Download Spreading of Semisolid Formulations: An Update

Spreading of
Semisolid Formulations
An Update
Alka Garg, Deepika Aggarwal, Sanjay Garg, and Anil K. Singla*
IMAGE 100
A considerable
problem associated
with the manufacture of topically applied pharmaceutical products is the
establishment of
reliable techniques for their characterization.
The efficacy of a topical therapy depends on
the patient spreading the drug formulation in
an even layer to administer a standard dose.
Spreadability is therefore an important characteristic of these formulations and is responsible for correct dosage transfer to the target
site, ease of application on the substrate,
extrudability from the package, and most
important, consumer preference. This article
discusses the various aspects of spreading,
including the factors affecting it, the techniques available for its assessment, and various additives and interactions that can alter
the spreadability of the final formulation.
Alka Garg and Deepika Aggarwal are
doctoral scholars at the University Institute of
Pharmaceutical Sciences, Panjab University,
Chandigarh, India; Sanjay Garg, PhD, is
an assistant professor at the National Institute
of Pharmaceutical Education and Research in
Punjab, India; and Anil K. Singla, PhD, is a
professor and chairman at the University
Institute of Pharmaceutical Sciences, Panjab
University, Chandigarh, India.
*To whom all correspondence should be addressed.
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Pharmaceutical Technology
SEPTEMBER 2002
P
harmaceutical semisolid preparations include ointments,
pastes, cream emulsions, gels, and rigid foams. Their
common property is the ability to cling to the application surface for a reasonable period of time before they
are washed off or worn off. They usually serve as vehicles for
topically applied drugs, as emollients, or as protective or occlusive dressings, or they may be applied to the skin and membranes such as the rectal, buccal, nasal, and vaginal mucosa, urethral membrane, external ear lining, or the cornea (1). These
preparations are widely used as a means of altering the hydration state of the substrate (i.e., the skin or the mucous membrane) and for delivering the drugs (topical or systemic) by
means of the topical–mucosal route.
One of the serious problems associated with the formulation
and manufacture of topical–mucosal preparations is the establishment of reliable techniques for their characterization, mainly
because of the complexity of their physical structure (2). Consumer preference for such products depends on various properties of the preparation, collectively known as the textural profile, which includes appearance, odor, extrudability (when
applicable), initial sensations upon contact with the skin, spreading properties, tackiness, and residual greasiness after application (3). Ultimate acceptability and clinical efficacy of such
preparations require them to possess optimal mechanical properties (ease of removal from the container, spreadability on the
substrate), rheological properties (viscosity, elasticity, thixotropy,
flowability), and other desired properties such as bioadhesion,
desired drug release, and absorption (4).
The efficacy of topical therapy depends on the patient spreading the formulation in an even layer to deliver a standard dose.
The optimum consistency of such a formulation helps ensure
that a suitable dose is applied or delivered to the target site. This
is particularly important with formulations of potent drugs. A
reduced dose would not deliver the desired effect, and an excessive dose may lead to undesirable side effects. The delivery
of the correct dose of the drug depends highly on the spreadability of the formulation. Spreadability, in principle, is related
to the contact angle of the drop of a liquid or a semisolid preparation on a standardized substrate and is a measure of lubricity, which is directly related to the coefficient of friction (5).
Spreadability is subjectively assessed at shear rates varying from
102 to 105 s1. The rate of shear during spreading, s1, is calwww.phar mtech.com
culated using the following equation for plane laminar flow between two parallel plates:
v
d
in which v is the relative velocity of the plates (cm s1) and d is
the distance between them (cm); that is, a measure of thickness
of the film between the skin surfaces (3).
Factors affecting spreading
To assess the spreadability of a topical or a mucosal semisolid
preparation, the important factors to consider include hardness or firmness of the formulation, the rate and time of shear
produced upon smearing, and the temperature of the target site
(3). The rate of spreading also depends on the viscosity of the
formulation, the rate of evaporation of the solvent, and the rate
of increase in viscosity with concentration that results from
evaporation (6).
Formulation characteristics. Formulation characteristics, including viscosity, elasticity, and rheology, are the most important
factors in the development and final behavior of semisolid formulations. Increasing the viscosity of the delivery vehicle increases
its retention time at the target site but also decreases its spreadability. Therefore, consistency of these formulations (varying from
fluid to very stiff texture) plays the most important role in their
final behavior, including their spreading qualities on the substrate. Spreadability can be measured with various types of viscometers and varies according to the formulator’s requirement.
In suspension ointments, a logarithmic regression with a negative correlation was found between viscosity and degree of
penetration, and a significant linear regression correlation was
found between degree of penetration and spreadability (7). This
correlation was further confirmed by Hegdahl and Gjerdet and
Vennat, Gross, and Pourrat (8,9), who proved the existence of
a strong negative correlation between the spreadability and viscosity of elastomeric materials. Also, spreadability of a formulation is inversely proportional to its cohesiveness because strong
cohesive forces within a formulation retard its flowability and
thereby its spreadability on the substrate. Therefore, the cohesiveness of the selected ingredients must be considered during
the development of topical and mucosal formulations (10). In
addition, each formulation must be specifically designed according to the desired purpose of its use, site of application,
and patient acceptability. Spreadability of a formulation can be
either increased or decreased as desired by the formulator to
suit the end purpose.
Increasing the viscosity of timolol eye drops by adding sodium
carboxymethylcellulose increased the effect three- to ninefold as
compared with that of nonviscous drops. The ocular penetration increased as a result of longer corneal contact, and systemic
absorption decreased as the result of slower spreading of the solution on the nasal mucosa (11). Nyman-Pantelidis et al. investigated the effect of viscosity on the retrograde spread of two
enema formulations and found a statistically significant difference in the spread between the low-viscosity and the highviscosity enema (12). The low-viscosity enema spread over a larger
area in the lower colon, mainly in the first 15 min following administration. In contrast, the enema with higher viscosity spread
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SEPTEMBER 2002
over a very small part of the rectum and took a longer time to
spread over the rectal mucosa. Also, the rate and extent of spreading was more variable with the latter formulations.
In another study, Ivens et al. compared the application and
spreading of four different pharmaceutical vehicles, including
solutions, ointments, creams, and low-viscosity creams, and
found the spreadability and retention of the ointment to be better than those of the other three (13). Whereas the ointment
spread evenly in the test area, other formulations were unevenly
spread and provided a lower dose in the periphery. The rapid
evaporation of water from creams and solutions influences the
spreadability and results in an uneven topical dose within the
treated area. The formulations also must be spread quickly and
at multiple sites to ensure correct dosage. Besides having the
advantage of spread, ointments have the disadvantage of stickiness, staining, and poor patient compliance.
In a very recent study, a thermoreversible gel formulation
was evaluated as a possible barrier to the transmission of
pathogens that cause sexually transmitted diseases, including
HIV and herpes simplex virus. It was found that this gel spread
evenly in the vagina and coated the herpes virus or entrapped
it in its micelles, thereby hindering its attachment to the target
cells and inhibiting its infectivity (14).
Rate and time of shear. Care must be taken that the operative
rate of shear for rheological measurement is attained in a time
comparable with the usual amount of time taken by the consumer to spread the preparation (3). In 1954, Kostenbauder and
Martin approximated the rate of shear in the spreading of an
ointment on a surface using the equation
S dv
dr
in which v is the velocity at which the ointment is being sheared
and r is the thickness of the layer (15). They estimated the shearing rates for a pharmacist compounding an ointment with a
spatula and for a consumer spreading an ointment on a surface such as skin as 200 s–1 and 120 s–1, respectively. A later
study demonstrated that 120 s–1 was the point of greatest resistance to flow at low rates of shear for ointment bases, thus confirming the rates cited earlier (16). In addition, the later study
concluded that the shearing region of 0–250 s–1 would be most
relevant when characterizing the spreading properties of pharmaceutical semisolids.
Later, Langenbucher and Lange reported that for topical
preparations, the apparent viscosity and spreading should be
measured at 30–35 C and at a shear rate of 104 s1. This rate
should be reached in a 10-s period (17).
Temperature. In a series of studies, Boylan obtained rheograms
of 13 different pharmaceutical semisolids at various temperatures ranging from 20 to 35 C using a Ferranti-Shirley coneand-plate viscometer (16,18). Many of the preparations appeared to present a straight-line relationship between thixotropic
area and temperature, but the viscosity of ointments is reduced
by a factor of 0.5 for every 5-C rise in temperature. He suggested that measurements for rheological properties should be
made at several points in this temperature range to simulate
most temperatures of use. However, a thin film of material
rapidly warms to the respective temperature after spreading at
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the target site. This temperature also may vary as a result of either increased blood flow induced by rubbing or of individual
physiological conditions (17). Therefore, rheological experiments for correlation with spreadability must be performed at
a suitable temperature according to the individual experiment.
Site of application. Pharmaceutical parameters of a formulation differ according to the target site of application. In the
case of topical formulations, evaporation of water after application affects the spread and retention. Ointments prove better in such cases because evaporation is minimal because of
their oily character, whereas solutions and creams tend to exhibit poor spreadability and rapid removal (13). In a very early
study, Kostenbauder and Martin, after consulting several dermatologists, categorized pharmaceutical ointments into the
following three classes:
● Class I consisted of ophthalmological ointments, which are
the softest products and possess the lowest viscosities. These
ointments spread at a shear rate as low as the action of a blink
of an eye.
● Class II consisted of common medicated ointments, which
although soft are stiff enough to stay at the point of application long enough to transfer the desired dose. They have a
slightly higher viscosity than that of Class I ointments and require a moderate shear to spread.
● Class III consisted of protective ointments, which are hard
and stiff so they remain at the site of moist ulcerative areas
(15).
For preparations that are instilled in the mucosal cavities of
the body such as the vagina or the eye, thinning of the vehicle
by the cavity fluids also plays a role in their final behavior. In
ocular formulations, thinning and drainage after mixing with
tear fluids must be critically considered (19). Similarly, in vaginal formulations the vehicle’s compatibility with the vaginal
fluids, their dilution after administration, and subsequent
drainage depending on posture are important factors that govern their behavior. The rheological properties after administration determine the critical functions of spreading and retention over the vaginal surfaces. Gels are usually the most
desirable dosage forms for this route. A study that compared
four different contraceptive gels and statistically evaluated their
shear thinning and viscoelasticity after application and subsequent dilution found that all gels that were tested exhibited
non-Newtonian behavior, including shear thinning and viscoelasticity. The gels differed in their response to dilution with
vaginal fluid simulant (20).
Measurement of spreadability
Acknowledging that each individual applies semisolid formulations to the skin with a slightly different motion, stroke, and
rate, any rheological estimation of this process, however good,
involves some degree of error. Nevertheless, good approximations can still be made. Tests and estimations are important to
the development of semisolid formulations and can influence
their final behavior.
Wood et al. developed several techniques to measure various
rheological properties of pharmaceutical semisolids and lotions
(21). They estimated the viscosity and elasticity required for ex88
Pharmaceutical Technology
SEPTEMBER 2002
trusion of a formulation from a plastic bottle with respect to
the bottle’s design, type of orifice, and thickness of the plastic.
They also measured the shearing rates involved in high-speed
tube filling and extrusion from collapsible tubes and assessed
their effect on the formulation contained within. In another
study they evaluated the increase in tackiness that occurs in
some formulations as they dry and devised an empirical test to
measure the cohesive–adhesive capability of skin surface during absorption after the rub-in.
Several authors have assessed spreadability using the theoretical equation of plane laminar flow between parallel plates
(17,22), whereas others have made evaluations with a correlation between non-Newtonian viscosities (23,24). The in vivo
methods reported use techniques such as gamma scintigraphy
(25) in addition to individual sensory assessment (17,26,27).
Parallel-plate method. The parallel-plate method is the most
widely used method for determining and quantifying the
spreadability of semisolid preparations. The advantages of the
method are simplicity and relative lack of expense. Also, the
assemblies can be designed and fabricated according to individual requirements of the type of data required, the route of
administration, the surface area to be covered, and the model
membranes to be considered. On the other hand, the method
is less precise and sensitive, and the data it generates must be
manually interpreted and presented.
The spreading behavior of various Witepsol suppository bases
was tested between two Plexiglas plates at 37 C, and optimum
bases were selected on the basis of their spreading properties
(28). Hadi et al. (29) evaluated polyethylene glycol ointment
bases for spreadability using a parallel-plate extensometer based
on the sliding-plates design. Later, Vennat et al. validated the
spreading-diameter measurements of hydrogels on the basis of
cellulose derivatives and established the linearity of spreadingdiameter measurement (30,31). The linear relationship between
spreading diameter, viscosity, and the concentration of gelling
agent depended on the cellulose derivative. The linear relationship between viscosity and spreading diameter was independent
of the derivative. Good repeatability and reproducibility of the
spreading measurement was found. The spreading capacity of
the gel formulations was measured 48 h after preparation by
measuring the spreading diameter of 1 g of the gel between two
20 20 cm glass plates after 1 min. The mass of the upper plate
was standardized at 125 g. Panigrahi et al. used a similar apparatus to assess the spreadability of lyncomycin hydrochloride
gels (32). The following equation was used for the purpose:
S m l
t
in which S is the spreadability of the gel formulation, m is the
weight (g) tied on the upper plate, l is the length (cm) of the
glass plates, and t is the time taken (s) for the plates to slide the
entire length.
DePaula et al. determined the spreadability of various ointment formulations by compressing the sample under several
glass plates of known weight (33). Twenty plates were subsequently placed over the sample at 1-min intervals. The spreading areas reached by the sample were measured in millimeters
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V
Fluid
X
Z
F
r
r
Z
Figure 1: Schematic representation of finger geometry as two parallel
plates (26). V finger velocity, Z thickness of the sample, X shearing stress, F shear force between the fingers, r radius of the
finger.
in the vertical and the horizontal axes. The results were expressed
in terms of the spreading area as a function of the applied mass
according to the following equation:
S i d 2
4
in which Si is the spreading area (mm2) resulting from the applied mass i (g), and d is the mean diameter (mm) reached by
the sample. The spreading area was plotted against the plate
weight to obtain the spreading profiles.
In another study, Arvouet-Grand et al. determined the spreadability of various oil-in-water creams by pressing 1 g of a sample
between two 20 20 cm horizontal plates, the upper of which
weighed 125 g (34). The spread diameter () was measured after
1 min. Under these experimental conditions, they applied the
term semistiff creams to samples with 50 mm and semifluid
creams to those with 50 mm but 70 mm. Lardy et al. recently used a very similar method to evaluate the spreadability
of various test hydrogels (35). The 1 0.01 g gel sample was
placed between two 20-cm2 horizontal glass plates, and was
measured after 1 min. The mass of the upper plate was 125 1
g. The study temperature was maintained at 21 0.5 C, and
the gels were evaluated 48 h after their preparation. They were
finally graded from fluid to very stiff on the basis of the value of
obtained. Principal component analysis, a powerful statistical method, was used to demonstrate the relationships among
the various parameters that describe the consistency of the hydrogels and their spreadability.
Lucero et al. used a Ranvier-type manual microtome to study
the compression deformation (i.e., spreading) of hydrophilic
gels of -tocopherol (36). The microtome that was used had a
perfectly flat 5-cm-diameter plate, a 1.2-cm-diameter screw
bore, and a 0.68-mm thread. A sequence of masses of 80, 150,
300, and 500 g equivalent to compression stresses of 3302, 6191,
12383, and 20638 dynes/cm2 respectively, were placed on the
cylinder of a 77-mm3 sample under ambient conditions. The
duration of each application of force was 1 min of compression with 30-s rest intervals. To evaluate the resulting deformation by each of the stresses, photographic plates were printed
with the areas of spreading produced using a lamp of constant
intensity placed at the same location. Also, these areas were de90
Pharmaceutical Technology
SEPTEMBER 2002
termined by a direct reading of the perimeter by means of a
planimeter.
Subjective assessment. As the name suggests, subjective assessment is based on the sensory assessment of human volunteers.
This mode of measurement is closest to the true spreadability assessment because the results are generated from the individual
feel of the formulation. However, because it requires human assessment it is unpredictable and variable, and the element of reproducibility is reduced because the individual attributes of the
subjects are involved. Therefore an element of bias always exists.
Lagenbucher and Lange described spreadability as a measure
of viscosity correlated to subjective preference. Oils with viscosities ranging between 0 and 10 P at 35 C were presented to
test subjects who rated the ease with which the formulation could
be spread on the backs of their hands. The scores obtained were
plotted against the viscosity of the sample. The most-acceptable
viscosity does not mean the most-viscous sample but the one
with the best spreadability according to the test subjects (17).
DeMartine and Cussler predicted various subjective attributes of liquid texture (26). They stated that subjective spreadability and viscosity are perceived as the shear stress on the fingers, whereas subjective stickiness of a formulation is perceived
as the time frame during which the finger is pulled away from
the sticky surface. Figure 1 shows a correlation between finger
geometry and two parallel plates. Assuming that when fingers
move against each other in an oscillating motion with constant
amplitude and for a constant period of time, the finger velocity varies little with changes in objective liquid viscosity. First
they developed equations for the thickness of the fluid film on
the fingers as a function of time, and then using those equations they developed more equations for predicting spreadability, viscosity, and stickiness. Subjective spreadability was
found to be inversely proportional to the shear stress. It was
also proportional to the ratio of viscosity of the sample to the
steady velocity of the fingers. For each textural characteristic,
the study used panels of between 15 and 24 members of both
sexes ranging in age from 20 to 50 years who had not been
trained before the present work.
Aust et al.’s study of sensory or skin-feel approach for the
evaluation of creams and lotions included a panel of nine judges
who rated various skin-feel attributes, including spreading
characteristics (27). The participants applied the test formulations to the inside surface of their forearm and scored the attributes numerically.
Solutions, ointments, creams, and low-viscosity creams were
tested on 29 healthy volunteers who applied a fixed amount (0.1
g) to the abdominal skin to assess the best vehicle for topical
therapy. Ointment proved to be the vehicle of choice because
it ensured even spreading and retention and therefore a correct
dose transfer (13).
Master-curve method. The master-curve method combines the
the advantages of both the subjective assessment of spreadability
and the use of instrumental measurements. It was brought forward by Barry et al. who, in their many studies, coupled the sensory assessment of spreadability with the master-curve concept
derived from rheological measurement of viscosities of the test
samples (3,37–40). The method determined the relationship
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Log shear stress
O
O
O
L
E
G
Log shear rate
Figure 2: Combination of master curves for lipophilic (L), hydrophilic
gels (G), and oil-in-water emulsions (E) showing the acceptable range
of viscosities for spreading on the skin (shaded area) and the optimum
values (O) (38). Reproduced with permission from Wiley & Sons, New
York, NY.
between the shear stress and the shear rate that operated during the spreading of topical preparations on the skin by deriving from the master curves for lipophilic preparations and hydrophilic preparations, including oil-in-water emulsions and
aqueous gels (3,38). A panel of volunteers compared a series of
formulations that varied in consistency from mobile liquids to
stiff semisolids with a range of Newtonian silicone oils of various viscosities. The participants spread the materials on the
inner surface of their forearm. The mean temperature of the
participants’ inner surface of the forearm was approximately
34 C, the rates of shear varied approximately from 400 to 2500
s1, and the shear stresses varied from 40 to 6000 Nm2. The
panel indicated which oil appeared to possess the same spreading properties as each test formulation. Flow curves of the materials were obtained with a Ferranti–Shirley cone-and-plate
viscometer and the intersection of the rheogram of the test formulation, and the selected Newtonian oil provided estimates
of the shearing conditions that operate during spreading of the
dermatological formulation on the skin. A double logarithmic
plot of shear stress against shear rate provided a master curve.
The preferred region of this master curve was bounded by
400–700 s1 and 200–700 Nm2. The panel then rated the
same preparation in terms of preferred spreadability. These
data, superimposed on the master curve, suggested the optimum and preferred spreading conditions for maximum patient
acceptability. The data obtained indicated a dynamic relationship between the rate of shear, the relative viscosity, and the
thickness of the oil film on the skin.
This procedure for continuous shear rheometry provides a
sound basis for assessing the rheological behavior of a mater92
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SEPTEMBER 2002
ial under moderate shear conditions (see Figure 2). Suzuki et
al. showed that the sensory-perceived property of the product
consistency, and therefore spreadability, is closely related to
Barry’s ground state (i.e., the state in which the structure of the
viscoelastic material is flexed but not destroyed) (23).
In vivo studies. In vivo studies are the best possible assessment
method for any pharmaceutical research. Little work has been
done in vivo for the measurement of spreadability of semisolids,
but a few animal and human study data are available. These studies bypass all elements of bias and instrumental limitations and
give an accurate picture in terms of the biological environment.
Animal models. Grant and Liversidge, in an attempt to assess the
rheological behavior of fatty suppository bases and their spreading characteristics, developed a method using rats (41). The rats
were deprived of food for 24 h, and their intestine was completely purged to remove any fecal pellets. The suppository then
was inserted into the rectum, and the rectum was sealed with
a cyanoacrylate ester adhesive. The rats then were placed in a
cage with food and euthanized after the allotted time. The dead
animals were dissected, and the distance of ingression of the
suppository base containing dye was measured from the external anal sphincter.
Richardson et al. studied the distribution and retention of a
novel bioadhesive intravaginal delivery system based on HYAFF
(a chemically modified hyaluronic acid ester) microspheres in
a sheep model (42). In a preliminary experiment, the dimensions of the ovine vaginal cavity were outlined and imaged by
gamma scintigraphy after administration of a suitable volume
of 99mTechnitium (99mTc)-labeled gellan gum. The gum solution gels after administration into the vagina and is hence able
to fully fill and outline the cavity. The data collected then was
used for subsequent comparison with the distribution of the
radiolabeled HYAFF formulations. In other groups of sheep,
99m
Tc-HYAFF microspheres were either administered as a dry
powder or suspended in a vaginal pessary, and the distribution
and intensity of radioactivity in the genital tract was measured
during a period of 12 h.
Human volunteers. In studies on human volunteers, the noninvasive technique of gamma scintigraphy has proved to be a very
valuable means to assess novel formulations aimed at optimizing retention and spread locally or in systemic drug delivery.
This technique is the most effective method for studying the
spreading and retention of pharmaceutical semisolids for insertion in mucosal cavities.
Nyman-Pantelidis et al. investigated the retrograde spread of
two budesonide enema formulations with different viscosities
(12). Three female and two male patients were given the enema
formulations containing budesonide and an unabsorbable radioactive marker (99mTc-labeled human serum albumin microcolloid), and the spread was monitored by gamma scintigraphy. In a similar study, Wilding et al. used the same technique to evaluate the colonic spreading of a rectal foam enema
in patients with quiescent ulcerative colitis (43). A single administration of a mesalazine foam enema containing 99mTc was
conducted on 10 patients, and the spread of labeled Tc was assessed during a period of 4 h by gamma scintigraphy.
Brown et al. assessed the vaginal spreading and clearance of
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a radiolabeled, fatty-based pessary formulation and a putative,
bioadhesive gel formulation (Replens, Columbia Laboratories
Inc., Aventura, FL) in six healthy postmenopausal female volunteers during a 6-h period using gamma scintigraphy (25). The
study was also designed to investigate whether any of the formulation was capable of migrating across the cervix into the
upper genital tract. The formulations were administered into
the posterior fornix of the volunteers, and immediately a sanitary dressing was applied to contain any leakage of the formulation. Dispersion and spreading of the formulation within the
vagina was monitored throughout the study day using a gamma
camera within a 40-cm field of view and fitted with a lowenergy parallel hole collimator. Anterior and posterior images
of 60-s duration were acquired at predetermined intervals. For
analysis, the images were displayed on a color monitor, and the
extent of spreading was assessed in terms of the anatomical location of the tracer. It was also observed that following placement of the formulation in the posterior fornix, no spread into
the cavity of the uterus or beyond was observed in any of the
volunteers for either the pessary or the gel formulation.
Miscellaneous methods. In addition to the methods previously
described for spreadability measurement, some techniques or
instruments originally designed for other purposes have been
used for the measurement of spreadability of semisolids. Four
of the instruments are described in this section.
Viscometers and penetrometers. Viscometers are by far the oldest
and most widely used instruments for the measurement of
spreadability. They measure spreadability as a function of viscosity of the formulation. Cone-and-plate viscometers are best
suited for estimating the viscosity of semisolids. The FerrantiShirley cone-and-plate viscometer was used by Boylan as early
as 1967 to evaluate the spreading properties of semisolids, and
he described various advantages and disadvantages of using
the instrument for this purpose. The advantages included the
provision of a multipoint rheogram, the ease of maintaining
a constant shearing rate for an indefinite period of time, and
a shearing geometry that closely duplicates that of the application of the materials with a circular motion on the skin. In
addition, it subjects all portions of the sample to uniform shearing stress. The disadvantages included slippage between the
rotating portion of the viscometer and the sample during measurement. However, rheological procedures by which the
spreading properties of pharmaceutical semisolids can be reproducibly measured were presented (18). In addition, Barry
et al. in their series of studies mentioned previously in this article correlated sensory assessment of spreadability to viscosity measured using a Ferranti-Shirley viscometer.
Penetrometers, usually used to measure the viscosity and consistency of semisolids, also can be used to determine the spreadability of semisolids (44). The following equation can be used
to yield the spreadability index of a formulation using a cone
penetrometer:
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Po m K b
(d p )n j
in which Po is the yield value for the sample (g/cm2), dp is the
depth of penetration of the cone (cm), m is the weight of the
cone plus the weight of other moving parts of the instrument
(g), and nj is the constant (2), the precise value of which depends on the properties of the sample. Kb can be calculated
using the following equation:
K b (1 ) cos(2ap) cot(ap)
in which ap is the half-life of the cone angle.
Extending the yield values obtained from the penetrometer,
the spreadability index can be calculated using the following
equation:
Si Po (u) 0.75(Po [u] Po [w])
in which Si is the spreadability index, Po[u] is the yield value
before working the sample, and Po[w] is the yield value after
working the sample on a roller mill for 30 min. The factor 0.75
is derived from a comparison of penetrometer data with panel
participants’ assessment of spreadability.
Various other penetrometers also have been used to determine a statistical correlation coefficient between spreadability
and firmness, including a needle penetrometer, a cone penetrometer, a sectilometer, and a FIRA-NIRD extruder. Spreadability data obtained in this way agreed closely with the consumerpanel assessment of the same formulations, and in fact the
instrumental technique proved to be more sensitive to small
variations in spreadability. A highly significant correlation was
identified between instrumental measurements of spreadability and hardness, the latter being assessed using a sectilometer (44). The regression equation used was
Resistance to spreading(g) 90.9 2.63 hardness(mg)
The standard deviation was 43.4 g, and confidence limits at 5%
significance levels were given as 86.7 g. It was concluded that
although the most important factor affecting spreadability was
hardness, certain other factors may also exert minor influences.
Texture analyzers. Texture profile analysis (TPA) was used by researchers to determine the mechanical and physical properties of
semisolid systems (4,10). These properties include compressibility, cohesiveness, adhesiveness, hardness, and physical properties. The texture analyzer (model TA-XT2, Stable Microsystems,
Surrey, UK) has an analytical probe that is depressed two times
into the sample at a defined rate to a desired depth, allowing a
predefined recovery period between the end of the first and the
beginning of the second compressions. The TPA characteristics
of the sample are evaluated from the resultant force–time curve.
This precise and convenient method allows a small sample to provide a large amount of data pertaining to the physical properties
of the semisolid formulations in a desired form. The data can be
statistically evaluated and presented with ease.
Spread meters. Spread meters are specially designed to measure
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SEPTEMBER 2002
spreading of semisolid preparations. These mechanized and
improvised parallel-plate instruments provide accurate, reproducible, and statistically relevant data.
Tamura et al. used a spread meter having a 115.5-g glass plate
(Rigosha and Co. Ltd., Tokyo, Japan) for the assessment of
spreadability of an oil-in-water–type cyclosporine gel ointment
(45). Spread diameters of the samples were measured at 1 min
after the beginning of compression at 20 C. In another study,
a spread meter (model 419, Rigosha and Co. Ltd., Tokyo, Japan)
was used to measure the spreadability of gel ointments of indomethacin. A 0.45-mL sample of the ointment was placed in the
sample hole on the spread meter. The spread diameter measured after 1 min was read at 25 C. This spread area was used
as an index of spreadability (46).
Improvement of spreadability
Because spreadability is such an important factor in the development of a wide variety of dosage forms ranging from topical and mucosal semisolids to lotions and drops, specific efforts
are required to achieve the desired formulation characteristics.
Various pharmaceutical excipients have been used to improve
the lubricity and spreadability of topical–mucosal formulations.
These include various polymers, surface active agents, and many
other miscellaneous materials.
Polymers. Various polymers have been added to formulations
to improve their spreadability. Product cohesiveness has been
found to be significantly affected by its degree of polymeric
concentration, and in nearly all cases increased polymer concentration has led to increased viscosity of the formulation.
Thermal gelation temperatures also play an important part in
a formulation’s behavior. Therefore the selection of polymer
combinations and their relative ratios plays a very important
role in formulation development and must be carefully considered to achieve the desired spreadability.
When various hydroxyethylcellulose (HEC) gels were formulated alone and in combination with polyvinylpyrrolidone
(PVP) and polycarbophil (PC), it was observed that increasing
the concentration of HEC from 1 to 3% led to increased hardness and cohesiveness, and a further increase from 3 to 5% had
an opposite effect. When PVP or PC were used in combination
with HEC, product cohesiveness depended on the individual
polymer ratios (10).
For hydroxypropyl methylcellulose (HPMC) gels, Ferrari et
al. reported that the gel strength or cohesiveness increased as
the concentration of the polymer was increased (47). In a quantitative evaluation of the changes of dynamic surface tension
and therefore the spreading behavior of HPMC aqueous solutions, various concentrations of the same were tested against
Avicel PH-101 (FMC Corp., Philadelphia, PA) tablets. It was
observed that by increasing the concentration of HPMC and
thereby increasing the viscosity, the dynamic contact angle values also increased, thus decreasing the spreading behavior of
the polymer solution on the tablet surface. It was also noted
that the presence of a hydrophilic-type plasticizer improves the
spreading pattern (48). McTaggart and Halbert suggested that
the gel strength of HPMC gels is related to the degree of crosslinking in the polymer network (49).
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To identify optimum bases for vaginal suppositories with
spreading (upon melting) as a parameter, it was determined that
Suppocire NA was the best lipophilic base and polyethylene glycol (PEG), a macrogel with low molecular weight, was the best
hydrophilic base. The use of Suppocire was strongly recommended for formulating suppositories for the treatment of
vaginitis (50). Hadi further stated that the type and amount of
PEG used greatly affects the spreadability of ointment bases (29).
PEG 2000 and PEG 6000 showed the best results as suppository
bases in a comparative study of PEGs of various grades. PEG
200 and PEG 400 have been used to impart desired flow properties to ophthalmic ointments (51). Semisynthetic glycerides,
as with Witepsols (H5, H15, W25) (Condea Chemie, Hamburg,
Germany), which consist of solid lipid nanoparticles, and Suppocires (AIM, NAI, A, AP) (Gattefossé, Weil-Am-Rhein, Germany), which consist of semisynthetic glycerides (C8–C18), have
been studied as suppository bases, and the Suppocires showed
better spreading properties (52).
A comparison of the spreadability of various light-bodied
elastomeric and reversible hydrocolloidal impression materials
showed that polysulfide had the maximum spreading ability, followed by silicones, hydrocolloids, and polyether materials (8).
DePaula et al. prepared ointments of Achyrocline satureioides
spray-dried extracts with various adjuvants, including colloidal
silicone dioxide, MCC plus colloidal silicone dioxide (1:1), and
-cyclodextrin plus colloidal silicone dioxide (1:1), each in a
glyceryl monostearate base (33). The physical properties, including spreading, viscosity, and pH were compared, and it was
concluded that the best spreading area was reached by the ointment prepared with the spray-dried extract containing MCC
plus colloidal silicone dioxide. Silicone dioxide alone gave the
lowest value, indicating the desireability of incorporating this
polymer (33).
An FAPG base (Syntex Pharmaceuticals Limited, St. Ives
House, Maidenhead, Berks, UK), which is a mixture of propylene glycol, stearyl alcohol, polyethylene glycol, and glycerine
combined to form a gel-like structure with a crystalline network,
was investigated as a vehicle for dermatological formulations,
and its rheological properties have been studied. This base is a
mixture of propylene glycol, stearyl alcohol, PEG, and glycerol
combined to form a gel-like structure with a crystalline network.
Patient acceptance of skin spreadability was assessed using the
master-curve concept. The spreading properties were close to
the preferred values for maximum patient acceptance (3,38,40).
Surfactants. Surfactants, or surface-active agents, are amphiphilic compounds that form oriented monolayers at interfaces and exhibit higher equilibrium concentrations at interfaces than do those in a bulk solution. They exhibit several
characteristics, including detergency, foaming, wetting, emulsifying, solubilizing, and dispersing. These agents are an integral part of the formulation of disperse systems for drugs and
cosmetics and impart the desired physical characteristics and
physical stability to these systems. Overall, they are responsible for the rheological properties of a formulation (53). Grant
and Liversidge demonstrated the importance of the rheological properties of a suppository base in terms of the release and
absorption of the drugs entrapped within (41). Softigen 701
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SEPTEMBER 2002
(Condea Chemie), which is a polyethylene glycol–caprylic glyceride, and stearyl heptanoate are agents known to enhance the
spreading of Witepsol suppository bases (28). In water-in-oil
ointment bases with high water content, Miglyol gel (stearalkonium hectorite-propylene carbonate) (Condea Chemie),
which is an ester of saturated coconut and palm kernel oil–
derived caprylic–capric fatty acids; Span 80 (sorbitan monooleate); and Imwitor 780K (isostearyl diglyceryl succinate)
(Condea Chemie), which is an ester from diglycerol isostearic
acid and succinic acid, were found to be the best emulsifying
agents for imparting favorable consistency, low thixotropy, and
good spreadability to the bases (54). On the other hand, spreadability was found to decrease with the increasing levels of tegins (glyceryl esters) when they were incorporated in lipophilic
bases (55). In yet another study, Eros and Hunyadvari investigated the effect of spans (sorbitans) on the physical properties
of ointments and concluded that the spreading of an ointment
decreases with the increasing length of the carbon chain of the
fatty acid residues of the sorbitans (56).
Sodium dodecyl sulphate as a salivary substitute was used to
improve the lubricity of the saliva at a bovine enamel interface,
and it reduced the interocular friction (57). Statherin, which is
a salivary acidic proline-rich protein and is another excipient
used as a boundary lubricant on enamel, exhibits comparable
lubricity to amphipathic molecules such as Gramicidin-S and
sodium dodecyl sulphate (58). Various organomodified silicone
emulsifiers have also been shown to improve spreading and lubricity along with other formulation parameters in topical formulations (59). Polyoxyethylated glycerides (e.g., Nikkol TMGS5, [Nikko Chemicals Co. Ltd., Tokyo, Japan]) have been used as
emulsifiers and spreading agents in various oral solutions and
hydrogel ointments (45, 60).
Fluorocarbons. Fluorocarbons and fluorocarbon moieties comprise a vast family of synthetic compounds. They have recently
found numerous applications in the pharmaceutical industry
because of their special properties, including exceptional chemical and biological inertness, low surface tension, excellent spreading characteristics, unique hydro- and lipophobicity, high density, high fluidity, absence of protons, and magnetic susceptibility
similar to that of water. Fluorinated lipids and fluorinated surfactants can be used to elaborate and stabilize various colloidal
systems such as various types of emulsions, vesicles, and tubules
as well as have the potential to be used for controlled-release
drug delivery. Fluorinated amphiphiles have helped provide a
variety of stable reverse and multiple emulsions and gels with
excellent spreading properties. These compounds, with their
polar heads, are significantly more surface active than their hydrocarbon analogues and thus display a greater tendency to
form well-ordered stable supramolecular assemblies (61–63).
Their potential as pulmonary, topical, and ophthalmological
drug delivery agents and as skin protection barriers is being investigated widely (64).
Miscellaneous. It has been observed that the levels of colloidal
silicone oxide–dioxides, which are 2% in suppository bases,
inhibit the spreading of molten suppositories. However, with
triglyceride bases and with cocoa butter, as much as 3% silica
can be added to improve the flow characteristics of molten supwww.phar mtech.com
positories (65). Colloidal silicone dioxide, coupled with cyclodextrin or microcrystalline cellulose, was shown to enhance the oil-index values of an herbal ointment, thereby imparting better spreading properties (33). Glycerine, when added
to formulations, also helped impart the desired rheological
characteristics (66). Cyclomethicone has been widely used as a
base fluid to formulate a variety of cosmetic and toiletry preparations because it imparts desirable lubricating and spreading
properties (67).
A comparative study of the hygroscopicity and viscosity of
glycerine, propylene glycol, and sorbitol and their effects on the
moisture loss, spreading, and stability of nonionic and ionic oilin-water lotions and cream emulsions found that all these polyols offered protection against water loss and provided emolliency, good spreadability, and stability to both lotions and
creams. The effect varied with the concentration and relative
humidity of the polyol used, and sorbitol offered the best results.
Low doses of eucalyptus oil have been used to improve the
surface properties of various surfactants including ALEC (Abbot
Labs, North Chicago, IL), which is a combination of dipalmitoyl lecithin and phosphatidyl glycerol; Exo-surf (Abbott Labs),
which is a synthetic surfactant containing cetyl alcohol, colfosceril palmitate, and tyloxapol; beractant (Survanta, Abbott
Labs), which is an exogenous surfactant; and a binary mixture
of dipalmitoylphosphatidylcholine and phosphatidylethanolamine (2:3). Eucalyptus oil–enriched surfactants form an
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Pharmaceutical Technology
open membranous structure, thereby exhibiting better surface
activity (68).
Lucero et al. described the effects of two antioxidants—
ascorbic acid (AA) and butylated hydroxytoluene (BHT)—on
the spreadability of -tocopherol gel formulations (36,69). Carbomer 940 (DFS Products, Honiton, Devon, UK) was used as
the gelling agent. -Tocopherol gels were individually prepared
with the two antioxidants and one without an antioxidant, and
the three preparations were compared for their spreading characteristics. Both AA and BHT reacted with the carbomer and exhibited significantly different properties. In gels with BHT, hydrogen bonds were produced between the hydroxyl groups of
-tocopherol and those of BHT and the free radicals CO of
the carbomer, thereby leading to an unwinding of the polymer
resin and an accompanying rise in the viscosity and thickening
and hence reduced spreading. In gels with AA a repulsion is created between the like (negative) charges originating in AA and
the carbomer, leading to the loss of spiral structure of the resin
and thus higher viscosity. However, this union still exhibits a statistically significant and improved spreading because the repulsion of the like charges forms hydrogen bonds between the hydroxyl groups of dehydroascorbic acid (an intermediate formed
by oxidation of AA) and the carboxyls of the polymer. This union
is very easily broken under pressure because of the nature of
these bonds. This formulation therefore exhibits very good
spreading characteristics.
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SEPTEMBER 2002
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Phospholipids such as phosphatidylcholine and triolein in
their hydrated, liquid crystalline state gave large values of spreading pressures, thereby enhancing the spreadability of vesicular
formulations (70,71). The use of physiological lipids that are
normally present in the tear fluid (i.e., phospholipids, saturated
and unsaturated fatty acids, and triglycerides) in eye drops provides better spreading behavior of these formulations in the eye
because of the small size of the lipid particles (53).
The addition of neutral oils such as Miglyol 812 and Estasan,
which is a medium-chain triglyceride consisting of glyceryl
tricaprylate–caprate, each in a 5% concentration, had a favorable effect on the spreading properties of a vaginal suppository
base (72).
Various drugs can also modify the spreading properties of
the base of a topical preparation, thereby altering its rheological properties. Sodium valproate, when added to fatty bases, increases the viscosity notably and therefore necessitates the use
of a spreadability aid. The addition of sodium valproate was
found to increase the viscosity of Witepsol H-15/Span 80 and
Suppocire As2–aerosil combinations when formulating suppositories. The active substance suspended in the molten base
provides nuclei for the crystallization of high-melting-point
glycerides, thus accelerating the separation and subsequent sedimentation of the suspended matter, altering the flow properties of the formulation (73).
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Conclusion
Spreadability is a very important property in the development
of semisolid preparations meant for topical–mucosal routes.
Because it is responsible for the overall performance of a formulation, it must be carefully taken into consideration and procedures must be devised for its effective measurement during
the formulation development stages. To date, little effort has
been directed toward this issue and more work must be applied
to its study.
On the basis of existing literature, an appropriate method for
the evaluation of spreadability can be chosen or customdesigned according to the formulator’s need. Various polymers,
plasticizers, and other materials can be incorporated into a formulation to alter its spreading characteristics. The polymers
that can be used, their compatibility with the active ingredient,
the prospective route of administration, and the rate and time
of shear are among the most important parameters to be considered at the time of formulation development. The method
to be used for assessing the spreadability must be selected carefully and modified according to individual requirements.
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