Current Medicinal Chemistry, 2006, 13, 2535-2563 2535

Drug Excipients
Huba Kalász*,1 and István Antal2

1Department of Pharmacology & Therapeutics, United Arab Emirates, University, P.O.Box 17666, Al Ain, UAE
2Department of Pharmaceutics, Semmelweis University, Budapest, Hungary
Abstract: The therapeutical use of drugs involves the application of dosage forms, serving as carrier systems
together with several excipients to deliver the active ingredient to the site of action. Drug delivery technology
combines an understanding of medicinal chemistry and pharmacology with the skill of formulation, aiming
the preparation of improved pharmaceuticals. The recently introduced Biopharmaceutical Classification
System provides guidance for dosage form design, taking the molecular and physico-chemical properties of
drugs into consideration through their solubility and permeability characteristics. Pharmaceutical excipients
used for oral dosage form have been traditionally assumed as being inert. However, recent experience and new
results have shown that they can interact with the active drug ingredient, affecting its dissolution, absorption
and bioavailability.
Classification of the excipients is based on their role in the pharmaceutical formulation and on their
interactions influencing drug delivery, based on their chemical and physico-chemical properties. The main
classes are the antioxidants, coating materials, emulgents, taste- and smell-improvers, ointment bases,
conserving agents, consistency-improvers and disintegrating materials. Some of the excipients may serve
multiple purposes; for example, methylcellulose is a coating material, is applied in the preparation of
suspensions, to increase viscosity, as a disintegrating agent or binder in tablets.
The aim of this paper is to review the drug-excipients with respect to their chemistry, importance and
interactions altering the pharmacokinetics of the drug substances. Emphasis will be given to two major classes
of excipients: the antioxidants and disintegrants (substances facilitating disintegration of the drug tablets in
the gastro-intestinal tract). Details will be given on the mechanisms through which they can alter drug
effectiveness and tolerance, and control their application. Examples and references will be given for their
analysis.
Keywords: Excipients, pharmaceutical excipients, role of excipients, analysis of excipients, antioxidants.

1. INTRODUCTION
Drugs have almost never been administered alone but
rather in the form of drug products. The term of drug
product refers to the finished dosage form (e.g. capsules,
solutions, tablets), containing the active drug ingredient in
association with the excipients (usually inactive non-drug
ingredients) that make up the vehicle or formulation matrix.
The leaflet in the box (container) of the drug product, and
the cover of the container of a drug product gives
information on its form, dose and the excipients. For
example, Silomat, an antitussive drug product (indicated for
the symptomatic treatment of irritable non-productive cough)
of Boehringer (Ingelheim, Germany) contains 40 mg of the
active drug either in one sugar-coated (s.-c.) tablet or in 10
mL syrup. The s.-c. tablets contain (detailed in the leaflet)
dibasic calcium phosphate, lactose, polyvidone 25, soluble
starch,; maize starch, magnesium stearate, shellack, talc,
acacia, erythrosine lacquer, titanium dioxide, polyethylene
glycol and canuaba wax as the excipients. Similarly,
information supplied with all other medicines, regardless
whether they are available only by prescription or over-the-
counter (OTC), provide the detailed composition of the
*Address correspondence to this author at the Department of
Pharmacology and Pharmacotherapy, Semmelweis University, 1089
Budapest, Nagyvárad tér 4, Hungary; E-mail: huba.kalasz@gmail.com
tablet, syrup, or any other form (but practically never the
exact weight amount of the excipient content).
Excipients have multiple functions in the drug products,
serving as chemical or physical stabilizers, preservatives and
buffers, and some of these are included in the majority of
drug formulations (Fig. 1). Other excipients are improving
the characteristics of certain formulations. Excipients used in
tablets also serve as diluents, binders, disintegrants,
lubricants, glidants, surfactants, dye- and flavoring agents:
they permit the efficient manufacturing of the compressed
tablets, affect the physical and chemical characteristics of the
active drug ingredients and their bioavailability.
Formulation of pharmaceuticals is an essential tool.
There are various excipients that serve as important
ingredients added to the active drug materials. Some
excipients (antioxidants, preservatives and conserving
agents) save the original composition of the drug; other
excipients (coating materials, emulsifiers, ointment bases,
binders/disintegrants, solubilizers) improve absorption of the
drug at the proper site of the body, while some other
excipients (flavoring and coloring agents) help the patients
to take the properly formulated drugs without any aversion.
The very same substances have also been used as
ingredients of certain foods, soft drinks and high-energy
drinks. This is the reason that an essential part of the
analytical methods is also used to detect and determine the
excipients in food.

0929-8673/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.

2536 Current Medicinal Chemistry, 2006, Vol. 13, No. 21
Fig. (1). Role and functions of drug excipients to ensure quality, safety and efficacy of the active drug.
Practically, all types of analytical methods can be
utilized for quality control of the excipients. However, their
quantitative determination is mainly carried out using
chromatography and electrophoresis. Chromatographic [1]
and/or electrophoretic [2] methods are detailed for excipients
that are used also as medicines. The particular procedures
have also been widely published; the electronic literature
references [3-5] can give valuable help.
Obviously, many excipients are used as even basic carrier
constituents (Table 1) constructing the dosage form
(solvents, liquid vehicles, ointment and suppository bases,
tablet and capsule diluents, propellants for aerosols, etc.). In
addition, processing aids may exert particular technological
functions for the good manufacturability of the proper
dosage form (e.g. homogeneity of powders, flow of
granules, compression of tablets, etc.) Varying the quality
and quantity of the excipient incorporated, the formulator is
able to optimize the characteristics of the final
pharmaceutical product [6]. Consequently, the traditional
concept of excipient has undergone considerable evolution
from simple, chemically and pharmacologically inert vehicle
to essential functional agent, guaranteeing and optimizing
the performance of the medicinal preparation [7].
In the case of tablets, excipients (such as diluents, binders,
disintegrants, lubricants, glidants, surfactants, dye- and
flavoring agents) are used to:
• Permit the efficient manufacturing of the compressed
tablets
Kalász and Antal
• Affect the physical and chemical characteristics of the
active drug ingredients
• Affect bioavailability.
This paper outlines the major groups of excipients with
some information on the most widely used substances.
2. EXCIPIENTS
An excellent source of information on pharmaceutical
excipients is the book of Bugay and Findlay [8]: it devotes
two pages to each major excipient, giving also their infrared
(IR), Raman, and nuclear magnetic resonance spectra. The
book includes a carefully compiled list of over 300
excipients (among them: the water).
The book of Kotkoskie and Wiener [9] outlines the
toxicity and safety requirements for pharmaceutical and food
excipients.
The majority of excipients may show incompatibility
with strong acids, strong bases, ferro- and ferri-ions, certain
other metals and metal ions.
3. DETAILED INFORMATION ON SELECTED
GROUPS OF EXCIPIENTS
3.1. Antifrictional Agents and Antiadherents
Formulation of tablets and capsules often requires
lubricants and antiadherents to avoid friction between the
Drug Excipients Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2537

Table 1. Classification of Carrier Constituents to Prepare Dosage Forms

Dosage form Carrier constituent Common excipients

Oral diluting agents

- aqueous vehicles Purified water, syrups, mucilages
- hydroalcoholic vehicles diluted alcoholic solutions,
Liquid aromatic elixirs (oil in diluted alcohol)

Diluting agents for injections Sterile water

- aqueous vehicles ethanol, liquid polyethylene glycol
- water miscible vehicles Fatty oils of vegetable origin (corn, cottonseed, peanut, sesame, etc.),
- nonaqueous vehicles fatty ester (ethyl oleate), polyols (propylene glycol)

Ointment bases
- hydrocarbon bases Hard and soft paraffin (yellow and purified white petrolatum),
- fats and oil bases cetyl ester wax, vegetable oils
- absorbent bases lanolin anhydrous (wool fat)
- emulsion bases cetostearyl alcohol, glyceryl monostearate, lanolin, stearic acid
Semisolid - water soluble bases polyethylene glycols (macrogols, carbowaxes)
- hydrogels cellulose derivates, polysaccharides, polyacrylates (carbomer)

Suppository bases
- fatty bases Hard fat triglyceride esters,
- water-soluble or dispersible bases polyethylene glycols
-hydrogel bases polymers such as polyvinyl alcohol, polyacrylates (carbomer), glycerynated gelatin

Aerosol Propellants to dispense dissolved or dispersed Hydrocarbon blends (n-butane, propane, isobutane, compressed gases (nitrogen,
colloidal particles nitrous oxide, carbon dioxide), liquified gases (e.g. hydrofluorocarbons)

Solid Diluents (filler) for powders, granules, tablets Starch, powdered cellulose, microcrystalline cellulose, calcium phosphates, lactose,
and capsule sucrose, mannitol, sorbitol, etc.

powder and the metal surfaces at the time of their
manufacture [10].
Water-insoluble lubricants are as follows: calcium
stearate, fumaric acid, glyceryl behenate, glyceryl
palmitostearate, hydrogenated vegetable oil, magnesium
stearate, stearic acid, and zinc stearate. Water soluble
lubricants are: sodium lauryl sulfate, polyethylene glycol
4000 or 6000, sodium stearyl fumarate, and starch.
To reduce friction between the powder and metal, a
complete hydrocarbon layer is required on the solid particles.
However, the increased hydrophobicity slows disintegration
and dissolution, and has been shown to cause bioavailability
problems. In addition, the direct contact between powder
particles decreases and the tablet structure and strength is
weakened [11]. The tablet properties depend on the
homogenous distribution of the lubricant, therefore the
homogenization is of first of importance [12].

Table 2. Primary Instability Problems in Pharmaceutical Dosage Forms

Dosage form Physical instability Manifestation of inadequacy

Solutions Discoloration Possible chemical decomposition in the

background

Adsorption to container wall Loss of potency

Precipitation intolerable

Suspensions and Sedimentation, caking, particle agglomeration, crystal growth and Improper content uniformity due to inhomogeneity
polymorphic changes and loss of dosing accuracy
Emulsions sorption
Creaming or cracking

Oinments and Changes in viscosity/consistency, hydration state, caking, bleeding Improper content uniformity, change in drug
suppositories delivery

Tablets Change in Brittleness or

- moisture content caking, and
- hardness improper drug delivery
- disintegration
- dissolution profile (extent and rate of release)

Capsules Changes in shell for Appearance

- moisture content chemical instability due to moisture transfer
- mechanical strength improper drug delivery
- dissolution
2538 Current Medicinal Chemistry, 2006, Vol. 13, No. 21
Magnesium stearate (0.25% and 5.0%) is a useful
lubricant when particles are compressed into tablets or filled
into capsules. A disadvantage of magnesium stearate may be
the reduction of the dissolution rate; however, this slow
down is generally overbalanced by the use of simultaneous
use of a wetting agent, such as a water-soluble surfactant or
hydrophilic diluents [10].
X-ray fluorescence spectroscopy was a powerful
instrumental method to detect the distribution and
homogeneity of magnesium stearate in solid dosage forms
[13].
Magnesium lauryl sulfate has been recommended as a
water-soluble substitute for magnesium stearate with wetting
action [14].
Excellent antiadherent agents are talc, magnesium stearate
and corn starch.
3.2. Antioxidants as Chemical Stabilizers
3.2.1. Function of Excipients on Stability
Products may contain excipients serving as stabilizers for
many reasons (Table 2). The stability of a medicinal
preparation relates to the resistance to the various chemical,
microbiological and physical changes to retain the required
quality during manufacture, transport, storage and
application.
Obviously, it is essential to avoid the chemical
degradation of the active ingredient, since changes in the
chemical composition may cause the loss of potency or the
increase of unwanted effects due to generation of toxic
molecular entities. Microbiological stability states that
sterility or resistance to microbial growth is retained
according to the specified requirements. Physical properties
of the preparation include the appearance, palatability,
uniformity (e.g. sedimentation of suspension related to
precision and accuracy of the dosage), and biopharmaceutical
profile.
3.2.2. Excipient Impact on Chemical Stability
The function of excipients to prevent or prolong chemical
degradation is determined by the factors that cause the
molecular transformation of drug substances [15].
- environmental components (air, water vapour, and
sunlight)
- interactions between adjacent ingredients to the drug
or between functional groups on the same molecule
- stresses during conversion to the dosage form
(sterilization, size reduction, compaction, etc.)
Selecting the appropriate excipient, even unstable drugs
can be incorporated into viable medicinal products.
Antioxidants belong to one of the most important
ingredients used for pharmaceutical formulations. In aqueous
solution, their relatively low redox potential is the basis of
their salvage mechanism, consuming oxygen faster than the
active drug in the formulation. Furthermore, antioxidants
may bind the free radicals generated during oxidations in
lipophilic media.
Kalász and Antal
Antioxidants serve to hinder (or at least to slow down)
oxidation of sensitive drugs and of some excipients required
for effective use, e.g. used as the basis of ointments.
Effective prevention of oxidation can only be reached by the
use of two different types of antioxidants: the so-called real
antioxidants directly binding oxygen, and the synergists,
serving to activate the real antioxidants.
3.2.3. Way of Antiooxidant Contribution to Chemical
Stability
Antioxidants are generally phenolic compounds, while
the synergists can be organic acids (Fig. 2). The salvage
mechanism starts with formation of a phenoxyl radical that
forms a stabile redox system with its parent phenol. The
synergist supplies its hydrogen to the phenoxyl radical part
to reform its reductive state. The process results in
consuming the energy rich peroxides to stop the chain
reaction.
Antioxidants and synergists of general use are ascorbic
acid; ascorbyl palmitate; butylated hydroxyanisole; butylated
hydroxytoluene; fumaric acid; maleic acid; sodium
metabisulphite; propyl gallate; alpha tocopherol. A wide
scale of antioxidants can be quantitatively determined using
HPLC [1] and/or capillary electrophoresis [2].
3.2.4. Major Antioxidant Excipients
Both ascorbyl palmitate and ascorbic acid are sensitive to
water (are to be kept in tightly closed containers). They are
stable, but decolorisation occurs under the effect of light and
high temperature. Ascorbyl palmitate is a typical lipophilic
compound: it is practically insoluble in water, and its lipid
solubility is good, about one part of ascorbyl palmitate in
3300 parts of oil. Due to its proper solubility and good
antioxidant ability ascorbyl palmitate is widely used in oil
constituents as antioxidant synergist. Ascorbic acid serves in
pharmaceutical preparations as both vitamin and synergist
antioxidant. It has a low toxicity (p.o. LD50 is over 3 g/kg
using rat or mice). Both ascorbyl palmitate and ascorbic acid
are incompatible to the salts of heavy metals, basic pH, and
compounds easy to reduce. Ascorbic acid can be identified
using spectroscopic methods, such as IR and NMR. Its
determination in pharmaceutical preparations also includes
stability and dissolution tests. Quantitative determination of
ascorbic acid is done using HPLC [16,17]; a reference source
[3] lists 343 references. Okamoto et al. [18] reported on the
simultaneous determination of ingredients in a cold
medicine, including also ascorbic acid, by cyclodextrin-
modified microemulsion electrokinetic chromatography.
Ascorbic acid is incompatible with oxidizing agents, and the
interactions are catalyzed by copper and iron ions.
Butylated hydroxyanisole and butylated hydroxytoluene
are widely used as antioxidant additives to pharmaceutical
preparations, and also as additives to various foods for the
same reason. Butylated hydroxyanisole is a mixture of
butylated-2-hydroxyanisole and butylated-3-hydroxyanisol
(or using their chemical name: 2-tertier-butyl-4-metoxy-
phenol and 3-tertier-butyl-4-metoxyphenol). Their separation
is overviewed by Prosek et al. [19]. The same compounds
exist on certain trade names, such as TENOX BHA;
EMBANOX BHA; NIPANTIOX BHA; NIPANOX BHA;
SUSTANE; as well as on certain code names) Their use is
generally done in combination with other antioxidants, such
Drug Excipients
R R
HO LOO
R R
R O CH3
Tocopherol
Ascorbyl radical
OH
LOO
CH3
H3CO
H3C CH3
BHA
Ascorbyl radical
Fig. (2). Synergist effect of ascorbic acid as co-antioxidant for regeneration of oxidized tocopherol and butylated hydroxyanisole.
as ascorbic acid, citric acid, gallates, etc. Widely used
concentration of butylated hydroxyanisole is in the range of
10 to 200 ppm (parts per millions). Its p.o. toxicity is 2.2
mg/kg (rats) or 2.0 mg/kg (mice); however, the
recommended human oral dose cannot overdue 0.1 mg/kg.
This value concerns the gross amount taken including
pharmaceutical products, crackers, etc. The real danger is the
consequence of the various names of the butylated
hydroxyanisole, and its uncontrolled ingestion from various
sources. Incompatibility is with oxidizing agents, iron ions.
Butylated hydroxytoluene has a slightly higher p.o.
toxicity (0.89 mg/kg for rats or 0.8-1.6 mg/kg for mice),
otherwise its indication and application fields and
application levels are very similar to those of butylated
hydroxyanisole. Its synonyms are BHT; Ralox BHT; Tenox
BHT; Embanox BHT; Antioxidant 30; Agidol; Vianol;
Ionol CP; Annulex BHT; Nipanox BHT, etc. It is
incompatible with strong oxidizing agents and ions of heavy
metals.
Butylated hydroxyanisole and butylated hydroxytoluene
can be determined by various chromatographic methods,
such as gas or liquid chromatography (mainly HPLC),
capillary electrophoresis and electrochromatographic
techniques. Recently a review has been published on their
Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2539
LOOH O
R O CH3
Tocopheroxyl radical
Ascorbate
O
LOOH
CH3
H3 CO
H3 C CH3
BHA radical
Ascorbate
determination [20]. Detection is possible using UV
absorbance, but mass spectrometry enhances both sensitivity
and specificity [21].
Fumaric acid and maleic acid are also antioxidants.
Combination with some other antioxidants for pH
adjustments and taste improvement of liquid pharmaceutical
formulations complete their application. Fumaric acid is also
called as allomelanic acid, and it is used in the treatment of
psoriasis. The p.o. LD50 of fumaric acid and maleic acid are
10.7 mg/kg and 4.73 mg/kg in rats, respectively. These
organic acids can be determined by HPLC analysis using an
Aminex HPX-87H column, thermostated at 65 °C, and with
diluted 4 mmol sulfuric acid used as mobile phase. Fumaric
acid and other acids were identified and quantified using a
UV detector with the wavelength set at 210 nm and by
comparison of the retention times and peak areas with
standard solutions of the known organic acids. Results of
reproducibility study of the chromatographic separation of
organic acids, expressed as RSD%, were as follow: 0.27 for
citric acid, 0.18 for shikimic acid and 0.16 for fumaric acid
[22]. Maleic acid can be determined using NMR
spectroscopy [23] and HPLC [24]. Recently ion-suppression
reversed-phase HPLC had also been used to determine
maleic acid and other organic acids [25]; this is a reliable
2540 Current Medicinal Chemistry, 2006, Vol. 13, No. 21
method for the simultaneous determination of the oxalic
acid, fumaric acid, maleic acid, and succinic acid content in
tartaric acid and malic acid . HPLC is carried out using a
Nova-Pak C18 column by isocratic elution, using water
adjusted to pH 2.10–2.15 with perchloric acid, and detection
by UV absorbance at a wavelength of 210 nm. Maleic acid is
incompatible with oxidizing agents.
Methyl hydroxybenzoate is used in a high number of
liquid oral pharmaceutical preparations, such as emulsions,
syrups, and ointments. Its concentration should be higher
when used in an aqueous phase. Methyl hydroxybenzoate is
usually determined using HPLC [1], for example in cough-
cold syrups [23] and nasal drops. Electrokinetic
chromatography presents a good tool for its determination in
pharmaceutical preparations [26] and cosmetics [27].
Propyl gallate has a good solubility in glycerol and
propylene glycol. Its possible concentration in ointments
covers the range of 10 through 2000 ppm, with 1500 ppm
(0.15%) as the most likely concentration. Its determination
is possible using HPLC [28]. Propyl gallate serves as an
antioxidant synergist, together with citric acid and
polyphenols. It is incompatible with bases and metals.
3.3. Binders
Binders increase cohesion and aggregation of a substance
mixture in tablets. Various solvents, semi-solid compounds
and solids can serve as binders. One classification divides
binders into several groups, such as liquids (e.g. water,
ethanol); sugar-syrups; solutions of natural macromolecules
(starch, gelatin); solutions of semi-synthetic or synthetic
macromolecules (cellulose derivatives, polyvinyl alcohol);
and dry binders (cellulose derivatives, gelatin, polyethylene
glycol 4000 – 6000).
A basic requirement is the homogenous distribution of
the drug with the binders. Some generally used binders are:
acacia (it is also an emulsifier), alginic acid (also a viscosity-
increasing agent), bentonite (also a viscosity-increasing
agent), dextrin (also a diluent for tablets and capsules),
ethylcellulose (also a coating material), hydroxyethyl
cellulose (also a coating material), hydroxypropyl cellulose
(also a coating material), sodium starch glycolate (also a
viscosity increasing and disintegrating agent), starch (also a
disintegrant), maltodextrin (also a diluent), magnesium
aluminum silicate (also a disintegrant), methylcellulose (also
a coating material), sodium alginate (also a viscosity
increasing and disintegrating agent), carbomer (also a
viscosity increasing agent), methacrylic acid polymers (also
coating materials), Povidone (also a consistency- and
viscosity increasing agent), and gelatin (also a coating
material).
3.4. Excipients for Convenience and Tolerability
Application of dosage forms should ideally be free of any
undesired adverse effects including tissue irritation or pain,
which concern is particularly important for large and small
volume parenterals, eye/nasal/ear drops. Buffers and tonicity
agents are required to provide the dosage form with
tolerability when the drug is delivered to the systemic
circulation or to a localized region of the human body with
Kalász and Antal
sensitive mucous membranes of organs such as eye, ear, and
nose. Several acidifying agents (citric acid, fumaric acid,
hydrochloric acid, phosphoric acid, tartaric acid, etc.) and
alkalizing agents (ammonia solution, ammonium carbonate,
diethanolamine, diisopropanolamine, sodium bicarbonate,
sodium borate, etc.) are used as well known ingredients to
warrant physiologically tolerable pH.
To avoid nonphysiological concentration of dissolved
solutes, commonly dextrose, sodium chloride, and mannitol
are used for tonicity adjustment. However, the colligative
property of solutions should be taken into consideration, as
each ingredient may contribute to the overall osmotic
pressure. On the other hand, the direct osmotic effect of
ingredients may also apply to therapeutic purposes, but than
the ingredients (glucose, glycerine, magnesium salts etc.)
play the active role (e.g. magnesium sulfate as an osmotic
laxative). Dextrose can be also used as a density modifier for
special case of formulating spinal anaesthetics.
3.5. Buffering Agents, Tonicity Agents
The pH of the pharmaceutical preparations has to be adjusted
considering the:
• physiological tolerance,
• optimum of effect, and the
• stability of the active drug ingredient.
Various substances are used as buffering and tonicity agents;
the most important compounds are listed below, indicating
their various uses:
Citric acid is used for the pH adjustment of solutions,
and also as a flavoring agent. It is used in the preparation of
effervescent tablets.
Dibasic sodium phosphate is used for the pH adjustment
of solutions, and also to make solutions isotonic.
Hydrochloric acid is used for pH adjustment (acidifying).
Lactic acid is used for the pH adjustment of preparations
for injection.
Monobasic sodium phosphate is widely used for the pH
adjustment of solutions.
Potassium citrate is used for the pH adjustment of
solutions, and also as a flavoring agent. Its usual
concentration is 0.3-2.0%.
Sodium bicarbonate is used for the pH adjustment of
pharmaceutical preparations; it is particularly used in
effervescent tablets and granulates, and also serves as a
disintegrant, as well as an antacid.
Sodium citrate is used for the pH adjustment of
solutions, in concentrations 0.3-2.0%.
Tartaric acid is widely used, especially in effervescent
tablets, combined with bicarbonates. It plays an important
role in pH adjustment as an acidic component. A 1.5%
aqueous solution of tartaric acid gives a pH of 2.2, and its
3.9% solution is isotonic with the human serum.
Further substances also used as buffering or tonicity
agents are dextrose (also a diluent); diethanolamine (also an
emulsifier); glycerin (also a solvent); mannitol (also a
Drug Excipients
diluent); monoethanolamine (also an emulsifier); potassium
chloride (also a diluent); triethanolamine (also an
emulsifier), and sodium chloride (also a diluent).
3.6. Carrier Constituents
For liquid dosage forms, ideally water soluble drugs
should be diluted with the agent which is the best solvent
for the drug, hence the categories are aqueous,
hydroalcoholic, and alcoholic diluents. For injections, the
preparations include various sterile aqueous solutions of
electrolytes and/or dextrose. For intramuscular
administration, nonaqueous diluting agents can dissolve oil-
soluble drugs or suspend the water-soluble one.
Among ointment bases, the chemically inert hydrocarbon
bases have a wide range for melting points and consistency
[29]. Vegetable oils are suitable to decrease the melting
temperature, and soften the ointment and animal fats. For
fats and fatty oils, free acid value, saponification value, ester
value, hydroxyl value, iodine number are the significant
characteristics to be tested according to methods listed in
pharmacopoeias. Anhydrous lanolin can be assigned as an
absorbent ointment base, because it is capable to emulsify
considerable quantities of water due to its cholesterol and
lanolin alcohol content [30].
Lanolin is an emulsion ointment base containing
significant amount of water (30%) as w/o (water/oil)
emulsion. Cetostearyl alcohol, glyceryl monostearate,
lanolin, and stearic acid are able incorporate additional water,
thus to produce emulsion sytems, which creams can be
removed from skin [31].
Oily silicones are for barrier creams due to high
hydrophobicity and water repellant property. Dimethicone as
a polydimethylsiloxane is obtained by hydrolysis and
polycondensation of dichlorodimethylsilane and
chlorotrimethylsilane [32]. Polyethylene glycols (PEGs) are
widely used in a variety of pharmaceutical formulations
including ointments, suppositories and also parenterals and
solids. In polyethylene glycols described with the
HOCH 2 (CH 2 OCH 2 )m CH 2 OH formula, m represents the
average number of oxyethylene groups. Polyethylene glycols
are water-soluble and are easily removed from the skin by
washing, making them useful as ointment bases [33].
The melting point of macrogols is above the body
temperature, thus they are functioning dissolving the drug in
the rectal fluid [34].
Polyethylene glycols are suitable to prepare solid
dispersions, where the aqueous solubility or dissolution
characteristics of poorly soluble compounds is increased [35]
Their molecular weight can be determined in pharmaceutical
preparations by gel permeation chromatography [36].
Pegylation, which involves attaching specific PEG polymers
to molecules, is a proven method for improving the
performance of peptides and proteins [37].
For suppositories, glyceride type fatty bases or water-
soluble polyethylene glycols (macrogols, carbowaxes) [38]
are applied. Although the hydroxyl number of hard fat
(Adeps solidus) due to presence of mono- and triglycerides
may cause stability problem (e.g. hydrolysis of aspirine).
Hydroxyl values indicate the risk of interaction with
chemically reactive compounds, and are also related to drug
Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2541
release and absorption rates [39]. Peroxide values give a
measure of the resistance of the base to oxidation. The
melting range is between 33-37 ºC, and the acid content is
lower than for the cocoa butter, which is advantageous
considering stability [40]. Cocoa butter is no longer
recommended due to its polymorphic changes.
Among gelling agents, carbomers are synthetic high-
molecular-weight polymers of acrylic acid that are cross-
linked with either allylsucrose or allyl ethers of pentaery-
thritol. Carbomers swell in water forming a three-dimen-
sionally crosslinked gel. The preparation of gels involves
first dispersion and then neutralization by the addition of a
base (e.g. sodium hydroxide, triethanolamine). The aqueous
gels may be sterilized by autoclaving, too [41]. Due to its
bioadhesive properties, carbomer polymers are used to
prepare patches as controlled release dosage forms [42].
Propellants (see later) are responsible to dispense the
liquid or solid colloidal particles. According to the Montreal
Protocol, the use of chlorofluorocarbons has been prohibited
from January 1996, but this prohibition does not restricts
the essential uses such as existing pharmaceutical
formulations for which no alternative chlorofluorocarbon-free
product is available [43]. New products need the use of
environmentally acceptable propellants, such as hydrocarbon
or a compressed gas.
Diluents ensuring the desired bulk volume of the solid
dosage form must not irritate the body, and their toxicity
should be low. Proper distribution of tiny amounts of the
active drug is usually done using diluents. Moreover,
preparation of tablets by pressing should be enhanced by the
use of adequate diluents, which can additionally improve the
stability of the drug. One of the most usually applied
combination of diluents is lactose—saccharose (9:1) with an
additional amount of starch. Silica compounds belong to
another type of diluents. Excipients used as diluents can
have a definite influence on the possible effect of drugs. An
example is the phenytoin intoxication of epileptic patients.
When sodium phenytoin was used with capsules containing
lactose, clinical feature of phenytoin overdose was developed
[10]. These patients were earlier treated with the same dose
of phenytoin in calcium sulphate dihydrate without the sign
of overdose. The possible difference between the diluents
calcium sulphate dihydrate and lactose was in the poor
solubility calcium—phenytoin complex that showed
decreased gastrointestinal absorption. The “mechanical”
transfer of the dose and frequency of administration from
lactose to calcium sulphate excipient achieved higher blood
level and sometimes toxic symptoms.
Dextrin is composed from glucose units, and it is a
widely used diluent and/or binder at industrial scale
production of tablets and capsules.
Glucose is widely used as sweetener, tonicity agent. It is
also a binder and diluent when tablets are prepared. Glucose
content has a basic role in vaginal tablets, when it improves
the glycogen incorporation and restoring the pH of vagina.
Parenteral use of glucose serves therapeutic energy supply.
Lactose has both a water-free and a water-containing
(lactose monohydrate) form. Both forms are used at
preparing tablets. Its mixture with starch is a generally used
diluent.
2542 Current Medicinal Chemistry, 2006, Vol. 13, No. 21
Sucrose is a diluent, flavoring component, and
sometimes a binder. It is also used as part of coating
mixture.
Sorbitol is used as a diluent in tablet formulations
prepared by either wet granulation or direct compression. It
is very hygroscopic and particularly useful in chewable
tablets due to the sweet taste and cooling sensation [44].
Calcium phosphate is used at preparation of tablets and
capsules. Its further use is important as basic constituents
and binder of powders made by dry granulation. It is
incompatible with tetracycline antibiotics.
Light kaolin is often used in the preparation of powders,
and sometimes in tablets as binder.
Calcium hydrogen phosphate is a widely used diluent for
preparing both tablets and capsules. A specially crystallized
calcium hydrogen phosphate has a special tixotropic
behavior, it is commercialized under the trade name of
Encompress ® . It can have either phosphor-supplier or
calcium-supplier function, and it is one component of tooth
pastes. It makes a delayed absorbance of tetracycline and
indomethacin.
Calcium carbonate and calcium sulfate are also diluents,
and calcium carbonate is used in tooth pastes.
Potassium chloride and sodium chloride are diluent of
tablets and capsules, they are also widely used to adjust the
parenteral and ophthalmologic solutions to be isotonic.
Potassium chloride has a beneficial therapeutic effect in the
case of hypokalemic patients.
Heavy- and light magnesium carbonate, as well as
magnesium oxide are diluent. Magnesium carbonate is an
antacid (in a dose of 250 or 500 mg), while its laxative
effect is significant in a dose of 2 to 5 g.
Maltodextrin is a nonsweet powder form mixture of
polymers consisting of D-glucose units prepared by partial
hydrolysis of starch. It is freely soluble in water, and
maltodextrin grades with a high dextrose equivalent value
are particularly useful in chewable tablet formulations [45].
Maltodextrin may undergo Maillard reactions with amino
acids to produce yellowing or browning under certain pH
and temperature conditions [46].
Maltodextrin serves a diluent in making both dry tablets
(at a content of 2% to 40%) and at wet granulation (3% to
10%). It is also used to prepare film coating, increase the
viscosity of certain solutions, as well as to avoid
crystallization of syrups.
3.7. Chelating Agents
Various chelating agents, such as edetic acid and edetates
are generally used as antioxidant synergists, sequestering
trace amounts of metal ions in order to inhibit catalytic
oxidation reactions. Edetic acid and edetates may be used
alone or in combination with primary antioxidants, the usual
concentration employed being in the range 0.005–0.1% w/v
[47].
The use of cyclodextrines as complexing agents for
stability enhancement is limited to cases when the reactive
groups are accommodated in the cyclodextrin cavity
Kalász and Antal
hindering inter- or intramolecular reactions. Cyclodextrin
hinders the oxidative degradation of vitamin D 3 by
inclusion, but in the opposite, the incorporation in
cyclodextrin accelerates vitamin K decomposition [48].
When the labile guest molecule will not be accommodated
within the cyclodextrin cavity, the complexation has not any
benefit [49].
3.8. Coating Substances
A wide range of compounds can be used as coating
substances, such as acryl acid esters; carboxymethyl
cellulose sodium; cellulose acetate phthalate; cetyl alcohol;
Carnauba wax; ethyl cellulose; gelatin; glucose;
hydroxyethyl cellulose; hydroxypropyl cellulose;
hydroxypropyl methyl cellulose; hydroxypropyl methyl
cellulose acetate succinate; hydroxypropyl methyl cellulose
phthalate; maltodextrin; methyl cellulose; microcrystalline
wax; polymethacrylates (Eudragits); polyvinyl alcohol;
Shellak; saccharose; talcum; titan dioxide and zein.
The classification of coating materials can be based on
their functions such as film-producers, softeners, adhesivity-
inhibitors, and syrups for dragee-making, or polarizing
agents.
Historically, the first pills were coated with mucilage,
honey and even silver by Avicenna to cover unpleasant taste
or odour, and imparting a more esthetic appearance [50].
From middle of the 19th century, sugar coating in pans
was the traditional method for dragee making, which
required a considerable expenditure of time and labor.
Traditional sugar coating can be divided into multistage
steps: sealing, subcoating, smoothing, coloring, polishing,
and printing, where different excipients are used.
Sealing is required to separate the ingredients from water
applied in the sugar syrup. Sealing coats usuallly consist of
alcoholic solutions of resins such as shellac, zein, cellulose
acetate phtalate or polyvinyl acetate phtalate.
Subcoating is performed by repeated layering a gum (e.g.
acacia or gelatin in the binder solution) as subcoating syrup
(filler syrup) and dusting powders (e.g. calcium carbonate,
titanium dioxide, talc, sucrose, etc.) alternatively.
Smoothing of surface roughness can be accomplished by the
application of a 60-70% syrup solution. If required,
colorants and pigments can be incorporated into the syrup
solutions for color coating of cores. The achieve final
elegance, sugar coated tablets are treated by applying
mixtures of waxy polishing materials (beeswax, carnauba
wax, solid paraffin, polyethylene glycol) as powders or as
dispersions in organic solvents.
The protective barrier function of the sugar coating
depends on the pore size of the coat formers, the use of
dense crystals for dusting powders may decrease the gas
(oxygen and vapour) penetration. There is a danger for the
inversion of disaccharide sucrose below pH=6 and at
temperature increase. The crystallization behaviour can cause
also stability problem, but the presence of other sugars
(glucose, lactose, etc.) may delay the crystallization of
sucrose. Liquid glucose prepared by the incomplete
hydrolysis of starch can be used to retard the crystallization
of the sucrose.
Drug Excipients Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2543

Sucrose can be replaced with other sugars (glucose, invert
sugars) and sugar alcohols (mannitol, sorbitol, for example
glucose syrups have lower viscosity. Benefits of mannitol
and sorbitol are that they do not contain reactive aldehyde
groups and are sugar-free. Nevertheless, sorbitol is very
hygroscopic, hence the coatings may tend to become soft
during storage. The semisynthetic sugar derivatives maltitol
and isomalt are advantegous considering reduced calorie,
missing of cariogenic action, inertness and low
hygroscopicity.
Hot sugar coating can be carried out without the
application of solvents by dispersing preferably
multiparticulates (beads) in the molten coating formers. For
fast dissolving dosage forms mixtures of xylitol and sorbitol
can be sprayed them onto the solid surfaces, because they are
stable above their melting point.
Film-producers may be soluble in inorganic or organic
solvents. Examples are: hydroxyethyl cellulose;
hydroxypropyl cellulose; Polyvidone, Luviskol VA64® ,
ethyl cellulose; Shellak; cellulose acetate phthalate;
hydroxypropyl methyl cellulose phthalate and acrylic acid
esters. Three types of the coating materials, such as cellulose
ethers; polyvinyl acetats and polymetacrylates are shown
here (Tables 3, 4, 5) in details. The Eudragit® group
represents acrylate dispersions: Eudragit® RL and Eudragit®
RS are soluble in organic solvents and swollen and
insoluble in water at Eudragit® E is soluble in organic
solvents and swollen and soluble in water at acidic (below
pH5) Eudragit® E 30D and Eudragit® L 30D serve to avoid
the use of organic solvents. Film-producers mean the
application of polymers, which are deposited on the cores
usually by spraying of a solution or dispersion, in the form
of solution or dispersion in which the polymer is dissolved
or suspended. After drying of the solvents or dispersing
agent the film-coating materials remain on the cores as a
coherent, dense film above the so-called minimum film-
forming temperature. The reasons for film-coating can be
summarized as follows [50-54]:
- protection of the active ingredient from the
environment (light, air, moisture),
- increasing the mechanical strength of solid dosage
form,
- taste and odor masking,
- ensuring product identification (e.g. with colorants),
- modifying the drug release.
The film-forming polymers can be classified according to
objective of the coat such as protective coatings and
modified release film-coatings. Among the latest, enteric
coatings may serve to protect gastrointestinal mucosa against
the drug, or can keep the drug stable in the digestive fluids.
In addition, sustained release coatings involve the use of
polymers with restricted water solubility or permeability to
control drug delivery [55].
Among enteric coating polymers, historically formalin
treated crosslinked gelatin was used as the earliest, but the
polymerization coud not be controlled for standardized drug
release rate. Zein is a prolamin obtained from corn and it
dose not dissolve in water under pH 11.5, but it is soluble
in aqueous alcohol or solutions or aqueous acetone
solutions.
Shellac is obtained by purification of the resin derived
from insects and contains a mixture of aliphatic (mainly

Table 3. Cellulose Derivatives Commonly Used as Film-Forming Polymers

H2C OR
H O O
H
OR H
O H

H OR
n
R

Hydroxypropyl methylcellulose (HPMC) -CH3

-CH2-CH(OH)-CH3

Hydroxy-ethyl-cellulose (HEC) -CH2-CH2-OH

Hydroxy-propyl-cellulose (HPC) -CH3

-CH2-CH(OH)-CH3

Methylcellulose (MC) CH3

Sodium carboxymethylcellulose (CMCNa) -CH2-O-CH2-COONa

Ethylcellulose (EC) -CH2-CH3

Cellulose acetate phtalate (CAP) -CO-CH3

-CO-C6H4-COOH

Hydroxypropyl methylcellulose phthalate (HPMCP) -CH3

-CH2-CH(OH)-CH3
-CO-C6H4-COOH
2544 Current Medicinal Chemistry, 2006, Vol. 13, No. 21 Kalász and Antal

aleuritic acid) and alicyclic hydroxy acids (mainly shelloic
acid), and polyesters. It is insoluble in acidic conditions but
is soluble at higher pH. Traditionally it was used for sealing
during the sugar coating process by dissolving in organic
solvent. Nowadays, there is a new interest toward this
moisture barrier coating agent, because it can be also applied
in aqueous dispersion form prepared by high pressure
homogenization, too [55].
The natural coating materials of protein origin were
replaced with partially or fully synthetic polymers available
in consistent qualities such as cellulose derivatives,
polymethacrylates, and polyvinyl acetates.
Cellulose ethers such as hydroxypropylmethylcellulose
(HPMC), hydroxypropylcellulose (HPC), hydroxypropyl-
ethylcellulose (HPEC), hydroxyethyl cellulose, methy-
cellulose and sodium carboxymethylcellulose (Table 3) are
widely used water soluble semi-synthetic film-formers
obtained by alkylation of cellulose. The low-molecular-
weight grades can be produced by partial hydrolysis [56].
The individual characteristics like solubility, viscosity and
thermal behaviour of these polymers depend both on the
degree of substitution of ether groups per glucose unit, and
the degree of polymerization [57,58].
The reduced hydration due to substitution makes them
less water-soluble at higher temperature, therefore their
colloidal solution is prepared dispersing first the powders in
hot water, then cooled down under stirring. Compared to
uncoated tablets and capsules, less adhesion is shown to the
esophageal mucosa for tablets coated with water-soluble
cellulose derivatives due to the lubrication of dissolving
cellulose on the surface [59].
Ethylcellulose is insoluble in water, thus and it can serve
as a hydrophobic coating agent to modify the drug release of
a drug and effective protective film-former [60]. It is
available also in aqueous dispersion forming a pseudolatex
Aquacoat ® ECD (FMC Biopolymer) or Surelease ®
(Colorcon) where the organic polymer solution is emulsified
by the aid of sodium lauryl sulfate, then the solvent is
evaporated.
Among cellulose esters, the solubility of cellulose acetate
is determined by the level of acetyl groups present. It is
especially used for semipermeable coating on tablets
functioning according to the osmotic pump principle. The
tablets hole drilled with laser allows extended drug release
independent on gastric motility and pH [61].
As phtalic acid ester derivatives, cellulose acetate phtalate
(CAP) and hypromellose phtalate (HPMCP) contain free
carboxylic groups and hence they are suitable for
gastroresistant coatings due to the insolubility in acidic
media under pH 5.5 [62]. Hypromellose phthalate is
insoluble in saliva, hence it is applicable to mask unpleasant
taste [63]. The purity tests of pharmacopoeias for these esters

Table 4. Polyvinyl Acetate Copolymers for Coating

CH2 CH CH2 CH CH2 CH

O OH O
Polyvinyl acetate phthalate C H3C C O
O
O
C
OH
m n o

H2C CH CH2 CH
O O N
Polyvidone acetate (physical mixture)
C O
CH3 m n

CH CH2 CH CH2
Vinylpyrrolidone-vinyl acetate copolymer N O O O
C

m CH3 m

CH2 O CH2 CH2 O CH2 CH2 O

O CH CH2 O CH2 CH O CH2
CH2 CH2
Polyvinyl alcohol-polyethylene glycol copolymer CH OH CH OH

CH2 CH2

CH OH CH OH
Drug Excipients Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2545

Table 5. Polymetacrylate Film-Forming Polymers

CH3 CH3

Methacrylic acid/methylmethacrylate copolymers CH2 C CH2 C

C O C O

OH CH3

CH3
CH2 C CH2 CH
Methacrylic acid/ethylacrylate copolymers
L100-55 C O C O

OH OC2 H5

CH3 CH3

CH2 C CH2 C

C O C O
Dimethylaminoethyl methacrylate copolymers
E100 O OR

CH2
CH3
H2 C N
CH3
R: CH3 , C4H9

CH3 R1

CH2 C CH2 C

C O C O

O OR2
Ammoniomethacrylate copolymers
RL-RS CH2
CH3
H2 C N Cl
CH3
R 1: H, CH3 CH3
R 2: CH3, C 2H5

CH3

Ethyl acrylate/methyl methacrylate copolymer CH2 CH CH2 C

NE
C O C O

OC2H5 OCH3

applies chromatographic method for phtalic acid
determination.
As polyvinyl acetate copolymer, polyvidone acetate
contains polyvinyl acetate and polyvinylpyrrolidone in a
physical mixture (Kollidon® SR, BASF). Missing of ionic
groups, the film-former is generally compatible with active
ingredients [64]. Polyvinyl acetate phthalate starts to
dissolve at pH 4.5, therefore it is suitable for enteric
coatings for the whole length of the duodenum [65] (Table
4).
Copovidone is the vinylpyrrolidone-vinyl acetate
copolymer in a mass ratio of 6:4. It is soluble in water
(Kollidon ® VA64) at all pH, and it is recommended to
combine with cellulose derivatives or shellac.
Polyvinyl alcohol-polyethylene glycol graft copolymer
consists of 75% polyvinyl alcohol units and 25%
polyethylene glycol. It is freely soluble in water and suitable
to ensure immediate drug release (Kollicoat® IR).
For polyvinyl acetate materials, the monomer vinyl
acetate is tested by HPLC method, the polyvinyl acetate
content is checked according to the saponification value.
Several types of polymetacrylates were developed in the
last decades for wide application in film-coating [66]
(Table 5). These polymers are synthetic cationic and anionic
polymers of dimethylaminoethyl methacrylates, methacrylic
acid, and methacrylic or ethacrylic acid esters in varying
ratios. The class of methacrylic acid copolymers can be
characterized with free carboxylic groups which make them
suitable for enteric coatings.
Methacrylic acid–methyl methacrylate copolymers are
products prepared in the molar ratio of 1:1 (Eudragit® L100)
or 1:2 (Eudragit® S100) and they dissolve at intestinal pH
above pH>6 and 7, respectively. Methacrylic acid–ethyl
2546 Current Medicinal Chemistry, 2006, Vol. 13, No. 21
acrylate copolymer (Eudragit® L100-55) prepared in a molar
ratio of 1:1 is soluble even in the small intestine (at higher
pH values than 5.5).
Dimethylaminoethyl methacrylate (Eudragit ® E) is
cationic polymer, it is soluble in acidic pH up to pH 5. It
serves as a film-former for protective coatings, especially to
mask taste. Organic solutions are used for the film-coating
procedure. The ammonium groups are present as salts in
ammoniomethacrylate copolymers offering pH-independent
permeability for drug release. The marketed product
Eudragit ® RS type contains 5%, and Eudragit RL® type
contains 10% of quaternary ammonium groups providing
high and low permeability in aqueous dissolution media.
These water insoluble polymers are available as granules,
solutions made by organic solvents, or aqueous dispersions.
Ethyl acrylate-methyl methacrylate copolymer (Eudragit®
NE) is available in aqueous dispersion. It insoluble in water,
but becomes permeable for pH-independent drug release due
to swelling.
Plasticizers or softeners are relatively low molecular
weight materials which have the capacity to improve the
physical and mechanical properties of the film-forming
polymer [67].
The mechanism of action for a plasticizer is to increase
the mobility of polymer chains, and to make elastic the
films. One fundamental property of a polymer which can be
determined by several techniques (e.g. by differential
Fig. (3). Effects of excipients eliminating the environmental attack.
Kalász and Antal
scanning calorimetry) is the glass transition temperature, at
which a polymer changes from a hard glassy material to a
softer rubbery material. Plasticizers may reduce the glass
transition temperature [68]. The commonly used plasticizers
can be categorized into three groups: polyols (glycerol,
propylene glycol, polyethylene glycols); organic esters
(phthalate esters such as diethyl, dibutyl sebacete, citrate
esters, triacetin) and oils/glycerides (castor oil, acetylated
monoglycerides, fractionated coconut oil). Glycols are used
in the cases of water-soluble films, such as cellulose
derivatives.
Plasticizers may have a marked effect on the release rate
of active ingredients from modified release dosage forms
where they are incorporated into the rate-controlling
membrane film [69].
Beside the polymer, solvent/vehicle and plasticizer, other
additives (e.g. pigments, antiadherents, surfactants,
antifoaming agents, pore-formers) may be added to coating
formulations to improve the appearance of the final dosage
form, to aid processing, and to reduce the tackiness of the
films. Drugs have also been incorporated directly into film
coating formulations [70]. Antiadherent materials such as
talc are generally included in coating formulations to reduce
the stickiness of the film and minimize agglomeration of the
coated substrates [71].
By the use of leachable pore-forming agents in the film-
layer, it is possible to modulate the drug release since the
Drug Excipients
diffusion may play a primary role through water-filled pores
and not through the insoluble polymeric membrane [72].
The films prepared from polymeric materials are
primarily evaluated taking the drug release profile, the
permeability of coating [73], and mechanical tensile testing
of free films [74] into consideration. Thermal analysis is
used to study the polymer properties as a function of
temperature, which properties that can be determined include
enthalpy, mass, melting temperature, heat of fusion, and the
glass transition temperature [75].
The mechanism of the film formation from aqueous
polymer dispersions is a complex process and several
interactions may occur among components of the coated
dosage form as demonstrated schematically on a coated
pellet (Fig. 3).
The use of organic solvents in the coating of
pharmaceutical dosage forms has become problematic due to
regulatory requirements, flammability and limits on solvent
residues in the coated product. Although aqueous coating
systems can overcome the problems of organic solvents, but
they suffer from certain limitations (e.g. evaporation of water
can increase process time; moisture-sensitive cores can be
damaged; problems of long-term stability arising due to the
inclusion of water) [76]. Thermoanalytical studies are
suitable to investigate degradation and interactions between
drug and excipients as well as among excipients. In
addition, mass spectrometry and infrared spectroscopy can be
applied to detect alterations and interactions. Film-formers
and plasticizers of an ester structure can undergo hydrolysis
during storage [77]. In contrast to cellulose ethers, whose
glucose units are linked via an oxygen bond hydrolysable by
acids and bases, polymethacrylates have a chemically very
stable, coherent carbon skeleton. For methacrylates, thermal
degradation can also be excluded as a reason for instability
in long term stability test even under stress conditions.
The instability can be due also to the additive, for
example tritethylcitrate undergoes considerable evaporation
at higher storage temperatures [78].
During long term storage the concentration of triethyl-
citrate is more stable in coatings than triacetin [79], which is
subject to hydrolysis.
In contrast to interactions within the coating, interactions
with components of different parts of the dosage form may
influence the stability of a dosage form. The CMC, CAP,
HPMCP as well as polymethacrylic acids are anionic and
therefore they are capable to interact with cations of
preservatives, colorants and surfactants, which latest are used
to form aqueous dispersion. Drugs and excipients may
migrate in the coating and they may alter the permeability of
the film-layer [80].
Melt-coating avoids the use of volatile materials and the
attendant issue of drying [81]. On the other hand, wax
coatings are capable to prolong the drug dissolution in the
gastrointestinal tract. The water soluble salt of the active
ingredient can be incorporated by dispersing it in the molten
wax (beeswax, carnauba wax, hard paraffin, etc.). Mixtures
with glyceryl monostearate, stearic acid, palmitic acid,
glyceryl monopalmitate, and cetyl alcohol are usueful to
control the melting temperature [82,83].
Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2547
Novel lipidic coating excipients are glyceryl behenate
[84] and glyceryl palmitostearate (Precirol ATO 5) [85].
The water insoluble film-forming polymers and
lipophilic coating materials may also be used as matrix
formers to bind sustained release tablets.
Softeners make elastic the films of lacks. Glycols are
used in the cases of water-soluble films, such as cellulose
derivatives. Triglycerides, phthalate esters (dibutyl phthalate;
diethyl phthalate), and esters of citric acid (Citroflex) can be
used. The concentration of softeners can be in the range of
10% – 20%
Either talcum or a 1:1 mixture of talcum and starch may
be used as an anti-adhesive excipient when either sugar-based
or pigment based coatings are used.
Syrups used for dragee making have sugar as their major
component. Talcum; colloid silicone dioxide, starch, etc.
can essentially facilitate drying the sugar layer.
Polarizing substances are the bee-wax and paraffin. Either
their solution in organic solvents or their melted form is
used to coat the pre-prepared dragee.
3.9. Coloring Agents
The use of colored medicinal preparations offers
psychological significance through appearance without
particular therapeutic advantage. Coloring agents are used to
improve the aspect of a drug and to avoid confusion during
the manufacturing phase or in administration. From the
chemical point of view, this colourants may be organic
compounds (Table 6) (e.g. beta carotene, indigo carmine,
sunset yellow, tartrazine, flavones) or mineral origin (like
red and yellow ferrous oxides), as well as several synthesised
compounds. The appearance and identity markedly relates to
safety in securing patient cooperation in taking or using the
recognized prescribed medication. Pharmaceutical coloring
agents can be classified according to the solubility: water
soluble dyes and water insoluble pigments. Preparations that
may be colored include most liquids, suspensions,
emulsion, powders, tablets and other coated dosage forms
(eg. pellets).
The dye concentration in liquids and solutions is in a
range from 0.0005% to 0.001%. Solid dosage forms (e.g.
powders) require about 0.1% of a coloring agent to produce a
pastel color.
Insoluble pigments such as the iron oxides, titanium
dioxide, and some of the aluminum lakes are especially
useful to ensure protection for light-sensitive active
ingredients when used in tablet coatings or gelatin shells
[86]. Lakes are water-insoluble forms of the common
synthetic water-soluble dyes by adsorbing a sodium or
potassium salt of a dye onto a very fine substrate of hydrated
alumina [87].
In general, concerns over the safety of coloring agents in
pharmaceuticals and foods are associated with reports of
hypersensitivity [88]. Most regulatory agencies of the world
hold positive lists of colors that may be used in medicinal
products. The legislation also defines purity criteria and
restricted amounts for the individual coloring agents [89].
2548 Current Medicinal Chemistry, 2006, Vol. 13, No. 21
Table 6. Coloring Agents
Name
CH3
Beta carotene
CH3
CH3
NaO3S
Indigo carmine
Sunset yellow
Tartrazine
NaO3S
Beta carotene is widely used by the pharmaceutical
industry. Its quantitative determination is generally done by
HPLC, and one can find in the literature a high number of
papers dealing with its analysis [1]. Simultaneous
determination of carotenes and tocopherols is possible in
various forms of pharmaceuticals [90]. A simple method for
the simultaneous extraction and HPLC determination of
provitamin A and vitamin E derivatives in vitamin
supplemens permits the complete separation of α-, β-, γ-,
and δ-tocopherol, α-tocopheryl acetate, all trans α- and β-
carotenes, and 9-cis and 13-cis β-carotene in less than 50
minutes, using UV detection. Recovery of the analytes and
reproducibility of HPLC determination proved to be
excellent. Eight commercial ATBC drinks were investigated
for their tocopherol and carotene contents. Due to the ease of
handling, the analytical system may find application both in
the food and pharmaceutical industry and in the Food
Inspection Board of the United Kingdom. A method is
given especially for the determination of carotin in tablets
[91].
Indigo carmine can be determined using micellar
electrokinetic chromatography [92]. Recent developments in
the analysis of Sunset yellow permits its quantitative
determination using HPLC [93,94] and micellar
electrokinetic chromatography [95].
3.10. Compression Aids for Direct Tableting
A compression aid helps to ensure the desired
compression characteristics of a powder intended for tablets
Kalász and Antal
Formula
CH3
CH3 CH3
H3C
CH3 CH3 CH3
O H
N
N SO3Na
H O
HO
NaO3S N N
SO3Na
NaOOC N
N SO3 Na
N N
OH
without using multistage processes of wet or dry granulation
[96]. Compression aids are special grades of diluents, such
as dibasic calcium phosphate (Emcompress® , Di-Tab® ),
tribasic calcium phosphate (Tri-Tab® ), calcium sulfate
(Compactrol ® ), microcrystalline cellulose (Avicel ® ,
Vivapur ® ), powdered cellulose (Elcema ® ), dextrates
(Emdex ® ), lactitol (Finlac® DC), lactose (Pharmatose
DCL30®, Pharmatose DCL21®), spray-dried lactose (Fast-
Flo®, Pharmatose DCL11®), lactose-cellulose coprocessed
mixture (Cellactose®), maltodextrin (Lycatab®, Maltrin®),
mannitol (Pearlitol® ), sorbitol (Neosorb® ), pregelatinized
starch (Starch 1500® , Starx 1500® ), sucrose–maltodextrin
coprecipitate (Des-Tab ® , Dipac® , Nu-Tab ® ), Xylitol
(Xylitab®).
3.11. Consistency- and Viscosity-Enhancing Agents,
Gel-Forming Agents
Consistency improving, viscosity increasing and gel-
forming agents are used in aqueous systems either to
increase the viscosity or to stabilize emulsions and
suspensions. Viscosity-enhancing agents are often used in
the formulation of dosage forms for p.o. (per os, through the
mouth) use. They can control such properties as palatibility,
ease of pouring, and (in the case of suspensions) the rate of
sedimentation of the dispersed particles. The viscosity-
enhancing agents are often hydrophilic polymers [97].
There are several mechanisms by which a viscosity-
enhancing agent may produce a change in the gastrointestinal
absorption rate of a drug. Complex formation between the
Drug Excipients
drug and a hydrophylic polymer can reduce the concentration
of the free drug in the solution that is available for
absorption. Viscous solutions or suspensions may produce
an increase in the viscosity of the gastrointestinal contents.
It could lead to a decrease in the dissolution rate and/or a
decrease in the rate of movement of drug molecules to
approach the absorbing membrane. In the case of
suspensions containing an active drug ingredient with being
dissolution-rate dependent bioavailability, an increase in the
viscosity could also lead to a decrease of dissolution of in
the gastrointestinal tract.
The following compounds belong to this group of
excipients: alginic acid, bentonite, carbomer, gelatin,
hydroxyethyl cellulose, hydroxypropyl cellulose, methyl
cellulose, carboxymethyl cellulose sodium, methyl
hydroxypropyl cellulose, polyvinyl alcohol, polyvinyl ethyl
cellulose; povidone, sodium alginate, sodium starch
glycolate, tragacanth and xanthan gum. Their positive effects
on the stability of the pharmaceutical formulations are
widely utilized. From them, alginic acid, hydroxyethyl
cellulose, hydroxypropyl cellulose, methyl hydroxypropyl
cellulose, carboxymethyl cellulose sodium, gelatin, methyl
cellulose, and polyvinyl ethyl cellulose are used in tablets to
stabilize their consistency as well as to improve their
disintegration after oral administration. Alginic acid has
definite incompatibility with strong oxidizing agents; it
gives a water-insoluble precipitate with calcium ions. Free
alginic acid is precipitated in the presence of mercury ions,
strong acids, strong bases, and certain electrolites.
Bentonite is generally used as binder of tablets, stabilizer
in suspensions, and also to improve the pigments used as
dragee-coatings. It is incompatible with strong electrolites,
acids and positively charged particles. Gel of bentonite binds
cations.
Carbomer increases the viscosity at natural pH. It is an
acid, thus insoluble in the stomach. It is dissolved in the
basic pH of the intestines, therefore carbomer can be used as
enterosolvent- coating material.
Polyvinyl alcohol can be a viscosity-increasing additive
in various topical pharmaceutical and ophthalmology
formulations. Its emulsion-forming ability is only limited,
but it stabilizes well emulsions. It is used in both sugar-
containing syrups and sugar-free coatings.
Povidone (polyvinyl pyrrolidone) increases the solubility
of some pharmaceuticals; it is also a binder in tablets.
Further uses of povidone are as film-forming and coating
components. Its water-soluble complex with iodine has a
desinfectant effect.
Sodium alginate (at pH between 6 and 7) can be used as
stabilizer of emulsions, suspensions, gels, and ointments
Sodium starch glycolate is generally used as viscosity
enhancer, disintegrant, and sometimes also as a binder.
Tragacanth is a mixture of water-soluble and water-
insoluble polysaccharides. It is used as a stabilizer of O/W
types of emulsions, and as a supporting inert component of
hydrophilic ointments. Its viscosity is essentially decreased
by strong acids.
Xanthan gum is composed of high molecular size
polymers of glucose, mannose and glucuronid acid. Its
Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2549
major use is to delay liberation of the active ingredient(s) of
sustained-release tablets. Otherwise, it is a good stabilizer
and/or suspending agent, widely used both in the
pharmaceutical and food industry.
3.12. Disintegrants
Disintegrants serve to break up granules, tablets and
capsules in an aqueous milieu into primary powder particles
[10]. The smaller are the particles, the larger is their surface.
The large surface enhances dissolution of the active material
from the pharmaceutical formulation. Delayed disintegration
may result in either incomplete absorption or a shift of the
onset of the action of the drug, or both. The higher
compaction force generates slower disintegration that can be
regulated by the use of disintegrants. Compounds belonging
to this group are differentiated on the basis of their action:
there are physical- and chemical disintegrants. The chemical
disintegrants are composed of a weak acid (e.g. citric acid)
and a weak base (generally sodium bicarbonate). Their
interaction yields carbon monoxide that improves
disintegration. However, chemical disintegrants are not used
widely.
Even a minor change in a formulation may result in
significant effects on dissolution and bioavailability. A
classical example is given by the two formulations of
tolbutamide, the commercial one, and the same formulation
with half the amount of disintegrants. Both tablets
disintegrated in vitro within 10 minutes meeting perfectly
the pharmacopoeial specifications. However, the commercial
tablet had a significantly greater bioavailability and
hypoglycaemic response when administered to healthy
volunteers [97].
Disintegrants are hydrophilic compounds. The process of
disintegration is probably based on their hydratation. The
most widely used disintegrating substances are various
starches from potato and corn; wheat starch is less perfect. In
the case of extremely compact pharmaceutical formulations,
other substances should also be used, such as
ultraamilopectin; carboxymethyl starch; formaldehyde-
gelatin, and alginates. Binder-type macromolecules are used
most recently, such as cellulose-derivatives, and polyvinyl
pyrrolidone.
The most widely used disintegrants are as follows:
carboxymethyl cellulose calcium, maize, potato, rice, tapioca
and wheat starch; aluminum magnesium silicate;
microcrystalline cellulose; crospovidone, powdered
cellulose, bentonite, and sodium alginate.
Alginic acid and sodium alginate are used in
concentrations of 1% - 5%; their functions are as binder and
disintegrants, depending on the environment they are.
Carboxymethyl cellulose calcium and carboxymethyl
cellulose sodium can serve either as a binder of tablets (5% -
15%) or a disintegrating component (1% - 15%); its p.o.
toxicity is extremely low, 27 mg/kg (both mice or rat).
Starch is a polysaccharide, built up from 300 to 1000
units of D-glucose. On the basis of its origin, various
starches (maize, potato, rice, tapioca, and wheat) exist.
Starch is widely applied in powder production, and also in
the preparation of tablets, improving their formulation.
2550 Current Medicinal Chemistry, 2006, Vol. 13, No. 21
Aluminum magnesium silicate (Veegum) consists of
61.1% silicon dioxide, 13.7% magnesium oxide, 9.3%
aluminum oxide, 2.7% calcium oxide, 2.9% sodium oxide
and 1.8% carbon dioxide. Aluminum magnesium silicate
has several uses, and the outcome depends on its
concentration: in 10% - 50% it is an absorbent, in 2% - 10%
a binder, in 1% - 5% a stabilizer in emulsions, and in 0.5%
to 2.5% a stabilizer in suspensions
Crospovidone is polyvinyl polypyrrolidone. Its effective
disintegrating property is based on capillary activity:
Crospovidone takes up the water, transfers it into the inner
part of the tablet, and the pressure generated in this way will
disintegrate the tablet.
Microcrystalline cellulose and powdered cellulose are
used in various concentrations, and serve as absorbent,
binder, stabilizer and disintegrant.
The name of so called superdisintegrants (croscarmellose
sodium, crospovidone, sodium starch glycolate) comes from
the very low level concentration (about 0.5-4%) in which
they are even completely effective.
3.13. Diluents
Even distribution and unique dosing of a very small
amount of the active drug can be very difficult and diluents
may make easier the proper formulation. Moreover, diluents
facilitate adhesion of the tablets prepared by pressing. It is a
basic requirement that the skeleton-forming diluents must
not be dissolved in the gastrointestinal tract but the solid
structure of the tablet should be kept; also, the liberation of
the pharmacologically active ingredient has to be possible by
its diffusion.
Diluents must not irritate the body, and their toxicity
should be low. Proper distribution of very small amounts of
the active drug is possible using diluents; also the
preparation of tablets by pressing is enhanced by the use of
adequate diluents, additionally improving the stability of the
drug.
3.14. Drug Delivery Agents
To achieve and maintain the drug concentration in the
body or at the targeted site is under enormous investigations
in the past decades in order to improve tolerability, efficacy
and compliance. Drug carrier systems are developed using
novel concepts to control drug release, increase
bioavailability and liberate the drug at the site of absorption
or at the target site. To review the large number of special
excipients for this field in details is beyond this discussion,
so only short attempt will be made for summary.
Drug release from prolonged action dosage forms can be
generally controlled by the permeation through polymer
membranes (e.g. film-forming polymers) or by diffusion
dispersing the drug in a polymer matrix.
In membrane controlled systems, film-forming polymers
(see under coating substances) work as membrane formers,
which are suitable to cover the surface of the drug reservoir.
The membrane is the critical part of the formulation as it
permits the permeation of water into the core and controls
the release of the drug out. Since the membrane must remain
Kalász and Antal
intact during the release period, primarily the water insoluble
ethylcellulose and acrylic polymers (Eudragit RL, RS, NE)
which are only permeable are used. Incorporating pore-
formers as less hydrophobic components allows to open
channels in the membrane in order to optimize the drug
release rate.
Osmotic pumps give a special form of membrane
controlled systems, where the reservoir is coated with a
semipermeable film made typically from cellulose ester
derivatives (e.g. cellulose acetate). If the osmotic pressure of
the dissolving drug is not sufficient to drive the release of
the drug through the laser-drilled hole, then an osmotic
agent (e.g. NaCl) is incorporated into the core to ensure
constant (zero-order) release [98]. In “push-pull” systems, a
water swellable polymer (e.g. HPMC) acts as an expanding
layer to push the poorly water-soluble suspended drug
through the orifice.
In monolithic matrix controlled systems, the drug
particles are homogenously distributed in a fatty or
polymeric matrix formers. Matrix systems are frequently
used for the preparation of sustained release dosage forms
because of the ease of manufacturing [99]. Excipients
involved to build insoluble matrices are ethylcellulose,
polyvinyl acetate, insoluble methacrylates, and waxes. Wax
coating materials (e.g. Carnauba wax) can be used also as
wax matrix formers, but they usually contain also a water
soluble channelling agent (e.g. NaCl, sugars, PEGs, etc.) to
ensure the diffusion of the drug from the hydrophobic
system through the water-filled pores [100]. The
hydrophobic and waxy materials, on the other hand, are
potentially erodable and control the release of drug through
pore diffusion and erosion.
Water soluble polymers (high viscosity grades HPMC,
sodium carmellose, alginates, xanthan gum, carbopol)
belonging to hydrophilic matrix systems swell to form a
moving hydrated matrix layer, which controls the
penetration of solvent for the drug incorporated in the
matrix. Salts of alginic acid with di- or trivalent cations
form true hydrogels characterized with a crosslinked
polymeric structure [101].
Beside alginates, chitosans are used for microspheres
with controlled drug delivery applications [102]. Chitosan
(poly-D-glucosamine) is a cationic polyamine, its functional
properties depend on the chain length, charge density, and
charge distribution [103-104]. For targeted delivery, lecithin
is a component of the lipid bilayer in liposomes to
encapsulate drug substances [105]. The phospholipid cations
(e.g. phosphatidylcholine, phosphatidylserine) precipitated
with calcium builds cochleate delivery vesicles, which are
capable to protect proteins from degradation. Among
nanostructures, cyclodextrins are well known for their ability
to include guest molecules inside their hydrophobic cavity
[106].
Biodegradable polymers (see later) as drug carriers are
primarily intended for long-term drug delivery applications,
where the degradation in the body to biologically inert and
compatible molecules is crucial [107-109].
Several chemical entities may function as penetration or
absorption enhancers to facilitate the delivery and transport
of a drug across biological membranes usually after non-
Drug Excipients Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2551

specific disrupting action. The resistance of the skin barrier
is reduced by sulphoxides (e.g. dimethylsulphoxide,
DMSO), azones (e.g. laurocapram), pyrrolidones (e.g. 2-
pyrrolidone), alcohols and alkanols (ethanol, or decanol),
fatty acids (oleic alic, palmitoylcarnitine), glycols,
surfactants and terpenes [110].
Chelating agents (EDTA, citric acid, salycilates) act
through calcium ions to open the tight junctions in the
membrane [111]. Bile salts (e.g. sodium deoxycholate,
sodium glycocholate. etc.) may help the absorption mainly
by denaturation of membrane proteins, decrease of mucus
viscosity and by solubilization effect [112].
The intestinal absorption of poorly water soluble drugs
can be increased by medium-chain glycerides (mainly C8–
C10), which are generally accepted for use in oral drug
administration [113]. For cyclodextrines, the mechanism of
transmucosal (e.g. buccal) absorption enhancement may be
due to solubilizing effect and extracting lipids from the
intercellular matrix [114].
3.15. Emulsifying and Suspending Agents
Emulsifying agents are surface-active compounds:
macromolecules and solid substances with extremely fine
particles. Adverse physical changes in emulsions can be
avoided selecting the proper emulsifying agent to reduce the
interfacial tension between the oily and aqueous phases and
to form a film at the interface. The so called auxiliary
emulsifying agents (cetyl alcohol, glyceril monostearate,
stearic acids, carmellose sodium, methylcellulose) are not
able to form stable emulsions, but may help in the
stabilization as thickening agents on the interfacial surface.
Synthetic emulsiying agents include the surface active
agents, which form a monomolecular film around the
droplets. Among natural emulsifying agents, polymeric
hydrophilic colloids such as acacia and gelatin produce
multimolecular films, but lecithin and cholesterol form
monomolecular films. Finely divided solids (e.g. bentonite
and magnesium hydroxyde) that are wettable particles may
act also as emulsifying agents forming a coherent solid film
that prevents coalescense.
In the case of suspensions, the stable dispersion of solid
particles is needed in the continuous liquid phase. The
formation of loose aggregates (flocs) is advantageous to
ensure resuspendibility. The controlled flocculation can be
achieved by the addition of flocculating agents, such as by
electrolytes reducing the electrical forces of repulsion
between particles, by polymers to be adsorbed on the surface

Table 7. Structure of Commonly Used Surface Active Agents

Name Formula

H H H2C CH2 OH
HO C C N
Triethanolamine
H H H2C CH2 OH

H H O

Sodium lauryl sulfate H C (CH2) 10 C O S O- Na+

H H O
CH3
H3C
O CH3
Dioctyl sodium sulfosuccinate
H3C O
O
O SO3Na

H2C R3

CH R2
Sorbitan Esters (Sorbitan Fatty Acid O Monoesters: R 2 and R 3 is H
Esters)
HO Dies ters: R 1 is H
R1 fatty acid such as laurate, oleate, palmiate, stearate

R1
R (OCH2CH2) n OH
Polyethylene glycol monostearate
O

CH3
O O
Poloxamers HO O H
a a
b
2552 Current Medicinal Chemistry, 2006, Vol. 13, No. 21 Kalász and Antal

of particles and bridging them. Surface active agents may
not only improve wetting of particles, but ionic detergents
may result in flocculation like electrolytes. Nonionic
detergents as stabilizers can decrease the electrokinetic
potential of dispersed particles, and can induce flocculation
also forming bridges like polymers. Suspending agents may
act as viscosity-enhancers to avoid sedimentation of
suspended particles acccording to the Stokes law. Effective
suspending agents are the anionic (carboxymethylcellulose
sodium) and nonionic (methylcellulose, ethylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose, hydroxypro-
pylmethylcellulose) cellulose derivatives, natural anionic
(alginates, carrageenan, xanthan gum, acacia, tragacanth) and
nonionic (guar gum) polymers, synthetic anionic (carbomers)
and nonionic (polyvinylpyrrolidone, polyvinyl alcohol,
poloxamer), and some clay materials (bentonite, magnesium
aluminium silicate).
Acacia is a complex aggregate of sugars and
hemicelluloses (Mw≈240 000–580 000), consisting of arabic
acid with calcium, magnesium, and potassium along with
different sugars (arabinose, galactose, and rhamnose). It is
mainly used in oral and topical pharmaceutical formulations
as viscosity-increasing agent or suspending agent (5-10%),
emulsifying agent (10-20%), and as a tablet binder (1-5%).
An oxidizing enzyme present in acacia may interact with
easily oxidizable substances, but the enzyme can be
inactivated by boiling for a short time [115].
The most important surface-active substances are given in
Table 7. Triethanolamine, natrii laurilsulfas (sodium lauryl
sulfate), natrii cetostearilsulfas (sodium cetylstearyl sulphate)
and acaciae gumni, and others are widely used. O/W
emulgents are used for preparations devoted for peroral
administration. Their names are Tween, Brij, Myrj, Tagat
and Emulgator with the chemical structure of polyethylene
glycol sorbitan laurylate, polyethylene glycol bound with an
Table 8. Flavoring and Taste Improving Agents
ether, polyethylene glycol bound to an ester, polyethylene
glycol bound to a glyceryl ester and mainly non-ionic
emulgents, respectively.
3.16. Flavoring and Taste-Improving Agents
Substances of this group of excipients serve to shadow
the aversion of the patients for the original smell and taste of
the pharmaceutical formulations. Aspartame, maltitol and
saccharin (Table 8) are such typical excipients. Aspartame
can be determined by isothermal thermogravimetry [116], as
well as by HPLC [116-119] and high-performance capillary
electrophoresis [119-120]. It is also used as a mobile phase
additive in the determination of amino acids with HPLC
[121].
Maltitol can be determined after derivatization with p-
nitrobenzoyl chloride to have UV-absorption at 260 nm
[122]. The results of the potentiometric determination (using
a silver electrode) of saccharin were comparable to that of
HPLC [123]. However, for its quantitative determination
HPLC remained the essential tool [124]. Micellar
electrokinetic capillary chromatographic determination of
artificial sweeteners in low-Joule soft drinks and other foods
is also used [97].
3.17. Lubricants and Glidants
Formulation of tablets and capsules requires lubricants to
avoid friction between the powder and the metal surfaces at
the time of their manufacture. Lubricants are often
substances of hydrophobic nature. The major application
field of calcium stearate utilizes its anti-adhesive effect in
powders; its usual concentration is about 1%.

Name Formula

H O COOCH3

Aspartame H2N C C NH CH CH2

CH2 COOH

CH2OH
O

CH2OH OH
Maltitol H OH OH
HO H OH
H O
H OH
CH2OH

O O
S
Saccharin NH

O
Drug Excipients
The particle size of colloidal anhydrous silica is
nanosized. It permits tablet formation from small amounts
of the active ingredients, and is also used as stabilizer of
suspensions and emulsions at 2% - 4%; and lubricant of
tablets at 0.1% - 0.5% concentrations.
Hydrogenated castor oil has multiple-purpose usages; its
effect is depending on the concentration. In tablets
hydrogenated castor oil is a lubricant at concentrations of
0.1% - 2%, and regulates the release of the active ingredients
when used at concentrations of 5% - 10%. Hydrogenated
castor oil is effective as a consistency-improving substance
in emulsions and ointments if used at concentrations of 5% -
20%.
Magnesium stearate is a constituent of certain powders
and capsules: it is the usual lubricant when the tablets are
compressed or capsules are filled. If the magnesium stearate
content is over 1 %, its disintegration ability is reduced. A
disadvantage of its use may be the reduction of the
dissolution rate: even if the shell of the capsule has
dissolved in the gastrointestinal tract, often a capsule-shaped
plug remains. This is the case when the contents of the
capsule was machine-filled as a consolidated plug. A similar
reduction in the disintegration and dissolution rate may be
observed when magnesium stearate is included in the tablet.
However, this reduction is generally overbalanced by the
simultaneous use of a wetting agent, such as a water-soluble
surfactant or hydrophilic diluent [10,97].
Sodium stearyl fumarate is used as a lubricant at the
concentration range of 0.5-2 %.
Talc is a mixture of various naturally occurring
magnesium silicates. Its lubricant and anti-adhesion effects
are widely utilized in tablet formation. Talc is the constant
constituent of various talcs; even the name of these powders
is talc powder.
Zinc stearate has a zinc content of about 10-13%. It is
used as a lubricant, at concentrations of 0.5-1.5%. It is also
used in ointments at 2.5% to improve adhesion.
Other glidants and lubricants are starch (also a
disintegrant), glyceryl monostearate (also an emulsifier);
sodium lauryl sulfate (also an emulsifier); stearic acid (also
an emulsifier); sodium benzoate (also a preservative);
polyethylene glycol (also an ointment base), and tribasic
calcium phosphate.
Glidants ensure the flowability of powders, granules
during processing by decreasing the friction and adhesion
between particle surfaces using e.g. calcium silicate,
powdered cellulose, powdered magnesium carbonate,
magnesium oxide, magnesium silicate, starch, talc. The
most frequently used glidant is the adsorbent colloidal
silicon dioxide (Aerosil®), which has a mean size of about
15-20 nm, and may fill surface irregularities of the solids.
The lubricant and glidant functions are different, but talc
has both glidant and lubricant effect. Colloidal silicon
dioxide is an excellent glidant, but it has no lubricant
action. Controversely, magnesium stearate is powerful
lubricant, but can hinder particle flowability.
Moisture residue can be incorporated from the starting
materials or acquired from the environment during
Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2553
processing, packaging or storage. Moisture binders and
adsorbents are capable of functioning as binders of volatile
residues. Significant vapour residue can also be emerged
from the presence of alcohols (methanol, ethanol,
isopropanol) used for synthesis and isolation [125]. In
addition, parts per million levels of formaldehyde included
in the packaging material may react with aldehydes [126].
Excipients such as amorphous silica and microcrystalline
cellulose are effective adsorbents [127-128]. The formulation
containing an excipient with higher affinity for moisture
compared with the drug could mean that the residue in the
product is bound by the excipient. The application of
adsorbents such as colloidal silicon dioxide - with a small
particle size of about 15 nm and hence with a large specific
surface area - is suitable also to avoid the contact of
individual constituents with each other.
3.18. Ointment Bases and Auxilliary Materials
According to their therapeutic use we differentiate three
groups: covering and protective ointments, lipogels, and
resorption ointments. Distribution of the active ingredients
makes the difference between solution-, emulsion- and
suspension-ointments.
Based on their gel structure, ointments are classified as
carbohydrogen gels, lipogels, macrogols (polyoxyethylene
gels), hydrogels and silicon gels. The ointment bases and
auxilliary materials must have the following properties:
• they must be adequately stable,
• interaction to the active ingredient must be avoided
• the physiological functions of the skin should not be
hindered,
• the active ingredient should be able to adequately
penetrate from the ointment to the skin, and
• they should have an adequate consistency and proper
appearance.
The usual ointment bases and auxilliary materials are, as
follows:
Ethyl oleate is used as the base of steroid-containing
ointments, etc. It is easily oxidized, so an antioxidant such
as propyl gallate or butylhydroxy toluene should be present
in the ointment.
Mineral oil (also called: liquid paraffin) is mainly used
in topical ointments. Its limited use is possible as lubricant
for tablets and capsules.
Isopropyl myristate is mainly used as a solvent. In
ointments it facilitates absorption of the active ingredient
into the skin. It is stable against oxidation and hydrolysis.
Isopropyl myristate is incompatible with rubber and certain
plastics, as it can dissolve them.
Isopropyl palmitate is used in ointments (and also in
emulsions and suspensions) for topical use. It penetrates
well into the skin, and therefore, it is a general constituent
of skin-care products and lipsticks. It is stable against
oxidation and hydrolysis. Isopropyl myristate is also
incompatible with rubber and certain plastics, because it can
dissolve them.
2554 Current Medicinal Chemistry, 2006, Vol. 13, No. 21 Kalász and Antal

White wax (also called: white beewax) is a constituent of
ointments and plasters. and sometimes it also serves as an
emulgent. Additional application field of white wax is
coating of dragee; it also decreases the melting point of
suppositories.
Miglyol (also called: triglycerida saturata media) can be
well tolerated in oral pharmaceutical formulations. It is a
softener of suppositories when used at 2.5% of the total
weight. It serves as an auxiliary medium in oral
suspensions, injections and eye-drops.
Polyethylene glycol (PEG, Polywax, etc.) may have a
wide range of polymerization degree, from the molecular size
of 200 to 6000 and higher. Its field of use as excipient
depends on the degree of polymerization that defines the

Table 9. Most Important Natural and Synthetic Biodegradable Polymers

Name Formula

CH2 OH CH2OH CH2 OH

O H O H H O H
H H
Starch H H H
OH H OH H OH H
OH O O OH

H OH H OH H OH

n= 300 to 1000

H2 C OH
O
Dextrin
OH
O
OH
n

H2C OH
CH3 O
O
Chitosan
OH
CH3

NHR
R: H or COCH3
n

Poly(glycolide) O CH2 C

O
Poly(lactyde)
O CH C

CH3 n

O O
Aliphatic polyanhydride C R C O
n

O O

Polyorthoester II O O O O R

n
Drug Excipients
consistency and phase form. PEG is used as the base of
ointments and suppositories, solvent, and lubricant in
tablets and capsules.
Poloxyl 20 cetostearyl ether and poloxyl 10 oleyl ether
(Synonyms: BRIJ; CREMOFOR; ETHOFATS;
TEXOFOR; etc.). Poloxyl 20 cetostearyl ether and poloxyl
10 oleyl ether are used as the base of ointments, emulsifier,
or solubility-increasing agent and also make possible the
dissolution of otherwise insoluble pharmacons, such as
vitamins.
Petrolatum (also called yellow soft paraffin) is
chemically indifferent. It is widely used in topical ointment
preparations.
Soft paraffin and lanolin alcohols are used as the basis of
certain ointments, and also as a softener.
Additional ointment bases and auxilliary materials are
peanut oil (also a solvent); glycerin (also a solvent);
cottonseed oil (also a solvent); soybean oil (also glidant and
lubricant and antiadhesive agent) and hydrogenated castor oil
(also a solvent).
3.19. Polymers, Biodegradable
Biocompatible polymers are usual excipients for drug
delivery purposes. Table 9, shows the chemical structure of
some well-known excipients with polymeric structure.
Aliphatic polyesters include poly(glycolide), poly(D,L-
lactide), and their related copolymers poly(D,L-lactide-co-
glycolide) tailored for various implantable drug delivery
systems [103]. For surface eroding dosage forms,
polyanhydrides were developed [104]. The fourth generation
Table 10. Preservatives
Name
Benzoic acid
Cetrimide
Chlorhexidine
Cl
Methylparabene
Propylparabene
Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2555
of polyorthoesters (POE) developed by modification of POE
II family is also acid labile, but the erosion rate and
mechanical properties can be excellently controlled during
the synthesis [105].
Aliphatic polyesters are a group of synthesized, nontoxic,
biodegradable polymers. In an aqueous environment, they
undergo hydrolytic degradation, through cleavage of the ester
linkages, into nontoxic hydroxycarboxylic acids. Aliphatic
polyesters are eventually metabolized to carbon dioxide and
water, via the citric acid cycle. Owing to their reputation as
safe materials and their biodegradability, aliphatic polyesters
are primarily used as biocompatible and biodegradable
polymers for formulation of many types of implantable and
injectable drug-delivery systems for both human and
veterinary use. Examples of implantable drug delivery
systems include rods, cylinders, tubing, films, fibers,
pellets, and beads. Examples of injectable drug-delivery
systems include microcapsules, microspheres, nanoparticles,
and liquid injectable controlled-release systems. The rate of
biodegradation and drug-release characteristics from these
systems formulated with the aliphatic polyesters can be
controlled by changing the physicochemical properties of the
polymers, such as crystallinity, hydrophobicity, monomer
stereochemistry, copolymer ratio, and polymer molecular
weight.
Aliphatic polyesters are a group of synthesized
homopolymers or copolymers. They are nontoxic and can
easily be fabricated into a variety of novel devices, such as
rods, screws, nails, and cylinders. The polymers are
commercially available in varying molecular weights as both
homopolymers and copolymers. Molecular weights of
polyesters range from 2000 to greater than 100 000.
Formula
OH
CH3
H3C (CH2 )n N CH3 Br
CH3
H H H H H H
N N N N N N
(CH2) 6
NH NH NH NH
Cl
H3CO
OH
O
O
CH3
O
HO
2556 Current Medicinal Chemistry, 2006, Vol. 13, No. 21
Co-monomer ratios of lactic acid and glycolic acid for
poly(DL-lactide-co-glycolide) range from 85:15 to 50:50.
3.20. Photostabilizing Agents
Excipients used photostabilzing may work through the
concept of spectral overlay, which involves formulating with
a material whose UV absorption spectrum overlaps (or
substantially overlaps) competing with the active compound
for the photons from the radiation source [129]. Although
suitable light-resistant packaging can prevent or reduce
degradation, excipients may be required even when exposure
to light can precipitate a some degradation reactions, e.g.
substitution reactions, polymerization, isomerization and
photo-oxidation [130]. Oxybenzone as UV absorber in the
film coat was shown to stabilize sulphisomidine tablets
[131]. Colorants or pigments, such as titanium dioxide
enhanced the photostability of an anti-psoriasis ointment
[132].
3.21. Preservatives
Microbiologically acceptable drug formulations are
manufactured minimizing the access to microorganisms, and
the basic role of the chemical stabilizers is to inhibit the
grow of microorganisms [10]. There is a wide choice of
chemicals with a potential use as stabilizers. A partial list of
preservatives: benzoic acid; benzyl alcohol (also a solvent),
benzalkonium chloride, benzyl hydroxybenzoate, bronopol,
cetrimide, chlorbutol, chlorocresol, cresol, ethanol (also a
solvent), ethyl hydroxybenzoate, glycerol (also a solvent),
isopropanol (also a solvent), methyl hydroxybenzoate,
phenol, phenoxyethanol, phenylmercuric acetate,
phenylmercuric borate, phenylmercuric nitrate, potassium
sorbate, propylene glycol (also a solvent), propyl
hydroxybenzoate, sodium benzoate, sorbic acid, thiomersal
and trimethyl tetradecyl ammonium bromide. This
multiplicity also indicates that these compounds may have
interactions with certain other components of the
pharmaceutical preparations. Quaternary ammonium
compounds tend to inactivate anionic substances. Table 10
shows the usual application of preservatives.
Benzoic acid is one of the most widely used
preservatives even in everyday’s life, when the housewives
save the cooked fruits and vegetables. It is mostly effective
solely in its non-ionized form because its activity decreases
over pH 4. Certain water- or oil-based p.o. liquid pharma-
ceutical preparations contains benzoic acid in a concentration
range of 0.01 - 0.2 %.
Benzalkonium chloride is a mixture of various alkyl-
dimethyl-benzylammonium chlorides, where the chain
length of the individual alkyl groups can be between 8 and
18. It is a widely used preservative in liquid preparations for
treatment in ophthalmology (eye-drops), nose-, and ear-
treatments. Contrary to benzoic acid, the effectiveness of
benzalkonium chloride shows less pH dependence.
Bronopol (2-bromo-2-nitropopane-1,3-diol) is well
soluble in water, ethanol and propylene glycol; its
application is mainly limited to preparations for topical use.
Cetrimide (trimethyl-tetradecyl-ammoniumbromide) is
used mainly as desinficient of the intact or wound skin
Kalász and Antal
(0.1% – 1%), as well as in ophthalmologic preparations
(0.005%), creams and emulsions.
Chlorbutol (1,1,1-trichloro-2-methyl-2-propanol) has a
characteristic smell, similar to that of camphor. It can be part
of eye-drops. Its possible therapeutic application is based on
its sedative and hypnotic effects.
Chlorocresol (4-chloro-3-methylphenol) is used in 0.05%
- 0.1% concentrations in parenteral formulations and
ointments, and in emulsions in 0.1% – 0.2% concentrations.
Its pH optimum is about 9. Its intensive smell and caustic
effect limits in application.
Ethyl hydroxybenzoate can be the preservative part of
peroral liquid pharmaceutical preparations at a concentration
range of 0.05 - 0.1%. Its application is accepted in the
cosmetic and food industry.
The toxic and harmful effects of phenol and its
incompatibility to a large number of drugs and excipients
prevents its wide application. However, the effectiveness of
chemical preservatives is usually given as their phenol
equivalent.
Phenoxyethanol is mainly used in topical
pharmaceuticals and ointments as a desinfectant. The
concentration of phenylmercuric acetate is 0.001 - 0.002 %
in ophthalmologic preparations, and 0.02% in preparations
used for topical vaginal treatment. Black precipitate can be
observed from mercury-containing solutions after their
prolonged storage.
The preservative application of phenylmercuric borate is
wide, including its use in aqueous injection solutions (0.002
– 0.02%), ophthalmologic drops, and rectally applied
pharmaceutical preparations. Its effect is more expressed over
pH 7. The application field of phenylmercuric nitrate is
similar to that of phenylmercuric borate.
Potassium sorbate is used in oral and topical
pharmaceutical preparations in a concentration range of 0.1%
- 0.2%. The pH optimum of its effectiveness is at about 6.
Propyl hydroxybenzoate is used for stable topical (0.01%
- 0.6%) and oral preparations (0.02% - 0.05%), as well as for
intravenous, intramuscular and subcutan injections (0.005%
- 0.2%). Sorbic acid is a white to pale-yellow powder, with
a good solubility in water. Sorbic acid has gained wide
acceptance as preservative of foods, cosmetics, and also in
the pharmaceutical industry. It is generally used at a
concentration range of 0.1% - 0.2%. Sorbic acid is sensitive
to light and oxidizing agents; the pH optimum of its
effectiveness is below pH 4.
Sodium benzoate is widely used in the food-, cosmetic
and pharmaceutical industries. In pharmaceutical products
sodium benzoate is used in syrups, emulsions, and
suspensions.
Sodium metabisulphite is an inorganic antioxidant, well
soluble in glycerol. Application in oral formulation is
avoided by its special smell.
Thiomersal {sodium-o-[ethyl-mercury(II)-tio]-salicylate}
can be part of various pharmaceutical preparations as
preservative. Its application scale covers parenteral
preparations (0.01% in intramuscular, intravenous, and
subcutan injections), and liquid formulations for
ophthalmologic, nose, and ear treatments.
Drug Excipients
Alpha-tocopherol is the official name of the pure
compound, however, the industrial product can be a mixture
of various tocopherols. It is well soluble in fats, oils and
organic solvents. It is usually applied in various fats and
volatile oils in the range of 0.05 - 0.75%.
3.22. Propellants
Propellants are important parts or aerosols, which are (at
least) two-phase systems. Aerosols can be applied either to
the outer or to the inner part of the body. They serve to
topical application, generally to avoid the systemic effects of
the drug.
Aerosol preparations contain at least three constituents:
1. The active drug ingredient (in association with certain
“helper” substances, such as water, glycerol, organic
solvents, etc.);
2. a propellant; and
3. the container
There are several basic requirements concerning the
propellants, such as they should be neither toxic nor
flammable. In addition, they should be compatible with the
active drug ingredient, and with the container.
Certain compressed gases are used as propellants, e.g.
nitrogen, dinitrogen oxide, carbon dioxide, and noble gases
(argon or helium). A common disadvantage is their limited
solubility in the solvents used for the active drug; also their
pressure is gradually decreasing through use, and therefore,
the production of fine particles will be changed. Fluorinated
hydrocarbons had a major role as propellants, as a
consequence of their good solubility in the generally used
solvents of the active drugs. Fluorocarbons are conveniently
assayed by gas chromatography, with flame ionisation or
electron capture detectors [133]. However, mainly as a
consequence of restrictions to fluorinated hydrocarbons
because of environmental problems, the role of propellants
has gradually been taken over by hand-pumped devices.
3.23. Solubilizers
Solubilizers are well-known excipients. The active drug
has to keep its basic pharmacological characteristics even in
its solubilized form; this is a basic condition. Solubilizers
are surface-active compounds, which generally form micelle
with the pharmaceutical agent in the range of their critical
concentration, and change certain essential physical
characteristics, such as surface tension, viscosity, osmotic
pressure, molar melting point change, and conductivity. The
most important solubilizers used in practice are: benzyl
alcohol, benzyl benzoate, cremophor (Polyoxyl 35 castor oil,
also emulsifier), cyclodextrins, ethanol (also a solvent),
glycerol monostearate (also an emulsifier), lectine (also an
emulsifier), BRIJ (polyoxyl 20 cetostearyl ether, polyoxyl
10 oleic ether), MYRJ (polyoxyl 40 and 50 stearate, also an
emulsifier), polypropylene glycol (also a solvent), polyvinyl
alcohol (also consistency- and viscosity increasing agent),
polyvinyl pyrrolidon (also consistency- and viscosity
increasing agent), fatty acid esters of sorbitan (Sorbitan
Monolaurate, sorbitan Monostearate, sorbitan monooleate,
Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2557
etc., also emulsifiers). Below, certain application fields of
the cyclodextrins are detailed.
Cyclodextrins act as host molecules which can form
host-guest complexes with certain hydrophobic drugs,
forming solid crystalline complexes. Stable tablets can be
manufactured from these cyclodextrin complexes. However,
the activity of certain preservatives changes when included in
cyclodextrin complexes and the pharmacokinetics of host-
guest complexes with cyclodextrin is not necessarily the
same as that of the non-complexed drugs.
The beneficial use of cylodextrins can be well illustrated
with their use together with itraconazole. Itraconazole is a
broad-spectrum antifungal agent, but several of its properties
limit its formulation: it has very poor water solubility (~1
ng/mL at neutral pH) and a high log P value (>5). The use
of hydroxypropyl-β-cyclodextrin (HPβCD), together with the
drug made it possible to produce pharmaceutically acceptable
dosage forms [134,135]. HPβCD solubilizes compounds
through a dynamic inclusion complex formation in which a
controlled portion of the itraconazol molecule is included in
the lipophilic cyclodextrin cavity [136]. Using this
technology, oral and parenteral i.v. (intravenous) formulation
of itraconazole have been developed (Sporanox oral solution
and i.v. solution of Janssen Pharmaceutica, Olen, Belgium)
[137]. A cyclodextrin-based, emulsified wax cream
containing itraconazole was also developed to use as an
effective vaginal delivery system. The formulation was not
toxic to rabbitS under either acute or subchronic exposure,
and the cyclodextrin-based itraconazol was retained in the
vaginal space. Clinical studies indicated that this
formulation was effective in combating vaginal candidiasis.
In addition it was well tolerated, systemic bioavailability
was practically zero.
3.24. Solvents
One or several active drug ingredient can be dissolved to
have a homogenous solution. The process can also be called
molecular dispergation:it takes place by solvatation by the
solvent or solvents. Solubility is defined by the interactions
between the drug and the solvent. The solvents can be polar
(hydrophylic), semi-polar or apolar. Ethanol, glycerol,
polyethylene glycol, etc. are semi-polar solvents, they give
the transition between the polar and apolar ones; semi-polar
solvents have the ability to dissolve both polar and apolar
drugs in a certain, limited extent.
The most widely used solvents are: arachidis oleum;
benzyl alcohol; benzyl benzoate; cottonseed oil; diethyl
phthalate; ethanol; glycerol; isopropyl alcohol; propylene
carbonate; propylene glycol; ricini oleum; soybean oil; and
triacetin.
3.25. Suppository Bases and Auxilliary Materials
Suppositories are formulation for rectal administration.
There are several requirements for a proper base and auxiliary
material. After having melted it should be adequately
viscous and homogenous (without any remaining solid part).
Further requirements are that the suppository base should be
compatible with the active drug ingredient, should
disintegrate rapidly and release the active drug ingredient
without any residue, giving the highest biological
2558 Current Medicinal Chemistry, 2006, Vol. 13, No. 21
availability. Other requirements are that the suppository
should show physical and chemical stability during storage.
Usual suppository bases are: butyrum cacao (synonyms:
oleum Cacao; cocoa butter; oleum theobromatis; adeps
cacao), various adeps solidus (also called hard fat; adeps
neutralis; massa estarimum; witepsol; massupol; suppocire;
wecobee; novata; imhausen).
There are nice varieties of adeps solidus, marked as
Witepsol E, Witepsol H; Witepsol S; Witepsol W as well as
Massa Estarinum A, Massa Estarinum AB, etc., each having
a code number. They differ from each other concerning their
dipersability, melting points, and number of hydroxyl
groups. They do not have instable modifications, their
compactibility is pretty good, and their water retaining
capacity is also high. Suppositories containing Adeps
solidus can be easily formed by casting or by pressing.
Suppository bases are incompatible with basic pH and
strong oxidizing agents.
Suppository auxilliary materials include various diluents
(e.g. 5 – 10% lactose, etc.); glidants and lubricants (e.g. 2-
3% Aerosil, or 5% glyceryl monostearate.); consistency
softeners (e.g. 10% liquid paraffin, or 10% oleyl oleate),
melting point increasers (e.g. stearine or cetyl alcohol),
dispergating agents (e.g. 2-5% natural oil), emulsifying
agents (e.g. 5-10% sorbitan laurate or 10-20% Polysorbatum
20), disintegrants (e.g. Tensides; or Miglyol 812), anti-
rancids (e.g. 0.2% Propyl Gallate). Generally, coloring
agents must not be used to differentiate auxilliary materials
each other.
Other suppository bases and auxiliary materials, such as
glycerol is solvent; while fractionated coconut oil,
polyethylene glycol, Poloxyl 20 cetostearyl ether and
Poloxyl 10 oleyl ether are also used to prepare suppository.
3.26. Surfactants
Various surfactants are used as stabilizers of emulsions
and suspensions, as well as wetting agents [10,97]. Their
Table 11. Analytical Methods to Study Drug Excipients and their Interactions
Method
Chromatogprahy
GC
HPLC
LC/MS
Spectroscopy
Vibrational
NIR
FTIR
Raman
Magnetic resonance
NMR (solid state)
Spectroscopy with imaging (NIR, FTIR, Raman)
X-ray diffraction
Energy-dispersive X-ray fluorescence analysis
Thermal analysis
TGA, DSC
Calorimetry
Microcalorimetry
Moisture sorption isotherm
Kalász and Antal
role is well over that of the neutral excipients because of
their possible effect on the drug transfer across certain
biological membranes. If they disrupt the integrity of
biological membrane, the surfactants enhance drug
penetration, such as absorption in the gastrointestinal tract.
Enhanced absorption may lead to toxic effects. Another type
of the outcome of surfactants is resulted in formation of
drug—surfactants micelles, that may also result in poor
absorption.
The use of surfactants is indicated for the release of
poorly soluble drugs from tablets and hard gelatin capsules.
Surfactants can reduce the solid/liquid interfacial tensions
between the drugs and the gastrointestinal fluid; thereby the
gastrointestinal fluid can better penetrate into the mass of
capsule contents.
It is worth to mention that addition of polysorbate-80 to
an aqueous suspension of phenacetin resulted in its
improved gastrointestinal absorption in humans. The
phenomenon can be explained by the surfactant preventing
aggregation and so increasing the effective surface area and
dissolution rate of phenacetin drug particles in the
gastrointestinal fluids. In general, multiple mechanisms can
influence the surfactant effect on the drug absorption, so the
gross effect will depend on which of the actions is the
overriding one. It can be influenced by the physicochemical
characteristics and concentration of the surfactants, the nature
of the drug, and the type of the biological membrane
involved in the penetration of the active drug component.
3.27. Viscosity-Enhancing Agents
Certain drugs are insoluble in the medium where they are
present; however, their administration requires homogenous
distribution in that liquid. Various semi-synthetic or
synthetic macromolecules can help in the proper dispersion
of the drug.
Viscosity enhancing agents have an important role in
aqueous systems, where their role is increasing the viscosity,
Characteristics
Stability, compatibility
purity/impurity,
decomposition products,
Quantitative distribution in the dosage forms
Identity and structure
Chemical interactions,
Phase characterization
Quantitative distribution in the dosage forms
Structure,
crystallinity/polymorphism,
distribution in the intact dosage form
Stability,
Compatibility,
Phase transitions,
Crystallinity, polymorphism
Hygroscopicity, hydrate formation
Drug Excipients
and to stabilize the active drug in emulsions and
suspensions. Mainly hydrophilic polymers are used as
viscosity enhancing agents to control palatability, ease of
pouring as well as the rate of sedimentation of suspensions
[10]. The administration of a viscous liquid may produce an
increase in the viscosity of the gastrointestinal content.
To increase viscosity of emulsions, polysaccharides
(acacia, tragacanth, alginates, starch and xanthan gum), water
soluble celluloses (methylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose, carmellose sodium) and
readily dispersed microcrystalline cellulose, carbomers
(carboxypolymethylene), and hydrated silicates (bentonite,
magnesium aluminium silicate) are often used.
4. Analysis of Excipients
Microspectroscopic mapping techniques combine the
image analysis of light microscopy, chemical analysis of
vibrational spectroscopy, and a mapping stage for different
areas of the dosage form (e.g. tablet) [137]. Spatial and
spectral information together offer the determination of drug
and excipient distribution, hence the understanding of
structure and performance of the formulation.
Various analytical methods have been used to investigate
various aspects of the excipients, and their relations to the
drugs (Table 11).
Bugay and Findlay [8] collected infrared (IR), Raman,
and nuclear magnetic resonance spectra of a large number of
excipients. Information source (for liquid chromatography)
was also given for the individual excipients.
A detailed procedure gives how carefully the excipients
are controlled. This form show the analysis of
hydroxypropyl beta-cyclodextrin, by Research Diagnostics
Inc, and can be obtained from the company (Pleasant Hill
Road, Flanders NJ 07836, USA; Tel: +1 (973) 584-7093;
Fax: +1 (973) 584-0210 [138]).
Fig. (4). Typical near infrared spectra of some excipients repressnting different structures.
Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2559
4.1. Testing and Characterization of Excipients
Besides the chemical characterization regarding identity,
purity and potency, the functionality of excipients depends
both on their physical properties and on the manufacturing
technology [139]. According to the functional roles of
excipients in the quality, safety, and efficacy of the
medicinal preparation, it is evident that their analytical
control is essential considering also physico-chemical
aspects.
Critical physico-chemical characteristics and
compatibility studies help to select the proper excipient and
to develop stable formulations. Beside chromatographic
analysis, excipient characterization can be approached by
using a variety of spectroscopic techniques, including IR,
near-IR, and Raman spectroscopy [140]. Crystalline state of
hydroxypropylcellulose was studied by IR and Raman
analysis [141]. Amorphous or crystalline state and quantity
of lactose was determined using X-ray diffraction and NIR
techniques comparatively [142].
Since near-infrared diffuse reflectance spectroscopy is
sensitive to both physical and chemical parameters, it has
special benefits for excipient characterization and
identification. Typical NIR spectra for some excipients are
shown in (Fig. 4), recording their reflectance (R%) in the
800-2400 nm wavelength range. The powder samples of
excipients were put into a 5 mm layered cell with 4x5 cm
sides and then placed into the sample container of the
UV/VIS/NIR spectrophotometer (Hitachi U-3501, Japan)
equipped with integrating sphere (diameter=60 mm) and
PbS detector. Developing a spectral database, excipients can
be identified and qualified rapidly.
Pharmaceutical formulations and their excipients can be
characterized also by solid-state NMR method to determine
the amount of a form present in a polymorphic mixture or a
mixture of crystalline and amorphous forms. Studying
mobility and interactions of constituents can be useful in
2560 Current Medicinal Chemistry, 2006, Vol. 13, No. 21
predicting the stability of a formulation, despite the time of
analysis and cost of instrument.
Usually excipients give the major fraction of the dosage
form, hence recognition of the drug/excipient interaction is a
prerequisite during the pre-formulation. Ideally, the
excipients used in the formulation should not interact with
the drug substance or introduce new impurities. Knowledge
of the chemistry and incompatibility of the drug substance is
a basis to select the excipients for certain classes of
compounds [143]. For example, primary and secondary
amines can react with reducing sugars (e.g., lactose, glucose,
and maltose), but mannitol and sucrose are alternatives
[144].
Degradation problems are frequently linked to moisture
content and many excipients are hygroscopic materials and
absorb water during processing (e.g. wet granulation).
Excipients generally contain more free moisture than the
bulk drug, therefore the dosage form may potentially expose
the drug to higher levels of moisture. Water associated with
the drug substance solid can influence chemical degradation
rates, dissolution, powder flow, and other physical
properties [145]. Moisture uptake rate for a material depends
on both the relative humidity of the environment and the
time-dependent moisture content of the solid has to be
investigated [146].
Another common source of formulation problems is the
interaction that can occur between residues found in
excipients and the drug substance, which can be expected
especially for polymers such as polyethylene glycols, film-
formers [147]. The interactions can be investigated both in
solution (phase-solubility studies, UV spectrophotometry,
fluorescence, circular dichroism, NMR, etc.) and in the solid
state (DSC, TGA, HSM, optical microscopy and SEM FT-
IR, NIR, X-ray diffraction, etc.).
In the case of solid state, binary powder mixture of the
drug and the excipient are stored at stressed conditions
[148]. For liquid formulations, chemical and physical
stability is studied over a range of pH values. For parenteral
liquids, admixing with lactated Ringer's injection, 5%
weight/volume (w/v), dextrose injection, and 0.9% w/v
sodium chloride injection solutions should be studied [149].
Thermal analysis serves as a rapid tool that can be used
to examine for incompatibilities between a drug substance
and excipients in the solid state [150].
On the other hand, isothermal microcalorimetry is
becoming useful as a method of detecting changes in the
solid state of drug-excipient mixtures through heat changes
[151]. Although thermal analysis reveal no information
concerning the cause or nature and of any incompatibility,
these methods can be indicative of whether formulations are
stable. However, the application of complementary
techniques may have benefits in determining chemical nature
of interactions.
Microscopic techniques are also suitable to study the
morphology of the drug substance and can determine the
nature of some physical transformations, thus indicating the
type of incompatibility [152].
Solid state characterization of materials (particle size,
crystalline habit, crystalline or amorphous, polymorphism,
Kalász and Antal
etc.) can be performed with different techniques (DSC, TGA,
SEM, FT-IR, NIR, X-ray diffractometry).
Analysis of the intact dosage form (e.g. tablet) or the
preprocessed material (powder, granules, etc.) by non-
destructive techniques (e.g. NIR, FTIR, Raman, X-ray
spectroscopy) is valuable, because the critical parameters
such as the distribution of an excipient in the formulation
can be controlled even at production line. The homogenous
distribution of magnesium stearate in a powder blend can be
studied applying energy-dispersive X-ray fluorescence
analyser [153].
The importance of physical properties such as particle
size is demonstrated in a comparative study of magnesium
stearate. Magnesium stearate batches with a smaller particle
size distribution and larger surface area produced increased
lubricity when compared with batches of similar quality but
larger particle size and smaller surface area [154]. In
addition, the particle size or shape may influence also the
flowability of the excipient or the drug/excipient mixture
also can be influenced by particle size, as well as the particle
shape of the excipient. Hence physical tests on solids such
as sieve analysis, angle of repose, tapped and bulk density
are essential [155].
Nevertheless, the effect of formulation variations (e.g.,
type and ratio of excipients to drug, , change in solubility or
hydrophobicity, homogeneity of excipient) on drug release
from solid pharmaceutical forms or semisolids (gel,
transdermal systems, etc.) should be determined by in vitro
methods (e.g. pharmacopoeial dissolution test) to evaluate
alterations.
In some cases it may be useful to include functionality-
related tests for excipients indicating their quality
influencing drug delivery mechanisms. For example, these
functionality tests should involve such as viscosity/rheology
studies for viscosity enhancing agents; contact angle
measurements for surfactants, specific surface are for
lubricants and adsorbents, swelling rate measurement for
hydrogels, etc.
Among compression aids, silicified microcrystalline
cellulose shows advantages over conventional
microcrystalline cellulose considering tablet strength,
flowability and compressibility. Parallel application of silica
content assay and near-infrared spectroscopy was suitable to
make distinction between these two excipients.
5. DISCUSSION
Many pharmaceutical dosage forms are significantly
complex sytems that may be subject to physical changes
during storage. Excipients are essential to maintain the
physical characteristics of the pharmaceutical dosage form
constructed with the carrier constituents. Physical stability
involves that the formulation remains unchanged throughout
it's shelf life and has not undergone changes considering the
appearance, organoleptic properties, homogeneity, particle
size distribution, hardness, etc. Physical structure of the
drug carrier system is crucial to ensure the drug delivery,
because of the drug delivery profile depends on the
physicochemical processes influencing rate and mechanism
of the drug release. Therefore, physical stability is related to
safety and efficacy of the formulation, and it determines not
Drug Excipients
only the appearance of the product, but the drug content 6. REFERENCES
uniformity and biopharmaceutical profile.
[1]
Excipients play an essential role in the relation between
the patient and the pharmaceutical products. The active [2]
components of the medicines are accompanied with
ingredients, serving to keep the quality of the drug during [3]
[4]
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patient and the product is administered. Certain other [6]
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[9]
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The application of excipients is regulated by some basic
requirements, permitting only the use of approved [11]
substances as ingredients. The amount of excipients may not
exceed the absolutely necessary amount. [12]
There are several reasons to limit the amount of excipient [13]
over the necessary level. One of the most important
arguments deals with the physiological effect of the [14]
excipient itself. Certain antioxidants of pharmaceutical
[15]
formulations, such as butylhydroxy anisol and butylhydroxy [16]
toluene have had the same (antioxidant) role in various food
products, e.g. oils or crackers. Yu et al. [156] evaluated the [17]
risk of cancer induced by artificial food constituents. The
present situation does not indicate any risk given by the [18]
antioxidant; however, animal experiments definitely warn [19]
that overdose may jeopardize the highly important
equilibrium of good health, the homeostasis [37]. [20]
Even the recent regulation of drug approvals indicate that [21]
the permitted amounts of drug excipients may be increased.
The present trend indicates an overload of the pharmaceutical [22]
formulation with excipient(s). Some recently commercialized [23]
generic drugs for cholesterol lowering have been shown to [24]
contain higher or much higher amounts of antioxidants
(ascorbic acid and butylated hydroxyanisole) than the [25]
original formulation (Zocor, a product of Merck Sharp &
Dohme B.V., Haarlem, the Netherlands) [157]. The practical [26]
implications of such overload are yet to be clarified. [27]
The use, role and legalization of pharmaceutical
excipients are well documented. In addition to an abundance [28]
of scientific papers, patents and leaflets, books are mainly [29]
dealing with the characterization of excipients. [30]
The excipients have remained and will continue to [31]
remain essential parts of pharmaceutical formulations. They [32]
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product which can be used for its proper administration.
Drug formulation with the proper types and amount of [34]
[35]
excipients makes possible to overcome aversion to the
medicine, prevent degradation of the active drug, and even [36]
the disintegration of the pharmaceutical formulation before [37]
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is required. At the same time, the knowledge of the role and [38]
[39]
limitation of excipients is as important as the knowledge of
the major characteristics of the active drug compound. [40]
[41]
ACKNOWLEDGEMENTS
[42]
This project was sponsored by a research grant of the
Hungarian National Science and Research Fund (OTKA [43]
T049492). Advices of Dr. L.S. Ettre are appreciated. [44]
Current Medicinal Chemistry, 2006 Vol. 13, No. 21 2561
Baselt, R.C. Disposition of Toxic Drugs and Chemicals in Man. 6th
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Received: January 03, 2006 Revised: May 09, 2006 Accepted: May 10, 2006