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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.
Audio Stop
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Excipients for solid dosage form and coating
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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Excipients for solid dosage form and coating
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
Clas
Immediat
e release
Immediat
e release
Immediat
e release
Immediat
e release
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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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Excipients for solid dosage form and coating
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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Excipients for solid dosage form and coating
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.