Recent Advances in

Semisolid Dosage Forms for

Dermatological Application
Piyush Gupta and Sanjay Garg*

S
emisolids constitute a significant proportion of pharma-
ceutical dosage forms. They serve as carriers for drugs
that are topically delivered by way of the skin, cornea,
rectal tissue, nasal mucosa, vagina, buccal tissue, urethral
membrane, and external ear lining (1). Because of their pecu-
liar rheological behavior, semisolids can adhere to the applica-
This article tion surface for sufficiently long periods before they are washed
discusses some off. This property helps prolong drug delivery at the applica-
of the recent tion site. A semisolid dosage form is advantageous in terms of
MIKE DEAN

advances in its easy application, rapid formulation, and ability to topically

deliver a wide variety of drug molecules.
semisolid dosage
Semisolids are available as a wide range of dosage forms, each
forms for dermatological application. Several having unique characteristics (2–4). Ointments are semisolid
studies have demonstrated the utility of preparations for external application to skin or mucous mem-
semisolid bases for systemic drug delivery by branes. Their composition softens but does not melt upon ap-
dermatological application. Studies about plication to the skin. Therapeutically, ointments function as
the effect of formulation excipients on the skin protectives and emollients, but they are used primarily as
vehicles for the topical application of drug substances. Creams
rheology of semisolids have contributed
are semisolid dosage forms that contain one or more drug sub-
significantly toward their characterization. stances dissolved or dispersed in a suitable base, usually an oil-
The development of computer-assisted in-water emulsion or aqueous microcrystalline dispersion of
instruments also has contributed long-chain fatty acids or alcohols that are water-washable and
substantially to their characterization and are cosmetically and aesthetically acceptable. Gels are semisolid
thereby to improving their quality. Moreover, systems that consist of either suspensions of small inorganic
particles or large organic molecules interpenetrated by a liquid.
some of the guidelines established by
Gels can be either water based (aqueous gels) or organic sol-
regulatory agencies, especially by FDA, are vent based (organogels) (5). Pastes are semisolid dosage forms
major steps toward the standardization of that contain one or more drug substances incorporated in a
these dosage forms. base with large proportions of finely dispersed solids.
A wide range of raw materials is available for the prepara-
tion of a semisolid dosage form. Apart from the usual pharma-
Piyush Gupta is a PhD scholar in the ceutical ingredients such as preservatives, antioxidants, and
Department of Pharmaceutical Technology solubilizers, the basic constituents of a semisolid dosage form
(Formulation) and Sanjay Garg, are unique to its composition. Figure 1 shows the basic raw
M Pharm, PhD, is an assistant professor materials used in the development of various semisolid dosage
in the Department of Pharmaceutics, both at
the National Institute of Pharmaceutical
forms. The choice of suitable raw materials for a formulation
Education and Research, Sector 67, SAS development is made on the basis of the drug delivery re-
Nagar, Punjab 160 062, India, tel.
91 172 quirements and the particular need to impart sufficient emol-
214682-87, fax
91 172 214692, liency or other quasi-medicinal qualities in the formulation.
[email protected]. Semisolid dosage forms usually are intended for localized
*To whom all correspondence should be addressed. drug delivery. In the past few years, however, these forms also
have been explored for the systemic delivery of various drug
144 Pharmaceutical Technology MARCH 2002 www.phar mtech.com
 Percutaneous drug
absorption
Semisolid dosage forms for der-
matological drug therapy are in-
tended to produce desired thera-
peutic action at specific sites in the
epidermal tissue. A drug’s ability to
penetrate the skin’s epidermis, der-
mis, and subcutaneous fat layers
depends on the properties of the
drug and the carrier base. Although
some drugs are meant primarily for
surface action on the skin, the tar-
get area for most dermatological
disorders lies in the viable epider-
mis or upper dermis. Hence, a
drug’s diffusive penetration of the
Figure 1: The basic constituents of various semisolid dosage forms. skin — percutaneous absorption
— is an important aspect of drug
therapy.
Table I: Penetration enhancers for transdermal drug delivery. The main portals of drug entry
Penetration Enhancer Drug Tested Reference into the skin (see Figure 2) are the
Menthol, carvacrol, linalool Propranolol hydrochloride 64 follicular region, the sweat ducts,
Limonene Indomethacin, ketoprofen 64 or the unbroken stratum corneum
Geraniol, nerolidol Diclofenac sodium 65 between these appendages (6,7).
Oleic acid Piroxicam 66 A substance’s particular route
Lecithin Hydrocortisone acetate, heparin 67,68 mainly depends on the physico-
Propylene-glycol-dipelargonate Heparin 68 chemical properties of the drug
Cyclodextrins Hydrocortisone 69 and the condition of the skin.

Advances in the formulation

Table II: Combinations of penetration enhancers and cosolvents for of semisolid dosage forms
The formulation of a suitable
transdermal drug delivery. semisolid dosage form involves the
Penetration Enhancer Cosolvent Drug Tested Reference selection of an appropriate drug-
Isopropyl myristate Propylene glycol Diclofenac sodium 70 carrier system, with a special em-
phasis on the drug’s physico-
Cineole Ethanol TRH analogue p-Glu-3-
chemical properties and required
methyl-His-Pro amide 71
therapeutic application. Drug de-
Ethanol Propylene glycol Aspirin 72 livery by means of semisolid
dosage forms has seen new chal-
candidates whose peroral bioavailability is questionable. Sev- lenges in the past few years in terms of altered drug-release pro-
eral novel drug-carrier systems have been examined that offer files as well as the enhanced stability of active pharmaceutical
enhanced release, controlled release, or a stable environment ingredients (APIs).
for the incorporated drug. Even greater interest has been shown Systemic drug delivery. The skin’s large surface area, 1.73 m2,
in the advancement of methods with which to characterize semi- facilitates its use as a potential site for the application of topi-
solid dosage forms. cal dosage forms (8). With this method, not only can some thera-
Skin, which is the most easily accessible organ of the human peutically active agents be delivered transdermally with ease,
body, continues to be the preferred site for the application of but first-pass gut and hepatic metabolism is avoided, constant
topical drug delivery systems. This article examines the major drug levels in the bloodstream are maintained for longer peri-
advancements in the formulation and characterization of semi- ods of time, potential side effects are decreased, bioavailability
solid dosage forms for application to the skin. The authors have is improved, the dosage is smaller, patient compliance is in-
compiled information from literature published in the past six creased, and drug termination in problematic cases is facilitated
to seven years and herein present the latest developments in as compared with other routes of drug administration (9). Semi-
semisolid dosage forms as well as project new directions for re- solid dosage forms have proven to be ideal carriers for this pur-
search in this fast-evolving field. pose, and several novel developments in their formulation tech-
nologies have emerged in recent years.
146 Pharmaceutical Technology MARCH 2002 www.phar mtech.com
 stratum corneum or by increasing the
thermodynamic activity of the drug
(10). Another class of penetration en-
hancers acts by increasing the amount
of drug in solubilized form at the skin
surface, resulting in the enhanced
permeability of lipophilic drug mole-
cules. A large number of chemicals
have been studied for penetration-
enhancement activity (11,12). The
search continues for new chemicals
with desirable activity at low concen-
trations and with minimal cutaneous
irritation potential. Table I lists some
of the chemicals studied in the past few
years for penetration-enhancing activi-
ty and those that meet this criterion.
In addition to the use of penetration
enhancers alone, their combination
with cosolvents that deliver a drug in
solubilized form has led to the achieve-
ment of higher drug permeability. Table
II lists some of the combinations that
recently have been studied.
Submicron emulsion vehicle system. Con-
ventional creams have a mean droplet
size ranging from 10 to 100 m. Such
formulations have demonstrated poor
penetration of drug-loaded oil droplets
into deep skin layers. It has been re-
ported that microparticles with diame-
ters ranging from 3 to 10 m selectively
penetrate follicular ducts, whereas
particles 10 m remain on the skin
surface, and those 3 m are distrib-
uted randomly into hair follicles and
stratum corneum (13,14). Taking these
constraints into consideration, re-
searchers have developed the submi-
cron emulsion vehicle system (SMEVS)
for improving drug permeation. The
submicron lipid particles of an SMEVS
penetrate the layers of the stratum
corneum, increasing its fluidity and
leading to the disruption of barrier
continuity. Significant hydration of the
stratum corneum, assisted by gap for-
mation, permits the penetration of sub-
Figure 2: Schematic representation of percutaneous absorption of a topically applied drug.
micron emulsion particles by forming
a drug depot in the skin. The result is
Gels with permeation enhancers. Skin can act as a barrier to the slow, continuous, and controlled systemic delivery of the drug.
deeper penetration of drug molecules. With the introduction An SMEVS can be formulated by processing a medium-chain
of various penetration enhancers, however, systemic drug de- triglyceride emulsion with a high-pressure homogenizer. In ad-
livery through the transdermal route has gained major footing. dition, the presence of lecithin, an efficient dispersing agent,
These chemicals, incorporated in a suitable drug-carrying semi- causes a drastic reduction in droplet size, usually to between
solid vehicle, enhance the amount of drug permeation through 100 and 300 nm. Such a system is highly valuable for the trans-
skin either by reversibly disordering the lamellar packing of port of hydrophobic drugs, which are incorporated into the oil
148 Pharmaceutical Technology MARCH 2002 www.phar mtech.com
 acute and cumulative skin irritation, and
the action of lecithin and isopropyl
palmitate as possible skin-penetration
modifiers.
The high diffusion rates of indometha-
cin and diclofenac show that lecithin mi-
croemulsion gel is a suitable matrix for
transdermal drug delivery. However, the
partition coefficient of the drugs from the
gel into the stratum corneum was found
to be unfavorable (18). Hence, relatively
large amounts of the drug had to be used
to obtain the required penetration rates.
Figure 3: Microemulsion-based gels: (a) schematic representation of the formation of lecithin
gels upon addition of water to small phosphatidyl choline reverse micelles in apolar solvents; (b)
Localized drug delivery. Localized drug
delivery by semisolid dosage forms con-
localization of solubilized guest molecules within lecithin gels (36). Reprinted courtesy of
tinues to be a major area of research. Ad-
Elsevier Science.
vances in formulation approaches have
led to increased drug stability as well as
phase of submicron emulsions and thereby improve penetra- improvement in the aesthetic appeal of semisolid dosage forms.
tion of the stratum corneum. Studies of SMEVSs have shown Oleo-hydrogel systems. Oleo-hydrogel systems for localized skin
effective transdermal delivery of diazepam (15) and various action have been explored successfully. Rhee et al. examined
steroidal and nonsteroidal anti-inflammatory agents (16). transdermal permeation using various vehicle systems to avoid
Volatile vehicle–antinucleant polymer systems. Studies have investi- systemic side effects and gastrointestinal irritation from keto-
gated various techniques to enhance the transdermal permea- profen upon oral administration (19). When compared with
tion of topically applied drug molecules. Increasing the thermo- conventional gel or plaster formulations, the oleo-hydrogel sys-
dynamic activity of drug molecules was found to be the most tem was found to be the optimal formulation because it de-
efficient approach. This increase can be achieved by the volatile creased systemic circulation of the drug and increased localized
vehicle–antinucleant polymer system (17). Enhanced permea- action. The researchers examined an oleo-hydrogel system that
tion of sodium nonivamide acetate (an antinociceptive agent) consisted of ketoprofen incorporated into an emulsion of oil
was observed with ethanol–buffer solutions (pH 4.2) contain- and carbomer hydrogel mixture, with N-methylpyrrolidone as
ing antinucleant polymers. The system used supersaturation a permeation enhancer. The greater bioavailability of keto-
(achieved by evaporation of the vehicle) for penetration en- profen in the oleo-hydrogel system was ascribed to good drug-
hancement. In supersaturated solutions the drug is in a high release properties, higher emulsion droplet stability of the
state of activity and has a great leaving tendency, resulting in carbomer gel, and the penetration-enhancing effect of N-
increased flux. However, supersaturated solutions are physi- methylpyrrolidone. A high degree of correlation was observed
cally unstable and can result in the crystallization of a drug between in vitro permeation and in vivo percutaneous ab-
upon preparation of the solution. This effect can be controlled sorption parameters. The formulation of ketoprofen oleo-
by antinucleant polymers such as methylcellulose and hydroxy- hydrogel that showed maximum percutaneous absorption was
propyl cellulose. These polymers are adsorbed on the hydro- one that contained 3% ketoprofen, 1% carbomer, 10% N-
phobic surface of crystals, thus stabilizing the precipitates and methylpyrrolidone, 10% oils, 8% surfactant, and water adjusted
increasing the thermodynamic activity of the drug. A higher to pH 4.6 using triethanolamine.
permeation of sodium nonivamide was observed when ethanol Deoxycholate hydrogels. Sodium deoxycholate (a low molecular
was replaced with n-propanol because of the higher drug solu- weight drug carrier) was found to be a better alternative to high
bility in an n-propanol–buffer solution (pH 4.2). This method molecular weight polymers as a gelling agent (20). It also acts
also resulted in a greater reduction of diffusional barriers by as a penetration enhancer for topically administered drug mole-
the extraction of stratum corneum lipids and proteins. cules. Sodium deoxycholate offers advantages such as low melt
Lecithin microemulsion gel. Lecithin microemulsion gel is a promis- viscosity, potential biocompatibility and biodegradability, and
ing matrix system for transdermal drug delivery (18). Micro- absence of toxic impurities from synthesis residues such as or-
emulsion gels are obtained by dispersing soybean lecithin (a ganic solvents, catalysts, and initiators. When it comes in con-
mixture of phosphatidyl cholines) in a nonpolar organic sol- tact with excess buffer systems, it forms a viscous thixotropic
vent, thereby forming an entangled network of long and flex- gel with enhanced membrane permeability. Sodium deoxy-
ible multimolecular aggregates (see Figure 3). Fatty-acid esters cholate gels leave no residue after application, and because of
such as isopropyl palmitate are preferred organic solvents be- their thixotropic behavior, they are easy to apply on large skin
cause of their relatively high viscosity and complete optical areas. The surfactant action of sodium deoxycholate facili-
transparency. Lecithin microemulsion gels are of particular in- tates the solubilization of several drugs by forming mixed mi-
terest because of their ability to solubilize drug molecules of celles. This system has been studied for its enhanced absorp-
various physicochemical properties, their low potential for tion of progesterone and prednisolone through hairless mouse
150 Pharmaceutical Technology MARCH 2002 www.phar mtech.com
skin by producing structural changes in the stratum corneum. their interaction with surface lipids and the action of bacterial
Cream containing lipid nanoparticles. For enhanced penetration of flora that are present. Thus the encapsulated drug is freed, al-
topical drugs, occlusion of skin is the prime criterion. This re- lowing it to penetrate (23). Small liposomes disintegrate quickly
quirement can be achieved easily by the incorporation of large on the skin surface and may form a lipid layer that prevents the
quantities of fats and oils, especially liquid and semisolid paraf- hydrophilic substance from reaching the skin (30). However,
fin. However, such formulations have the limitations of poor this action enhances the absorption of lipophilic substances.
cosmetic properties characterized by a greasy feel and glossy Liposomes may penetrate the stratum corneum and epidermis,
appearance. The development of a water-in-oil cream containing either intact by means of intercellular channels or appendageal
small particles of solid paraffin was studied as an alternative shunt routes (29,31–33) or as fragments of lipid bilayers
(21). A high degree of occlusivity was obtained with smooth, (23,32,34), thus delivering the lipophilic drug entrapped in the
flexible films prepared by drying aqueous dispersions of solid- lipid bilayer.
paraffin particles with a mean size of 200 nm (nanoparticle A study of the liposomal form of triamcinolone acetonide
dispersion). However, this nanodispersion revealed a rough tex- (TRMA) showed that because of the affinity of their cell sur-
ture when applied. The development of a water-in-oil cream face (with a net negative charge at physiological pH), positive
wherein the aqueous phase was divided into small droplets multilamellar vesicles (MLVs) had a significantly higher skin
solved this problem. Nanoparticles were incorporated in the retention of the drug than did neutral small unilamellar vesi-
aqueous phase. Hence, the oil phase in which the water droplets cles (35). In addition, TRMA skin permeation was enhanced to
were dispersed served as a lubricant for nanoparticles, thereby a significantly higher degree by liposomes consisting of skin
preventing a rough feel during application. lipid composition (ceramide, cholesterol, palmitic acid, and
Solid lipid nanoparticles. Solid lipid nanoparticles of glyceryl be- cholesteryl sulfate) as compared with other liposomes. The en-
henate have been investigated as efficient carrier systems for hanced permeation was attributed to the optimum solubility
topical use (22). They provide both burst and sustained drug of these constituents with lipid layers of skin, which can facili-
release. Burst release improves the penetration of drug into the tate the release and transport of TRMA from the formulation
skin. Because of the presence of a solid matrix, sustained drug to deeper layers of skin.
release is exhibited. This effect helps prolong drug delivery and A study that proposed the use of topical retinoids (e.g., vita-
minimizes the irritation potential of certain drug candidates. min A acid [isotretinoin]) in liposome form found that non-
Solid lipid nanoparticles possess the advantages of better drug liposomal forms are susceptible to oxidation and show irritant
penetration because the small particle size of their drug-carrier action as a result of the large dose of drug in the formulation
system ensures close contact to the stratum corneum and in- (23). Liposomal encapsulation allowed a large portion of the
creases the amount of encapsulated drug penetrating the skin. applied dose in enclosed form to be released in small amounts
Solid lipid nanoparticles can be incorporated in topical dosage for prolonged periods, thus reducing local irritation. In addi-
forms such as aqueous gels or creams in which stability is main- tion, the enclosed drug was found to be less susceptible to the
tained. Because a film forms when the gel or cream is applied, risk of deactivation by oxidation. Other drugs that yielded bet-
occlusive properties on the skin also are obtained. ter results with liposomal formulations include methyl nicoti-
Localized and systemic drug delivery. Liposomes as drug carriers. Li- nate (36), hydrocortisone, betamethasone valerate, econazole
posomes have shown great potential as novel drug carriers for base and its nitrate, minoxidil, tetracaine, lidocaine, dibucaine,
dermal and transdermal systems. Liposomes are microscopic interferons, methotrexate, tobramycin, and silver sulphadiazine
vesicles composed of membrane-like lipid layers surrounding (23,29).
an aqueous compartment (23). Phospholipids most often are Solutions and aqueous gels are two of the most common
used in the preparation of liposomes. Because of the amphi- forms in which liposomes are applied to skin. The choice of
philic nature of phospholipids, when they are dispersed in aque- hydrophilic polymers that minimally influence the stability as
ous solutions they arrange in bilayers, with the fatty-acid tails well as the rate of penetration of liposome-entrapped sub-
(nonpolar) located in the membrane’s interior and the polar stances into the skin is a crucial factor in their efficient func-
heads pointing outward. One of the advantages of using lipo- tioning. Aqueous gels of carboxymethylcellulose were found
somes as drug carriers is that both lipophilic as well as hydro- not to influence the stability of the hydrogenated soya lecithin-
philic drugs can be incorporated within the lipid bilayers and cholesterol liposomes for several weeks and appeared to be
aqueous compartment, respectively. They also serve as a reser- convenient vehicles for liposome formulations as compared
voir for the prolonged release of drugs within various skin with xanthan gum (37).
layers (23–28), thereby reducing the rapid elimination of drug Classical liposomal formulations for skin application present
into the blood or lymphatic circulation (29). This quality makes two significant limitations: they are inefficient in terms of deep
the liposome delivery system useful for treating various skin penetration of skin layers, and they compromise the quality
disorders. Because they are nongreasy and nontacky, liposomal of the drug being delivered. Ethanol has been used widely as a
preparations are cosmetically acceptable. skin permeation enhancer, but only in small concentrations. In
Various mechanisms have been proposed for the delivery of addition, the amount of ethanol incorporated into the liposo-
drugs through the skin using liposomes as a drug carrier. In mal vesicles is limited. A novel system, ethosomes, is composed
these systems, liposomes carry a drug in dissolved form to the of phospholipids, ethanol, and water, with sufficiently high con-
skin surface, and their lipid bilayer ruptures as a result of both centrations of ethanol (38). With these systems, increased mi-
152 Pharmaceutical Technology MARCH 2002 www.phar mtech.com
 surements of these parameters and co-
relation with clinical applications.
Rheological behavior. Gels as semisolid
systems exhibit both liquid- and solid-
like properties, called viscoelastic behav-
ior. The relative contributions of elastic
and viscous elements within a polymer
solution are governed by the extent of
intermolecular association–aggregation
and chain entanglement, respectively.
Characterization has been conducted
using conventional rheometers and other
devices to determine the spreadability,
pourability, and processability of gel for-
mulations. Modification of rheological
behavior using various additives is an-
other research-intensive area of study. A
rheological study with hydroxypropyl
cellulose gels reported an increase in ap-
parent viscosity and decrease in non-
Newtonian index with an increase in
polymer concentration and molecular
weight (40).
Observations about the consistency
of hydroxyethyl cellulose (HEC), car-
boxymethyl cellulose, and hydroxy-
propyl methylcellulose gels showed that
Figure 4: A Plexiglas flow-through cell (59). Reprinted courtesy of Elsevier Science.
an increase in cosolvent (ethanol, propy-
lene glycol, or glycerol) content pro-
duced an increase in gel consistency as
noxidil penetration into deeper skin layers was observed as com- high as the maximum, after which a further increase reduced
pared with that of ethanolic, hydroethanolic, or phospholipid the consistency or, in some cases, completely destroyed the gel
ethanolic micellar solutions. An optimized formulation was ob- (41). This behavior was attributed to the swelling of polymers
tained with 2% soy phosphatidyl choline, 30% ethanol, and in the cosolvents, leading to an increase in consistency. When
water to 100% w/w. Electron microscopy was used to confirm the proportion of cosolvent was increased, the hydration of
the multilamellar-vesicle form of the formulation, and the bi- polymers was reduced, resulting in loss of structure.
layer configuration of the lipids was confirmed by 31P nuclear Carbopol (Noveon, Inc., Cleveland, OH) forms a low-
magnetic resonance. Calorimetry and fluorescence measure- viscosity acidic solution in water that transforms into gel as the
ments confirmed the flexibility of vesicular bilayers. Differen- solution pH is increased. The effect of HEC used as a viscosity-
tial light-scattering measurements showed the ethosomes to be enhancing polymer in Carbopol gel was studied (42). It was
stable for at least two years at room temperature with respect found that a network is formed between Carbopol and HEC
to their average size and size distribution. A high entrapment during the process of neutralization and swelling of adjacent
capacity for molecules of various lyophilicities was observed chains of Carbopol.
with experiments involving fluorescent probes and ultracen- A study of gels of Carbomer-940 (Acofarma, Tarrasa, Spain)
trifugation. In conventional liposomes, both highly lipophilic with tretinoin (43) and -tocopherol (44,45) as drugs and ascor-
molecules and amphiphilic molecules usually are confined to bic acid as an antioxidant showed the change in rheological be-
the bilayer and do not enter the aqueous core. In contrast, these havior of the formulation during storage. The pH of the for-
molecules were found to fill the entire volume of the vesicle. mulation was adjusted to 5.4, considering the stability of
Ethosomal systems have been characterized and tested clini- ascorbic acid and Carbomer as well as the nonirritability of the
cally for dermal delivery of acyclovir (39). formulation to human skin. When stored, the gel decreased in
pH as the result of oxidation of ascorbic acid to dehydroascor-
Characterization of semisolid dosage forms bic acid, a process that also decreased the apparent viscosity.
Characterization of semisolid dosage forms is another area that The change resulted from the coiling of polymer molecules at
is gaining wide attention. Because of the complex nature of a a lower pH, which increased the spreading area with time.
semisolid network, several mechanisms interplay in their in Few reports exist about the combination of polymers and
vitro release, rheology, structural integrity, and so forth. New their synergistic behavior. Xanthan and locust bean gums do
methods have been suggested for precise quantitative mea- not gel individually but form thermoreversible elastic gel in
154 Pharmaceutical Technology MARCH 2002 www.phar mtech.com
 in which Q is the amount of drug released into the
receptor phase per unit area of exposure (mg/cm2),

C0 is the initial drug concentration in the dosage

form (mg/mL), D is the apparent diffusion coef-
ficient of the drug (cm2/s), t is time after appli-
cation (s), and  is a constant (48). To date, no
single device has been universally accepted for
measuring in vitro drug release from semisolid
dosage forms. Several reviews have cited the im-
portant considerations to be made when design-
ing such devices (49,50). Various approaches, de-
scribed in the literature, include custom-designed
assemblies (51–53), Bronaugh diffusion cells
(54,55), Franz diffusion cells (51), and modified
Franz diffusion cells (56–58). The current trend is
toward the development of systems with auto-
mated operations, better instrument controls, and
minimal instrument-related variables.
Plexiglas flow-through cells. Plexiglas cells have been
developed for studies of in vitro drug release from
semisolid dosage forms (see Figure 4) (59). The
system consists of a base plate supporting a plate
containing a sample reservoir. A receptor-fluid
Figure 5: Insertion cell in a compendial flow-through cell: (a) insertion cell; (b) spring reservoir is placed above it, and a semipermeable
support used during turbulent-flow studies; (c) insertion cell inside compendial flow- membrane is supported between the receptor-fluid
through cell (60). Reprinted courtesy of Elsevier Science. reservoir and sample reservoir. The receptor-fluid
reservoir is divided into two equal sections, one
combination, exhibiting greater synergy at a 1:1 ratio (46). Xan- carrying the inlet and the other carrying the outlet for the re-
than gum existed in equilibrium between its two conforma- ceptor fluid. A solid Plexiglas block seals the top of the recep-
tional states. Its helix-to-coil transition at a temperature range tor-fluid reservoir. The entire cell is immersed in a constant-
of 50–70 C suggested that the disordered form of xanthan gum temperature water bath. The system is automated and computer
might be necessary for interaction with locust bean gum. controlled by connecting it to a pump for the receptor fluid, a
Gel-strength measurement. Gels have gained wide acceptance medium splitter, and a fraction collector. This instrument is es-
as semisolid dosage forms. It has been postulated that the pecially useful for measuring the effect of variables such as mem-
strength rather than the viscosity of a gel layer plays a major brane type, flow rate of a receptor fluid, and temperature upon
role in determining the amount of drug release from hydrophilic release rates.
matrices. Recent advances have occurred in the development Insertion cell. An insertion cell, whose dimensions permit the
of an optimal apparatus to characterize gel strength. One pro- cell to be used with the compendial flow-through cell, has been
posed apparatus consists of a sample holder placed on an elec- devised (see Figure 5) (60). It is easier to use and does not re-
tronic microbalance connected to a computer (47). A probe is quire the removal of air bubbles from the membrane–liquid in-
lowered into the sample by means of a motor equipped with a terface, a common problem with the use of Franz-diffusion
speed transformer, and the force required to penetrate the gel cells. The upper section of the insertion cell consists of an ob-
is measured. The increase in force with time is a function of the long Plexiglas block with a 9-mm circle cut out of it. The mid-
mechanical resistance of the sample to the penetration of the dle section consists of a matching oblong Plexiglas block with
probe. Because the lowering speed is known, the displacement a similar 9-mm circle cut out of it, which acts as the sample
covered by the probe as a function of time is calculated and used holder. The lower component is a solid Plexiglas block. All three
to compute the gel-strength parameter or mechanical resistance sections are screwed together. A membrane is placed between
of the gel system. the upper section and the sample-holder section. A stainless
In vitro release study. The release of an API from semisolid steel spring supports the insertion cell (for the turbulent-flow
dosage forms is an important quality control tool. The drug re- mode), and a layer of glass beads in the conical section of the
leased from a semisolid dosage form in which the drug is com- flow-through cell supports the insertion cell (for the laminar-
pletely dissolved is described by the Higuchi diffusion equation flow mode). The insertion cell is positioned 10 mm from the
156 Pharmaceutical Technology MARCH 2002 www.phar mtech.com
conical section of the flow-through cell when it is used with the qualities of the conventional semisolid dosage forms. Signifi-
spring support. The entire assembly is automated in the same cant attention has been placed on the exploitation of semisolid
way as for the Plexiglas flow-through cell. To study the effect of dosage forms for systemic delivery of a topically applied drug
the flow of receptor fluid on drug release, it is recommended on the skin. Incorporation of drug-in-emulsion droplets of sub-
that the insertion cell be used in a downward orientation. micron size has eliminated the need for a drug’s physico-
Modified USP Type II dissolution apparatus. A USP Type II dissolution chemical properties to be responsible for successful drug per-
apparatus was modified for studying the in vitro release of phe- meation. New systems have been proposed that function on the
nol from ointment (61). It comprised a 200-mL vessel, 2.5 principle of occlusivity but are devoid of the drawbacks of con-
1.5 cm paddle, and an Enhancer diffusion cell (VanKel, Cary, ventional ointments. Liposomes have been introduced as suit-
NC) composed entirely of PTFE. The cell contained an able drug carriers for topical use, although with variable results.
adjustable-capacity sample reservoir, a washer for controlling Major efforts are being made to study characteristics such as
the exposure of the surface area, and an open screw-on cap to the rheological behavior of dosage forms and the effect of var-
secure the washer and membrane over the sample reservoir. The ious excipients on the rheology of formulation as well as the
water bath was maintained at 37 C. Filled cells were placed in need for establishing in vitro release profiles of dosage forms.
the bottom of the vessels, and the paddles were lowered to 1 cm Various instruments have been proposed for this purpose and
above the sample surface. Fifty milliliters of high-performance have generated reproducible and reliable results. Great oppor-
liquid chromatography–grade filtered water, degassed and pre- tunities for the development of semisolid dosage forms exist
warmed to 37 C, was used as the dissolution medium. The sys- because of the diverse class of drugs, with unique characteris-
tem was found to yield reproducible results with good relia- tics, that are proposed for topical delivery.
bility in the data generated.
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