a r Paper Coordinator

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Pharmaceutical sciences

Product Development 1

Excipients for solid dosage form and coating

Paper Coordinator

Content Reviewer

Dr. Vijaya Khader

Dr. MC Varadaraj

Principal Investigator

Dr. Vijaya KhaderFormer Dean, Acharya N G Ranga Agricultural University

Content Writer

Prof. Farhan J Ahmad Jamia Hamdard, New Delhi

Paper No: 05 Product Development 1

Module No: 15 Excipients for solid dosage form and coating

Development Team

Dr. Gaurav Kumar Jain Jamia Hamdard, New Delhi

Prof Roop K. Khar BSAIP, Faridabad

Prof. Dharmendra.C.Saxena

SLIET, Longowal

Dr. Gaurav Kumar Jain Jamia Hamdard, New Delhi

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Introduction

Excipients for conventional oral solid dosage form Drug product is most frequently administered orally in a solid dosage form which includes tablets,

coated dosage form, capsules, troches and lozenges. An oral formulation cannot be simply made using

an API, major part of the formulations consists of excipients which include diluents, binders,

disintegrants, glidants and lubricants.

Diluents:

Usually, the dose of API is small and thus an inert substance needs to be added to increase the bulk

of the formulation so as to make it easier for compression during manufacturing operation. Diluents may

also be added for secondary reasons as well, improves cohesion to provide better tabletting properties,

to permit direct compression of excipients and to promote flow. Several types of diluents are available

such as microcrystalline cellulose (brand name- Avicel), starch, mannitol (Brand name- Mannogen),

lactose, dicalcium phosphate (brand name- Encompress), kaolin, calcium sulphate. However, while

developing a new dosage form for the drug substance, its compatibility with the diluents should be

considered as it might have a deleterious effect, if found incompatible. The most common example to

illustrate this possibility is that of calcium salts with tetracycline. Calcium salts if used as diluent for the

antibiotic tetracycline, interferes with its absorption through gastrointestinal tract (GIT). Similarly,

amine salts if combined with lactose in the presence of an alkaline lubricant such as magnesium stearate,

leads to color discoloration in the tablets on storage. The reactions may also take place between the

components which are tightly compressed in a tablet, for ex., substances which can form eutectic

mixtures, if compressed together in a tablet can soften it and hence making the tablet unacceptable. Video

stop

Another important consideration in using diluents for tablet formulation, is the form in which the

diluents are available. Diluents which exist in the common salt form as hydrates contain bound water as

water of crystallisation which makes it unsuitable for water-sensitive drugs, provided that the water of

crystallisation is not released under elevated storage condition to which product is exposed. Diluents

such as dibasic calcium phosphate (DCP) and calcium sulphate are most suitable for the formulation of

tablet dosage form of water-sensitive drugs, as they possess low concentrations of unbound moisture and

also have low affinity for the atmospheric moisture. Diluents may also serve other purpose in the same

formulation, for ex. Corn starch is used as binder in paste form and as disintegrant in suspension form.

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Binders and Adhesives

Binders are the agents which impart cohesiveness to the dosage form and ensure, they remain intact

after compaction. Further improves the free flowing ability due to the formation of granules of

appropriate size and hardness. Some of the frequently used binders include, natural & synthetic gums

(sodium alginate, guar gum), starch, gelatine, carboxymethylcellulose, poly vinylpyrrolidone,

hydroxypropyl methylcellulose (HPMC), maltodextrin. Meltable binders include polyethylene glycols,

waxes, fatty acids & alcohols, glyecrides. Alcohols and water are not originally regarded as binder, but

since they produce solvent action on some components such as lactose or starch, which change them to

granules. Video stop

Binder can be used either as liquid or in dry form. The amount of binding agent used has a

significant influence on the tablet characteristics. Too much or too harder binding agent result in hard

tablet that causes excessive wear of the punches and dies and does not disintegrate easily. Binding agent

in solution form is more effective than the dry from. This is because of the complete wetting of the

particles surface with the liquid binder.

Granulation refers to the unit operation through which small powdery particles can be

agglomerated into bigger entities called granules. Granules formed by using binders exhibit improve

flow property and also the compressibility. Granules have several other advantages as well, such as,

improvement in the mixing properties and appearance, reduction in the dust generation in the tabletting

operation, densify the material and also further reduces segregation potential of the particles. Binders are

used in all the three tabletting operation, direct compression, dry granulation and wet granulation. For

Direct Compression, the directly compressible binders are used which exhibit sufficient powder

compressibility and flowability. These are selected on the basis of flow behaviour, compression

behaviour and volume reduction under the applied pressure so as to have optimum binding performance.

Mechanism of granule formation-

As the granulating liquid is added to the powder particles, it forms films at the surface of particles

which combines at the point of contact to form discrete liquid bridges. The liquid bridges so formed have

negative capillary pressure which provides cohesive force resulting in a ‘pendular state’. With the

increase in liquid content, a ‘funicular’ state is obtained which is caused by the coalescence of the

bridges. With further increase in the amount of liquid alongwith the kneading of the mass so formed,

eliminates the void spaces within the granule bringing the particles closer. A ‘capillary’ state is obtained

due to the bonding by interfacial forces at the surface of granule and by the negative capillary pressure

present in the liquid space in the interior. Finally a ‘droplet’ is obtained in which the particles are held

together by the surface tension but in the absence of intragranular forces.

The formation of granules depends upon several factors such as compatibility of binder with the

API and other excipients, properties of the drugs and the excipients like particle size and surface area,

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compressibility, hydrophobicity and several others, the extent of spreading of binder, the type, quantity,

temperature and viscosity of the binder used, the method of addition of the binder.

Audio stop

Disintegrating agents

Disintegrants are added to promote the penetration of moisture in the matrix of the dosage form

resulting in its dispersion in dissolution fluids. Some of the frequently used disintegrants include

cellulose, cross-linked polymers, starches, gums, algins, clays. Starch is the most commonly used tablet

disintegrant, in a concentration of 5-20% w/w. Certain low substituted carboxymethyl starches called as

modified starch have been developed which can be used in low concentrations of 1-8%, eg. ‘Primogel’

and ‘Explotab’. Video stop Starch can also be modified as pre-gelatinzed starch which can be employed

as disintegrant in a further low concentration of 5%. A new class of disintegrants called superdisntegrants

have also been developed which include modified cellulose (AcDiSol), modified starch (sodium starch

glycolate- Explotab, Primojel), cross-linked polyvinylpyrrolidone (Crospovidone). There are several

mechanisms by which disintegrants act-

Disintegrants can be added at two stages viz intragranular addition and extragranular addition.

Intrgranular refers to the addition of disintegrating agent during granules formation, prior to wetting with

the granulating fluid. Extragranular disintegrants are added at the second mixing stage, during the

compaction of the granules into the tablet. Extragranular disintegrants cause the tablet to break into

Mechanism ofdisintegration

Wicking

Enhance porosity and provides pathwaysthrough which liquid is drawn up by capillaryaction resulting in rupturing of interparticulatebonds and hence disntegration

SwellingSwell when they come in contact with waterand overcome the adhesiveness leading todisintegration

Heat of wettingdisintegrants possessing exothermic propertiesgets wet and generates a localised stress due tocapillary air extension resulting in disntegration

RepulsionNon-swellable disintegrants draws water intothe pores, generating electrical forces causingrepulsion of particles

Deformationparticles get deformed under pressure andswells when come in contact with water

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granules while the intragranular disintegrants break down the granules into fine particles.

Audio Stop

Glidants, Lubricants and Antiadherents

The three terms, glidants, lubricants and antiadherents are employed together due to their

overlapping functions. Glidants are the substances which improve the flow properties of the powder by

decreasing the friction between the particles. Lubricants are the agents which reduces the friction

between the tablet and the die walls during ejection of the tablet. Antiadherents prevent the adherence of

the tablet granules or the powder to the surface of punches and die wall. Talc, starch, magnesium stearate

and various colloidal silicas possess antiadherent properties. Glidants used in pharmaceutical industry

include talc (5%), corn starch (5-10%), colloidal silica such as Cab-O-Sil, Syloid, Aerosil (0.25-3%).

Glidant promote the flow by lodging into the irregularities on the surface of granules, reducing the

interparticulate friction producing a more spherical structure. Colloidal silica also acts as moisture

scavangers giving an added advantage to the glidant action. Video Stop

Lubricating agents serve multiple purpose in the tablet manufacturing- prevent material from being

adhered to the surface of punches and dies, interparticle friction reduction, facilitates tablets to eject from

die cavity, and also improves the flow characteristics of granules. Lubricants are mostly used in a low

concentration (~1%) except talc, which is used at a high concentration (~5%), when used alone.

Lubricants can act by four mechanisms viz hydrodynamic lubrication, elastohydrodynamic lubrication,

mixed lubrication (all three applicable in liquid lubricants) and boundary lubrication (commonly applied

in pharmaceutical industry). In boundary lubrication, the lubricant forms layers/film between the

surfaces or at interfaces to reduce friction, thus penetrating itself into the asperities. Lubricants

possessing the boundary lubrication mechanism include long chain molecules having active end-groups

such as stearic acid and its metallic salts, ex. –OH (long chain alcohol); –NH2 (long chain amine); –

COOH (long chain fatty acids) and metal ions such as Mg2+. Commonly used lubricants in

pharmaceutical industry include metallic salts of fatty acids (magnesium stearate, stearic acid), fatty acid

esters (glyceride esters, sugar esters), inorganic materials (talc) and polymers (polyethylene glycol 4000).

Glyceride esters include glyceryl monostearate, glyceryl dibehenate and glyceryl tribehenate while sugar

esters imclude sucrose monopalmitate and sorbitan monostearate. Lubrication is a coating process, thus

a finer particle size is desirable to produce an optimum lubricant action. However, a deleterious effect

can be observed with water insoluble lubricant. The hydrophobic surface of the particle slows the

dissolution process thus causing bioavailability problems and also the tablet structure is weakened due

to the direct contact between adjacent hydrocarbon layers. Thus, the selection of an appropriate lubricant

for a tablet manufacturing process is based on several criterias including- non-toxicity, chemically

compatibility with APIs and other excipients in the formulation, low shear strength, should be capable

of forming a durable layer on the surface/particles, low batch to batch variability, optimal concentration

and mixing time and should have minimum adverse effects on the tablet performance. The optimal

concentration of lubricant should be used as lower concentration (other than that specified) and

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inadequate mixing can cause inefficient lubrication resulting in sticking and capping and binding in the

die cavity while excessive amounts of lubricants lead to tablet waterproofing, resulting in inappropriate

disintegration and dissolution of the API. Therefore, selecting an appropriate lubricant is an important

requisite for a formulation so as to have a desirable performance of both product and the process.

Audio Stop

Multifunctional Excipients

The development of new drug moieties with the diverse physicochemical and stability

characteristics, is resulting in a necessity to develop newer excipients to achieve the desired

functionalities. However, the development of a new excipient is relatively uneconomical as it involves

high cost, thus formulators are now concerned with the modification of the physicochemical properties

of the already existing excipients. Multifunctional excipients are those that serve various purpose through

a single ingredient for the development of formulation. Multifunctionality can be achieved by either

supplementing the attributes of the excipients or the parent excipient can be coprocessed with another

excipient. A multifunctional excipient provides several advantages in terms of formulation development,

manufacturing and further in marketing, as given as- Video stop

Formulation: increase rework potential, smaller quantities are required, flow properties can be

enhanced, the blending process may be improved, decrease strain rate sensitivity, enhanced

compression ratio, optimize content uniformity, material handling can be facilitated, improve

stability, and also reduce environmental concerns.

Manufacturing: the direct compaction of the tablet dosage form may be achieved thus reduced

time, the excipients with enhanced flow and compaction behaviour increase production capacity,

machine wear and tablet tooling may be reduced, and eliminate the facility need of solvent

recovery.

Marketing: the better formulation characteristics with improved and faster manufacturing

process leads to enhanced marketing potential of the dosage form.

Some multifunctional excipients with their key components and their advantages have been listed in the

table below:

Trade name Coprocessed excipient Added advantages

Cellactose 80

α -Lactose monohydrate (75%) and cellulose powder (25%)

Highly compressible, good mouth feel, better tableting at low cost

StarLac α -Lactose monohydrate (85%) and maize starch

Good flow, optimized disintegration, excellent tablet hardness

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(15%)

Pharmatose DCL14

Anhydrous b-lactose (95%) and lactitol (5%)

High compactibility, superior flowing properties, low lubricant sensitivity

Avicel CE-15 MCC and guar gum

Less grittiness, reduced tooth packing, minimal chalkiness, creamier mouth feel, improved overall palatability

Formaxx CaCO370

Calcium carbonate (70%) and sorbitol (30%)

High compressibility, excellent taste masking, free flow, superior content uniformity, controlled particle size distribution

Di-Pac Sucrose (97%) and dextrin (3%)

Directly compressible, Low hygroscopicity

Kollidon CL, CL-F,

CL-M Crosslinked water-insoluble

polyvinyl pyrrolidone Size modified according to application for disintegration and solubility enhancement

Xylitab 100 Xylitol and polydextrose Directly compressed sugar with improved mouth-feel

Eudragit RL and RS Methacrylic acid polymers Modified for sustain release

Table 1: Adopted from Lachman/Lieberman. IV Edition, 2013

Excipients for Coating solid dosage form:

Tablet coating is a key step in the manufacturing of tablet dosage form with specific desirable

properties such as controlled release or delayed release. The coating is applied to the tablets to achieve

one or more of the following objectives-

Masking the taste, odour and color of the API

To provide the physical and chemical protection to the drug.

To control drug release from the tablet.

To provide enteric coating to the tablets so as to protect the API from the degradation in the

gastric environment of the stomach.

To avoid chemical incompatibilities or to provide sequential release of drug by incorporating an

adjuvant in the coating.

To enhance the pharmaceutical elegance with the use of contrast printing or special colors.

Video Stop

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The coating material can be physically deposited on the tablet surface or may form a continuous layer of

film. An ideal film coating material should possess the following attributes-

It should be soluble in the solvent of choice to be used for coating.

It should have the desirable solubility for the intended use, ex., pH dependent solubility for enteric

coating

It should produce a formulation with elegant appearance.

It should be stable in the presence of environmental conditions such as air, moisture, heat and

light.

It should be compatible with common coating solution additives.

It should be non-toxic, ease of application to the tablets.

It should be resistant to cracking and should have a sufficient barrier to the entry of moisture,

light or air.

No-bridging or filling of debossed tablet surface by the film former. Audio Stop

Biopharmaceutics classification system and coating requirements:

US Food and Drug Administration (FDA) has published several guidelines for the in vitro/in vivo

correlations of immediate-release and extended-release dosage forms, so as to facilitate regulatory

submissions for generic drugs and also for postapproval changes. As per FDA, Guidance for Industry

document, dissolution profiles of a drug serve as a ‘sensitive, reliable, and reproducible surrogate to

ensure bioequivalence. Therefore, the pharmaceutical excipients used in the preparation of dosage form

have to provide consistency in the dissolution profile of the API. Additionally, FDA has also published

the Biopharmaceutics classification system (BCS) offering general guidance regarding how the products

could qualify for bio waiver, thus enabling pharmaceutical industries to avoid some in vivo

bioavailability and bioequivalence studies. Video Stop

BCS classifies drugs into four classes- Class I drugs have high aqueous solubility and high

Permeability: Class II drugs have low aqueous solubility and high membrane permeability; Class III

drugs have high solubility and low membrane permeability; Class IV drugs have low aqueous solubility

and low membrane permeability. Excipients with specific characteristics can be purposefully employed

to optimize drug delivery; however, the challenge is in the compatibility of drug with the excipients so

as to achieve desired pharmacokinetic profile of the pharmaceutical dosage form. API can be formulated

as immediate release or sustained–release dosage form altering the delivery profiles of drug product.

Immediate-release dosage form produces rapid onset of drug action while the sustained–release

formulations provide prolong and less-fluctuating drug plasma level, thereby minimizing toxicity, and

side effects associated with the drug. The physicochemical and pharmacokinetic characteristics of the

drug influence the type of dosage form that could be formulated for the drug. Furthermore, site specific

delivery system such as enteric coated system can also be developed to ensure highest therapeutic

efficacy. Class I drugs are readily released from the dosage forms and dissolve in the small intestine and

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are efficiently absorbed across the intestinal epithelium thus are anticipated to minimize variation in oral

absorption. Therefore, class I drugs can be formulated in sustained– and immediate-release dosage forms,

with the exception of those which undergoes extensive first-pass metabolisms. More variations and lower

bioavailability of drug may be observed if the sustained–release of drug is below the level of saturating

the intestinal and hepatic first-pass enzymes. Class II drugs have the limitation of low aqueous solubility

thus limiting the drug absorption. The excipients that can increase the aqueous solubility of the API can

be used to strategically enhance the oral absorption of class II drugs. Class III drugs have reduced

intestinal absorption leading to higher variations and thus limiting the choice of sustained release

formulation for BCS Class III drugs. Class IV drugs are not the good candidates for sustained–release

formulation, because of the poor aqueous solubility and lower membrane permeability. Suitable

formulation strategies that can be applied to the four classes in BCS is summarized in figure 1.

Figure 1: Formulation strategies for each class in BCS

Thus, the excipients can also serve the purpose of enhancing drug dissolution and membrane permeation

in a dosage form. Audio Stop

Excipients used in Sustained–Release Formulations

Extended release dosage form, as per USP, is the one which allows atleast a 2 fold decrease in dosing

frequency or an increase in therapeutic performance of the dosage form when compared to the conventional

dosage form. The terms such as, ‘sustained release’, ‘prolonged release’, ‘controlled release’ and ‘long acting’ are

the synonyms for the extended release dosage form. Sustained release delivery systems are the drug delivery

system which when administered in a single dose prolongs the therapeutic effect of the medication by continuously

releasing it over extended period of time. Video Stop

Sustained–Release Matrix:

Sustained–release matrix can be a single tablet or multiple small sustained–release tablets may

be housed inside an external coating. In the sustained release matrix dosage form, the drug molecule is

Clas

Clas Clas

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Immediat

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Immediat

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dispersed or embedded in the matrix of sustained release material, which may be compressed in a tablet

form or encapsulated in a particulate form. The factors determining rate of drug release from a matrix

dosage form are permeation of matrix by water, erosion of matrix, drug leaching from the matrix. These

matrices may be prepared by erodible or insoluble materials. Drug release from the matrix follows

Higuchi release kinetics which states that the drug release per unit surface area at time t depends on drug

diffusion coefficient in elution medium, tortuosity and porosity of the matrix, drug solubility in the

elution medium and the initial loading dose of the drug in the matrix.

Materials used to form matrix tablets are classified into three types- Insoluble inert materials

which include polyvinyl chloride, PEG; insoluble erodible materials such as stearyl alcohol, carnauba

wax, castor wax; hydrophilic materials including methylcellulose, sodium CMC, HPMC and several

others. The rate limiting step in controlling drug release from insoluble inert polymers is penetration of

liquid into the matrix. Wetting agents included into the matrix allows drug dissolution and diffusion

through the channels created in the matrix due to the wetting agents. Waxes and lipids control drug

release through pore diffusion and erosion. Thus release characteristics of such systems are more

dependent on the digestive fluid composition.

Polyacrylic acid is the most widely used matrix for sustained–release formulations, available as

Carbomer 910, 934, 934P, 940, 941, 971P, and 974P. Polymers of acrylic acid which are cross-linked

with polyalkenyl ethers or divinyl glycol are called as Carbopol polymers. Without crosslinkers, the

polymers will exist as linear chains which will be intertwined but not chemically bonded. Carbopol

polymers contain 56% to 68% of –COOH group (carboxylic acid). When exposed to intestinal fluid, it

swell and form hydrogel-like structures which release drug molecules in a controlled manner.

Sustained–release film coating:

Sustained–release film coating can be applied to several dosage forms. The important prerequisite

for the API to be formulated as a sustained–release formulation is that it should not undego extensive

first-pass metabolism. Two types of membranes can be formed using sustained–release film coatings:

permeable membrane and semipermeable membrane.

The permeable membrane is the one which allows the intestinal fluid to enter the formulation,

dissolve the drug and allow it to permeate out through the membrane of the dosage form. They are

permeable to both the intestinal fluid and the drug molecules. However, semipermeable membranes

permeate only the intestinal fluid and are impermeable to dissolved drug molecules. Rate of drug release

through a permeable membrane depends upon several factors such as membrane thickness, drug

solubility in intestinal fluid, concentration gradient of drug across the membrane, drug diffusion

coefficient through the membrane, dosage form surface area and the drug particles. Materials capable of

forming a permeable membrane include fats and waxes (bee wax, carnauba wax), cetylsteryl alcohol,

cetyl alcohol, zein, silicone elastomers and ethylcellulose. Aqueous dispersions of hydrophobic polymers

are generally used to provide sustained–release film coatings. Examples include aqueous polymer

dispersions of ethylcellulose available with the brand name, ‘Aquacoat’, various acrylates such as

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Eudragit RS 30 D, Eudragit RL 30 D, Eudragit NE 30 D. Plasticizers such as polyethylene glycol (PEG),

diethylphthalate, triacetin , can be used with Eudragits so as to reduce glass transition temperatures of

Eudragit films.

Most common example of system utilizing semipermeable membrane is that of osmotic pumps.

Water is allowed to enter table matrix through the semipermeable membrane due to the osmotic pressure

build up in the system preventing permeation of drug substance across the membranes. Drug is delivered

through the orifice at the membrane. BCS Class I and II are the best suited candidates to formulate as

osmotic tablets. Polyvinyl alcohol, ethylcellulose and cellulose acetate are some of the material used to

make the semipermeable membranes.

Coprecipitates:

Coprecipitation refers to a phenomenon where a solute unlike in solutions, precipitates out on a

carrier which overcomes its dipersibility and forces it to bind together. Coprecipitates formed using

pharmaceutical excipients are an attractive strategy to control drug release. Copreciptates of Ibuprofen

with acrylate polymers, Eudragits, have been developed by researchers. Ibuprofen belongs to BCS class

I, which has high solubility and membrane permeability for it to be orally absorbed completely.

Coprecipitates deterred drug release rates with no significant interactions been observed between

ibuprofen and Eudragit. Eudragits swell and slowly dissolve which slowed the release of ibuprofen.

Audio Stop

Film formers:

Film coating of solid dosage forms is a high sophisticated process, first described in 1930. Film

coatings are applied for following reasons:

- Taste masking and moisture/ light protecting coatings

- improved product appearance

- improved mechanical resistance of the coated product (e.g. reduced friability)

- modified drug release (e.g. gastric resistant or extended release coatings)

The polymer for film coating may be classified as protective or functional coating. Based on their

origin or preparation, film forming polymers can be classified as natural, semi-synthetic or synthetic

polymers. Natural polymers are subjected to several purification steps and then used as such without any

chemical modification. Semi-synthetic polymers are derived after the chemical modification of natural

substance, eg, cellulose derivatives. Synthetic polymers are completely chemically synthesised

polymers, ex. methacrylic acid copolymers. Based on the function they perform, film coating polymers

can be classified as those which are used for protective coating and those which impart functional

coating. Video Stop

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Protective coatings:

Protective coatings are applied with several objectives such as taste or odour masking, improving

stability of moisture sensitive products, for improving the mechanical resistance of product during

handling. They remain intact for a short period of time of swallowing the dosage form and then dissolve

instantaneously to cause the immediate drug release without retardation. Some polymers for film coating

are summarized below-

Ethyl cellulose:

Ethyl cellulose is obtained by the reaction of cellulose (dissolved in NaOH) with ethyl sulphate

or ethyl chloride. Different viscosity grades of ethyl cellulose are available depending on the degree of

ethoxy substitution. It is insoluble in water and GIT fluids. It produces films of low water solubility on

combination with hydroxypropyl methyl cellulose. Aqueous polymeric dispersions of ethyl cellulose

have been developed by Banker and co-workers from Purdue University. These are a type of psuedolatex

systems as high solids and low viscosity compositions. It is commercially available in the name of

Aquacoat by FMC Corporation. It is listed in Generally Recognized as Safe (GRAS) ingredients list,

accepted as food additive and also included in FDA Inactive Ingredients Guide (IIG) for use in oral

capsules, suspensions and tablets, vaginal preparations and topical emulsions.

Hydroxyethyl Cellulose (HEC)

HEC is a partially substituted poly (hydroxyethyl) ether of cellulose. It occurs as a white,

yellowish-white or grayish-white, tasteless, odorless hygroscopic powder. Several viscosity grades are

available with varying dispersion in water. It is used as coating agent, thickening agent, suspending

agent, viscosity-increasing agent and tablet binder. Aqueous solutions of HEC are less stable below pH

5 because of the hydrolysis while at high pH, they may undergo oxidation. Glyoxal-treated HEC should

not be used for oral pharmaceutical preparations or topical formulations that can be used on mucous

membranes. Its use in parenteral products is also not recommended. HEC is included in FDA Inactive

Ingredients Database (IID) for use in ophthalmic preparations, oral syrups and tablets, otic and topical

formulations. It is also included in nonparenteral medicines licensed in UK and in Canadian List of

Acceptable Non-medicinal Ingredients. However, it is not currently approved for direct use in food

products in USA or Europe, although permitted for use in indirect applications like packaging, due to

the high levels of ethylene glycol residues formed during its manufacturing.

Hydroxypropyl cellulose (HPC)

HPC is a partially substituted poly (hydroxypropyl) ether of cellulose, available in different

grades with the molecular weight in the range of 50 000–1 250 000. It is used as a coating agent,

stabilizing agent, emulsifying agent, suspending agent, thickening agent, tablet binder and viscosity-

increasing agent. HPC in a concentration range of 15–35% w/w is used to produce extended drug release

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formulation. The rate of a drug release increases with the decrease in the viscosity of HPC. The tableting

characteristics can be improved using the blends of HPC with other cellulosic polymers. HPC at 5% w/w

concentration is used as film coating material. HPC has been listed in GRAS list, in nonparenteral

medicines licensed in the UK and in Canadian List of Acceptable Non-medicinal Ingredients, acceptable

as a food additive in Europe. Also included in FDA IID for use in oral capsules and tablets, transdermal

and topical preparations.

Hydroxypropyl methylcellulose (HPMC):

HPMC or hypromellose is a partly O-methylated and O-(2-hydroxypropylated) cellulose. HPMC

is the most versatile excipient in pharmaceutical industry serving a range of purposes such as coating

agent, bioadhesive material, controlled-release agent, emulsifying agent, suspending agent, dispersing

agent, emulsion stabilizer, dissolution enhancer, extended-release agent; film-forming agent, granulation

aid, foaming agent, mucoadhesive, modified-release agent, solubilizing agent, sustained-release agent,

thickening agent, tablet binder and viscosity-increasing agent. It is used in a concentration of 2-5% w/w

as a binder in tableting operation, in 0.25–5.0% as suspending or thickening agent in liquid oral dosage

form, at 2-20% as film forming agent. Furthermore, it can be used as adhesive in plastic bandages and

as wetting agent for hard contact lenses. Also used in food products and cosmetics. HPMC has been

listed as GRAS excipient, accepted as food additive in Europe. It is included in IID of FDA for use in

ophthalmic and nasal preparations, suspensions, oral capsules, syrups and tablets, in vaginal and topical

preparations. It is also included in nonparenteral medicines licensed in UK and in Canadian List of

Acceptable Non-medicinal Ingredients.

Povidone:

Povidone is a synthetic polymer consisting of linear 1-vinyl-2-pyrrolidinone groups, available in

four viscosity grades identified by K value. It can be used as disintegrating agent, dissolution enhancer,

coating agent, suspending agent and tablet binder. Povidone can form molecular adducts thus making it

useful in the formulation of slow-release solid-dosage forms, solutions and parenterals, ex. povidone–

iodine is used as a topical disinfectant. The acceptable daily intake of povidone, as per WHO, is upto 25

mg/kg body-weight. It has been accepted as a food additive in Europe, included in FDA IID for use in

intramuscular (i.m.) and intravenous (i.v.) injections, in ophthalmic preparations, drops, oral capsules,

suspensions, tablets, topical and vaginal preparations. Furthermore, it is also included in nonparenteral

medicines licensed in UK and in Canadian List of Acceptable Non-medicinal Ingredients.

Polyethylene glycol (PEG):

The general formula for PEG is HOCH2 (CH2OCH2) mCH2OH, where m represents average

number of oxyethylene groups. It is used as coating agent, ointment and suppository base, plasticizer,

solvent, lubricant. PEGs are used in various pharmaceutical formulations such as parenteral, ophthalmic,

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topical, oral and rectal preparations and in controlled-release systems. PEG 300 and 400 in a

concentration of 30% v/v are used as vehicle for parenteral dosage forms. For film coatings, PEG can be

used alone for tablet film-coating or as hydrophilic polishing materials. Liquid grades of PEG increases

the water permeability of film coats thus reducing protection against enteric coating films at low pH.

PEG also serve as plasticizers in microcapsules to avoid rupture of coating film when they are

compressed into tablets. PEG 200–600 are liquids while PEG grades 1000 and greater are solids at room

temperatures. PEG is included in FDA IID establishing its use in dental preparations, i.m. and i.v.

injections, ophthalmic preparations, syrups, oral capsules and tablets, topical, rectal and vaginal

preparations. it is also included in Canadian List of Acceptable Non-medicinal Ingredients and in

nonparenteral medicines licensed in UK.

Acrylates:

Acrylate polymers, called as Eudragit (trademark), are widely used coating agents in

pharmaceutical dosage forms. They are synthetic anionic and cationic polymers of dimethylaminoethyl

methacrylates, methacrylic acid, and methacrylic acid esters in different ratios. Eudragit E, RL, RS are

specifically used film formers. The chemical name for Eudragit E is Poly (butyl methacrylate, (2-

dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2:1, for Eudragit RL is Poly(ethyl acrylate,

methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 and Eudragit RS is

Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1.

Polymethacrylate polymers can be used to form matrix layers of transdermal drug delivery systems and

can also be used in the preparation of novel gel formulations meant for rectal administration. Large

concentrations of 5–20% are used to control drug release from a tablet matrix. Eudragit E serves as a

plain or insulating film former having solubility in gastric fluid (at pH<5). Eudragit RL, RS are capable

of forming water-insoluble film coats to obtain sustained-release products. Films formed by Eudragit RL

are more permeable than those formed by Eudragit RS. Eudragit E is commercially available as 12.5%

solution in propan-2-ol–acetone (60: 40). Eudragit RL and RS are copolymers of ammonio methacrylate

with differing amount of ammonium group present. Eudragit RL (Type A) and Eudragit RS (Type B)

have 10% and 5% functional quaternary ammonium groups, respectively. Eudragit RL 30 D and RS 30

D are aqueous dispersions of acrylic acid and methacrylic acid esters copolymers consisting of low

concentration of quaternary ammonium groups. A pH-independent drug release is observed from tablets

film coated with both the polymers. Addition of plasticizers is carried out to improve film properties.

Eudragits are approved as excipient in nonparenteral medicines licensed in UK and in Canadian List of

Acceptable Non-medicinal Ingredients. It is included in FDA IID for use in oral capsules and tablets.

Functional coatings

Functional film coatings, also called as modified-release coatings, are applied to modify the

dosage form so as to achieve a certain required release profile of the API. Enteric coating is applied to

protect API from acidic environment of GIT preventing its release in the stomach. Gastric resistant

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polymers are used to prepare enteric coatings. The enteric coated dosage form remain intact in the acidic

environment of GIT while rapidly dissolve at elevated pH of intestine. The applied enteric coating

depends on the chemical structure of the polymer used. Polymers with carboxylic acid groups (pKa of

3-5) are the most efficient enteric polymers.

Objectives for enteric coating are:

To protect acid-labile drugs from acidic environment of gastric fluid.

To deliver API intended for local action in the intestine,

To protect gastric distress or nausea that may be caused due to irritation from a drug.

To deliver drugs which absorb in the intestine in their most concentrated form.

To provide delayed release part for repeat action tablets. Video Stop

Polyvinyl acetate phthalate (PVAP):

PVAP is used as enteric coating material. It acts as viscosity modifier to produce enteric coats

for products producing a robust film and also applied for sealing of tablet core before sugar-coating

process. Plasticizers can be added to produce a continuous, homogeneous and noncracking film. It

dissolves along duodenum. It is included in FDA IIG to produce sustained action oral tablet and in

nonparenteral medicines licensed in Europe. Also included in Canadian List of Acceptable Non-

medicinal Ingredients.

Cellulose acetate phthalate (CAP):

CAP is one of the frequently used enteric film coating material and serves other purpose as well,

such as, matrix binder for capsules and tablets. CAP coatings dissolve in mildly acidic or neutral

environment of small intestine, resisting prolonged contact with gastric fluid. CAP is used in a

concentration of 0.5–9.0% of the weight of core. A sealer subcoat should be applied to CAP films as

they are permeable to certain ionic matter like ammonium chloride and potassium iodide. CAP is an

established excipient as per the various regulatory authorities and have been included in FDA IID for

use in oral tablets, nonparenteral medicines licensed in UK and in Canadian List of Acceptable Non-

medicinal Ingredients.

Acrylates:

A wide variety of polymethacrylates are available commercially differing in the applications and

properties. Eudragit L and S are the two widely used enteric coated polymers due to the solubility at pH

6–7, protecting drug from releasing in gastric media. These are copolymers of methacrylic acid and

methyl methacrylate, differing in the ratio of free -COOH groups to –COO groups with ester 1:1 ratio in

case of Eudragit L (Type A) and 1:2 in Eudragit S (Type B). They are available in a concentration of

12.5% in propan-2-ol with or without plasticizer (dibutyl phthalate). Eudragit S and FS solublizes at pH

> 7. Tablet coating can be done using S grade while flexible FS 30 D dispersion are used to coat particles.

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Eudragit L 30 D-55 is an aqueous polymeric dispersion of methacrylic acid and ethyl acrylate. Films

prepared, dissolve above pH 5.5 releasing drugs in small intestine. Eudragits are approved by the

regulatory authorities and included in several important documents such as Canadian List of Acceptable

Non-medicinal Ingredients, nonparenteral medicines licensed in UK and FDA IID for use in oral

capsules and tablets. Kollicoat MAE 30 DP and Eastacryl 30 D are aqueous dispersions of copolymer of

methacrylic acid–ethyl acrylate. They can also provide enteric coatings to solid-dosage forms.

Shellac:

Shellac is the common word for refined form of lac, which is a natural polyester resin secreted

by insects. Lac consists of mixture of alicyclic and aliphatic acids. The major components are jalaric,

aleuritic and shellolic acids, and also butolic and kerrolic acids as well. It is used as film-forming agent,

coating agent, matrix forming agent, encapsulating agent and modified-release agent. Shellac has the

advantage of low water vapor and oxygen permeability. It has been accepted for use as food additive in

USA, Europe and Japan, included in the FDA IID for use in oral capsules and tablets, in nonparenteral

medicines licensed in UK for tablets and capsules and in printing ink formulations and in Canadian List

of Acceptable Non-medicinal Ingredients.

Hydroxypropyl methylcellulose phthalate (HPMCP):

HPMCP is cellulose consisting of methyl ethers, 2-hydroxypropyl ethers, or phthalyl esters in

place of hydroxyl groups. It is frequently used in oral formulations in the form of enteric coating material

in granules and tablets. It dissolves in the upper intestine and is insoluble in gastric fluid. It is generally

used in a concentration of 5–10%. HPMCP is available in various grades differing in the degrees of

substitution and also physical properties, graded as HP-50, HP-55 and HP-55S. The number following

‘HP’ designates the pH value (X10) of the solubility of polymer while ‘S’ denotes grade with higher

molecular weight, which produces films that have greater resistance to cracking. It is included in FDA

IIG for use in oral capsules and tablets, in nonparenteral medicines licensed in UK and in Canadian List

of Acceptable Non-medicinal Ingredients.

Plasticizers:

Polymers employed for coating frequently results in brittle films which can cause crack

formation, leading to the failure of functionality of the coating. Plasticizers are the agents added to

prevent internal strain which lead to these defects and hence ensure suitable film properties. Plasticizers

are low molecular weight non-volatile liquids with a high boiling point and insoluble in water.

Appropriate amount of plasticizer should be used so as to reduce the brittleness of the polymer,

efficiently and sticking of the product at the stage of processing or storage is avoided. Plasticizers are

generally used in a concentration range of 5-30% w/w of the dry polymer weight basis. The plasticizer

act by increasing the polymer’s molecular mobility by interpenetrating with the segments of polymer

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chain leading to the decrease in cumulative intermolecular forces present along the polymer chains

causing reduction in cohesion and hence providing a more open structure of the polymer.

Plasticizer can act internally or externally. Internal plasticizing refers to the alteration of the basic

polymer by chemical modification causing variation in the physical properties of the polymer. External

plasticizing refers to the addition of an external plasticizer such as non-volatile liquid or an another

polymer which along with the primary polymeric film former alters the tensile strength, flexibility or

adhesion characteristics of the resulting films.

Opaquant-extenders:

Opaquant-extenders are very fine inorganic powders added to the coating solution to impart

more pastel colors and enhance the film coverage. They mask the color of tablet core. Commonly used

materials as opaquant-extenders are titanium dioxide, magnesium carbonates and magnesium oxide,

talc, aluminum silicate, aluminum hydroxide. Audio Stop

Conclusion

Pharmaceutical excipients deliver drugs through various desirable mechanisms such as immediate

release, sustained–release and site-specific release. Advancement in particle engineering has provided

great avenues for designing the excipients with predefined functionality requirements. Co-processed

excipients exemplifies this arduous innovation, wherein two excipients are co-processed to give products

with enhanced functionality, retaining their favourable characteristics and avoiding their unfavourable

properties. Knowledge of excipients properties is essential when designing or optimizing a dosage form.

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