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					Tablet Coating
The transit of pharmaceuticals in the
        gastrointestinal tract
                   Once a drug is placed in the mouth it is moved down the
                   oesophagus by the swallowing reflex. The transit time of the
                   dosage form in the oesophagus is rapid usually 10-14 seconds.

The transit time in the stomach is highly variable and depends
on the dosage form and the fed or fasted state of the stomach.


                   The transit time is relatively constant, at around 3 hours. This
                   contrasts with the stomach as it does not discriminate between
                   different dosage forms or between fed or fasted state. It the main site
                   for absorption for most drugs. Hence, an important parameter for
                   drug targeting.


The transit time is long and variable and depends on
the following; type of dosage form, diet, eating pattern
and disease state.
    What is the rationale for coating a
           solid dosage form?
    Coating of a solid dosage form is often designed to perform a specific function. For
    example; protection against moisture, taste masking pH or time controlled release.

    Tablets can be easily coated and a variety of products are available on the market.
    Generally, the coating process gives rise to;
   Increased bioavailability
   Improved patient acceptance
   Formulation stability

    The rationale for coating pharmaceutical dosage form such as a tablet can be
    categorised into three main headings:

   Therapy
   Technology
   Marketing
    What is the rationale for coating a
           solid dosage form?
                                  Therapy

   To minimise irritation of the oesophagus and stomach.

   Minimise inactivation in the stomach.

   Improve drug effectiveness.

   Improve patient compliance e.g. easier to swallow, masks unpleasant taste.
    What is the rationale for coating a
           solid dosage form?
                                 Technology

   Minimise dust formation and contamination with respect to tablets.

   Masks batch differences in the appearance of raw materials.

   Facilitates their handling on high speed automated filling and packaging
    equipment.

   Improves drug stability e.g. Protection of active ingredient from
    environment such as sunlight, moisture.
    What is the rationale for coating a
           solid dosage form?
                                Marketing

   Aid sales appeal as improved appearance and acceptability with respect to
    gloss and colouration.

   Mask unpleasant taste.



   Improve product identity.
Main coating processes


   1.Film coating


  2. Sugar coating


  3. Press coating
                        Sugar coating
   Traditionally sugar coatings formed the bulk of coated tablets but today film coatings
    are the more modern technology in tablet coating.
   Description of tablets: Smooth, rounded and polished to a high gloss.
   Process: Multistage process involving 6 separate operations.
                                             1.   Seal tablet core
                                             2.   Sub coating
                                             3.   Smoothing
                                             4.   Colouring
                                             5.   Polishing
                                             6.   Printing




                                         Examples of sugar coated tablets
                 Multistage process
1.   Sealing tablet core- application of a water impermeable polymer such as
     Shellac, cellulose acetate phthalate and polyvinyl acetate phthalate, which
     protects the core from moisture, increasing its shelf life.

2.   Sub coating -by adding bulking agents such as calcium carbonate or talc in
     combination with sucrose solution.

3.   Smoothing process               -remove rough layers formed in step 2 with the
     application of sucrose syrup.


4.   Colouring       - for aesthetic purposes often titanium based pigments are
     included.

5.   Polishing - effectively polished to give characteristic shine, commonly using
     beeswax, carnauba wax.

6.   Printing -indelible ink for characterisation.
    Example of sugar coated tablets
Brufen® POM
   Available in 200mg and 400mg
    strength

Premarin® POM
   Conjugated oestrogens 625mcg
    (maroon) and 1.25mcg (yellow)

Colofac ® P
   Mebeverine hydrochloride
    100mg Round, white, sugar
    coated

Kalms ® GSL
   45mg Hops powder,90mg
    Gentian powdered extract, and
    135mg Valerian powdered
    extract
Simplified representation of sugar
          coating process
                            Film coating
    Modern approach to coating tablets, capsules, or pellets by surrounding them with
     a thin layer of polymeric material.
    Description of tablets: Shape dictated by contour of original core.

    Process: Single stage process, which involves spraying a coating solution
     containing the following;
1.   Polymer
2.   Solvent
3.   Plasticizer
4.   Colourant

     The solution is sprayed onto a rotating tablet bed followed by drying, which
     facilitates the removal of the solvent leaving behind the deposition of thin film of
     coating materials around each tablet.
Film Formation
                 latex particles dispersed
                 in aqueous phase




                 formation of thin film with
                 water evaporation through film



                  continuous film
                     Film coating

Advantages
Produce tablets in a single step process in relatively short
period of time. Process enables functional coatings to be
incorporated into the dosage form.

Disadvantages
There are environmental and safety implications of using
organic solvents as well as their financial expense.


   Why film coating is favoured over sugar coating?
                          Accela Cota




The vast majority of film coated tablets are produced by a process which
involves spraying of the coating material on to a bed of tablets. Accela Cota is
one example of equipment used for film coating.
  Why is film coating favoured over
            sugar coating ?
Film coating                              Sugar coating
Tablet appearance                         Tablet appearance
 Retains shape of original core           Rounded with high degree of polish
 Small weight increase of 2-3% due to  Larger weight increase 30-50% due to
   coating material                          coating material
 logo or ‘break lines’ possible           Logo or ‘break lines’ are possible
Process                                   Process
 Can be automated e.g. Accela Cota        Difficult to automated e.g. traditional
 Easy training operation                    coating pan
 Single stage process                     Considerable       training     operation
 Easily adaptable for controlled release
                                             required
   allows for functional coatings.         Multistage process
                                           Not able to be used for controlled
                                             release apart from enteric coating.
Polymer used in film coating
Examples;
 Cellulose derivatives
 Methacrylate amino ester copolymers.
Plasticizer used in film coating

Examples;
 Polyols - Polyethylene glycol 400
 Organic esters - diethyl phthalate
 Oils/glycerides - fractional coconut
  oil
Colourants used in film coating
Examples;
 Iron oxide pigments
 Titanium dioxide
 Aluminium lakes.


    Water insoluble pigments are more favourable than water
    soluble colours for the following reasons;
   Better chemically stability in light
   Optimised impermeability to water vapour
   Better opacity
   Better covering ability
          Environmental
Venting of untreated organic solvent vapour
into   the    atmosphere   is ecologically
unacceptable but removal of gaseous effluent
is expensive.
                    Safety
Organic solvents are a safety hazard, such that they are:

          Toxic

          Explosive

          Fire hazard
                Financial
The hazards associated with organic solvents
necessitates the need for building flame- and
explosive- proof facilities. In addition, the cost
of their storage and ingredients are relatively
expensive.
         Solvent residues
For a given process the amount of residual
organic     solvent in the film must be
investigated. Thus, stringent regulatory
controls exist.
                     Solvents
    Traditionally, organic solvents had been used to
    dissolve the polymer but modern techniques rely on
    water because of significant drawbacks. Below lists
    some of the problems associated with organic
    solvents.
   Environmental
   Safety
   Financial
   Solvent residues
                    Press coating
Press coating process involves compaction of coating material around a
preformed core. The technique differs from sugar and film coating process.

Advantages
This coating process enables incompatible materials to be formulated
together, such that one chemical or more is placed in the core and the other
(s) in the coating material.

Disadvantages
Formulation and processing of the coating layer requires some care and
relative complexities of the mechanism used in the compressing equipment.
             Functional coatings
    Functional coatings are coatings, which perform a
    pharmaceutical function.
    These include;

   Enteric coating
-   The pH status of enteric coated polymers in the
    stomach
-   The ideal properties of enteric coated material

   Controlled release coating
                        Enteric coating
    The technique involved in enteric coating is protection of the tablet core from
    disintegration in the acidic environment of the stomach by employing pH sensitive
    polymer, which swell or solubilize in response to an increase in pH to release the
    drug.

    Aims of Enteric protection:
   To mask taste or odour
   Protection of active ingredients, from the acidic environment of the stomach.
   Protection from local irritation of the stomach mucosa.
   Release of active ingredient in specific target area within gastrointestinal tract.




                        Examples of enteric coated OTC products
    Examples of enteric coated OTC
              products

   Enteric coated aspirin E.g. Micropirin®
    75mg EC tablets



   Enteric coated peppermint oil E.g.
    Colpermin®
  The pH status of enteric coated
     polymers in the stomach
                  The polymers used for enteric coatings remain unionise
   STOMACH
                  at low pH, and therefore remain insoluble. As the pH
                  increases in the gastrointestinal tract the acidic functional
     LOW          groups are capable of ionisation, and the polymer swells
                  or becomes soluble in the intestinal fluid.


      pH          Thus, an enteric polymeric film coating allows the coated
                  solid to pass intact through the stomach to the small
                  intestine, where the drug is then released for absorption
                  through the intestinal mucosa into the human body where
    HIGH          it can exert its pharmacologic effects.

SMALL INTESTINE
     The ideal properties of enteric
            coated material?
   Permeable to intestinal fluid
   Compatibility with coating solution and drug
   Formation of continuous film
   Nontoxic
   Cheap and ease of application
   Ability to be readily printed
   Resistance to gastric fluids
Summary of Polymers used in pharmaceutical
   formulations as coating materials.
          Polymer              Trade name               Application
Shellac                      EmCoat 120 N     Enteric Coatings
                             Marcoat 125      Taste/Odor Masking

Cellulose acetate            Aquacoat CPD®    Enteric Coatings
                             Sepifilm™ LP     Taste masking
                             Klucel®          Sustained release coating
                             Aquacoat® ECD    Sub coat moisture and barrier
                             Metolose®       sealant pellet coating
Polyvinylacetate phthalate   Sureteric®         Enteric Coatings


Methacrylate                 Eudragit®        Enteric Coatings
                                              Sustained Release Coatings
                                              Taste Masking
                                              Moisture protection
                                              Rapidly disintegrating Films
                          Shellac
   Material of natural origin- purified resinous secretion of the
    insect Laccifer lacca.

   Oldest known material used for enteric coatings.

   Suited for drug targeting in the distal small intestine as soluble
    at pH 7.0

   Its use is now less popular in commercial pharmaceutical
    applications for enteric coatings. Due to poor batch to batch
    reproducibility, which is a crucial requirement.
Shellac
    Cellulose acetate phthalate
               (CAP)
 Chemical name: Cellulose acetate phthalate
 Trade name: CAP, Aquateric
 Application form: organic or aqueous
  dispersion
 Functional groups: acetyl, phthalyl
 Soluble above pH: 6
 Additional remarks: sensitive to hydrolysis,
  5-30% plasticizer required.
 Polyvinyl acetate phthalate
           (PVAP)
 Chemical name: polyvinyl acetate phthalate#
 Trade name: Opadry enteric (aqueous),
  Coloron
 Application form: organic solution, aqueous
  dispersion.
 Functional      groups:     acetyl, phthalate,
  vinylacetat :crotonic acid ratio 90:10.
 Soluble above pH: 5
 Additional remarks: Plasticizer is required.
        Acrylic polymers
 Chemical  name: Methacrylic
 Trade name: Eudragit®
 Application form: organic solution or
  aqueous dispersion.
 Functional groups: methyacrylic acid
 Soluble above pH: 5 * depends on co-
  polymers used.
          Polymer dissolution
    Factors affecting the release of a drug from a
    polymer:
   Thickness of the coating material

   pH

   Other excipients

   Ionic state
Thickness of a coating material
   How much polymer is required for enteric protection?
    To achieve enteric protection of the core 3-4 mg/cm2 of the polymer is required to
    be applied to the dosage form.
   Do different polymers require                     different amounts for
    application?
    Methacrylic acid copolymers require a lower amount of polymer compared to
    cellulose derivatives which usually require higher amounts of polymer to achieve
    the same core protection as the former.
   What effect does increasing polymer layers have on
    dissolution?
    The more polymer layers that are applied the greater the rate of dissolution of the
    drug.
                   pH
Dissolution of polymers intended for enteric
targeting is dependent upon the dissolution
medium. This is influenced by the composition
of the polymer, the monomers, or the type and
degree of substitution.
                 Ionic state
   The rate of polymer dissolution is dependent
    upon the type of ions present in the dissolution
    medium.

   It was shown that sodium chloride prevented
    dissolution of some polymers.
            Other excipients
   Influence the dissolution of polymer.

   Plasticizers may decrease or increase
    dissolution rate, depending on the nature of the
    plasticizer, whether it is lipophilic or
    hydrophilic.
  General structure of Eudragit®
             Polymers

       CH 3(H)                               CH3
       C                   C                 C          C

       COO-ALKYL                             R

Changing the R group gives rise to polymers with different physiochemical
                               properties.
            Possible R groups
-COOCH3 or COOC4H9                -COO-CH2-CH2N+(CH3)3 3CL-


            CH 3(H)                    CH3
            C             C            C          C

            COO-ALKYL                  R
                General structure of Eudragit ®
                           polymers

  -COOH                         -COOH-CH2-CH2N(CH3)2
         FUNCTIONAL GROUP

 METHACRYLIC COPOLYMER
 E.g. anionic
           -COOH

Application:
 Gastro resistance
 Delivery to the colon
         FUNCTIONAL GROUP

Aminoalkyl methacrylate copolymer
E.g.
     -COOH-CH2-CH2N(CH3)2

Application:
 Taste, odour and moisture protection.
  Dissolves in the stomach.
         FUNCTIONAL GROUP

 Methacrylate copolymer
 E.g. neutral
      -COOCH3 or COOC4H9

Applications:
 Delayed and sustained release (insoluble)
   Delayed release: The drug is not release
    immediately after administration but at a later
    time.

   Sustained release: An initial release of the
    drug soon after administration, followed by
    gradual release over an extended period.
         FUNCTIONAL GROUP

 Aminoalkyl methacrylate copolymer
 E.g.
       -COO-CH2-CH2N+(CH3)3 3CL-

Application
 Delayed and sustained release
                 Polymer Quantities
    Depending on the desired function of a coating, the following
      values are figures for the amount of polymer required :

Enteric coatings:
   4 – 6 mg for round tablets
   5 – 10 mg for oblong-shaped tablets
   5 – 20 mg for gelatin or HPMC capsules

Taste-masking coatings:
   1 – 2 mg for round tablet
   1 – 4 mg for oblong-shaped tablets

Moisture protection:
  1 – 6 mg for round tablets
  2 – 10 mg for oblong-shaped tablets
  5 – 10 mg for gelatin or HPMC capsules
                Eudragit® Polymers
   Eudragit® is the trade name for the class of polymers known as the methacrylates.

   Mostly commonly used polymer for enteric coating.
    Advantages:
   Pharmacologically inactive
   Excreted unchanged

   These are copolymers derived from esters of acrylic and methacrylic acid in, which
    properties are determined by the R group.

   Different grades of polymers are obtained by mixing monomers in different ratios.
                             ACID –NEUTRAL- ALKALINE

   They contain –COOH as a functional group. They dissolve at ranges from pH 5.5 to
    pH 7.

          General structure of Eudragit®
Normal Coating                 Average
                Reconstitution
  Description                  weight     Application examples
                level
                               gain
  HPMC based                              Amoxycillin, Azithromycin, Atenolol,
  Aqueous       11% to 15%        2.5 %   Amlodipine, Amitriptyline, Ampicilin
  system                                  Ciprofloxacin, Cephadroxil ,
                                          Cimitidine, Calcium Tablets, Citrizine
  HPMC based                              , Chloroquine Phosphate,
  Organic                                 Clarithromycin, Erythromycin,
                5%                2.5%
  solvent                                 Ferrous Fumarate, Famotidine,
  system                                  Ferrous Sulphate, Ibuprofen,
                                          Indapamine, Losartan Potassium,
  HPMC based                              Levamisole, Methyl-Dopa,
  Aqueous/      Aqueous 11%
                                          Metronidazole+Tinidazole,
  Organic       Organic Solvent           Metronidazole, Methyl Coblamine,
  Solvent/      5%                2.5%    Mefenamic Acid, Metoprolol Tartrate,
  Hydro                                   Norfloxacin, Nifidipine,
                Hydro Alcoholic
  Alcoholic                               Norfloxacin+Tinidazole, Ofloxacin,
                9%
  system                                  Paracetamol, Quinine Sulphate,
                                          Roxythromycin, Secnidazole,
  PVA based                               Sildenafil Citrate, Trimetazidine,
  Aqueous       20% to 25%        2.5%    Tinidazole, Tinidazole-Doxycycline,
  system                                  Tinidazole + Tetracycline, Verapamil
Enteric-coated
 coating resists dissolution or disruption in
  stomach but not in intestines
 used for drugs that are unstable, irritating
  to stomach
Enteric Coating
                                     Average
                      Reconstitution
Description                          weight    Application ** examples
                      level
                                     gain
Organic Enteric
Coating system,                                Aspirin, Bisacodyl
                      5%                8%
Cellulose Acetate
Phthalate based
                                               Diclofenac Sodium
Aqueous coating
system & Organic
enteric coating                                Doxylamine Succinate
                      Organic: 5%
system. Hydroxy                         8%
                      Aqueous: 10%
Propyl Methyl
Cellulose Phthalate                            Garlic Tablets, Omeprazol,
based system.                                  Pentaprazole,

                      Aqueous 20%
Methacrylic acid                               Pentoxyfyline, Rabeprazol ,
                      Hydro Alcoholic
copolymer type "C"
                      10%               9%
USP/NF based
system                Organic System           Serrosipeptadise
                      10%
Coating Process
   coating pans
Coating Process
   fluid beds
Important Processing
Parameters
 inlet and bed temperatures
 relative humidity
 atomization air pressure
 liquid spray rate
 droplet size
 drying time
Coating Problems
       picking/chipping

       roughness

       sticking

       film cracking/peeling

				
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