BASF ExAct

page 4 No. 1, November 1998

Scientific:

Kollicoat MAE
Effectiveness and Economy in Enteric Coating
K. Kolter, BASF Aktiengesellschaft, Product Development, 67056 Ludwigshafen, Germany S. Scheiffele and G. Schepky, Fachhochschule, Pharmatechnik Dept., 72488 Sigmaringen, Germany Introduction Usually, methacrylic acid copolymers and cellulose derivatives are used as the film-forming agent in the manufacture of enteric dosage forms. For ecological and economical reasons, enteric film-forming agents that can be applied in aqueous systems are finding increasing use. The aqueous systems can take the form of polymer dispersions or ammoniacal polymer solutions. This paper investigates a number of commercially available products to determine how the polymer type, the physicochemical constitution of the polymer and the processing method affect resistance to gastric juice, processing properties and process times. Experimental Methods Materials Hydroxypropyl methylcellulose acetate succinate HPMCAS (Aqoat, Shin-Etsu), hydroxypropyl methylcellulose phthalate HPMCP (HP-55S, ShinEtsu; HP 55, Eastman), cellulose acetate phthalate, CAP (Aquateric, FMC), ethyl acrylate/methacrylic acid copolymer 1:1 (Kollicoat MAE, BASF AG). Apparatus Accela Cota 24 (Manesty Machines Ltd.), Diosna Mixer V 50, tablet press RL 15 (Kilian & Co. GmbH), disintegration tester (DES-4AS, Krmer Elektronik). Composition and preparation of caffeine cores Caffeine anhydrous 50 mg (Knoll AG), Ludipress 229 mg (BASF AG), Avicel PH 101 40 mg (FMC), Kollidon CL 10 mg (BASF AG), Magnesium stearate 1 mg (Brlocher). The ingredients of the formulation were mixed in a Diosna mixer and compressed with a force of 10 kN into cores of the following description: 9 mm diameter, 12 mm radius of curvature, 330 mg weight. Composition and preparation of the spray dispersions (Table 1) The composition of the spray suspensions and solutions, the method of preparation and the process parameters were taken from the respective manufacturer's technical data sheets. Preparation of isolated films Isolated films were prepared by spraying the pigmented suspension onto a heated plate. Determination of the acid permeation of isolated films
Ingredients [%] CAP aqueous Kollicoat MAE aqueous HP 55 aqueous HP-55S organic HPMCAS aqueous

Film-former Ammonia (30 %) Ethanol Kollidon 30

11.04

15.00

9.70 1.80

5.00

7.00

79.19 0.50 0.21 0.26 0.50 2.00 0.26 3.35 1.50 0.10 84.99 80.00 84.34 13.97 88.25 0.50 0.33 2.50 0.33 1.00 1.96 0.17 1.50 0.17 0.24 2.10 0.24

Composition of the spray dispersions according to technical data sheets. (Table 1)

Sodium lauryl sulfate Sicovit Talc Titanium dioxide Triacetin Triethyl citrate Tween 80 Water

The proton permeability was determined in 0.1 N HCI, as the donor medium, in a permeation cell. Preparation of enteric film-coated tablets (Table 2) Determination of the increase in weight of enteric coated tablets during the resistance tests Six film-coated tablets were agitated in 0.1 N HCI in a disintegration tester for 1 hour and 2 hours at a temperature of 37 C. The increase in weight is given as a percentage of the initial weight. Results and Discussion The degree of resistance to gastric juice was determined both from the increase in weight of film-coated tablets during the resistance test and by permeation tests on isolated films. The tested products demonstrated considerable differences in both tests.
Process Parameter CAP aqueous

In the resistance test, Kollicoat MAE applied as an aqueous suspension and HP 55S applied as an organic solution, both in a quantity of 8.0 mg/cm2, demonstrated relatively low weight increases of 24 %, and therefore excellent resistance to gastric juice, both after 1 hour and after 2 hours. After treatment for 1 hour, the other film-coated tablets absorbed much more gastric juice, in the order HPMCAS, CAP and HP 55. The reasons for the poorer resistance to gastric juice can be found in the type of polymer, in the case of the dispersions HPMCAS and CAP, and the fact that their particle size is much larger than that of Kollicoat MAE. When the film-forming agent is applied in ammoniacal solution, residual traces of ammonia remain in the film and make it much more permeable (Figure 1) [1]. The proton permeation test on isolated films (Figure 2) gives similar results to the gastric juice absorption test on the film-coated tablets. While
Kollicoat MAE aqueous HP 55 aqueous HP-55S organic HPMCAS aqueous

Process parameters in coating and subsequent treatment according to technical data sheets. (Table 2)

Inlet air temperature [ oC] Product temperature [ oC] Rate of spraying [g/min] Drying Heat treatment [min/oC]

78 3233 60

50 3538 30

70 >32 30

60 36 60

70 3335 40

5 minutes at 50 oC 60/60 No heat treatment 30/60

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BASF ExAct

s after 1 hour s after 2 hours

40
34.98

35
35.63

Increase in weight [%]

30 25
20.32

33.76 24.24 25.41

20 15 10 5
2.15 3.66 2.24 3.91 Kollicoat MAE HPMCAS aqueous aqueous
Film-former

Increase in weight of film-coated tablets (8.0 mg/cm2) in gastric juice. (Figure 1)

Proton permeation coefficient [moly100myl/m2ydymol]

Kollicoat MAE and HP 55S demonstrate only slight permeability, the cellulose derivatives which are processed as aqueous dispersions give much higher values. The acid permeation results show that to achieve resistance to gastric juice, different minimum film thicknesses are required for each film-forming agent. It must be borne in mind that greater film thicknesses increase the coating costs due to higher material, time and energy costs, considerably increasing the overall costs. Taking into account the different coating weights required to achieve good resistance to gastric juice (5.5 mg/cm2 for Kollicoat MAE and HP 55S; 11.0 mg/cm2 for HP 55, HPMCAS and CAP), the production times are as shown below (Figure 3): The different processing times in the preparation of spray suspensions are not taken into account here. More time and effort are always required for preparing suspensions from the powders (HPMCAS, CAP, HP 55 and HP 55S) than for mixing in an aqueous dispersion such as Kollicoat MAE. References [1] P. C. Schmidt and F. Niemann, Drug Dev. Ind. Pharm. 18, 196979 (1992)

0
HP-55S organic CAP aqueous HP 55 aqueous

s after 1 hour s after 2 hours

0.01 0.001 0.0001 1E05 1E06 1E07 1E08 1E09 1E10 1E11
HP-55S organic Kollicoat MAE HPMCAS aqueous aqueous Film-former CAP aqueous HP 55 aqueous

Proton permeability through isolated films. (Figure 2)

Conclusion To achieve adequate resistance towards gastric juice, a coating of only 5.5 mg/cm2 is required with Kollicoat, which is just as little as with HP 55S applied in an organic solution. HPMCAS only achieves similar impermeability with 11.0 mg/cm2; tablets film-coated with CAP and ammoniacal HP 55 still absorb over 20 % by weight of gastric juice even at this film thickness. The proton permeation rates of the isolated films correlate well with the gastric juice absorption of film-coated tablets. The resistance to gastric juice decreases in the following order: Kollicoat MAE, HP 55S (organic) HPMCAS CAP HP 55 (ammoniacal). The times required for the film-coating process to achieve maximum resistance to gastric juice, or up to a weight of 11.0 mg/cm2 are three times higher for HPMCAS and CAP than for Kollicoat MAE, for a 5-kg batch, because the spray rate is slower and tempering is required.

s Heat treatment time [min.] s Drying time [min.] s Spraying time [min.]

120

Production time [min.]

100 80 60 40 20 0 HP-55S organic Kollicoat MAE HP 55 aqueous aqueous

Film-former

30 5 5

60

Production times for maximum resistance to gastric juice or a coat weight of 11.0 mg/cm2. (Figure 3)

5 5 44 30

86

78

5 40

HPMCAS aqueous

CAP aqueous