Coarting Materials Used In Pharmaceutical Formulations
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Coating materials used in pharmaceutical formulations Click to start tutorial
By Mahya Akbarzadeh
AIMS
Aims and objectives
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
MAIN MENU Oral drug delivery system Coatings Polymers used in coating processes Quiz Useful links
Oral drug delivery system
Oral drug delivery system
Anatomy and physiology of the gastrointestinal tract
Physiological factors affecting bioavailability
Coatings
What is the rationale for coating a solid dosage form?
Main coating processes
Functional coatings
Polymers
Summary of Polymers used in pharmaceutical formulations
Eudragit® Polymers
Polymer dissolution
Polymer Quantities
Oral drug delivery The oral route constitutes as the most familiar means of administering drugs, system mainly because it is the most natural and convenient for the patient. Solid oral dosage forms include;
Tablets
Capsules
Lozenges
Pastilles
Powders
Granules
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
Disadvantages Difficult to swallow
Physical and chemical stability –long shelf life
Difficult to dilute
Accurate dose of drug
Difficult for liquid drugs
Economic- mass production
Can be formulated as controlled release
Can mask unpleasant taste
Drug delivery market
Oral drug delivery system Drug Delivery Market $75.3 billion in 2004 32%
13% 8% 27%
Transdermal Pulmonary
11% 9%
Oral
Other Injectable and implantable Nasal
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.
Anatomy and physiology of the gastrointestinal tract The gastrointestinal tract is complex system and below outlines the key structures involved oral drug absorption.
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
Bioavailability The proportion of drug that reaches the target organs and tissues, which is expressed as a % of the dose administered.
OESOPHAGUS:
STOMACH:
SMALL INTESTINE:
LARGE INTESTINE OR COLON: Final part of
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.
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.
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.
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.
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
Gastrointestinal pH The pH varies considerably along the length of the gastrointestinal tract. Different regions along the tract will exhibit different pH values. F A S T E D
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.
F E D
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.
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.
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.
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
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.
Dissolution Release of a drug from solid dosage form into a bioavailable form .
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.
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.
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
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.
The transit of pharmaceuticals in the tract Thegastrointestinal 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: 11. Oesophagus 12. Stomach 13. Small intestine 14. Large intestine or colon
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
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
application of sucrose syrup.
Colouring included.
-remove rough layers formed in step 2 with the
- for aesthetic purposes often titanium based pigments are
Polishing - effectively polished to give characteristic shine, commonly using beeswax, carnauba wax.
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; 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.
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 coating pan Easy training operation Considerable training operation Single stage process required Easily adaptable for controlled release 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 STOMACH LOW
pH HIGH SMALL INTESTINE
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.
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 Marcoat 125
Enteric Coatings Taste/Odor Masking
Cellulose acetate
Aquacoat CPD® Sepifilm™ LP Klucel® Aquacoat® ECD Metolose®
Polyvinylacetate phthalate
Sureteric®
Methacrylate
Eudragit®
Enteric Coatings Taste masking Sustained release coating Sub coat moisture and barrier sealant pellet coating Enteric Coatings
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 copolymers 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 application?
different amounts for
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 CH3(H) C
CH3 C
COO-ALKYL
C
C
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-
CH3(H) C
CH3 C
COO-ALKYL
C
C
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®
Quiz 1.
Biomaterials only include synthetic solid materials? True False
Correct! Well done
Incorrect! Try again
2. Which one of the following is NOT a type of biomaterial? Active material Inert material Potent material Biodegradable
Correct! Well done
Incorrect! Try again
3. Drugs taken orally have a much higher bioavailability compared to drugs administered intravenously? True False
Correct! Well done
Incorrect! Try again
4. Gastric fluid in the stomach has a pH ranging between 3-7 in the fed state. True False
Correct! Well done
Incorrect! Try again
5. Film coating is a multistage process giving rise to the production of smooth, rounded tablets. True False
Correct! Well done
Incorrect! Try again
6.Weight increase due to coating material is minimal for Sugar coated tablets. True False
Correct! Well done
Incorrect! Try again
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
Correct! Well done
Incorrect! Try again
8. The polymers used for enteric coatings ionises as the pH increases, and therefore becomes soluble in the intestinal fluid. True False
Correct! Well done
Incorrect! Try again
9. The trade name for methacrylate polymer is ... Sureteric® Eudragit® EmCoat 120 N
Correct! Well done
Incorrect! Try again
Q10. The amount of polymer required for enteric protection is less than that need for moisture protection? True False
Correct! Well done
Incorrect! Try again
END OF QUIZ Thank-you for taking time to look through this package.
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
By Mahya Akbarzadeh
AIMS
Aims and objectives
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
MAIN MENU Oral drug delivery system Coatings Polymers used in coating processes Quiz Useful links
Oral drug delivery system
Oral drug delivery system
Anatomy and physiology of the gastrointestinal tract
Physiological factors affecting bioavailability
Coatings
What is the rationale for coating a solid dosage form?
Main coating processes
Functional coatings
Polymers
Summary of Polymers used in pharmaceutical formulations
Eudragit® Polymers
Polymer dissolution
Polymer Quantities
Oral drug delivery The oral route constitutes as the most familiar means of administering drugs, system mainly because it is the most natural and convenient for the patient. Solid oral dosage forms include;
Tablets
Capsules
Lozenges
Pastilles
Powders
Granules
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
Disadvantages Difficult to swallow
Physical and chemical stability –long shelf life
Difficult to dilute
Accurate dose of drug
Difficult for liquid drugs
Economic- mass production
Can be formulated as controlled release
Can mask unpleasant taste
Drug delivery market
Oral drug delivery system Drug Delivery Market $75.3 billion in 2004 32%
13% 8% 27%
Transdermal Pulmonary
11% 9%
Oral
Other Injectable and implantable Nasal
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.
Anatomy and physiology of the gastrointestinal tract The gastrointestinal tract is complex system and below outlines the key structures involved oral drug absorption.
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
Bioavailability The proportion of drug that reaches the target organs and tissues, which is expressed as a % of the dose administered.
OESOPHAGUS:
STOMACH:
SMALL INTESTINE:
LARGE INTESTINE OR COLON: Final part of
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.
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.
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.
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.
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
Gastrointestinal pH The pH varies considerably along the length of the gastrointestinal tract. Different regions along the tract will exhibit different pH values. F A S T E D
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.
F E D
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.
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.
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.
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
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.
Dissolution Release of a drug from solid dosage form into a bioavailable form .
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.
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.
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
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.
The transit of pharmaceuticals in the tract Thegastrointestinal 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: 11. Oesophagus 12. Stomach 13. Small intestine 14. Large intestine or colon
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
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
application of sucrose syrup.
Colouring included.
-remove rough layers formed in step 2 with the
- for aesthetic purposes often titanium based pigments are
Polishing - effectively polished to give characteristic shine, commonly using beeswax, carnauba wax.
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; 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.
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 coating pan Easy training operation Considerable training operation Single stage process required Easily adaptable for controlled release 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 STOMACH LOW
pH HIGH SMALL INTESTINE
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.
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 Marcoat 125
Enteric Coatings Taste/Odor Masking
Cellulose acetate
Aquacoat CPD® Sepifilm™ LP Klucel® Aquacoat® ECD Metolose®
Polyvinylacetate phthalate
Sureteric®
Methacrylate
Eudragit®
Enteric Coatings Taste masking Sustained release coating Sub coat moisture and barrier sealant pellet coating Enteric Coatings
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 copolymers 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 application?
different amounts for
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 CH3(H) C
CH3 C
COO-ALKYL
C
C
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-
CH3(H) C
CH3 C
COO-ALKYL
C
C
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®
Quiz 1.
Biomaterials only include synthetic solid materials? True False
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2. Which one of the following is NOT a type of biomaterial? Active material Inert material Potent material Biodegradable
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3. Drugs taken orally have a much higher bioavailability compared to drugs administered intravenously? True False
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4. Gastric fluid in the stomach has a pH ranging between 3-7 in the fed state. True False
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5. Film coating is a multistage process giving rise to the production of smooth, rounded tablets. True False
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6.Weight increase due to coating material is minimal for Sugar coated tablets. True False
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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
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8. The polymers used for enteric coatings ionises as the pH increases, and therefore becomes soluble in the intestinal fluid. True False
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9. The trade name for methacrylate polymer is ... Sureteric® Eudragit® EmCoat 120 N
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Q10. The amount of polymer required for enteric protection is less than that need for moisture protection? True False
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END OF QUIZ Thank-you for taking time to look through this package.
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
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