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Polymer suspension plasticizer

VIEWS: 22 PAGES: 38

									Generic Drug Formulations
with Kollicoat® MAE 30 DP
and Kollicoat® MAE 100 P
Generic Drug Formulations
with Kollicoat® MAE 30 DP
             ®
and Kollicoat MAE 100 P



  Kollicoat® MAE grades
  (methacrylic acid - ethyl
  acrylate) are “state of the
  art“ filmforming agents for
  a reliable, convenient and
  cost-saving enteric coating
  of solid oral dosage forms.
Generic Drug Formulations with Kollicoat® MAE grades


Contents

GENERAL NOTES
1.       Calculation
1.1.     Determination of the tablet surface
1.2.     Calculation of the spray suspension

2.       Processing notes
2.1.     Kollicoat MAE grades
2.2.     Excipients
2.3.     Preparation of the spray suspension


COATING
Enteric coating
3.       Enteric film coatings for pellets, crystals and granules
3.1.     Acetylsalicylic acid crystals
3.2.     Indomethacin pellets
3.3.     Diclofenac sodium pellets

4.       Enteric film coatings for soft gelatine capsules
4.1      Transparent Coating
4.2      White Coating

5.       Enteric film coatings for tablets
5.1.     Acetylsalicylic acid tablets
5.2.     Diclofenac sodium tablets
5.3.     Propranolol-HCl tablets – coloured enteric film coatings
5.4.     Propranolol-HCl tablets – colourless enteric film coatings
5.5.     Caffeine tablets


Taste masking

6.       Kollidon 30 as pore former

SUBSTANCES

LITERATURE

Page 3 /38                                                            Contents
Generic Drug Formulations with Kollicoat® MAE grades




                    Kollicoat® MAE grades


                          GENERAL NOTES




Page 4 / 38
Generic Drug Formulations with Kollicoat® MAE grades


1.      Calculation [1]
1.1.    Determination of the tablet surface




                                                  r




                                                                         h



                                                                     H       s




                               RC




                          Tablet surface:     O =2π (rs + r² + h²)
                                              h = RC − RC² − r ²




Page 5/ 38                                                                       Calculation
Generic Drug Formulations with Kollicoat® MAE grades


1.2.    Calculation of the spray suspension


                                                                     Formulation 1    Formulation 2
                                                                       Proportion        Proportion
                                                                          [%]                [%]

         Polymer suspension               Kollicoat® MAE 30 DP           50.00            539.00
                                          Propylene glycol                2.25             24.26
                                          Water                          32.25            347.65

         Pigment suspension               Sicovit® Red 30                 0.50              5.39
                                          Titanium dioxide                0.50              5.39
                                          Talc                            4.00             43.12
                                          Water                          10.50            113.19
                                                                        100.00           1078.00

         Solids content of the spray suspension                       22.25 %
         Content of polymer dry substance                             15.00 %
         Polymer applied (as solids)                                 4 mg/cm²
         Total solids applied                                        6 mg/cm²



        For example:

             Batch size:       5.0 kg         batch size / tablet weight = tablets
             Tablet weight:    250 mg         5000 g / 0.25 g = 20 000 tablets


                                              tablets x tablet surface = total surface
             Tablet surface:   2 cm²
                                              20 000 x 2 cm² = 40 000 cm²


                                              total surface x coating level = total solids
             Coating level:    6 mg/cm²
                                              40 000 cm² x 6 mg/cm² = 240 000 mg = 240 g


                                              22.25 % solids content = 240 g solids
             Solids content:   22.25 %
                                              100 % spray suspension = 1078 g




        The usual amount of polymer to achieve gastric resistance is 4-6 mg/cm² of tablet
        surface, or 10 to 30 % by weight on particles such as pellets, granules or crystals with
        sizes in the range of about 0.5 to 3.0 mm.




Page 6/ 38                                                                                   Calculation
Generic Drug Formulations with Kollicoat® MAE grades


2.      Processing notes [2]

2.1.    Kollicoat® MAE grades

        A number of factors may cause aqueous dispersions to coagulate during processing,
        rendering them unusable:
              The addition of finely divided pigments
              High shear gradients on stirring and grinding
              Addition of emulsifying agents, stabilizers or wetting agents
              Changing in pH
              Cationic additives
              Organic solvents
              The formation of foam


        Re-dispersion of Kollicoat® MAE 100P

        Stirring the Kollicoat® MAE 100 P powder into water yields an aqueous dispersion
        with technical and processing properties similar to those of the Kollicoat® MAE 30 DP
        dispersion on which it is based.

        Procedure:
        Add the powder to the specified quantity of water with stirring. When adding the
        powder, ensure that

              it does not form lumps
              it is immediately wetted
              the speed of the stirrer always matches the viscosity,
              not too much foam is formed.

        To avoid lump formation and deposits on the stirrer, a stirrer with no horizontal
        surfaces, e.g. a bar or gate-type should be used.

        When the powder has been incorporated, the viscosity rises and the falls again on
        further stirring. The dispersion should be stirred for 2-4 hours to ensure complete
        redispersion. It must be ensured that not too much air is entrained in the dispersion
        when it thickens.

        A concentration of 20 % has been found to be the optimum. The further steps in the
        preparation of a sprayable suspension are essentially the same as for Kollicoat® MAE
        30 DP.

        It is not necessary to add any other auxiliaries such as alkali to redisperse Kollicoat®
        MAE 100 P. The powder already contains the necessary proportion of neutralized
        methacrylic acid groups.




Page 7 / 38                                                                        Processing notes
Generic Drug Formulations with Kollicoat® MAE grades


2.2.    Excipients

        Plasticizers are essential to improve the flexibility of the films.

        Suitable plasticizers are
              1, 2-propylene glycol
              Triethyl citrate
              Polyethylene glycol
              Triacetin

        The amount of plasticizer to add is 10 to 25 % of the dry polymer.

        1, 2-propylene glycol improves the processability and barrier properties of the film
        coatings.


        The Kollicoat® MAE grades are incompatible with magnesium stearate. However, any
        magnesium stearate in the product to be coated presents no problem.


        The following excipients can be included in a film-coating formulation:
              Talc
              Glycerol monostearate
              Silica
              Kaolin
              Pigments


        Foam formation during processing can be prevented by adding simethicone, a
        silicone antifoam emulsion such as Pharsil® 21046.




Page 8 / 38                                                                       Processing notes
Generic Drug Formulations with Kollicoat® MAE grades


2.3.    Preparation of the spray suspension


         Polymer suspension                Kollicoat® MAE 30 DP:
                                           The plasticizer is first stirred into the specified amount
                                           of water, followed by Kollicoat® MAE 30 DP.

                                           Kollicoat® MAE 100 P:
                                           Kollicoat® MAE 100 P is carefully stirred into the given
                                           amount of water. The stirrer speed is adapted to the
                                           viscosity from time to time avoiding foam formation.
                                           To complete the redispersion the system is stirred for
                                           2 to 4 hours. Finally the plasticizer is added.

         Pigment suspension                Sicovit Red 30, titanium dioxide and talc are
                                           intensively stirred into the specified amount of water
                                           and homogenized in a corundum disk mill or using an
                                           ultra-turrax.

         Spray suspension                  Incorporate the pigment suspension into the polymer
                                           suspension with stirring. The suspension must be
                                           stirred during the spraying process to prevent settling.



        Spray suspensions with a 15 to 30 % solids content give good results and save time
        in spraying.


        To avoid problems in incorporating auxiliaries in the aqueous suspensions, we
        recommend to:

              Dilute the dispersion to a solids content of 20 %
              Stir the desired auxiliary into the dispersion in the form of a dilute solution


        The properties and processing requirements of latices produced with Kollicoat® MAE
        100 P are the same as those of Kollicoat® MAE 30 DP, from which it is manufactured.




Page 9 / 38                                                                            Processing notes
Generic Drug Formulations with Kollicoat® MAE grades




                    Kollicoat® MAE grades


                                    COATING




Page 10 / 38
Generic Drug Formulations with Kollicoat® MAE grades


Enteric coating

3.      Enteric film coatings for pellets, crystals and granules
3.1.    Acetylsalicylic acid crystals [5]

a)      Formulation

        The formulation is designed for 0.5 kg of acetylsalicylic acid crystals
        (Chemische Fabrik Aubing GmbH, Mannheim, Germany), diameter 0.5-0.8 mm

                                                                   Formulation 1      Formulation 2
                                                                     Proportion         Proportion
                                                                        [%]                [%]

          Polymer suspension            Kollicoat® MAE 30 DP            50.00
                                        Kollicoat® MAE 100 P                              15.00
                                        Propylene glycol                 2.25              2.25
                                        Water                           32.25             67.25

          Pigment suspension            Sicovit® Red 30                          0.50
                                        Titanium dioxide                         0.50
                                        Talc                                     4.00
                                        Water                                   10.50
                                                                       100.00            100.00

          Solids content of the spray suspension                     22.25 %
          Content of polymer dry substance                           15.00 %
          Polymer applied (as solids)                               2 mg/cm²
          Total solids applied                                      3 mg/cm²

b)      Preparation of the spray suspension

          Polymer suspension            Kollicoat® MAE 30 DP:
                                        The plasticizer is first stirred into the specified amount
                                        of water, followed by Kollicoat® MAE 30 DP.
                                        Kollicoat® MAE 100 P:
                                        Kollicoat® MAE 100 P is carefully stirred into the given
                                        amount of water. The stirrer speed is adapted to the
                                        viscosity from time to time avoiding foam formation.
                                        To complete the redispersion the system is stirred for
                                        2 to 4 hours. Finally the plasticizer is added.

          Pigment suspension            Sicovit® Red 30, titanium dioxide and talc are
                                        intensively stirred into the specified amount of water
                                        and homogenized in a corundum disk mill or using an
                                        ultra-turrax.

          Spray suspension              Incorporate the pigment suspension into the polymer
                                        suspension with stirring. The suspension must be
                                        stirred during the spraying process to prevent settling.

Page 11 / 38                                                               Acetylsalicylic acid crystals
Generic Drug Formulations with Kollicoat® MAE grades


c)      Coating

        The coating is applied on 0.5 kg crystals in a fluidized bed coater (top spray method)
        under the following conditions:

          Process parameters                                        Machine                                       Aeromatic, Strea 1
                                                                    Batch size                                    0.5 kg
                                                                    Inlet air temperature                         60°C
                                                                    Outlet air temperature                        35°C
                                                                    Spraying rate                                 30-35 g/min
                                                                    Nozzle diameter                               1 mm
                                                                    Spray pressure                                1 bar
                                                                    Final drying                                  60°C/2min

        The coating weight of 3 mg/cm² given here was determined from the surface area of
        the crystals. Since the particle size distribution and surface structure influence the
        polymer quantity required, calculating the surface area is recommended as a means
        of estimating the required coating weight in each specific case.



d)      Dissolution

                                                     Drug release of film-coated ASA crystals (Kollicoat MAE 30 DP)
                                                       compared with release of uncoated crystals in either fluid
                             100




                             80
          Drug release [%]




                             60




                             40
                                                                                                       3mg/cm²
                                                                                                       Uncoated (gastric fluid only)
                                                                                                       Uncoated (intestinal fluid only)
                             20

                                        Resistance test                                                 Release in
                                        in gastric fluid                                              intestinal fluid
                              0
                                   0   30     60      90      120      5       10      15        20         25         30         35      40   45      50
                                                                                    Time [min]




Page 12 / 38                                                                                                           Acetylsalicylic acid crystals
Generic Drug Formulations with Kollicoat® MAE grades


3.2.    Indomethacin pellets [6]

a)      Formulation

        The formulation is designed for 0.5 kg of indomethacin pellets
        (composition of pellets: 10% indomethacin, 2.5 % Kollidon® VA 64, 43.7 % Avicel® PH
        101, 43.7 % Granulac® 230), diameter 0.7-1.4 mm

                                                                   Formulation 1     Formulation 2
                                                                     Proportion        Proportion
                                                                        [%]               [%]

         Polymer suspension             Kollicoat® MAE 30 DP            50.00
                                        Kollicoat® MAE 100 P                             15.00
                                        Propylene glycol                 2.25             2.25
                                        Water                           32.25            67.25

          Pigment suspension            Sicovit® Red 30                          0.50
                                        Titanium dioxide                         0.50
                                        Talc                                     4.00
                                        Water                                   10.50
                                                                       100.00           100.00

         Solids content of the spray suspension                      22.25 %
         Content of polymer dry substance                            15.00 %
         Polymer applied (as solids)                                2 mg/cm²
         Total solids applied                                       3 mg/cm²



b)      Preparation of the spray suspension

        Polymer suspension              Kollicoat® MAE 30 DP:
                                        The plasticizer is first stirred into the specified amount
                                        of water, followed by Kollicoat® MAE 30 DP.
                                        Kollicoat® MAE 100 P:
                                        Kollicoat® MAE 100 P is carefully stirred into the given
                                        amount of water. The stirrer speed is adapted to the
                                        viscosity from time to time avoiding foam formation.
                                        To complete the redispersion the system is stirred for
                                        2 to 4 hours. Finally the plasticizer is added.
        Pigment suspension              Sicovit® Red 30, titanium dioxide and talc are
                                        intensively stirred into the specified amount of water
                                        and homogenized in a corundum disk mill or using an
                                        ultra-turrax.
        Spray suspension                Incorporate the pigment suspension into the polymer
                                        suspension with stirring. The suspension must be
                                        stirred during the spraying process to prevent settling.




Page 13 / 38                                                                     Indomethacin pellets
Generic Drug Formulations with Kollicoat® MAE grades


c)      Coating

        The coating is applied on 0.5 kg pellets in a fluidized bed coater under the following
        conditions:

         Process parameters                                 Machine                                   Aeromatic, Strea 1
                                                                                                      Wurster equipment
                                                            Batch size                                0.5 kg
                                                            Inlet air temperature                     60°C
                                                            Outlet air temperature                    35°C
                                                            Spraying rate                             30 – 35 g/min
                                                            Nozzle diameter                           1 mm
                                                            Spray pressure                            1 bar
                                                            Final drying                              60°C/2min

        The coating weight of 3 mg/cm² given here was determined from the surface area of
        the pellets. Since the particle size distribution and surface structure influence the
        polymer quantity required, calculating the surface area is recommended as a means
        of estimating the required coating weight in each specific case.



d)      Dissolution

                                            Drug release of film-coated indomethacin pellets (Kollicoat MAE 30 DP)
                                                  compared with release of uncoated pellets in intestinal fluid
                             100

                                            Resistance test                                                 Release in
                                            in gastric fluid                                              intestinal fluid
                             80
          Drug release [%]




                             60




                             40




                             20

                                       3mg/cm²
                                       Uncoated (intestinal fluid only)
                              0
                                   0   30            60             90            120            15            30             45            60
                                                                               Time [min]




Page 14 / 38                                                                                                         Indomethacin pellets
Generic Drug Formulations with Kollicoat® MAE grades


3.3.    Diclofenac sodium pellets [6]

a)      Formulation

        The formulation is designed for 0.5 kg of diclofenac sodium pellets
        (composition of pellets: 10 % diclofenac sodium, 2.5 % Kollidon® VA 64, 43.7 %
        Avicel® PH 101, 43.7 % Granulac® 230), diameter 0.7-1.4 mm

                                                                   Formulation 1       Formulation 2
                                                                     Proportion          Proportion
                                                                        [%]                 [%]

         Polymer suspension             Kollicoat® MAE 30 DP            50.00
                                        Kollicoat® MAE 100 P                               15.00
                                        Propylene glycol                 2.25               2.25
                                        Water                           32.25              67.25

         Pigment suspension             Sicovit® Red 30                          0.50
                                        Titanium dioxide                         0.50
                                        Talc                                     4.00
                                        Water                                   10.50
                                                                       100.00            100.00

         Solids content of the spray suspension                      22.25 %
         Content of polymer dry substance                            15.00 %
         Polymer applied (as solids)                                2 mg/cm²
         Total solids applied                                       3 mg/cm²



b)      Preparation of the spray suspension

         Polymer suspension             Kollicoat® MAE 30 DP:
                                        The plasticizer is first stirred into the specified amount
                                        of water, followed by Kollicoat® MAE 30 DP.

                                        Kollicoat® MAE 100 P:
                                        Kollicoat® MAE 100 P is carefully stirred into the given
                                        amount of water. The stirrer speed is adapted to the
                                        viscosity from time to time avoiding foam formation.
                                        To complete the redispersion the system is stirred for
                                        3 to 4 hours. Finally the plasticizer is added.

         Pigment suspension             Sicovit® Red 30, titanium dioxide and talc are
                                        intensively stirred into the specified amount of water
                                        and homogenized in a corundum disk mill or using an
                                        ultra-turrax.

         Spray suspension               Incorporate the pigment suspension into the polymer
                                        suspension with stirring. The suspension must be
                                        stirred during the spraying process to prevent settling.


Page 15 / 38                                                                  Diclofenac sodium pellets
Generic Drug Formulations with Kollicoat® MAE grades


c)      Coating

        The coating is applied on 0.5 kg pellets in a fluidized bed coater under the following
        conditions:

         Process parameters                                       Machine                               Aeromatic, Strea 1
                                                                                                        Wurster equipment
                                                                  Batch size                            0.5 kg
                                                                  Inlet air temperature                 60°C
                                                                  Outlet air temperature                35°C
                                                                  Spraying rate                         30 – 35 g/min
                                                                  Nozzle diameter                       1 mm
                                                                  Spray pressure                        1 bar
                                                                  Final drying                          60°C/2min

        The coating weight of 3 mg/cm² given here was determined from the surface area of
        the pellets. Since the particle size distribution and surface structure influence the
        polymer quantity required, calculating the surface area is recommended as a means
        of estimating the required coating weight in each specific case.



d)      Dissolution

                                               Drug release of film-coated diclofenac sodium pellets (Kollicoat MAE 30 DP)
                                                       compared with release of uncoated pellets in intestinal fluid
                             100




                             80
          Drug release [%]




                             60




                             40

                                                                                                          3mg/cm²
                                                                                                          Uncoated (intestinal fluid only)
                             20

                                       Resistance test                                                   Release in
                                       in gastric fluid                                                intestinal fluid
                              0
                                   0   30     60     90     120     5      10      15      20     25       30     35      40     45      50   55
                                                                                   Time [min]




Page 16 / 38                                                                                                     Diclofenac sodium pellets
Generic Drug Formulations with Kollicoat® MAE grades


4.      Enteric film coatings for soft gelatine capsules [2]

        There are three basic requirements for the coating of soft gelatine capsules

        •      The coating should be very flexible; at least as flexible as the gelatine shell.
               This is achieved by using a high plasticizer concentration and a plasticizer, which
               does not diffuse into the gelatine shell. Triethyl citrate (25 % related to polymer)
               was found to be highly suitable.
        •      The coating process has to be performed in a way that maintains the flexibility of
               the shell.
               Therefore, any evaporation of water from the gelatine shell has to be avoided.
               Prewarming of the capsules should be shortened as much as possible or it should
               be combined with the spraying of pure water.
        •      The coating should adhere strongly to the gelatine shell.


        Sometimes soft gelatine capsules are covered by an oil film, which reduces the
        adhesion of a polymer coating. The oil can be removed by washing the capsules with
        hexane or cyclohexane. Instead of a washing procedure, which is costly, the capsules
        can be blended with colloidal silica. If these procedures do not show a sufficient
        effect, the capsules should be roughened using abrasive surfaces in a mixing,
        tumbling or spheronizing equipment.


4.1.    Transparent Coating

a)      Formulation

                                                                      Formulation 1      Formulation 2
                                                                       Proportion           Proportion
                                                                           [%]                 [%]

            Polymer suspension             Kollicoat® MAE 30 DP            66.7
                                           Kollicoat® MAE 100 P                               20.0
                                           Triethyl citrate                 5.0                5.0
                                           Water                           28.3               75.0
                                                                         100.00             100.00

            Solids content of the spray suspension                      25.0 %
            Content of polymer dry substance                            20.0 %
            Polymer applied (as solids)                              16 mg/cm²
            Total solids applied                                     20 mg/cm²




Page 17 / 38                                                                        Soft gelatine capsules
Generic Drug Formulations with Kollicoat® MAE grades


b)      Preparation of the spray suspension

          Polymer suspension            Kollicoat® MAE 30 DP:
                                        The plasticizer is first stirred into the specified amount
                                        of water, followed by Kollicoat® MAE 30 DP.
                                        Kollicoat® MAE 100 P:
                                        Kollicoat® MAE 100 P is carefully stirred into the given
                                        amount of water. The stirrer speed is adapted to the
                                        viscosity from time to time avoiding foam formation.
                                        To complete the redispersion the system is stirred for
                                        2 to 4 hours. Finally the plasticizer is added.



c)      Coating

        The coating machine is prewarmed with an inlet air temperature of 55°C and loaded
        with the soft gelatine capsules. After 2-3 min prewarming the soft gelatine capsules,
        the coating process is started. It is also advantageous to reach a better transparency
        150 g of demineralized water sprayed onto the capsules at a spraying rate of 30 g/min
        starting directly after loading the capsules. Directly after the application of water the
        enteric coating formulation is sprayed.

        The coating is applied on 4 kg soft gelatine capsules in a 24-inch Accela Cota under
        the following conditions:


          Prewarming                    2 - 3 min at 55°C
                                        or 5 min at 55°C spraying 150 g demineralized water
                                        at a spraying rate of 30 g/min.



          Process parameters            Machine                      Accela Cota, “24“
                                        Batch size                   4 kg
                                        Inlet air temperature        55°C
                                        Product temperature          32 - 34°C
                                        Spraying rate                25 - 30 g/min
                                        Spraying time                80 - 90 min
                                        Final drying                 55          25°C/5min


        Immediately after finishing application of the coating dispersion, the temperature of
        the inlet air is reduced to 25°C. This is on the one hand sufficient for drying and on the
        other hand it avoids a high water loss from the gelatine shell.


d)      Disintegration
        The coated soft gelatine capsules remained unchanged in gastric fluid for 2 h.




Page 18 / 38                                                                   Soft gelatine capsules
Generic Drug Formulations with Kollicoat® MAE grades


4.2.    White Coating


a)     Formulation

                                                                                   Proportion
                                                                                      [%]


          Polymer suspension            Kollicoat® MAE 30 DP                             30.00
                                        Triethyl citrate                                  5.00
                                        Water                                            35.00

          Pigment suspension            Titanium dioxide                                 4.00
                                        Talc                                             6.00
                                        Water                                           20.00
                                                                                       100.00

          Solids content of the spray suspension                                     24.00 %
          Content of polymer dry substance                                            9.00 %
          Polymer applied (as solids)                                               6 mg/cm²
          Total solids applied                                                     15 mg/cm²



b)     Preparation of the spray suspension

          Polymer suspension            Kollicoat® MAE 30 DP:
                                        The plasticizer is first stirred into the specified amount
                                        of water, followed by Kollicoat® MAE 30 DP.

          Pigment suspension            Titanium dioxide and talc are intensively stirred into
                                        the specified amount of water and homogenized in a
                                        corundum disk mill or using an ultra-turrax.

          Spray suspension              Incorporate the pigment suspension into the polymer
                                        suspension with stirring. The suspension must be
                                        stirred during the spraying process to prevent settling.




Page 19 / 38                                                                   Soft gelatine capsules
Generic Drug Formulations with Kollicoat® MAE grades


c)      Coating


        The coating machine is prewarmed with an inlet air temperature of 40 - 42°C and
        loaded with the soft gelatine capsules. After 2 - 3 min prewarming the soft gelatine
        capsules, the coating process is started by a subcoating with a 14% solution of
        Kollicoat IR in water until a weight gain of 0.5 % was achieved. The necessity of a
        subcoating depends on the surface properties of the soft gelatine capsules.

        The coating is applied on 4 kg soft gelatine capsules in a 24-inch Accela Cota under
        the following conditions:

          Process parameters              Machine                     Accela Cota, 24“
                                          Batch size                  4.0
                                          Inlet air temperature       42 - 44°C
                                          Outlet air temperature      30 - 33°C
                                          Spraying rate               20 g/min
                                          Nozzle diameter             1 mm
                                          Spray pressure              3.2 bar
                                          Final drying                5 min



c)     Disintegration
       The coated soft gelatine capsules remained unchanged in gastric fluid for 2 h.




Page 20 / 38                                                                 Soft gelatine capsules
Generic Drug Formulations with Kollicoat® MAE grades


5.     Enteric film coatings for tablets
5.1.   Acetylsalicylic acid tablets [5]

a)     Formulation

       The formulation is designed for 5 kg of acetylsalicylic acid tablets
       (composition of tablets: 100 mg ASA, 148.5 mg Ludipress®, 50 mg Avicel® PH 102,
       1.5 mg magnesium stearate; tablet properties: diameter 9 mm, weight 300 mg)

                                                                     Formulation 1        Formulation 2
                                                                       Proportion            Proportion
                                                                          [%]                   [%]

         Polymer suspension               Kollicoat® MAE 30 DP            50.00
                                          Kollicoat® MAE 100 P                                15.00
                                          Propylene glycol                 2.25                2.25
                                          Water                           32.25               67.25

         Pigment suspension               Sicovit® Red 30                           0.50
                                          Titanium dioxide                          0.50
                                          Talc                                      4.00
                                          Water                                    10.50
                                                                         100.00              100.00
         Solids content of the spray suspension                        22.25 %
         Content of polymer dry substance                              15.00 %
         Polymer applied (as solids)                                  2 mg/cm²
         Total solids applied                                         3 mg/cm²


b)     Preparation of the spray suspension

         Polymer suspension               Kollicoat® MAE 30 DP:
                                          The plasticizer is first stirred into the specified amount
                                          of water, followed by Kollicoat® MAE 30 DP.
                                          Kollicoat® MAE 100 P:
                                          Kollicoat® MAE 100 P is carefully stirred into the given
                                          amount of water. The stirrer speed is adapted to the
                                          viscosity from time to time avoiding foam formation.
                                          To complete the redispersion the system is stirred for
                                          2 to 4 hours. Finally the plasticizer is added.

         Pigment suspension               Sicovit® Red 30, titanium dioxide and talc are
                                          intensively stirred into the specified amount of water
                                          and homogenized in a corundum disk mill or using an
                                          ultra-turrax.

         Spray suspension                 Incorporate the pigment suspension into the polymer
                                          suspension with stirring. The suspension must be
                                          stirred during the spraying process to prevent settling.

Page 21 / 38                                                                    Acetylsalicylic acid tablets
Generic Drug Formulations with Kollicoat® MAE grades


c)          Coating

            The coating is applied on 5 kg tablets in a 24-inch Accela Cota under the following
            conditions:

                          Process parameters                   Machine                                    Accela Cota, 24“
                                                               Batch size                                 5 kg
                                                               Inlet air temperature                      60°C
                                                               Product temperature                        32 - 35°C
                                                               Spraying rate                              30 - 35 g/min
                                                               Nozzle diameter                            1 mm
                                                               Spray pressure                             2 bar
                                                               Final drying                               50°C/5min



d)          Dissolution

                                                 Drug release of film-coated ASA tablets (Kollicoat MAE 30 DP)
                                                   compared with release of uncoated tablets in either fluid
                          100




                          80
       Drug release [%]




                          60




                          40
                                                                                                3mg/cm²
                                                                                                Uncoated (gastric fluid only)
                                                                                                Uncoated (intestinal fluid only)
                          20

                                    Resistance test                                            Release in
                                    in gastric fluid                                         intestinal fluid
                           0
                                0   30      60         90     120        5        10       15           20           25            30   35     40
                                                                              Time [min]




Page 22 / 38                                                                                                         Acetylsalicylic acid tablets
Generic Drug Formulations with Kollicoat® MAE grades


5.2.    Diclofenac sodium tablets [6]

a)      Formulation

        The formulation is designed for 5 kg of diclofenac sodium tablets
        (composition of tablets: 49.7 mg diclofenac sodium, 201.4 mg Ludipress®, 14.9 mg
        Kollidon® VA 64, 5 mg Kollidon® CL, 1.2 mg Aerosil® 200, 2.8 mg magnesium
        stearate; tablet properties: diameter 9 mm, weight 275 mg)

                                                                   Formulation 1       Formulation 2
                                                                     Proportion          Proportion
                                                                        [%]                 [%]

         Polymer suspension               Kollicoat® MAE 30             50.00
                                          Kollicoat® MAE 100                               15.00
                                          Propylene glycol               2.25               2.25
                                          Water                         32.25              67.25

         Pigment suspension               Sicovit® Red 30                        0.50
                                          Titanium dioxide                       0.50
                                          Talc                                   4.00
                                          Water                                 10.50
                                                                       100.00            100.00
         Solids content of the spray suspension                      22.25 %
         Content of polymer dry substance                            15.00 %
         Polymer applied (as solids)                                       2
         Total solids applied                                              3


b)      Preparation of the spray suspension

         Polymer suspension             Kollicoat® MAE 30 DP:
                                        The plasticizer is first stirred into the specified amount
                                        of water, followed by Kollicoat® MAE 30 DP.
                                        Kollicoat® MAE 100 P:
                                        Kollicoat® MAE 100 P is carefully stirred into the given
                                        amount of water. The stirrer speed is adapted to the
                                        viscosity from time to time avoiding foam formation.
                                        To complete the redispersion the system is stirred for
                                        2 to 4 hours. Finally the plasticizer is added.

         Pigment suspension             Sicovit® Red 30, titanium dioxide and talc are
                                        intensively stirred into the specified amount of water
                                        and homogenized in a corundum disk mill or using an
                                        ultra-turrax.

         Spray suspension               Incorporate the pigment suspension into the polymer
                                        suspension with stirring. The suspension must be
                                        stirred during the spraying process to prevent settling.



Page 23 / 38                                                                  Diclofenac sodium tablets
Generic Drug Formulations with Kollicoat® MAE grades


c)      Coating

        The coating is applied on 5 kg tablets in a 24-inch Accela Cota under the following
        conditions:

         Process parameters                                      Machine                               Accela Cota, 24“
                                                                 Batch size                            5 kg
                                                                 Inlet air temperature                 60°C
                                                                 Product temperature                   32 - 35°C
                                                                 Spraying rate                         30 - 35 g/min
                                                                 Nozzle diameter                       1 mm
                                                                 Spray pressure                        2 bar
                                                                 Final drying                          50°C/5min



d)      Dissolution

                                               Drug release of film-coated diclofenac sodium tablets (Kollicoat MAE 30 DP)
                                                       compared with release of uncoated tablets in intestinal fluid
                              100

                                        3mg/cm²
                                        Uncoated (intestinal fluid only)
                              80
           Drug release [%]




                              60




                              40




                              20

                                              Resistance test                                            Release in
                                              in gastric fluid                                         intestinal fluid
                               0
                                    0    30          60          90        120         5          10         15           20     25        30
                                                                                   Time [min]




Page 24 / 38                                                                                                   Diclofenac sodium tablets
Generic Drug Formulations with Kollicoat® MAE grades


5.3.    Propranolol-HCl tablets - Coloured enteric film coatings [7]

        Propranolol-HCl was used as a model drug in order to investigate the enteric
        properties of the coating. Usually this drug is not enteric-coated.


a)      Formulation

        The formulation is designed for 5 kg of propranolol-HCl tablets
        (composition of tablets: 40 mg propranolol-HCl, 97.5 mg Ludipress®, 12.5 mg
        Kollidon® VA 64, 97.5 mg Avicel® PH 102, 1.2 mg Aerosil® 200, 2.5 mg magnesium
        stearate; tablet properties: diameter 9 mm, weight 250 mg)

                                                                Formulation 1     Formulation 2
                                                                  Proportion        Proportion
                                                                     [%]               [%]

          Polymer suspension            Kollicoat® MAE 30 DP        50.00
                                        Kollicoat® MAE 100 P                         15.00
                                        Propylene glycol             2.25             2.25
                                        Water                       32.25            67.25

          Pigment suspension            Sicovit® Red 30                      0.50
                                        Titanium dioxide                     0.50
                                        Talc                                 4.00
                                        Water                               10.50
                                                                   100.00           100.00
          Solids content of the spray suspension                  22.25 %
          Content of polymer dry substance                        15.00 %
          Polymer applied (as solids)                            4 mg/cm²
          Total solids applied                                   6 mg/cm²




Page 25 / 38                                                               Propranolol-HCl tablets
Generic Drug Formulations with Kollicoat® MAE grades


b)      Preparation of the spray suspension

          Polymer suspension            Kollicoat® MAE 30 DP:
                                        The plasticizer is first stirred into the specified amount
                                        of water, followed by Kollicoat® MAE 30 DP.
                                        Kollicoat® MAE 100 P:
                                        Kollicoat® MAE 100 P is carefully stirred into the given
                                        amount of water. The stirrer speed is adapted to the
                                        viscosity from time to time avoiding foam formation.
                                        To complete the redispersion the system is stirred for
                                        2 to 4 hours. Finally the plasticizer is added.

          Pigment suspension            Sicovit® Red 30, titanium dioxide and talc are
                                        intensively stirred into the specified amount of water
                                        and homogenized in a corundum disk mill or using an
                                        ultra-turrax.

          Spray suspension              Incorporate the pigment suspension into the polymer
                                        suspension with stirring. The suspension must be
                                        stirred during the spraying process to prevent settling.


c)      Coating

        The coating is applied on 5 kg tablets in a 24-inch Accela Cota under the following
        conditions:

          Process parameters            Machine                      Accela Cota, 24“
                                        Batch size                   5 kg
                                        Inlet air temperature        50°C
                                        Product temperature          32 - 35°C
                                        Spraying rate                30 - 35 g/min
                                        Nozzle diameter              1 mm
                                        Spray pressure               2 bar
                                        Final drying                 50°C/5min




Page 26 / 38                                                                  Propranolol-HCl tablets
Generic Drug Formulations with Kollicoat® MAE grades


d)       Dissolution



                                                        Comparison of dissolution rates of Kollicoat MAE 30 DP
                                                               and Kollicoat MAE 100 P coated tablets
                           100

                                     Resistance test                Release in
                                     in gastric fluid             intestinal fluid
                           80
        Drug release [%]




                           60




                           40




                           20

                                                                                                   Kollicoat MAE 30 DP
                                                                                                   Kollicoat MAE 100 P
                            0
                                 0          60           120            3                6         9             12             15          30
                                                                                     Time [min]




Page 27 / 38                                                                                                          Propranolol-HCl tablets
Generic Drug Formulations with Kollicoat® MAE grades


5.4.    Propranolol-HCl tablets – Colourless enteric film coatings [7]

        Propranolol-HCl was used as a model drug in order to investigate the enteric
        properties of the coating. Usually this drug is not enteric-coated.

a)      Formulation

        The formulation is designed for 5 kg of propranolol-HCl tablets
        (composition of tablets: 40 mg propranolol-HCl, 97.5 mg Ludipress®, 12.5 mg
        Kollidon® VA 64, 97.5 mg Avicel® PH 102, 1.2 mg Aerosil® 200, 2.5 mg magnesium
        stearate; tablet properties: diameter 9 mm, weight 250 mg)

                                                                   Formulation 1     Formulation 2
                                                                     Proportion        Proportion
                                                                        [%]               [%]

          Polymer suspension            Kollicoat® MAE 30 DP             61.8
                                        Kollicoat® MAE 100 P                            18.54
                                        Propylene glycol                  3.7            3.70
                                        Water                            34.5           77.76
                                                                        100.0          100.00

          Solids content of the spray suspension                     22.25 %
          Content of polymer dry substance                           18.54 %
          Polymer applied (as solids)                               5 mg/cm²
          Total solids applied                                      6 mg/cm²



b)      Preparation of the spray suspension

          Polymer suspension            Kollicoat® MAE 30 DP:
                                        The plasticizer is first stirred into the specified amount
                                        of water, followed by Kollicoat® MAE 30 DP.
                                        Kollicoat® MAE 100 P:
                                        Kollicoat® MAE 100 P is carefully stirred into the given
                                        amount of water. The stirrer speed is adapted to the
                                        viscosity from time to time avoiding foam formation.
                                        To complete the redispersion the system is stirred for
                                        2 to 4 hours. Finally the plasticizer is added.




Page 28 / 38                                                                  Propranolol-HCl tablets
Generic Drug Formulations with Kollicoat® MAE grades


c)      Coating

        The coating is applied on 5 kg tablets in a 24-inch Accela Cota under the following
        conditions:

                           Process parameters                       Machine                                     Accela Cota, 24“
                                                                    Batch size                                  5 kg
                                                                    Inlet air temperature                       50°C
                                                                    Product temperature                         32 - 35°C
                                                                    Spraying rate                               30 - 35g/min
                                                                    Nozzle diameter                             1 mm
                                                                    Spray pressure                              2 bar
                                                                    Final drying                                50°C/5min



d)      Dissolution



                                                              Dissolution rate as a function of coating level

                           100

                                     Resistance test                 Release in
                                     in gastric fluid              intestinal fluid
                            80
                                                                 Kollicoat MAE 100 P, 4mg/cm²
                                                                 Kollicoat MAE 100 P, 6mg/cm²
                                                                 Kollicoat MAE 100 P, 12mg/cm²
        Drug release [%]




                            60




                            40




                            20




                            0
                                 0          60          120              3                6            9             12            15          30
                                                                                      Time [min]




Page 29 / 38                                                                                                              Propranolol-HCl tablets
Generic Drug Formulations with Kollicoat® MAE grades


5.5.    Caffeine tablets [8]

        Caffeine was used as a model drug in order to investigate the enteric properties of the
        coating. Usually this drug is not enteric-coated.

a)      Formulation

        The formulation is designed for 5 kg of caffeine tablets
        (composition of tablets: 50 mg caffeine, 229 mg Ludipress®, 10 mg Kollidon® CL,
        40 mg Avicel® PH 101, 1 mg magnesium stearate; tablet properties: diameter 9 mm,
        weight 330 mg)

                                                                   Formulation 1     Formulation 2
                                                                     Proportion           Proportion
                                                                        [%]                   [%]

         Polymer suspension             Kollicoat® MAE 30 DP             50.0
                                        Kollicoat® MAE 100 P                                 15.0
                                        Propylene glycol             1.5 - 4.5           1.5 - 4.5
                                        Water                         ad 84.5             ad 84.5

          Pigment suspension            Sicovit® Red 30                           0.50
                                        Titanium dioxide                          0.50
                                        Talc                                      4.00
                                        Water                                    10.50
                                                                        100.0               100.0
         Content of polymer dry substance                              15 %
         Total solids applied                                       3 mg/cm²



b)      Preparation of the spray suspension

         Polymer suspension             Kollicoat® MAE 30 DP:
                                        The plasticizer is first stirred into the specified amount
                                        of water, followed by Kollicoat® MAE 30 DP.
                                        Kollicoat® MAE 100 P:
                                        Kollicoat® MAE 100 P is carefully stirred into the given
                                        amount of water. The stirrer speed is adapted to the
                                        viscosity from time to time avoiding foam formation.
                                        To complete the redispersion the system is stirred for
                                        2 to 4 hours. Finally the plasticizer is added.

          Pigment suspension            Sicovit® Red 30, titanium dioxide and talc are
                                        intensively stirred into the specified amount of water
                                        and homogenized in a corundum disk mill or using an
                                        ultra-turrax.

         Spray suspension               Incorporate the pigment suspension into the polymer
                                        suspension with stirring. The suspension must be
                                        stirred during the spraying process to prevent settling.

Page 30 / 38                                                                             Caffeine tablets
Generic Drug Formulations with Kollicoat® MAE grades


c)               Coating

                  The coating is applied on 5 kg tablets in a 24-inch Accela Cota under the following
                  conditions:

                          Process parameters                Machine                                Accela Cota, 24“
                                                            Batch size                             5 kg
                                                            Inlet air temperature                  50°C
                                                            Product temperature                    32 - 35°C
                                                            Spraying rate                          30 - 35g/min
                                                            Nozzle diameter                        1 mm
                                                            Spray pressure                         2 bar
                                                            Final drying                           50°C/5min



d)                Dissolution

                                          Dissolution of enteric coated caffeine tablets (Kollicoat MAE 30 DP)

                          100

                                         Resistance test
                                         in gastric fluid
                           80

                                                                                                                   Release in
                                                                                                                 intestinal fluid
       Drug release [%]




                           60




                           40

                                                                                                                 10% Propylene glycol

                                                                                                                 15% Propylene glycol
                           20
                                                                                                                 20% Propylene glycol

                                                                                                                 25% Propylene glycol
                           0
                                0   30           60             90            120            5             10              15           20
                                                                           Time [min]




Page 31 / 38                                                                                                            Caffeine tablets
Generic Drug Formulations with Kollicoat® MAE grades


6.      Taste masking and protective coatings

        Kollicoat MAE applied in low coat weights, viz. 0.5 – 2.0 mg/cm² (solids) can be used
        for the following purposes:
               Masking unpleasant tastes and odours
               Protecting incompatible active substances
               Protection against atmospheric humidity (short term)



6.1     Kollidon® 30 as pore former

a)      Formulation

        The formulation is designed for 5 kg of caffeine tablets
        (composition of tablets: 50 mg caffeine, 229 mg Ludipress®, 10 mg Kollidon® CL,
        40 mg Avicel® PH 101, 1 mg magnesium stearate; tablet properties: diameter 9 mm,
        weight 330 mg)

                                                                      Formulation 1   Formulation 2
                                                                       Proportion      Proportion
                                                                           [%]             [%]

          Polymer suspension              Kollicoat® MAE 30 DP             31.0
                                          Kollicoat® MAE 100 P                             9.3
                                          Propylene glycol                  1.4            1.4
                                          Kollidon® 30                      9.3            9.3
                                          Water                            58.3           80.0
                                                                          100.0          100.0

          Solids content of the spray suspension                         20.0 %
          Content of polymer dry substance                                9.3 %



b)      Preparation of the spray suspension

          Polymer suspension              Kollicoat® MAE 30 DP:
                                          Kollidon® 30 is first dissolved in the specified amount
                                          of water, followed by propylene glycol and Kollicoat®
                                          MAE 30 DP.
                                          Kollicoat® MAE 100 P:
                                          Kollicoat® MAE 100 P is carefully stirred into the given
                                          amount of water. The stirrer speed is adapted to the
                                          viscosity from time to time avoiding foam formation.
                                          To complete the redispersion the system is stirred for
                                          2 to 4 hours. Finally the Kollidon® 30-solution and the
                                          plasticizer are added.




Page 32 / 38                                                                           Taste masking
Generic Drug Formulations with Kollicoat® MAE grades


c)      Coating

        The coating is applied on 5 kg tablets in a 24-inch Accela Cota under the following
        conditions:

                           Process parameters   Machine                 Accela Cota, 24“
                                                Batch size              5 kg
                                                Inlet air temperature   50°C
                                                Product temperature     32 - 35°C
                                                Spraying rate           30 - 35 g/min
                                                Nozzle diameter         1 mm
                                                Spray pressure          2 bar
                                                Final drying            50°C/5min



d)      Dissolution


                           100




                            80




                            60
        Drug release [%]




                            40




                            20




                            0
                                 0        3     6              9        12          15               30
                                                           Time [min]




Page 33 / 38                                                                             Taste masking
Generic Drug Formulations with Kollicoat® MAE grades




                    Kollicoat® MAE grades


                              SUBSTANCES




Page 34 / 38
Generic Drug Formulations with Kollicoat® MAE grades


Substances
Actives
 Propranolol-HCl                              BASF Aktiengesellschaft
 Caffeine                                     Carl-Bosch Str. 38
                                              67056 Ludwigshafen, Germany

 Acetylsalicylic acid crystals                Chemische Fabrik Aubing GmbH
                                              Mannheim, Germany

 Indomethacin                                 Synopharm GmbH
                                              22885 Barsbüttel, Germany

 Acetylsalicylic acid                         E. Merck
                                              64271 Darmstadt, Germany

 Diclofenac sodium                            Irotec Laboratories
                                              Little Island, Cork, Ireland

Excipients

 Kollicoat MAE 30 DP                         BASF Aktiengesellschaft
 Kollicoat MAE 100 P                         Carl-Bosch Str. 38
 Kollidon 30 (povidone)                      67056 Ludwigshafen, Germany
 Kollidon VA 64 (copovidone)
 Kollidon CL (crospovidone)
 Ludipress
 (lactose/povidone/crospovidone)
 Propylene glycol
 Sicovit Red 30 (red iron oxide)
 Avicel PH 102                               FMC Corp. Food + Pharmaceutical Products
 (microcrystalline cellulose)                 735 Market Street
 Avicel PH 101                               Philadelphia, PA 19103, USA
 (microcrystalline cellulose)

 Granulac 230 (lactose)                      Meggle Milchindustrie
                                              Postfach 40

 Aerosil 200 (silica)                        Degussa-Hüls AG
                                              Weissfrauenstr. 9
                                              60287 Frankfurt, Germany

 Talc                                         Riedel-de-Haen AG
                                              Wunstdorferstr. 40
                                              30926 Seelze, Germany
 Titanium dioxide                             Kronos Titan GmbH
                                              Postfach 100720
                                              51307 Leverkusen, Germany
 Magnesium stearate                           Bärlocher GmbH
                                              80992 Munich, Germany


Page 35 / 38                                                                    Substances
Generic Drug Formulations with Kollicoat® MAE grades




                    Kollicoat® MAE grades


                                LITERATURE




Page 36 / 38
Generic Drug Formulations with Kollicoat® MAE grades


Literature

[1] K. H. Bauer, K. Lehmann, H. P. Osterwald, G. Rothgang
   Coated Pharmaceutical Dosage Forms
   medpharm Scientifc Publishers, (1998)


[2] BASF AG Ludwigshafen
    Technical Information Kollicoat MAE grades, July (1999)


[3] A. Flößer, K. Kolter, H.-B. Reich and G. Schepky
    Variation of composition of an enteric formulation based on Kollicoat MAE 30 D
    Drug Development and Industrial Pharmacy, 26(2), 177-187 (2000)


[4] C. Dangel, G. Schepky, H.-B. Reich and K. Kolter
    Comparative studies with Kollicoat MAE 30 D and Kollicoat MAE 30 DP in aqueous spray
    dispersions and enteric coatings on highly swellable caffeine cores
    Drug Development and Industrial Pharmacy, 26(4), 415-421 (2000)


[5] C. Dangel, K. Kolter, H.-B. Reich and G. Schepky
    Aqueous enteric coatings with methacrylic acid copolymer type C on acidic and basic
    drugs in tablets and pellets, part I: Acetylsalicylic acid tablets and crystals
    Pharmaceutical Technology, 24(3), 64-70 (2000)


[6] C. Dangel, K. Kolter, H.-B. Reich and G. Schepky
    Aqueous enteric coatings with methacrylic acid copolymer type C on acidic and basic
    drugs in tablets and pellets, part II: Dosage forms containing indomethacin and diclofenac
    sodium
    Pharmaceutical Technology, 24(4), 32-38 (2000)


[7] S. Scheiffele, H. Ascherl, F. Ruchatz and K. Kolter
    Gastric resistance of Kollicoat MAE 100 P – A redispersible powder of methacrylic acid
    copolymer type C
    Proceedings of the AAPS Annual Meeting, Toronto, November 1999


[8] K. Kolter, H.-B. Reich, C. Dangel, G. Schepky
    Optimization of an enteric coating formulation based on Kollicoat MAE 30 DP
    Proceedings of the AAPS Annual Meeting, San Francisco, November 1998




Page 37 / 38                                                                          Literature
Generic Drug Formulations with Kollicoat® MAE grades


Note

The data submitted in this publication are based on our current knowledge and experience.
They do not constitute a guarantee in the legal sense of the term and, in view of the manifold
factors that may effect processing and application, do not relieve processors from the
responsibility of carrying out their own tests and experiments. Any relevant patent rights and
existing legislation and regulations must be observed.




                                                        BASF Aktiengesellschaft
                                                        Unternehmensbereich Fine Chemicals
                                                        67056 Ludwigshafen, Germany




Page 38 / 38

								
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