Coating materials used in pharmaceutical formulations

1
Coating materials used in pharmaceutical
formulations

• By Mahya Akbarzadeh

Click to start tutorial
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Aims and objectives

• AIMS
• After finishing the package what should you
  understand?
• You should understand the term biomaterials and
  their role in pharmaceutics.
• You should be able to discuss the rationale for
  coating solid dosage form.
• You should know aims of functional coatings.
• OBJECTIVES
• After completing the package what should you be
  able do?
• Appreciate the importance of coating with respect
  to oral bioavailability .
• Describe the different coating processes sugar,
  film and press.
• State the different types of polymers, which can
  be used for enteric coating.
• PREREQUISITES
• What do you need to do before starting the
  activity?
• Basic pharmaceutics
• Human biochemistry

3
MAIN MENU

• Oral drug delivery system
• Coatings
• Polymers used in coating processes
• Quiz
• Useful links

4
Oral drug delivery system

• Oral drug delivery system
• Anatomy and physiology of the gastrointestinal
  tract
• Physiological factors affecting bioavailability

5
Coatings

• What is the rationale for coating a solid dosage
  form?
• Main coating processes
• Functional coatings

6
Polymers

• Summary of Polymers used in pharmaceutical
  formulations as coating materials
• Eudragit Polymers
• Polymer dissolution
• Polymer Quantities

7
Oral drug delivery system

• The oral route constitutes as the most familiar
  means of administering drugs, mainly because it
  is the most natural and convenient for the
  patient.
• Solid oral dosage forms include
• Tablets
• Capsules
• Lozenges
• Pastilles
• Powders
• Granules

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Oral drug delivery system
Tablets are the most commonly prescribed dosage
form, below summarises the advantages and
disadvantages of tablets.

• Advantages
• Convenient, clean and safe way
• Physical and chemical stability long shelf life
• Accurate dose of drug
• Economic- mass production
• Can be formulated as controlled release
• Can mask unpleasant taste

• Disadvantages
• Difficult to swallow
• Difficult to dilute
• Difficult for liquid drugs

Drug delivery market
9
Oral drug delivery system
The oral drug delivery market continues to
dominate the industry, but alternate routes of
delivery such as pulmonary and transdermal are
being developed to provide patients with less
invasive routes of delivery.
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Anatomy and physiology of the gastrointestinal
tract
The gastrointestinal tract is complex system and
below outlines the key structures involved oral
drug absorption.
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Anatomy and physiology of the gastrointestinal
tract

• The oral route is main route in which
  pharmaceuticals are administered, therefore it is
  important to be aware of how these materials
  behave during their passage through the GI tract.
  Drugs taken orally have a much lower
  bioavailability compared to drugs administered
  intravenously, which have a bioavailability of
  100 .
• Facts
• GI tact is a muscular tract approximately 6
  meters in length with varying diameters.
• It starts at the mouth and ends at the anus and
  consists of FOUR main anatomical areas.
• 1. OESOPHAGUS
• 2. STOMACH
• 3. SMALL INTESTINE
• 4. LARGE INTESTINE OR COLON

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Bioavailability

• The proportion of drug that reaches the target
  organs and tissues, which is expressed as a of
  the dose administered.

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• OESOPHAGUS The mouth is the main entry, it links
  the oral cavity to the stomach. Composed of a
  thick muscular layer, 250 mm long and 20mm in
  diameter.
• STOMACH It is situated between the lower
  oesophagus and the small intestine. It is the
  most dilated part of the GI tract. It has a
  capacity of 1.5L although in fasted state it
  usually contains no more than 50ml of fluid.
• SMALL INTESTINE It is longest and most
  convoluted part of the GI tract, 4-5 meters in
  length. It begins from the pyloric sphincter of
  the stomach to the ileocaecal junction where it
  joins the large intestine.
• LARGE INTESTINE OR COLON Final part of the GI
  tract which spans from the ileocaecal junction to
  the anus. It makes up 1.5 meters of the 6 meters
  of the GI tract.

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Physiological considerations that affect oral
bioavailability

• The transit of pharmaceuticals in the
  gastrointestinal tract
• Gastrointestinal pH
• Enzymatic status
• Presence of foods and liquids in the
  gastrointestinal tract

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Gastrointestinal pH
The pH varies considerably along the length of
the gastrointestinal tract. Different regions
along the tract will exhibit different pH values.
STOMACH Gastric fluid in the stomach is highly
acidic, ranging between pH1-3.5 in the fasted
state. In the fed state the pH rises in the
range of pH3-7 depending on the composition of
the meal.

FASTED

FED
The variability in pH of the stomach is an
important consideration when taking a medicament
with respect to the drugs chemical stability or
achieving drug dissolution or absorption.

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Gastrointestinal pH

• SMALL INTESTINE
• Intestinal pH is much higher than gastric fluid
  due to neutralisation with bicarbonate ions
  secreted into the small intestine by the
  pancreas. The pH values increase along the small
  intestine e.g. from ph 6.1 in duodenum to 7.8
  in the ileum.
• LARGE INTESTINE
• The pH of the caecum is around 6-6.5, which
  increases towards the distal parts of the colon
  to pH 7-7.5.

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Enzymatic status

• Luminal enzymes of the small intestine
• Pepsin is the primary enzyme found in gastric
  fluid. Other enzymes such as lipases, amylases
  and peptides are secreted into the small
  intestine via the pancreas in response to
  ingestion of food. Pepsins and proteases are
  responsible for the breakdown of protein and
  peptide drugs in the lumen. Drugs which resemble
  nutrients such as fatty acids and nucleotides are
  susceptible to enzymatic attack.
• Colon
• Presence of bacterial enzymes in the colonic
  region of the gastrointestinal tract, which
  digest material not yet digested in the small
  intestine.

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Presence of foods and liquids in the
gastrointestinal tract

• The rate and extent of drug absorption in the
  gastrointestinal tract depends on the following
  factors
• Presence of food
• Dietary intake
• Delayed gastric emptying
• Increased viscosity of the gastrointestinal
  contents
• Stimulation of gastrointestinal secretion

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Presence of food

• Food tends to increase the pH of the stomach by
  acting as a buffer. Increase in pH is likely to
  decrease the rate of dissolution and thus
  absorption of a weakly basic drug but increase
  that of a weakly acidic drug.

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Dissolution

• Release of a drug from solid dosage form into a
  bioavailable form .

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Dietary intake

• Certain foods such as milk, iron preparations or
  indigestion remedies which contain magnesium or
  aluminium can form insoluble complexes with
  drugs. Therefore, reducing the bioavailability of
  the drug to exert its therapeutic effect.

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Delayed gastric emptying

• Foods which are high in fat tend to reduce
  gastric emptying, therefore delaying the onset of
  action of various drugs.
• In addition, the presence of fat stimulates the
  release of bile salts which are surface active
  agents which enhance the absorption of poorly
  absorbed drugs. However, they have been found
  to form insoluble and non-absorbable complexes
  with certain drugs.

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Increased viscosity of the gastrointestinal
contents

• The presence of food increases the viscosity of
  gastrointestinal content which may result in a
  reduction in rate of drug dissolution

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Stimulation of gastrointestinal secretion

• Gastrointestinal secretions in response to food
  such as pepsin may result in enzymatic
  degradation of drugs which are susceptible
  therefore reducing their bioavailability.

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The transit of pharmaceuticals in the
gastrointestinal tract

• The transit time simply refers to the contact
  time of the drug within any part of the GI tract.
  Various factors affect transit time, which
  include
• Age and gender of patient
• Presence of disease
• Posture
• Emotional state
• Dietary intake
• Size and density of dosage form
• Location and transit time within the GI tract
• Oesophagus
• Stomach
• Small intestine
• Large intestine or colon

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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.
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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

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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.

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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.

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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.

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Main coating processes
1.Film coating 2. Sugar coating 3. Press
coating
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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.

Examples of sugar coated tablets
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Multistage process

• 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.
• Sub coating -by adding bulking agents such as
  calcium carbonate or talc in combination with
  sucrose solution.
• Smoothing process -remove rough layers formed in
  step 2 with the application of sucrose syrup.
• Colouring - for aesthetic purposes often titanium
  based pigments are included.
• Polishing - effectively polished to give
  characteristic shine, commonly using beeswax,
  carnauba wax.
• Printing -indelible ink for characterisation.

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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

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Simplified representation of sugar coating process
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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
• Polymer
• Solvent
• Plasticizer
• 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.

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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?
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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.
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Why is film coating favoured over sugar coating ?

• Film coating
• Tablet appearance
• Retains shape of original core
• Small weight increase of 2-3 due to coating
  material
• logo or break lines possible
• Process
• Can be automated e.g. Accela Cota
• Easy training operation
• Single stage process
• Easily adaptable for controlled release allows
  for functional coatings.

• Sugar coating
• Tablet appearance
• Rounded with high degree of polish
• Larger weight increase 30-50 due to coating
  material
• Logo or break lines are possible
• Process
• Difficult to automated e.g. traditional coating
  pan
• Considerable training operation required
• Multistage process
• Not able to be used for controlled release apart
  from enteric coating.

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Polymer used in film coating

• Examples
• Cellulose derivatives
• Methacrylate amino ester copolymers.

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Plasticizer used in film coating

• Examples
• Polyols - Polyethylene glycol 400
• Organic esters - diethyl phthalate
• Oils/glycerides - fractional coconut
• oil

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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

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Environmental

• Venting of untreated organic solvent vapour into
  the atmosphere is ecologically unacceptable but
  removal of gaseous effluent is expensive.

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Safety

• Organic solvents are a safety hazard, such that
  they are
• Toxic
• Explosive
• Fire hazard

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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.

46
Solvent residues

• For a given process the amount of residual
  organic solvent in the film must be
  investigated. Thus, stringent regulatory controls
  exist.

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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

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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.

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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

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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
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Examples of enteric coated OTC products

• Enteric coated aspirin E.g. Micropirin 75mg EC
  tablets
• Enteric coated peppermint oil E.g. Colpermin

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pH
The pH status of enteric coated polymers in the
stomach
The polymers used for enteric coatings remain
unionise at low pH, and therefore remain
insoluble. As the pH increases in the
gastrointestinal tract the acidic functional
groups are capable of ionisation, and the polymer
swells or becomes soluble in the intestinal
fluid. 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 it
can exert its pharmacologic effects.
STOMACH
LOW
HIGH
SMALL INTESTINE
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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

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Summary of Polymers used in pharmaceutical
formulations as coating materials.
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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.

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Shellac
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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.

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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 9010.
• Soluble above pH 5
• Additional remarks Plasticizer is required.

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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.

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Polymer dissolution

• Factors affecting the release of a drug from a
  polymer
• Thickness of the coating material
• pH
• Other excipients
• Ionic state

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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.

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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.

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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.

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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.

65
General structure of Eudragit Polymers

• Changing the R group gives rise to polymers with
  different physiochemical properties.

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Possible R groups
-COOCH3 or COOC4H9
-COO-CH2-CH2N(CH3)3 3CL-
General structure of Eudragit polymers
-COOH
-COOH-CH2-CH2N(CH3)2
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FUNCTIONAL GROUP

• METHACRYLIC COPOLYMER
• E.g. anionic
• -COOH
• Application
• Gastro resistance
• Delivery to the colon

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FUNCTIONAL GROUP

• Aminoalkyl methacrylate copolymer
• E.g.
• -COOH-CH2-CH2N(CH3)2
• Application
• Taste, odour and moisture protection. Dissolves
  in the stomach.

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FUNCTIONAL GROUP

• Methacrylate copolymer
• E.g. neutral
• -COOCH3 or COOC4H9
• Applications
• Delayed and sustained release (insoluble)

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• 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.

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FUNCTIONAL GROUP

• Aminoalkyl methacrylate copolymer
• E.g.
• -COO-CH2-CH2N(CH3)3 3CL-
• Application
• Delayed and sustained release

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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

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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
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Quiz

• Biomaterials only include synthetic solid
  materials?
• True
• False

75

• Correct!
• Well done

76

• Incorrect!
• Try again

77

• 2. Which one of the following is NOT a type of
  biomaterial?
• Active material
• Inert material
• Potent material
• Biodegradable

78

• Correct!
• Well done

79

• Incorrect!
• Try again

80

• 3. Drugs taken orally have a much higher
  bioavailability compared to drugs administered
  intravenously?
• True
• False

81

• Correct!
• Well done

82

• Incorrect!
• Try again

83

• 4. Gastric fluid in the stomach has a pH ranging
  between 3-7 in the fed state.
• True
• False

84

• Correct!
• Well done

85

• Incorrect!
• Try again

86

• 5. Film coating is a multistage process giving
  rise to the production of smooth, rounded
  tablets.
• True
• False

87

• Correct!
• Well done

88

• Incorrect!
• Try again

89

• 6.Weight increase due to coating material is
  minimal for Sugar coated tablets.
• True
• False

90

• Correct!
• Well done

91

• Incorrect!
• Try again

92

• 7. Which one of the following is NOT an ideal
  property of coating material used in enteric
  protection?
• Resistance to intestinal fluid
• Compatibility with coating solution and drug
• Formation of continuous film

93

• Correct!
• Well done

94

• Incorrect!
• Try again

95

• 8. The polymers used for enteric coatings ionises
  as the pH increases, and therefore becomes
  soluble in the intestinal fluid.
• True
• False

96

• Correct!
• Well done

97

• Incorrect!
• Try again

98

• 9. The trade name for methacrylate polymer is ...
• Sureteric
• Eudragit
• EmCoat 120 N
•  

99

• Correct!
• Well done

100

• Incorrect!
• Try again

101

• Q10. The amount of polymer required for enteric
  protection is less than that need for moisture
  protection?
• True
• False

102

• Correct!
• Well done

103

• Incorrect!
• Try again

104

• END OF QUIZ
• Thank-you for taking time to look through this
  package.

105
Useful links

• Listed below are some useful links providing
  further information
• Pharmpedia tablet coating
• Dipharmatech pharmaceuticals technical articles
  
• An overview of current oral modified release
  technologies
• Degussa for pharmaceuticals