition h e tempoint limits peratur (760 e torr) C C vol.-% 425 + 16 3.5-15.0 508 + 5.5-26.5 6.5 634 2.0-12.0 160 + 15 1.7-36.0 540 - 40 2.5-13.0 - 19 220 1.0-6.0 -5 605 13.0n.d. 22.0 -

= further tests pending, n.d. = no data available

Layer buildup by ladling 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 m is sufficient for coloring, so that the approx. 20 m 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


Ladling: aqueous or organic formulations

Spraying, aqueous or organic formulations through -colored polymer layer pigmented final coat

Sugar layer up to several mm

Transition phase approx. 10 m

pigmented final coat approx. 10 m through-colored enteric layer, approx. 25 m

Enteric layer approx. 15 m

enteric layer approx. 15 m

Dusting phase approx.10 m

sealing coat approx. 5 m

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 cm 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 (mm), d = diameter (mm), h = overall height (mm) Tablets: S = (d h + 0.5 d) = mm Capsules, oblongs: S = d h = mm Spherical shapes (microtablets, pellets, granules): S = d = mm

If we divide the surface area of a substrate S (mm) 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 cm. If lower or higher coating weights are specified for certain dosage forms, we must multiply by this additional amount A = mg polymer per cm. S (mm) A (mg/cm) ___________________ w (mg) Note that mm in this formula refers to the surface area and mg per cm 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 (R Bw + R + Ch) =mm 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 , we arrive at S = 2 (R H + (R Cr - Cr - R)) = mm This formula may look rather complicated, but it can easily be stored in a modern pocket calculator to be at hand when needed.

Coating weight (%) =

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: F= desired batch size (kg) ______________________ 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) Talc Polyethylene glycol 6000 Water

260 g 39 g 16 g 345 g 660 g

7.14 = 7.14 = 7.14 = 7.14 =

1,856 g 278 g 114 g 2,464 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) _______________________________________ 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%.

EUDRAGIT factor EF =

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) Acetyl triethyl citrate Talc Silicone antifoam emulsion Water

50,000 g 1,500 g 7,500 g 150 g 36,850 g

0.4 = 0.4 = 0.4 = 0.4 = 0.4 =

20,000 g 600 g 3,000 g 60 g 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 260 g 39 g 16 g 345 g 660 g 11.8% 5.9% 2.5% 79.9% 100.0% 260 g 78 g 16 g 306 g 660 g standard 11.8% 11.8% 2.4% 74.0% 100.0%

EUDRAGIT L 30 D-55 (30% aqueous dispersion) Talc Polyethylene glycol 6000 Water

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 Rhm GmbH & Co. KG, Darmstadt, Germany

Potrebbero piacerti anche