Coating materials used in pharmaceutical formulations : Coating materials used in pharmaceutical formulations By Mahya Akbarzadeh Click to start tutorial Aims and objectives : 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.
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.
What do you need to do before starting the activity?
Human biochemistry MAIN MENU : MAIN MENU Oral drug delivery system
Polymers used in coating processes
Useful links Oral drug delivery system : Oral drug delivery system Oral drug delivery system
Anatomy and physiology of the gastrointestinal tract
Physiological factors affecting bioavailability Coatings : Coatings What is the rationale for coating a solid dosage form?
Main coating processes
Functional coatings Polymers : Polymers Summary of Polymers used in pharmaceutical formulations as coating materials
Polymer Quantities Oral drug delivery system : 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;
Granules Oral drug delivery system : Oral drug delivery system 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 Tablets are the most commonly prescribed dosage form, below summarises the advantages and disadvantages of tablets. Drug delivery market Oral drug delivery system : 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. Anatomy and physiology of the gastrointestinal tract : 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 : 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 %.
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.
3. SMALL INTESTINE
4. LARGE INTESTINE OR COLON Bioavailability : Bioavailability The proportion of drug that reaches the target organs and tissues, which is expressed as a % of the dose administered. Slide 13: 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. Physiological considerations that affect oral bioavailability : Physiological considerations that affect oral bioavailability The transit of pharmaceuticals in the gastrointestinal tract
Presence of foods and liquids in the gastrointestinal tract Gastrointestinal pH : 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. Gastrointestinal pH : 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.
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 : 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.
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 : 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
Delayed gastric emptying
Increased viscosity of the gastrointestinal contents
Stimulation of gastrointestinal secretion Presence of food : 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 : Dissolution Release of a drug from solid dosage form into a bioavailable form . Dietary intake : 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 : 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 : 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 : 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 gastrointestinal tract : 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
Size and density of dosage form
Location and transit time within the GI tract:
Large intestine or colon The transit of pharmaceuticals in the gastrointestinal tract : The transit of pharmaceuticals in the gastrointestinal tract The transit time is long and variable and depends on the following; type of dosage form, diet, eating pattern and disease state. 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 in the stomach is highly variable and depends on the dosage form and the fed or fasted state of the stomach. 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. What is the rationale for coating a solid dosage form? : 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;
Improved patient acceptance
The rationale for coating pharmaceutical dosage form such as a tablet can be categorised into three main headings:
Marketing What is the rationale for coating a solid dosage form? : 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? : 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? : 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 : Main coating processes 1.Film coating
2. Sugar coating
3. Press coating Sugar 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. Examples of sugar coated tablets Multistage process : 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. Example of sugar coated tablets : Example of sugar coated tablets Brufen® POM
Available in 200mg and 400mg strength
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 : Simplified representation of sugar coating process Film coating : 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;
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 : 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.
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 : 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 ? : Why is film coating favoured over sugar coating ? Film coating
Retains shape of original core
Small weight increase of 2-3% due to coating material
logo or ‘break lines’ possible
Can be automated e.g. Accela Cota
Easy training operation
Single stage process
Easily adaptable for controlled release allows for functional coatings. Sugar coating
Rounded with high degree of polish
Larger weight increase 30-50% due to coating material
Logo or ‘break lines’ are possible
Difficult to automated e.g. traditional coating pan
Considerable training operation required
Not able to be used for controlled release apart from enteric coating. Polymer used in film coating : Polymer used in film coating Examples;
Methacrylate amino ester copolymers. Plasticizer used in film coating : Plasticizer used in film coating Examples;
Polyols - Polyethylene glycol 400
Organic esters - diethyl phthalate
Oils/glycerides - fractional coconut
oil Colourants used in film coating : Colourants used in film coating Examples;
Iron oxide pigments
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 covering ability Environmental : Environmental Venting of untreated organic solvent vapour into the atmosphere is ecologically unacceptable but removal of gaseous effluent is expensive. Safety : Safety Organic solvents are a safety hazard, such that they are:
Fire hazard Financial : 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 : Solvent residues For a given process the amount of residual organic solvent in the film must be investigated. Thus, stringent regulatory controls exist. Solvents : 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.
Solvent residues Press coating : Press coating Press coating process involves compaction of coating material around a preformed core. The technique differs from sugar and film coating process.
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.
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 Functional coatings are coatings, which perform a pharmaceutical function.
The pH status of enteric coated polymers in the stomach
The ideal properties of enteric coated material
Controlled release coating Enteric 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 : Examples of enteric coated OTC products Enteric coated aspirin E.g. Micropirin® 75mg EC tablets
Enteric coated peppermint oil E.g. Colpermin® pH : pH HIGH 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 SMALL INTESTINE The pH status of enteric coated polymers in the stomach LOW The ideal properties of enteric coated material? : The ideal properties of enteric coated material? Permeable to intestinal fluid
Compatibility with coating solution and drug
Formation of continuous film
Cheap and ease of application
Ability to be readily printed
Resistance to gastric fluids Summary of Polymers used in pharmaceutical formulations as coating materials. : Summary of Polymers used in pharmaceutical formulations as coating materials. Shellac : 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 : Shellac Cellulose acetate phthalate (CAP) : 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) : 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 : 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 : Polymer dissolution Factors affecting the release of a drug from a polymer:
Thickness of the coating material
Ionic state Thickness of a coating material : 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 : 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 : 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 : 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 : General structure of Eudragit® Polymers Changing the R group gives rise to polymers with different physiochemical properties. Possible R groups : Possible R groups -COOH -COOH-CH2-CH2N(CH3)2 -COOCH3 or COOC4H9 -COO-CH2-CH2N+(CH3)3 3CL- General structure of Eudragit ® polymers FUNCTIONAL GROUP : FUNCTIONAL GROUP METHACRYLIC COPOLYMER
Delivery to the colon FUNCTIONAL GROUP : FUNCTIONAL GROUP Aminoalkyl methacrylate copolymer
Taste, odour and moisture protection. Dissolves in the stomach. FUNCTIONAL GROUP : FUNCTIONAL GROUP Methacrylate copolymer
-COOCH3 or COOC4H9
Delayed and sustained release (insoluble) Slide 70: 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 : FUNCTIONAL GROUP Aminoalkyl methacrylate copolymer
Delayed and sustained release Polymer Quantities : Polymer Quantities Depending on the desired function of a coating, the following values are figures for the amount of polymer required :
4 – 6 mg for round tablets
5 – 10 mg for oblong-shaped tablets
5 – 20 mg for gelatin or HPMC capsules
1 – 2 mg for round tablet
1 – 4 mg for oblong-shaped tablets
1 – 6 mg for round tablets
2 – 10 mg for oblong-shaped tablets
5 – 10 mg for gelatin or HPMC capsules Eudragit® Polymers : Eudragit® Polymers Eudragit® is the trade name for the class of polymers known as the methacrylates.
Mostly commonly used polymer for enteric coating.
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 : Quiz Biomaterials only include synthetic solid materials?
False Slide 75: Correct!
Well done Slide 76: Incorrect!
Try again Slide 77: 2. Which one of the following is NOT a type of biomaterial?
Biodegradable Slide 78: Correct!
Well done Slide 79: Incorrect!
Try again Slide 80: 3. Drugs taken orally have a much higher bioavailability compared to drugs administered intravenously?
False Slide 81: Correct!
Well done Slide 82: Incorrect!
Try again Slide 83: 4. Gastric fluid in the stomach has a pH ranging between 3-7 in the fed state.
False Slide 84: Correct!
Well done Slide 85: Incorrect!
Try again Slide 86: 5. Film coating is a multistage process giving rise to the production of smooth, rounded tablets.
False Slide 87: Correct!
Well done Slide 88: Incorrect!
Try again Slide 89: 6.Weight increase due to coating material is minimal for Sugar coated tablets.
False Slide 90: Correct!
Well done Slide 91: Incorrect!
Try again Slide 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 Slide 93: Correct!
Well done Slide 94: Incorrect!
Try again Slide 95: 8. The polymers used for enteric coatings ionises as the pH increases, and therefore becomes soluble in the intestinal fluid.
False Slide 96: Correct!
Well done Slide 97: Incorrect!
Try again Slide 98: 9. The trade name for methacrylate polymer is ...
EmCoat 120 N Slide 99: Correct!
Well done Slide 100: Incorrect!
Try again Slide 101: Q10. The amount of polymer required for enteric protection is less than that need for moisture protection?
False Slide 102: Correct!
Well done Slide 103: Incorrect!
Try again Slide 104: END OF QUIZ
Thank-you for taking time to look through this package. Useful links : 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