Coarting materials used in pharmaceutical formulations

Coating materials used

in pharmaceutical formulations

By Mahya Akbarzadeh Click to start tutorial

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.

OBJECTIVESAfter 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.

PREREQUISITESWhat 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


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 as coating materials

Eudragit® Polymers

Polymer dissolution

Polymer Quantities

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


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


Drug Delivery Market $75.3 billion in 2004

32%

8%27%

13%

9%11%

Oral

Transdermal

Pulmonary

Other

Injectable andimplantable

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.


The gastrointestinal tract is complex system and below outlines the key structures involved oral drug absorption.


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. OESOPHAGUS2. STOMACH3. SMALL INTESTINE4. 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: 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

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.

STOMACHGastric 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 pH3-7depending 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

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 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:1. Oesophagus 2. Stomach 3. Small intestine 4. Large intestine or colon

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?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


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.


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.


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

6. Printing 5. Polishing 4. Colouring 3. Smoothing 2. Sub coating 1. Seal tablet core

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 1. Sealing tablet core- application of a water impermeable polymer such as

Shellac, cellulose acetate phthalate and polyvinyl acetate phthalate, which protects the core from moisture, increasing its shelf life.

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

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

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

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

6. Printing -indelible ink for characterisation.

Example of sugar coated tablets Brufen® POM

Available in 200mg and 400mg strength

Premarin® POM Conjugated oestrogens 625mcg

(maroon) and 1.25mcg (yellow)

Colofac ® P Mebeverine hydrochloride

100mg Round, white, sugar coated

Kalms ® GSL 45mg Hops powder,90mg

Gentian powdered extract, and 135mg Valerian powdered extract

Simplified representation of sugar coating process

Film coating Modern approach to coating tablets, capsules, or pellets by surrounding them with

a thin layer of polymeric material. Description of tablets: Shape dictated by contour of original core.

Process: Single stage process, which involves spraying a coating solution containing the following;

1. Polymer 2. Solvent 3. Plasticizer 4. Colourant

The solution is sprayed onto a rotating tablet bed followed by drying, which facilitates the removal of the solvent leaving behind the deposition of thin film of coating materials around each tablet.

Film 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 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.

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.

SolventsTraditionally, 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.

AdvantagesThis 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®

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?

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®

Enteric Coatings Taste masking Sustained release coating Sub coat moisture and barrier sealant pellet coating

Polyvinylacetate phthalate Sureteric® Enteric Coatings

Methacrylate Eudragit® Enteric Coatings Sustained Release Coatings Taste Masking Moisture protection Rapidly disintegrating Films

Shellac Material of natural origin- purified resinous secretion of the

insect Laccifer lacca.

Oldest known material used for enteric coatings.

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

Its use is now less popular in commercial pharmaceutical applications for enteric coatings. Due to poor batch to batch reproducibility, which is a crucial requirement.

Shellac

Cellulose acetate phthalate (CAP)

Chemical name: Cellulose acetate phthalate Trade name: CAP, Aquateric Application form: organic or aqueous

dispersion Functional groups: acetyl, phthalyl Soluble above pH: 6 Additional remarks: sensitive to hydrolysis, 5-

30% plasticizer required.

Polyvinyl acetate phthalate (PVAP)

Chemical name: polyvinyl acetate phthalate# Trade name: Opadry enteric (aqueous), Coloron Application form: organic solution, aqueous

dispersion. Functional groups: acetyl, phthalate,

vinylacetat :crotonic acid ratio 90:10. Soluble above pH: 5 Additional remarks: Plasticizer is required.

Acrylic polymers Chemical name: Methacrylic Trade name: Eudragit® Application form: organic solution or

aqueous dispersion. Functional groups: methyacrylic acid Soluble above pH: 5 * depends on co-

polymers used.

Polymer dissolution

Factors affecting the release of a drug from a polymer:

Thickness of the coating material

pH

Other excipients

Ionic state

Thickness of a coating material How much polymer is required for enteric protection?

To achieve enteric protection of the core 3-4 mg/cm2 of the polymer is required to

be applied to the dosage form. Do different polymers require different amounts for

application?

Methacrylic acid copolymers require a lower amount of polymer compared to

cellulose derivatives which usually require higher amounts of polymer to achieve

the same core protection as the former. What effect does increasing polymer layers have on

dissolution?The more polymer layers that are applied the greater the rate of dissolution of the

drug.

pH

Dissolution of polymers intended for enteric targeting is dependent upon the dissolution medium. This is influenced by the composition of the polymer, the monomers, or the type and degree of substitution.

Ionic state

The rate of polymer dissolution is dependent upon the type of ions present in the dissolution medium.

It was shown that sodium chloride prevented dissolution of some polymers.

Other excipients

Influence the dissolution of polymer.

Plasticizers may decrease or increase dissolution rate, depending on the nature of the plasticizer, whether it is lipophilic or hydrophilic.

General structure of Eudragit® Polymers

C C C C

CH3CH3(H)

COO-ALKYL R

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

Possible R groups

C C C C

CH3CH3(H)

COO-ALKYL R

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

-COOCH3 or COOC4H9 -COO-CH2-CH2N+(CH3)3 3CL-

General structure of Eudragit ® polymers

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 tablets5 – 10 mg for oblong-shaped tablets5 – 20 mg for gelatin or HPMC capsules

Taste-masking coatings:1 – 2 mg for round tablet1 – 4 mg for oblong-shaped tablets

Moisture protection: 1 – 6 mg for round tablets2 – 10 mg for oblong-shaped tablets5 – 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 technol

ogies Degussa for pharmaceuticals

Documents

Coarting materials used in pharmaceutical formulations