18
Semisolids
BERNARD IDSON and JACK LAZARUS*
Pharmaceutical semisolid preparations include
ointments, pastes, cream emulsions, gels, and
rigid foams. Their common property is the abil­
ity to cling to the surface of application for rea­
sonable duration before they are washed or worn
off. This adhesion is due to their plastic rheo­
logic behavior, which allows the semisolids to
retain their shape and cling as a film until acted
upon by an outside force, in which case they de­
form and flow. 1
Ointments, in general, are composed of fluid
hydrocarbons meshed in a matrix of higher­
melting solid hydrocarbons. While most oint­
ments are based on mineral oil and petrolatum,
there are alternative types. Polyethylene can be
incorporated into mineral oil to yield a plastic
matrix (e.g., Plastibase, manufactured by
Squibb). Mixtures of polyethylene glycols can
yield products of ointment consistency that are
water-soluble. Most ointments are prepared by
melting the components together. Drugs or
other components are added in the fluidized
state. If the solids are insoluble and to be sus­
pended, the system is put through a milling
process (a colloid mill, homogenizer, or ultra­
sonic mixer) so that the solids are fully dis­
persed.
Pastes are basically ointments into which a
high percentage of insoluble solids has been
added. They are valuable as protective barriers
on the skin, such as for treating diaper rash or
protecting the face and lips from the sun. Pastes
are usually prepared by incorporating a solid di­
rectly into a congealed system by levigation with
a portion of the base to form a paste-like mass.
The remainder of the base is added with contin-
*Deceased.
534
ued levigation until the solids are uniformly dis­
persed in the vehicle.
Creams are semisolid emulsion systems with
opaque appearances, as contrasted with translu­
cent ointments. Their consistency and rheologic
character depend on whether the emulsion is a
water-in-oil or oil-in-water type and on the na­
ture of the solids in the internal phase. The sub­
ject of emulsions is treated in Chapter 17.
Gels are semisolid systems in which a liquid
phase is constrained within a three-dimensional
polymeric matrix (consisting of natural or syn­
thetic gums) in which a high degree of physical
(or sometimes chemical) cross-linking has been
introduced. The polymers used to prepare phar­
maceutical gels include the natural gums traga­
canth, pectin, carrageen, agar, and alginic acid
and such synthetic and semisynthetic materials
as methylcellulose, hydroxyethylcellulose, car­
boxymethylcellulose, and the Carbopols, which
are synthetic vinyl polymers with ionizable car­
boxyl groups. Gels are prepared by either a fu­
sion process or a special procedure necessitated
by the gelling characteristics of the gellant.
The bulk of these semisolid preparations are
applied to the skin, where they usually serve as
vehicles for topically applied drugs, as emol­
lients, or as protective or occlusive dressings. A
lesser portion of topical semisolid dosage forms
are applied to mucous membranes, such as rec­
tal tissue, buccal tissue, vaginal mucosa, ure­
thral membrane, external ear lining, nasal mu­
cosa, and cornea. The mucous membranes
permit more ready access to the systemic circu­
lation, whereas normal skin is relatively impene­
trable. The emphasis of this chapter is on the
skin and on dermatologicals, but the general
concepts and rationale apply to all semisolid top­
ical therapy.
Skin
The skin is a large multilayered organ that in
the average adult weighs about eight pounds,
excluding fat. It covers a surface exceeding
20,000 cm2 and has varied functions and prop­
erties. The skin serves as a barrier against physi­
cal and chemical attack. Some materials, such
as nickel ions, mustard gas, and the oleoresins
from Rhus toxicodendron, commonly known as
poison ivy, can penetrate the barrier, but most
substances cannot. The skin acts as a thermo­
stat in maintaining body temperature, shields
the body from invasion by micro-organisms, pro­
tects against ultraviolet rays, and plays a role in
the regulation of blood pressure.
Anatomically, the skin has many histologic
layers, but in general, it is described in terms of
FIG. 18-1. Stratified organizatian of the skin. (From Pillsbury, D. M.: A Manual of Dermatology. W. B. Saunders, Phila­
delphia, 1971).
three tissue layers: the epidermis, the dermis,
and the subcutaneous fat layer. Figure 18-1 rep­
resents an idealized section of the skin, showing
the glands, hair follicles, nerves, blood vessels,
and other skin accessories. The outermost layer
is the stratum comeum, or horny layer, which
consists of compacted, dead, keratinized cells in
stratified layers with a density of 1.55. Because
of the dense nature of the stratum comeum, val­
ues of diffusion coefficients in this tissue are a
thousand or more times smaller than in any
other skin tissue, which results in higher resist­
ance and general impenetrability.2
The stratum comeum is the rate-limiting bar­
rier that restricts the inward and outward move­
ment of chemical substances. Structurally, the
stratum comeum is a heterogeneous tissue com­
posed of flattened keratinized cells, the outer
SEMISOLIDS • 535

layers of which are less . densely packed than
those adjacent to the underlying granular layer.
The stratum corneum exhibits regional differ­
ences in thickness over the body. It is as thick as
several hundred micrometers on the palms of
the hand and soles of the feet in an adult, but
over most of the body it is about 10 µ,m thick
when dry, increasing to about 40 to 50 µ,m when
fully hydrated.3
There is limited knowledge of the chemical
composition of the barrier. The main cellular
components are the proteins, lipid, and water,
combined into an ordered structure. The ap­
proximate composition in the dry state is 75 to
85% protein, 15 to 20% lipid, and 15% water.
Although the surface lipids offer little resistance
to the passage of compounds, studies of the re­
moval· of lipids from the cutaneous surface indi­
cate that they participate in epidermal water
function.4-10 Barrier function is restored when
the extracted lipids are returned to the skin,
which suggests variations in biologic membrane
permeability, depending largely on the specific
nature or distribution of the lipid contained in
the cell membrane.
Beneath the stratum corneum are the meta­
bolically active layers of the epidermis. The
basal or germinal layer lies right above the der­
mis. Epidermal cells start their mitotic journey
upward to the surface; the cells flatten and
shrink as they slowly die from lack of oxygen
and nutrition.
The next distinctive histologic layer shown in
Figure 18-1 is the dermis, or corium, which is
approximately one eighth of an inch thick and
constitutes the main mass of the skin. The der­
mis essentially consists of about 80% of protein
in a matrix of mucopolysaccharide "ground sub­
stance."11
Contained and supported within the dermis
are numerous blood vessels, lymphatics, and
nerves, as well as the epidermal appendages
such as the hair follicles, sebaceous glands, and
sweat glands. Hair follicles are distributed over
the entire skin surface with the exception of the
soles of the feet, the palms of the hand, the red
portion of the lips, and select portions of the sex
organs. Each hair follicle is associated with one
or more sebaceous glands, which are outgrowths
of epithelial cells. The fractional area of the skin
surface occupied by the hair follicles has been
estimated to be roughly 1/1000 of the total sur­
face.12 The sweat glands are divided into the
eccrine and apocrine types. They are widely dis­
tributed over the surfaces of the body. The ec­
crine glands are particularly concentrated in the
palms and soles. The principal function of the
glands is for heat control, as they secrete a dilute
536 • The Theory and Practice of Industrial Phannacy
1
salt solution. The apocrine glands are found in
I
the axillae (armpits), in anogenital regions, and
around nipples. They are coiled tubular glands
about ten times larger than eccrine glands and
extend entirely through the dermis and well into
the subcutaneous layer. 11
Percutaneous Absorption
The usual object of dermatologic drug therapy
is to produce a desired therapeutic action at spe­
cific sites on the epidermal tissue. While certain
topical drugs such as emollients, antimicrobials,
and deodorants act primarily on the surface of
the skin, the target area for most dermatologic
disorders lies in the viable epidermis or upper
dermis. This requires diffusive penetration of
the skin or percutaneous absorption.
Routes of Penetration
When a drug system is applied topically, the
drug diffuses out of its vehicle onto the surface
tissues of the skin. There are three potential por­
tals of entry: through the follicular region,
through the sweat ducts, or through the unbro­
ken stratum corneum between these append­
ages. There is little convincing evidence that
eccrine sweat glands play any significant role in
cutaneous permeability. Material may enter the
ducts, and even the glands, but there appears to
be no penetration from these areas to the der­
mis.
For substances absorbed by the transepider­
mal route, penetration is fairly rapid, although
slower than intestinal tract absorption, and is
almost always accompanied by some degree of
pilosebaceous penetration as well. For sub­
stances that are absorbed through both path­
ways, the transepidermal route is the principal
portal of entry because of the total, relatively
small, absorbing surface offered by the piloseba­
ceous units. The epidermis presents a surface
area 100 to 1000 times greater than the other
routes of absorption. The appendages, sweat
glands, and hair follicles are scattered through­
out the skin in varying numbers, but are com­
paratively sparse; their total cross-sectional area
is probably between 0,1 and 1.0% of the skin
area.
The particular route a substance may take
and the relative importance of one in contrast
with the other, depend almost entirely on the
physicochemical properties of the drug and the
condition of the skin. Under the appropriate
conditions, each of the contending routes of per­
meability may change and be the overwhelm­
ingly dominant one. In particular, the transient
 diffusion that occurs shortly after the, applica­
tion of a substance to the surface of the skin is
shown to be potentially far greater through the
appendages than through the matrix of the stra­
tum comeum. After steady-state diffusion has
been established, the dominant diffusion mode
is probably no longer intra-appendageal, but oc­
curs through the matrix of the stratum cor­
neum. Flux through shunts is difficult to mea­
sure experimentally, except possibly through
hair. The recognition of transient diffusion, oc­
curring primarily via follicles and ducts, and
steady-stafe diffusion, occurring primarily
through the intact stratum comeum, results in a
considerably more self-consistent and orderly
treatment of the process of percutaneous absorp­
tion.
Once a substance passes through the stratum
comeum, there is apparently no significant fur­
ther hindrance to penetration of the remaining
epidermal layers and corium; there is then a
ready entry into the circulation via the capillar­
ies. The concentration gradient essentially ends
in the dermal layer at the beginning of the circu­
lation. The systemic circulation acts as a reser­
voir or "sink" for the drug. Once in the general
circulation, the drug is diluted and distributed
rapidly with little systemic buildup.1
Diffusion through the horny layer is a passive
process. There is little evidence to support spe-
. cialized active transport systems for cells of the
stratum comeum. The passive process is af­
fected only by the substance being absorbed, by
the medium in which the substance is disper­
sed, and by ambient conditions. On the other
hand, percutaneous absorption is a more compli­
cated process, of which epidermal diffusion is
the first phase, and clearance from the dermis
the second. The latter depends on effective
blood flow, interstitial fluid movement, lymphat­
ics, and perhaps other factors that combine with
dermal constituents. 5
Study Methods
In Vitro Technique. The principal in vitro
technique for studying skin penetration involves
use of some variety of a diffusion cell in which
animal or human skin is fastened to a holder and
the passage of compounds from the epidermal
surface to a fluid bath is measured. The simplic­
ity of methods and equipment ranges from just
stretching human skin over the mouth of a fun­
nel to using special glass chambers. The pene­
tration rates can be quantitated, particularly by
radioactive measurements. The area of spread of
radioactive agent on the surface is detected with
autoradiographs, allowing expression in terms of
quantity per unit area per unit time. Radioactive
agents have not taken over completely. Many
chemical agents penetrate in sufficient concen­
tration to be determined by one or the other
techniques of physical or chemical analysis.
More recently, model systems hav.e been used
that do not use membranes. Solvents such as
alcohol-water have been utilized as models cho­
sen to have negligible solubility in the phase
representing the skin, but in which the drug is
fairly soluble.13-17 A receptor phase or "sink" is
used to receive the penetrant. Chloroform and
isopropyl myristate have served as sinks. Since
they are immiscible with the alcohol-water, it is
not necessary to introduce an artificial mem­
brane to separate these sinks from the vehicles.
The important factors influencing the release
into the receptor phase are the solubility in the
vehicle and the partition coefficient of the drug
between the vehicle and the receptor phase.
Optimal release is obtained from vehicles con­
taining the minimum concentration of solvent
required for cmp.plete solubilization of the
drug.13
In Vivo Technique. The major in vivo
methods are histologic techniques, use of trac­
ers, analysis of body tissues and fluids, and elici­
tation of a biologic response. Tissue changes in
skin following the application of various sub­
stances to the cutaneous surface can yield infor­
mation about the specific tissue affected, so that
not only absorption, per se, is revealed, but also
the route of penetration. The method is limited
to dyes and to a small number of other sub­
stances that yield perceivable colored end prod­
ucts with specific chemical reactions.. Following
the movements of penetrants through dyes, flu­
orescence and radioactive labeling represent the
most widespread tracer methods. The studies
are always combined with other techniques
such as histologic or chemical analysis of tissues
or fluids. While radioactive methods give infor­
mation on the amount of the compound that
moves across the skin, they yield little or no in­
formation on the route of penetration or on the
localization of the penetrant within the structure
of the skin.
Urine analysis is by far the most frequently
used method. Although the urinary method is
extremely valuable, caution is indicated since
the recovered agent will not necessarily by the
original material or the amount needed to pene­
trate the skin. Some of the applied agent may
have gone- elsewhere than into the urine; some
may have been metabolized and therefore may
be no longer detectable. A steady state between
absorption and excretion needs to be reached
before measurements can be accepted. The use
SEMISOLIDS • 537

of topical agents that elicit a physiologic reaction
when they reach the dermis makes it possible to
demonstrate not only penetration, but also the
time required for a reaction to occur. The
method is intriguing because it is simple and
has practical applications. For example, re­
sponses such as sweat secretion, vasoconstric­
tion, vasodilation, pigmentation, and vascular
permeability can be recorded with reasonable
accuracy by visual observation.
Various methods have been used for studying
in vitro and in vivo percutaneous absorption.
There are three variables in all the methods:
application of the medicament, apparatus, and
measurement of the medicament. The combina­
tions of these variables lead to numerous meth­
ods, and comparisons between investigations is
difficult. 18
Factors in Skin Penetration. The factors
that influence skin penetration are essentially
the same as those for gastrointestinal absorp­
tion, with the rate of diffusion depending pri­
marily on the physicochemical properties of the
drug and only secondarily on the vehicle, pH,
and concentration. Differing physiologic varia­
bles involve the condition of the skin, i.e.,
whether it is intact or injured, the skin age, the
area of skin treated, the thickness of the skin
barrier phase, the species variation, and the skin
moisture content.
The principal physicochemical factor in skin
penetration is the hydration state of the stratum
comeum, which affects the rate of passage of all
substances that penetrate the skin. Hydration
results from water diffusing from underlying
epidermal layers or from perspiration that accu­
mulates after application of an occlusive vehicle
or covering on the surface. Under occlusive con­
ditions, the stratum comeum is changed from a
tissue that normally contains little water (5 to
15%) to one that contains as much as 50%
water. The clinical importance of hydration can
be found in the use of occlusive plastic film in
steroid therapy. Here, the prevention of water
loss from the stratum comeum and the subse­
quent increased water concentration in this skin
layer apparently enhances the penetration of the
steroid. The temperature of the skin and the
concentration of drug play significant roles, but
they are secondary to that of hydration.
The solubility of a drug determines the con­
centration presented to the absorption site, and
the water/lipid partition coefficient influences
the rate of transport. An inverse relationship
appears to exist between the absorption rate and
the molecular weight. Small molecules pene­
trate more rapidly than large molecules, but
within a narrow range of molecular size, there is
538 • The Theory and Practice of Industrial Pharmacy
r
I
little correlation between the size and the pene­
tration rate. Materials of higher molecular
weight also show variable penetration. Very
large molecules, such as proteins and ,Eolysac­
charides, go through poorly, if at all. 19· 0
Vehicles and Skin Penetration. The effi­
ciency of various types of vehicles in aiding pen­
etration can be reasonably predicted by the way
in which the vehicle alters the activity of water
in the stratum comeum and influences the
stratum comeum/vehicle partition coefficient.
Greases and oils are the most occlusive vehicles
and induce the greatest hydration through sweat
accumulation at the skin-vehicle interface. This
is accentuated if the skin is covered with occlu­
sive bandages or plastic. Emulsions of the water­
in-oil type are somewhat less occlusive than
greases. Substances in the vehicle, such as
humectants, which have a high affinity for
water, may under certain circumstances dehy­
drate the stratum comeum and decrease pene­
tration. Similarly, powders increase the surface
area and increase the rate of evaporation of
water, and so decrease the extent of hydration.
Conversely, vehicles may also affect penetration
by their ability to reduce loss of water vapor on
the skin surface. Paraffin bases suppress trans­
epidermal water diffusion, whereas a number of
other standard vehicles cause a lesser degree of
transepidermal water loss suppression.
The role of vehicles on skin penetration is
often confusing and contradictory, since the
emphasis has generally been placed on the com­
patibility, stability, and appearance of the prod­
uct. Only in recent years has attention been
given to the influence of components in the ve­
hicle on the movement of the drug through the
skin. The release of a substance is favored by the
selection of vehicles that have a low affinity for
the penetrant or in which the drug is least solu­
ble. This is consistent with the view that the rate
of release is governed by the vehicle-to-receptor
phase (stratum comeum) partition coefficient.
For a given concentration of drug in certain ve­
hicles, the activity coefficient of the drug at that
concentration may vary by as much as 1000-fold
from one vehicle to the other. The thermody­
namic activity of the drug in the vehicle is the
product of the concentration of the drug and the
activity coefficient of the drug in the vehicle.
Solutes held firmly by the vehicle, such as those
occurring when the drug forms a soluble. com­
plex with the vehicle, exhibit low activity coeffi­
cients: hence, the rate of release from such
drug-vehicle combinations is slow. Solutes held
"loosely" by the vehicle (with less affinity of the
vehicle for the drug or solute) exhibit high activ­
ity coefficients; thereforEo, the rate of release
from such drug-vehicle combinations is fast.
Varied materials require individual formulation
based on solubility characteristics, and the for­
mulation may also need modification for differ­
ent concentrations of the agent to obtain maxi­
mal release rates.
Materials have been experimentally studied in
attempts to increase the rate of absorption of
topically applied drugs. These agents are often
called "accelerants." They appear to swell the
stratum corneum and leach out essential struc­
tural material, thus reducing the diffusional re­
sistance and increasing the permeability. The
most effective is dimethylsulfoxide (DMSO) fol­
lowed by dimethylformamide (DMF), dimethyl­
acetamide (DMA), urea, propylene glycol, and
surface-active agents. DMSO, DMF, and DMA
are all strongly hygroscopic and it is likely that
the presence of these substances in the stratum
comeum increases the hydration of the tissue
and therefore its permeability. These agents are
currently restricted to experimental use. Sur­
face-active agents appear to increase the perme­
ability of the skin to water by altering the physi­
cal state of water in the skin in such a way as to
permit greater freedom to the passage of charged
hydrophilic substances. When penetration oc­
curs, anionics penetrate best, followed by
cationics and nonionic surfactants. Among ani­
onic substances, the laurate ion is reported to
have the greatest penetration and the greatest
effect on the penetration of other solutes. Soaps
of different fatty acids have this property in vary­
ing degrees, with penetration more significant
for salts of fatty acids having a carbon length of
10 or less. The penetration of fatty acid soaps
varies inversely with pH. At higher pH (approxi­
mately 11), the action of the anionic surfactant
appears to be attenuated or overshadowed by the
influence of the more alkaline pH itself.
Raw Materials
More raw materials are available for use on
the skin than for oral use, and in tum, more are
available for oral use than for parenteral use.
The difference in the number of materials avail­
able for each route of administration is due to
the type of absorption barrier and physicochemi­
cal environment surrounding the absorption
sites. Substances such as isopropyl myristate
and butyl stearate may be used topically without
toxic effects, yet these esters may not be used
orally, because hydrolysis of the esters by diges­
tive enzymes yields poorly tolerated alcohols.
The absence of comparable hydrolytic enzymes
on the skin surface makes these compounds sat­
isfactory for dermatologic medication.
The Federal Food and Drug Administration
(FDA) approves chemical substances and states
the maximum concentration that is considered
to be safe for use in a particular food or cosmetic.
The information is published in the "Federal
Register," and a compilation of all such sub­
stances is available.2 1 All raw materials should
be checked against this list if there is any doubt
regarding the current status of a particular sub­
stance; however, each new pharmaceutical dos­
age form must receive individual approval. The
supplier of a chemical substance usually indi­
cates in his brochure, or upon request, the safety
tests that have been performed and whether
appr ,val from the FDA has been received for its
use in a particular form. The tests should be
thorough and well designed; they should include
human patch tests, eye irritation studies, deter­
mination of minimum lethal dose on at least two
animal species, and chronic toxicity studies.
Names of suppliers of various raw materials
for semisolids, manufacturing equipment, and
other pertinent information can be obtained
from trade and scientific journals. Consultation
with representatives of suppliers frequently re­
duces the development time required for a new
pharmaceutical semisolid, but independent crit­
ical judgment is needed.
The suppliers of raw materials such as emol­
lients, emulsifiers, fats, oils, waxes, cellulose
derivatives, humectants, lanolin derivatives,
and water absorption bases have detailed knowl­
edge of their specific products. Many of the sup­
pliers have well-equipped laboratories in which
workers are constantly developing new uses for
their materials in the pharmaceutical, cosmetic,
toiletries, ,;nd chemical specialties fields. The
formulator must be cautious, however, in ac­
cepting a supplier's claims about the utility of a
raw material. It is necessary to ascertain the bio­
logic properties as well as the significant physi­
cal and chemical parameters of the substance
and its stability on storage at different tempera­
tures.
It is a fundamental concept in formulating
any dosage form that chemical and physical in­
compatibilities that affect the therapeutic effi­
cacy of a drug must be avoided. In advance of
any formulation, the physicochemical properties
of the drug must be evaluated. The stability of
the active substance under alkaline or acidic
conditions can be established from its pH pro­
file. The sensitivity of the drug to oxidation and
reduction, moisture, and light, and its solubility
in various materials, indicate the type of base
most suitable for the stability of the drug and for
its absorption. Compatibility with the container
is of equal importance, and it is necessary to
SEMISOLIDS • 539
conduct stability studies of the product in the
finished container.
Perfumes generally are not included in the
semisolid formulations because in the past
many dermatologists have objected to their use
for the treatment of a skin condition in view of
the danger of sensitization. Many manufactur­
ers of fragrances have run toxicity, sensitization,
and irritation tests on the various perfume mate­
rials and can supply fragrances that have suc­
cessfully passed critical testing in animals. How­
ever, such animal tests do not obviate the need
for testing on humans.
The industrial pharmacist who develops the
dosage form must be aware of the chemical com­
position of the materials at his disposal and their
physical properties, so that he can set or have
specifications set for the raw materials. Broad
specification limits may lower the cost of a raw
material, but represent false economy if the
quality of the product is affected. New raw mate­
rials suitable for use in semisolids are continu­
ally being introduced. Flynn has published an
excellent compilation of these materials that in­
cludes their functions in formulations. 1
Hydrocarbons
Except for water, petrolatum and mineral oil
are perhaps the most widely used substances in
semisolids. Petroh1tum is a complex mixture of
semisolid hydrocarbons, containing aliphatic,
cyclic, saturated, unsaturated, branched, and
unbranched substances in varying proportions.
Although extensively used for more than 85
years, petrolatum still has broad physical and
chemical specifications in the USP. Wide den­
sity and melting point ranges, as well as varia­
tion in chemical composition, are permitted in
the official compendia throughout the world.
Petrolatum is available in the form of a short
or long "fiber." The type of fiber possessed by the
petrolatum is usually determined by dipping the
index finger into the petrolatum sample and
then withdrawing it slowly. The long fiber type
tends to form a transparent continuous film or
thread joining the finger and the sample. The
short fiber variety ruptures easily and does not
exhibit this film. The long fiber petrolatum is
preferred for an occlusive dressing because of
the continuous film it forms over the surface of
the skin.
Mineral oil is obtained from petroleum, as is
petrolatum, by collection of a particular vis­
cosity-controlled fraction. It is produced in many
viscosity and specific gravity ranges. The lower
viscosity oils are preferred for semisolids, since
540 • The Theory and Practice of Industrial Phannacy
they are less tacky and greasy. An excellent re­
view of the chemistry and the properties of pet­
rolatum and mineral oil has been published. 22
Hydrocarbon Waxes
Hydrocarbon waxes frequently are employed
in the manufacture of creams and ointments to
increase the viscosity of mineral oil in order to
prevent its separation from an ointment. Ozoke­
rite is a mined wax with a melting point range of
65 to 75°C and consists of a mixture of saturated
hydrocarbons ranging in carbon content from
C35 to C55 . Paraffin wax is obtained from petro­
leum and is available in a variety of melting
points ranging from 35 to 75°C. Another wax
that is often used is ceresin, which is a mixture
of ozokerite and paraffin wax. Its melting point
varies, depending on the paraffin wax content.
Ozokerite and ceresin possess the property of
retaining oils within a matrix-like structure
without the sweating or oozing of the oils.
Synthetic waxes have been developed from
vegetable oils and naturally occurring waxes by
a process of hydrogenation and catalytic splitting
that involves long C 18-C36 hydrocarbon chains.
Like all true waxes, the synthetic waxes exhibit
thermoplastic, crystalline properties and are not
pure chemical compounds but complex mix­
tures of mainly long chain saturated aliphatic
chemical entities. The synthetic waxes are
chemically closely related to the naturally occur­
ring waxes in that they contain long chain wax
fatty acids, but are not considered to be direct
replacements for them. However, they may be
used in conjunction with or can replace the nat­
ural waxes in some formulations to achieve cer­
tain desired properties. Synchrowaxes, * the
brand name of a series of such waxes, have
unique gelling characteristics that may be used
in formulating synthetic petrolatums with occlu­
sive properties to help moistuhze the skin with­
out the inelegant properties of natural petrola­
tum.
Oleaginous Substances
Vegetable oils such as peanut oil, almond oil,
sesame oil, and olive oil are mono-, di-, and tri­
glycerides of mixtures of unsaturated and satu­
rated fatty acids. Trace metal contaminants in
the oils may catalyze oxidation reactions that
can be prevented by the addition of antioxidants,
such as butylated hydroxyanisole, butylated
*Synchrowaxes are available from Croda, Inc., New York,
NY.
hydroxy toluene or propyl-gallate, and by the
addition of metal chelating agents such as salts
of ethylenediamine tetraacetic acid.
Antioxidants may produce problems of drug
compatibility or dermal sensitivity in some pa­
tients. The exact chemical composition of a par­
ticular vegetable oil varies from lot to lot because
of its natural origins. Its composition depends on
the climatic conditions, the soil, the amount of
rainfall during the growth of the vegetable crop,
and the storage conditions of the harvested crop
and the oil.
The trend toward the isolation and synthesis
of pure chemical entities present in the vegeta­
ble oils is evident in the literature and supplier's
catalogs. Perhaps when these chemically pure
substances are available in quantity, the influ­
ence of a homologous series of compounds, ei­
ther individually or in combination, on the qual­
ity of an emulsion and the release of a drug from
such a base can be more rigidly controlled.
Fatty Acids and Alcohols
The commercially available fatty acids are
really mixtures of related fatty acids. Stearic and
palmitic acids are present in the greatest propor­
tion in triple pressed stearic acid along with
varying quantities of other fatty acids. Various
fixed ratios of stearic/palmitic acids can be ob­
tained from the suppliers. A slight change in the
ratio of the saturated fatty acids changes the
structure and size of the fatty acid crystal, the
x-ray diffraction pattern, and the solubility. For
this reason, stearic acid of rigidly controlled pu­
rity is used in many topical preparations.
Similar variations in chemical structure exist
in almost all materials of natural origin, in poly­
meric substances having a long chain length,
and in combinations of polymers with fatty acids
or alcohols. The number of moles of ethylene
oxide, for example, in a polyethylene reaction
product such as ROCH2CH2 [OC2 H4 ] nOH
merely represents an average rather than an
exact amount. Rigid purchasing and quality con­
trol specifications must be established for such
materials if variations in the quality and consist­
ency of semisolid emulsions are to be avoided.
Stearic acid is used in water-removable
creams as an emulsifier to develop a certain con­
sistency in the cream and to give a matt effect on
the skin. When a stearate soap is used as an
emulsifier, enough potassium hydroxide or tri·
ethanolamine usually is added to react with
about 8 to 20% of the stearic acid. The unre­
acted fatty acid increases the consistency of the
cream. These creams are soft and develop a
sheen or luster upon aging, owing to the forma-
tion of stearic acid crystals. Creams formed with
sodium stearate are much firmer in consistency.
Stearyl alcohol and cetyl alcohol (palmityl al­
cohol) are used in creams as auxiliary emulsifi­
ers and emollients. In sufficient quantity, stearyl
alcohol produces a firm cream that may be soft­
ened with cetyl alcohol.
For a description.of waxes of animals, insect,
and vegetable origin such as lanolin, beeswax,
camauba wax, candelila wax, silicones,
branched chain compounds, isopropylesters,
polyols, cellulose ethers, and other raw materials
suitable for creams and ointments, the reader is
advised to check sources such as the CTFA Cos­
metic Ingredient Dictionary,23 as well as suppli­
ers' catalogs.
A list of the various raw materials and their
functions has recently been published. 1 Another
listing of cosmetic raw materials appeared in the
FD&C Reports ("The Rose Sheet")24 which was
reproduced from the Japan Cosmetic Ingredient
Dictionary of 148 government-approved raw
materials. The dictionary is the result of a collab­
orative effort between the Cosmetic, Toiletry and
Fragrance Association (CTFA), the U.S. Com­
merce Department, the Japanese Government,
and the Japan Cosmetic Industry Association
(JCIA). The second supplement to the dictionary
lists 1 73 raw materials and is reproduced in a
later issue of the same trade periodical.24 The
dictionary will eventually list approximately
2,000 to 3,000 raw materials. According to the
CTFA, inclusion of the raw materials in the dic­
tionary is based on "(1) chemical (not brand
name), (2) whether the substance is free from
patent and/or 'technical know-how problems,'
(3) whether it is free of safety problems, and (4)
a specified alkyl group." The interest and pur­
pose of CTFA is "to eliminate testing, certifica­
tion, and standards activities that act as barriers
to trade with Japan."
Emulsifiers
The water-soluble soaps were among the first
emulsifiers used for semisolid oil-in-water emul­
sions. The viscosity of the cream or ointment
prevents coalescence of the emulsified phases
and helps to stabilize the emulsion. The addition
of fatty polar substances, such as cetyl alcohol
and glyceryl monostearate, tends to stabilize the
semisolid oil-in-water emulsion. The interfacial
film formed around the dispersed phase globules
in such a system is generally solid, thereby mak­
ing the emulsified preparation more rigid. Poly­
valent ions, such as magnesium, calcium, and
aluminum, tend to stabilize water-in-oil emul­
sions by cross-linking with the polar groups of
SEMISOLIDS • 54)
the fatty materials. Nearly all semisolid creams Formula #2
and emulsified ointments require more than one %(wlw)
emulsifier. The combination of a surface active
agent with an oil-soluble auxiliary emulsifier is A Magnesium aluminum silicate (MAS)* 2.0
referred to as a mixed emulsifier system. Trieth­ Purified water 37.0
anolamine stearate soap combined with cetyl B Mineral oil, hght 20.0
alcohol is an example of an oil-in-water mixed Petrolatum 9.0
emulsifier; beeswax and divalent calcium ions Isopropyl myristate 5.0
or small quantities of a water-soluble surface Lantrol (lanohn oil)t 3.0
active agent exemplify mixed emulsifiers for a 70% sorbitol solution 20.0
water-in-oil emulsion. Maximum stability of an Arlacel 186 (glyceryl oleate and propylene
emulsion occurs when a complex interfacial film gl��l 1.0
is formed. Such a film forms when an oil-soluble Polysorbate 80 1.0
substance is added and reacts at the interface Preservative q.s.
with the water-soluble surfactant. Soft water-in­
*Available from Veegum, R.T. Vanderbilt Co., Norwalk, CT.
oil cream bases can be made with calcium ions tAvailable from Emery Industries, Cincinnati, OH.
as an auxiliary emulsifier. The bases can be !Available from !CI Americas, Inc., Wilmington, DE.
made firmer by decreasing the mineral oil con­ Procedure: Add the MAS to the water slowly, agitating continu-
tent. Formula #1 is used to make a soft water­ ally until smooth. Heat A to 70 to 75'C. Heat B with stirring to 70
in-oil cream base employing divalent calcium to 75'C. Add A to B, and mix until cooled.
ions in the form of water-soluble saccharated
lime. The soap-type emulsion may be unstable in
the presence of acidic substances. Cationic or
nonionic emulsifiers are preferable for drugs
requiring an acid pH. Quaternary ammonium
Formula #1 compounds like cetyl trimethyl ammonium
% chloride help to stabilize these emulsions in
combination with such fatty alcohols as cetyl
A Mineral oil, 65 to 75 viscosity 30.00 alcohol.
Lantrol* 3.00 The nonionic emulsifiers are employed for
Microcrystalline waxt 2.00 both oil-in-water and water-in-oil emulsified
Acidlan 20* 4.00 pharmaceutical semisolids because they are
Propylparaben 0.20 compatible with many drug substances. The_
B Borax 0.20 nonionic emulsifiers are versatile and may be
Methylparaben 0.20 used with strongly acidic salts or with strong
Water 49.75 electrolytes.
C Saccharated lime 0.65
Purified water 10.00 Formula #3
•Available from Emery Industries, Cincinnati, OH. Tripelennamine Hydrochloride Cream*
tShould have a melting point of 75 to 79°C and should be tested %(wlw)
for safety on animal and human skin, since petroleum residues
may be present in the wax. Oil Phase
Procedure: Heat parts A, B, C separately to 78°C. Add B to A. Cetyl alcohol 5.0
After the emulsion has formed, add C. Cool and pass through a Glyceryl monostearate 15.0
homogenizer. Sorbitan monooleate 0.3
Polysorbate 80, USP 0.3
Aqueous Phase
The clay, magnesium aluminum silicate, has Tripelennamine HCl 2.0
been used as a thickener, suspending agent, and Methylcellulose 100 cps 1.0
oil-in-water emulsion stabilizer because of the Purified water, q.s. ad 100.0
colloidal structure of its aqueous dispersions. It Preservative q.s.
also contributes to the stability of water-in-oil
emulsions when used with suitable emulsifiers, 'Available from !CI Americas, Inc., Wilmington, DE.
probably owing to its thickening action on the Procedure: Disperse the methylcellulose in hot water in which
the preservative has been dissolved, and then chill at 6°C until
internal phase whereby it inhibits coalescence. dissolved. Heat the oil phase to 70°C. Heat the methylcellulose
The magnesium aluminum silicate may migrate solution to 72'C, and add to the oil phase, stirring continuously.
to the interfacial area, resulting in a stronger Add the tripelennamine HCI at 35'C, and stir continuously until
film.25 dissolved.

542 • The Theory and Practice of Industrial Pharmac11

 Recently, a series of emulsifiers have been To achieve adequate stability in creams in
marketed that contain chemically bonded lactic which the oil content exceeds 10%, the supplier
acid with fatty acids. These acyl lactylates are recommends the use of a co-emulsifier to
claimed to be mild and nonirritating to the skin achieve adequate stability. The HLB system
and eyes,* to produce an emollient feel to the should be utilized to calculate the ratio between
skin, and to serve as oil-in-water or water-iri-oil the two emulsifiers for the lipid(s) being used.
emulsifiers. The sodium salts are suggested for Several ratios should be checked to either side of
use in oil-in-water. The particular fatty acid lac­ the calculated HLB value to optimize the emul­
tylate that is selected should be based on the sion.
desired application of the final product as well as
on the most COPJ.patible fatty acid derivative.
Some of the available lactylates and the calcu­ Fonnula #5
lated HLB values are as follows: Antiperspirant Cream
%(wlw)
Types of A Oil Phase
Fatty Acid Calculated HLB Mineral oil 23.0
Calcium stearoyl-2-lactylate 3.2
1. Stearic 6.5 PEG 400 dioleate 0.8
2. Stearic/Palmitic 8.3
3. Lauric/Myristic 14.4 B Aqueous Phase
4. Capric/Lauric 11.3 Glycerine 3.0
5. Isostearic 5.9 Sodium lactate (60%) 10.0
Purified water 20.0
Items 3 and 4 are foamers. Item 4 shows good C Aluminum chlorohydrate (50%) 40.0
bacteriostatic properties, owing to the presence Procedure: Heat A, B, and C to 70 C in separate vessels.. Add B
°
of the moderately short chain capric acid. to C immediately before adding to A. Mix with moderate agitation
An example of an oil-in-water cream utilizing while cooling.
one of the emulsifiers that can serve as a vehicle
for a compatible active substance follows: The Promulgens* are a series of nonionic
emulsifiers composed of a mixture of fatty alco­
Fonnula #4 hols and their ethoxylates. Two types, D and G,
%(w!w) are available and are described in the boxed area
below.
A Oil Phase The two types differ in melting point and in
Cetearyl alcohol 5.0 consistency of the emulsions that they form.
Silicone oil, 200 fluid 1.0 According to the supplier, the emulsions formed
Isopropyl myristate 2.0 with type D are usually thicker in consistency.
Sodium stearoyl-2-lactylate 2.0
Since there are no ester linkages, these emulsifi-
B Aqueous Phase ers are not subject to hydrolysis. In addition,
Propylene glycol 5.0 they are compatible with anionic surfactants of
Sodium citrate 0.2 the sodium lauryl sulfate type or with cationics
Preservative q.s. such as quaternary aminonium compounds.
Purified water, q.s. ad 100 Type D tends to form creams, and type G tends
Procedure: Mix A and heat to 65°C. Combine B and heat to
to form liquid emulsions. It is suggested that
70°C. Add B to A with suitable agitation. Mix with moderate agita­ they be used in combination to achieve a desired
tion while cooling. viscosity level.

Promulgen D Promulgen G
CTFA adop.ted name­ Cetearyl alcohol and Ceteareth-20 Stearyl alcohol and Ceteareth-20
Chemical description- Cetearyl alcohol and ethoxylated Stearyl alcohol and ethoxylated
cetearyl alcohol cetearyl alcohol
Melting point- 47 to 55°C 55 to 63°C

*Available from Patco Products, Kansas City, MO. • Available from Amerchol Corporation, Edison, NJ.

SEMISOLIDS • 543
 Polyols
Glycerine, propylene glycol, sorbitol 70%, and
the lower molecular weight polyethylene glycols
are used as humectants in creams. The choice of
a humectant is based not only on its rate of mois�
ture exchange, but also on its effect on the tex­
ture and viscosity of the preparation. These ma­
terials prevent the cream from drying out and
prevent the formation of a crust when the cream
is packaged in a jar. They also improve the con­
sistency and rub-out qualities of the cream
when it is applied to the skin, permitting the
cream to be spread without rolling. Increasing
the humectant content tends to cause tackiness.
Sorbitol 70% is more hygroscopic than glycer­
ine and is used at a lower concentration, usually
3% as compared to 10% for glycerine. Propylene
glycol and the polyethylene glycols occasionally
are used in combination with glycerine, since
their ability to absorb moisture is less than that
of glycerine.
Insoluble Powders
Insoluble drugs must be uniformly dispersed
throughout the vehicle to ensure homogeneity
of the product. The solid must be impalpable to
the touch; otherwise, grittiness results. Particles
less than 74 microns in size, equivalent to the
mesh openings in a 200-mesh sieve in the U.S.
Standard Sieve series, are impalpable to most
people. Milling to a finely divided state provides
more surface area for contact with the dermal
site and increases the rate of dissolution of
poorly soluble substances.
Some powders do not disperse uniformly, but
tend to aggregate in the base, whereas others
present no difficulties even though the particle
size is the same. The difference may be due to
the electrically charged surface condition of the
particles after milling. Aggregation of particles
becomes a problem for those that are 5 microns
or smaller in size. For particles below 0.5 mi­
crons in size, the dispersion problems increase
exponentially. Different powdered substances
show similar problems of aggregation in the sub­
micron size.
Many drug substances used in topical prepa­
rations (e.g., prednisolone; fluorocortisone ace­
tate) exist in several polymorphic states. Com­
pounds that exist in different crystalline forms
at room temperature possess varying amounts of
·1 free energy or thermodynamic activity. The
physiologic activity and availability of a drug
substance often ate directly related to its ther­
modynamic activity26 and the choice of the
proper crystalline form for use in the semisolid
544 • The Theory and Practice of Industrial Pharmacy
is vitally important. Following its incorporation
into the semisolid, the maintenance of the se­
lected polymorphic form in the semisolid is of
equal concern. The components of the vehicle
and the method of preparation of the semisolid
dosage form affect the stability of the polymor­
phic form.
Types of Vehicles
The vehicle used for a pharmaceutical differs
from that used for a cosmetic because with a
cosmetic, penetration into the skin is not de­
sired. Penetration or protection is desired in a
pharmaceutical semisolid, and its cosmetic ef­
fect or appearance on the skin is less important.
A well-formulated pharmaceutical semisolid
should be both therapeutically effective and cos­
metically appealing, with the major effort in the
medical direction.
The therapeutic preparations included in the
semisolids classification are products intended
for application to the skin, scalp, and certain
body orifices. These preparations include oph­
thalmic ointments, nasal jellies, gels, and sterile
lubricants for surgical use. In this chapter, how­
ever, attention is given to those dosage forms
that are used in the prevention or treatment of
skin disease.
The solubility and stability of the drug in the
base, as well as the nature of the skin lesion,
determine the choice of the semisolid vehicle.
The United States Pharmacopeia (USP) XX
recognizes four classes of semisolids under the
general classification of ointments: hydrocarbon
bases, absorption bases, (anhydrous form and
emulsion form), water-removable bases, and
water-soluble bases.27
Hydrocarbon Bases
Petrolatum and white ointment, which is pet-­
rolatum with 5% beeswax, are typical of this
class of lipophilic vehicles. The most commonly
used raw material in ointment vehicles is petro­
latum because of its consistency, its bland and
neutral characteristics, and its ability to spread
easily on the skin. These bases are difficult to
wash off the skin and may be used as occlusive
coverings to inhibit the normal evaporation of
moisture from the skin. A thin film of petrola­
tum produces a sensation of warmth on the skin
because the insensible moisture does not evapo­
rate. Very little water can be incorporated into
these greasy bases without the addition of other
substances.
 Absorption Bases
The absorption bases are formed by the addi­
tion of substances miscible with hydrocarbons
and possessing polar groupings, such as the sul­
fate, sulfonate, carboxyl, hydroxyl, or an ether
linkage. Lanolin, lanolin isolates, cholesterol,
lanosteroi and other sterols, acetylated sterols, or
partial esters of polyhydric alcohols (e.g., sorbi­
tan monosterate or monooleate) may be added to
make the hydrocarbon bases hydrophilic. Such
hydrophilic mixtures have been known as "ab­
sorption bases," although the term "absorption"
is a misnomer. The bases do not absorb water on
contact, but with sufficient agitation, they do
absorb aqueous solutions and can be considered
water-in-oil emulsions. (The notations o/w for
oil-in-water and w/o for water-in-oil are conven­
ient abbreviations for the respective emulsion
types.)
The absorption bases are of two types: the
anhydrous form and the emulsion form. Anhy­
drous lanolin and hydrophilic petrolatum are
examples of anhydrous vehicles that absorb
water to form water-in-oil emulsions.
wate�-in-oil emulsions. A typical example of a
lanolin absorption base follows:
Formula #7
Lanolin Absorption Base
%
Lanolin alcohols 10
Lanolin 25
Mineral oil, low Viscosity 30
Purified water 35
Mineral oil is added to reduce the tackiness of
the base. No:pionic _water-in-oil emulsifiers,
such as glyceryl monostearate, cholesterol, cetyl
alcohol, and the sorbitan fatty acid derivatives,
may be added for improved stability and water­
absorbing capacity. These vehicles have "emol­
lient" properties and deposit an oily film upon
the skin. Examples of water-in-oil emulsion ve­
hicles that utilize the absorption base principle
are given in Formulas #8 and #9.

Fonnulas # 8* #9f
Formula #6 % %
HydT<Yphilic Petrolatum (USP XX)
Oil Phase
g
Lanolin, anhydrous USP 3.1 15.0
Cholesterol 30.0 Petrolatum, white, USP 25.0
Stearyl alcohol 30.0 Mineral oil, heavy 25.0 8.0
White wax 80.0 Beeswax (white wax, USP) 10.0 7.0
White petrolatum 860.0 Sorbitan sesquioleate 1.0
1000.0 Propylparaben 0.05 0.05
Amerchol CAB 20.0
Aqueous Phase
The maximum amount of water that can be Sodium borate, USP 0.7
added to 100 g of such a base at a given tempera­ Polyethylene glycol 1500 5
ture is known as the water number. To deter­ Methylparaben 0.15 0.15
mine the water number, the base is stirred con­ Purified water 35.0 49.8
tinuously as the water is being added. Distilled
or deionized water should be used. The end *Available from Hans Schott, Temple University, Philadelphia,
PA.
point is reached when no more water can be "ab­ tAvailable from Amerchol, a Unit of CPC International, Inc.,
sorbed" into the base, as evidenced by droplets Edison, NJ.
of water remaining in the container. Procedure: Heat the oil phase to 70°C, and add the aqueous
In a study involving the separate addition of a solution at 72°C to the oil phase, stirring continuously.
series of surfactants to a semisolid base, it was
found that the water-absorbing capacity of the Cold cream base, which reportedly dates back
base increased as the HLB number (hydrophilic­ to Galen, was the forerunner of these water-in­
lipophilic number) of the surfactant decreased28 oil emulsion vehicles.
(see Table 18-1). The cold cream type of emulsion frequently
Hydrous lanolin was the prototype or forerun­ utilizes a borax-beeswax combination as the
ner of the absorption bases because of its ability emulsifier, with mineral oil or a vegetable oil as
to absorb water. Various absorption bases were the continuous phase. A protective oil film re­
developed as various lanolin isolates and deriva­ mains on the skin following the evaporation of
tives became commercially available. Many of the water. The slow evaporation of water gives
these lanolin fractions aid in the formation of the skin a cooling effect.

SEMISOLIDS • 545
 TABLE 18-1. Determination of Water Numbers Using 10-g Samples
Surfactant HLB Grams Water Absorbed Water Number
Sample I Sample 2
(Control: White petrolatum) 0.40 0.40 4.0
Sorbitan monolaurate 8.6 5.21 5.41 53.1
Sorbitan monopalmitate 6.7 8.20 8.52 83.6
Sorbitan monostearate 4.7 10.59 10.17 103.8
Sorbitan monooleate 4.3 24.75 25.25 250.0
Sorbitan sesquioleate 3.7 29.84 31.04 304.4
Sorbitan trioleate 1.8 41.95 40.31 411.3
From Mendes, R.W., et al.: Drug Cosm. Ind., 95:34, 1964.

Semisolid water-in-oil emulsions of the borax­ Hydrophilic ointment is an example of a

beeswax type frequently exhibit poor long-term water-in-oil absorption base type vehicle that
physical stability. The development and large­ does not have any lanolin or its derivatives in the
scale commercial manufacture of water-in-oil formula.
emulsifiers have made it possible to prepare
stable semisolids that are oily to the touch. Also,
relatively nongreasy water-in-oil emulsions may
be prepared by a judicious combination of raw
materials.
Synthetic substances are replacing natural Formu/,a #11
raw materials as the latter become restricted in Hydraphilic Ointment (USP XX)
availability. As an example, the supplies of natu­ %
ral beeswax have declined with the steady price
rises that result from both supply and inflation. Methylparaben 0.25
A number of synthetic beeswaxes have appeared Propylparaben 0.15
with properties quite similar to the natural. Syn­ Sodium lauryl sulfate 10.00
thetic spermaceti types have replaced the natu­ Propylene glycol 120.00
ral grade since the latter was banned as a result Stearyl alcohol 250.00
White petrolatum 250.00
of endangering the whale. Formula #10 illus­ Purified water 370.00
trates the use of synthetic beeswax in a rela­
tively nongreasy cold cream.

Formula #10
Cold Cream29 This ointment can be used as a vehicle for
% many drug substances, but is not a cosmetically
elegant preparation. The high petrolatum con­
A Purified water 34.60 tent leaves an unctuous residue upon the skin
Borax 1.00 that may be uncomfortable. Modification of the
Methylparaben 0.25 formulation by reducing the petrolatum content,
B Ligl:J.t mineral oil 50.00 and the addition of other emollients such as
Synthetic beeswax cetyl alcohol, hexadecyl alcohol, and fatty acid
flakes 13.00 esters (isopropyl myristate or palmitate), can add
Glyceryl monostearate, pure 1.00 cosmetic appeal to the preparation. The effect of
Propylparaben 0.15 such modifications on the activity of a drug sub­
Procedure: Dissolve the methylparaben and borax in water at
stance incorporated in the base must be deter­
. 75 to 80°C. Dissolve the propylparaben in a well-mixed mixture of mined.
phase B heated to 75 to 80°C. Add phase A to phase B while Formulas #12 and #13 represent different
stirring rapidly. types of hydrophilic ointment bases.

546 • The Theory and Practice of Industrial Pharmacu

 ishing cream bases in which different types of
Formula #12
emulsifiers are used are given in Table 18-2.
Hydrophilic Ointment Base*
Removal of these creams from skin or clothing
%
is facilitated by the oil-in-water emulsifiers they
Oil Phase contain. Creams may be applied to moist skin
Amerchol CAB* 50.0 lesions, since the oil-in-water vehicle tends to
Cetyl alcohol 2.0 absorb any serous discharge. The water remova­
Stearyl alcohol 2.0 ble bases form a semipermeable film on the -site
Aqueous Phase
of application following the evaporation of water.
Sodium lauryl sulfate 2.0
The semisolid water-in-oil emulsions, however,
Water 34.0 tend to form a hydrophobic layer on the skin.
Methyl gluceth-20 10.0 Semisolid emulsions are intimate, relatively
Preservative q.s. stable mixtures or dispersions of a hydrophilic
phase with a lipophilic phase. The phase that is
'Available from Amerchol, a Unit of CPC International, Inc., dispersed in the form of fine microscopic glob­
Edison, NJ.
Procedure: Add the water phase at 80°C to the oil phase at 80°C.
ules is referred to as the discontinuous or inter­
Cool while mixing to just above congealing temperature. nal phase; the other is the continuous or exter­
Variatians: For greater firmness, increase ratio of stearyl to cetyl nal phase. The vanishing cream type vehicles
alcohol. are representative of the oil-in-water emulsions,
whereas the absorption bases are generally
water-in-oil emulsions.

Formula #13
Hydrophilic Ointment Base*
%
Water-Soluble Bases
Water-soluble vehicles are prepared from
Oil Phase mixtures of high- and low-molecular-weight
Acetylated lanolin* 5.0 polyethylene glycols, which have the general
Mineral oil 70 vis. 5.0 formula: HOCHdCH20CH2 J nCH20H. The
Amerchol L-500* 10.0 low-molecular-weight glycols in this category.­
Amerchol CAB* 15.0 are liquids; those with a moderately higher mo­
Microcrystalline wax, l 95°C 5.0 lecular weight are somewhat unctuous; and the
Cetyl alcohol 5.0 higher molecular weight polyethylene glycols
Brij 52t 6.0 are solids. Suitable combinations of high- and
Brij 58t 4.0 low-molecular-weight polyethylene glycols yield
products having an ointment-like consistency,
Aqueous Phase
Water 40.0
which soften or melt when applied to the skin.
Methyl Gluceth-20 5.0
No water is required for their preparation. They
Preservative q.s. are water-soluble because of the presence of
many polar groups and ether linkages.
'Available from Amerchol, a Unit of CPC International, Inc., If the polyethylene glycol ointment has a high
Edison, NJ. percentage of crystalline material, the softening
tAvailable from IC! Americas, Inc., Wilmington, DE.
Procedure: Add the water phase at 80°C to the oil phase at 80°C.
and melting of the ointment rubbed onto the
Cool while mixing to just above congealing temperature. skin will not be as gradual as with petrolatum,
since the crystali:ine material melts sharply with
an increase in temperature. The polyethylene
glycol ointments are much less occlusive than in
water-in-oil emulsions of the absorption base
Water-Removable Bases type; they mix with skin exudates and are read­
The water-removable bases are oil-in-water ily washed from the skin. The polyethylene gly­
emulsions and are referred to as "creams." The col vehicles are softened by the addition of
vanishing cream bases fall into this category. water, owing to solution of the glycols. The USP
The vanishing creams are so termed because states that 5% of the polyethylene glycol 4000
upon application and rubbing into the skin, may be replaced with an equal amount of stearyl
there is little or no visible evidence of their alcohol when 6 to 25% of aqueous solution is to
former presence. Formulas for some typical van- be added to the vehicle.

SEMISOLIDS• 547
 The "water-soluble" bases are also known as
greaseless ointment bases. The compatibility of
these bases with drug substances and their re­
lease rate must be evaluated for each class of
drugs.
Pastes, Gels, and Jellies
Pastes are dispersions of high concentrations
of insoluble powdered substances (20 to 50%) in
a fatty or aqueous base. The fatty bases are less
greasy as well as stiffer in consistency than oint­
ments because of the large amount of powdered
material present. These pastes adhere well to
the skin and are of benefit in the treatment of
chronic or lichenified lesions. Zinc gelatin paste,
USP XX, for example, is used when a protective
film on the skin is desired following the evapora­
tion of water. Pastes provide a protective layer,
and when covered with suitable dressings, pre­
vent excoriation of the patient's skin by scratch­
ing.
Jellies are water-soluble bases prepared from
natural gums such as tragacanth, pectin, algi­
nates, and boroglycerin, or from synthetic deriv­
atives of natural substances such as methylcel­
lulose and sodium carboxymethylcellulose.
Gels are usually clear transparent semisolids
containing the solubilized active substance. Car­
bomer 940 swells when dispersed in water in the
presence of such alkaline substances as trietha­
nolamine or diisopropanolamine to form a semi­
solid.
Fonnula #18
% added should not appreciably raise the melting
A Carbomer 940• 0.5
Water 42.5
Sorbitol 70% solution 2.0
B Ameroxol OE 20t 10.0
Solufan 98t 3.0
Polyvinylpyrrolidone (PVP) K-30 1.0
Triethanolamine 1.0
S.D. alcohol #40 40.0
'Available from B.F. Goodrich Company, Clevel,md, OH.
tAvailable from Amerchol, a unit of CPC International, Inc.,
Edison, NJ.
Procedure: Phase A-Disperse Carbomer 940 thoroughly in
water with good stirring. Add sorbitol solution. Phase B-Add the
Ameroxol OE 20 to the alcohol, warm to 35°C, and stir until uni­
form. Add Solulan 98, PVP, and triethanolamine consecutively,
mixing after each addition. Add phase B to phase A with gentle
mechanical mixing until gel forms.
548 • Th6 Theory and Practice of Industrial Phannacy
Fonnula #19
%
Carbomer 940 0.75
Purified water 34.25
Solulan 98* 3.00
S.D. alcohol #40 50.00
Diisopropanolamine, 10% in water 12.00
'Available from Amerchol, a unit of CPC International, Inc.,
Edison, NJ.
Procedure: Prepare a Carbomer slurry in water with gentle agi­
tation, and add mixture of SDA #40 and Solulan mixture, mixing
until no particles are visible. Neutralize carefully with
diisopropanolamine solution to avoid incorporating air.
For greater firmness, increase the concentration of the Carbo­
mer and dtisopropanolamine.
Gels are also formed with celluloses such as
hydroxypropylcellulose and hydroxypropyl­
methylcellulose. A popular over-the-counter
benzoyl peroxide gel contains 6% polyoxy­
ethylene lauryl ether, 40% ethyl alcohol, colloidal
magnesium aluminum silicate, hydroxypropyl­
methylcellulose, citric acid, and purified water.
Ophthalmic Ointments
Semisolid ophthalmic vehicles frequently con­
tain soft petrolatum, a bland absorption base, or
a water-soluble base. The water-soluble base
may be prepared with polyethylene glycols or
with a water-soluble gum. Mineral oil is fre­
quently added to petrolatum to lower its fusion
point, but its addition introduces a problem of
separation upon storage. Such oil separation
may be prevented by the addition of small quan­
tities of natural waxes such as ozokerite, ceresin,
or microcrystalline wax. The amount of wax
point of the base.
All materials used in the ophthalmic ointment
should be impalpable to avoid eye discomfort
and possible 1rritation. Ophthalmic ointments,
especially when used on injured eyes, should be
sterile.
Numerous variations of the aforementioned
basic vehicles are possible because of the availa­
bility of new raw materials, which permit the
pharmacist to vary his formulation to obtain th_e
desired therapeutic effect and to make a semi­
solid that is both convenient and comforta�le for
the patient to apply. A minimal number of mate­
rials should be used in a semisolid dosage form,
since fewer constituents reduce inventory, de­
crease the possibility of chemical interference
J
with the analytic procedure, and decrease the
 TABLE 18-2. Fonnulas for Vanishing Cream Bases
#14 #15 #16 #17
Anionic Stearate Anionic Nonionic Cationic
Emulsifier Emulsifier Emulsifier Emulsifier
% % % %
By Weight By Weight By Weight By Weight30
Stearic acid 13.0 7.0 14.0
Stearyl alcohol 1.0 5.0
Cetyl alcohol 1.0 2.0 1.0
Glyceryl monostearate 10.0
Isopropyl p�itate 1.0
Lanolin 2.0
Methylparaben 0.10 0.10 0.10 0.1
Propylparaben 0.05 0.05 0.05
Sorbitan monostearate 2.0
Glycerin 10.0 10.0 15.0
Sorbitol solution [70%] 3.0
Potassium hydroxide 0.90
Sodium lauz-yl sulfate 1.0
Polysorbate 60 1.5
Stearyl colamino fonnyl methyl 1.5
pyriclinium chloride
Purified water. q.s. ad 100 100 100 100

danger of allergic reactions in unusually sensi­ Preservation from Microbial

tive patients.
Many formulas for creams and ointments can
be found in the scientific literature, formularies,
and catalogs of chemical suppliers of emulsifiers
and other raw materials. These formulas should
only serve as a guide for developmental work,
because many of them have not been checked
for stability, ease of application, or ability to re­
lease the drug to the absorption site. The re­
quirements of the drug should determine what
materials are used. Only by subsequent experi­
mentation can the typical problems regarding
consistency, application, and stability be over­
come.
In the past, many pharmaceutical semisolids
used to treat skin disease lacked the elegance
and aesthetic appeal of the better cosmetics and
toiletries. However, the availability of a host of
new and safe raw materials suitable for use as
dermatologic semisolids has made it possible for
. the patient to apply to his skin a preparation that
is therapeutically effective and cosmetically ac­
ceptable. For cosmetic appeal, the semisolid
should be easy to apply and feel comfortable on
the skin. It should not feel clammy, excessively
moist, or too dry. When a protective film is
formed or deposited on the skin, the film should
not be tacky or excessively adhesive. All these
properties may be summed up under the expres­
sion "pharmaceutical elegance."
Spoilage
Chemical preservatives for semisolids must be
carefully evaluated for their stability with regard ·
to the other components of the formulation as
well as to the container. Plastic containers may
absorb the preservative and thereby decrease
the quantity available for inhibiting or destroy­
ing the microorganisms responsible for spoilage.
Some preservatives may sting or irritate the
mucous tissues of the eye or nasal passages.
Methylparabens and propylparabens tend to be
more irritating when applied in the nose than
quaternary ammonium compounds (e.g. benzal­
konium chloride) or the phenylmercuric salts.
Boric acid may be used in the ophthalmic prepa­
rations, but is omitted from products to be used
in the nose because of possible toxic effects if
absorbed in large quantities.
The preservatives are added to semisolids to
prevent contamination, deterioration, and spoil­
age by bacteria and fungi, since many of the
components in these preparations serve as sub­
strates for these microorganisms. Several terms
are used to describe microbial organisms associ­
ated with pharmaceutical and cosmetic prod­
ucts: "harmful/' "objectionable,." and "opportun­
istic."
The USP XX uses the term "harmful" to refer
to microbial organisms or their toxins that are

SEMISOLIDS • 549
responsible for human disease or infection. Ex­
amples of organisms that must not be present in
a product are given, namely, Salmonella species,
Escherichia coli, certain species of Pseudomo­
nas, including P. aeruginosa, and Staphylococ­
cus aureus. An "objectionable" organism can
cause disease, or its presence may interrupt the
function of the drug or lead to the deterioration
of the product. Organisms are defined as "oppor­
tunistic" pathogens if they produce disease or
infection under special environmental situa­
tions, as in the newborn or the debilitated per­
son. Included in the latter group are the aged,
those undergoing extensive surgical or acciden­
tal trauma, and the compromised host, defined
as those who are on antibiotic, anticancer, or
immunosuppressive therapy. The newborn has
increased susceptibility to gram-negative infec­
tions, while the other individuals have various
forms of immunologic deficiency, which in­
crease the susceptibility to infections. Recog­
nized opportunistic pathogens are "objectiona­
ble. "3 1 The following objectionable organisms
should not be present in a pharmaceutical or
cosmetic product: P. putida, P. multivorans, P.
maltophilia, Proteus mirabilis, Serratia marces­
cens, Klebsiella sp., Acinetobacter anitratus
(Bacterium anitratum), and Candida sp.32
The success or failure of a preservative in pro­
tecting a formulation against microbial spoilage
depends upon many factors. The interaction of
the preservative with surfactants, active sub­
stances, other components of the vehicle, sorp­
tion by polymeric packaging materials, and
product storage temperature may change the
concentration of the unbound or free preserva­
tive in the aqueous phase.
Perfumes, high concentrations of glycerine,
and electrolytes make the environment less fa­
vorable to microbial growth, thus enhancing the
effectiveness of the preservatives. Preservative
action appears to depend on the concentration of
the free preservative in the aqueous phase. Sur­
factant solubilized preservative may be bound
within the micelles and there inactivated, or on
the contrary, the micelles may act as reservoirs
of preservative in an actively preserved system.
The minimum inhibitory concentration of
preservative necessary to prevent microbial
spoilage may be estimated by (1) the use of ex­
perimentally determined physicochemical pa­
rameters such as the oil/water partition coeffi­
cient, concentration of surfactant, the number of
independent binding sites on the surfactant, oil/
water phase ratio, and concentration of free pre­
servative in the aqueous phase;33 (2) an ultra­
centrifuge technique; 34 and (3) direct dialysis.33
These techniques provide an approximate
550 • The Theory and Practice of Industrial Phannacy
value for the minimum preservative concentra­
tion required for a formulation, but to ensure
quality, the product must be tested for its ability
to withstand accidental and deliberate microbial
contamination. 35
Preservative efficacy in a formulation is deter­
mined by the addition of pure or mixed cultures
of microbial organisms to the finished prepara­
tion. The number of microorganisms initially
present in the inoculated material is determined
by plating aliquots of suitable dilutions. Table
18-3 gives the USP XX procedure and the inves­
tigational FDA procedure for topicals, including
the organisms used, the levels of inoculum,
sampling periods, and the measure of effective­
ness. Various neutralizers for the preservative
are added to the culture media to recover a max­
imum number of organisms. A TAT broth con­
sisting of tryptone (2%), azolectin (0.5%), and
polysorbate 20 (4%) has been found to be a suit­
able medium for topical products. Azolectin is a
neutralizing agent for quaternary ammonium
compounds and polysorbate 20 inactivates para­
bens. The samples should be tested at intervals
for both slow-growing and rapidly proliferating
organisms.
The USP XX has procedures for determining
the microbial content of raw materials and fin­
ished products. Suitable limits on the number
TABLE 18-3. PreseTll_ative Efficacy (High-Level
Inocula Challenge) Test�
A. USP XX Procedure
1. Organisms used: C. albicans, A. niger, E. coli, S.
aureus: P. aeruginosa.
2. Inoculum: D.lml/20 ml; 100,000 to 1,000,000 cells/
ml.
3. Sampling at 7, 14, 21, and_2_8 dayi; following inocu­
lation.
4. Effectiveness: vegetative cells not more than of
0.1% of initial concentrations by 14th day; concen­
tration of viable yeasts and molds at or below initial
concentration after 14 days; concentration of each
test organism remains at or below these levels after
28 days.
B. Investigational FDA Procedure for Topicals
1. Organisms used: same as USP XX plus P. putida, P.
multivorans, Klebsiella sp., S. marcescens.
2. Inoculum: 0.2 ml/20 ml; _0.8-1.2 x 106 cells/ml.
3. Sampling: weekly observations.
4. Effectiveness: vegetative cells <0.01% survival by
28 days; C. albicans <1% survival; A. niger <10%
survival.
5. Re-inoculate: vegetative cells: 1-2 x 105 cells/ml;
0.1% survival in 28 days.
Modified from Bruch: Drug and Cosm. Ind., 110:32, 1972.
and types of microorganisms have not been offi­
cially specified, however.All materials must be
free of the harmful microorganisms listed in the
USP XX.Manufacturers have set up their own
microbiologic specifications suitable to their raw
materials and finished products. A typical man­
ufacturer's microbiologic specification may read
as follows: (1) The material must be free of via­
ble organisms restricted by the USP XX.(2 ) The
total aerobic count must not be more than 5000
microorganisms per gram; (3) not more than
100 molds per gram; (4) not more than 100
yeasts per gram; and (5) not more than 90 coli­
forms per gram.
Microbiologic quality guidelines have been
established by The Cosmetic, Toiletry and Fra­
grance Association, Inc.36 These have been
grouped according to product type:
1. Baby products-not more than (nmt) 500
microorganisms per gram or milliliter;
2. Products used about the eye-nmt 500 mi­
croorganisms per gram or milliliter;
3. Oral products-nmt 1000 microorganisms
per gram or milliliter;
4. All other products-nmt 1000 microorgan-
isms per gram or milliliter.
There is a further specification that the products
must be free from microorganisms recognized
"as harmful to the user as determined by stan­
dard plate count procedures."36
Limits on the maximal microbial content of
potable and purified water are stated in the
United States Public Health Service regula­
tions.3 7 The test is made for the presence of the
coliform group of bacteria, since experience has
shown that this group is a significant indicator
of pollution. The membrane filter technique, as
well as the fermentation tube method, is used
for detecting and estimating the number of coli­
form bacteria present.
Raw materials of botanical or animal origin
TABLE 18-4. Residue Limits of Ethylene Oxide and Derivatives (Parts per million)
_Drug product Ethylene oxide
Ophthalmics (for topical use)
lnjectables (including veterinary
intramammary infusions)
Intrauterine device
(containing a drug)
Surgical scrub sponges
(containing a drug)
Hard gelatin capsule shells
From Federal Register, 43(122), June 23, 1978, part 221, p. 27482.
that contain high levels of microorganisms must
be treated before use to remove these contami­
nants.The greatest source of contamination in
nasal jellies, for example, are the natural gums,
but treatment of the thickener with ethylene
oxide vapor destroys the bacterial and fungal
contaminants.Tests for ethylene oxide residues
should be made before using the material. The
amount of allowable ethylene oxide residues
have not been established.The residues are eth­
ylene oxide (ETO), ethylene chlorohydrin
(ETC), and the various monomeric forms of eth­
ylene glycol (ETG). Bruch has stated: "Recent
studies have shown the LD 50 (Gm./Kg.) by dif­
ferent routes for different animal species to ap­
proximate the following: ETC>ETO>ETG
(least toxic). Acute topical irritation studies
show on Gm./Kg. basis that the activity is
ETO>ETC>ETG."
The FDA has proposed the following: 38
"Each drug product of a type listed in this para­
graph for which ethylene oxide is used as a ster­
ilant in the manufacture of the finished product,
its components, or its market container shall
not, when tested as packaged in its market con­
tainer, exceed the following residue levels ... ."
(See Table 18-4.)
The manufacturer cannot depend on the pre­
servative or a type of sterilizing process, such as
radiation sterilization or a liquid chemical steril­
ant, to eliminate organisms introduced during
the manufacturing process or by contaminated
raw materials.Though the microbiologic quality
of a product may be high as a result of the sterili­
zation process, endotoxins may be present as a
result of lysing of the bacterial cells. Some endo­
toxins have been shown to be allergens. These
substances should be absent from semisolids
just as sterile products should be free of pyro­
gens. Methods for detection of endotoxins are
being investigated.39
A manufacturer can lessen the microbial haz­
ards in his products by following the Good Man­
ufacturing Practices (GMPs) recommended by
Ethylene chlorohydrin Ethylene glycol
10 20 60
10 10 20
5
25 250 500
35 10 35
SEMISOLIDS• 551

the FDA. 40 These procedures do not spell out
the specific details that a manufacturer should
follow to avoid contamination with microbial or
foreign matter in pharmaceutical products. An
interesting sanitary guideline was developed
with the food industry in mind, but it is applica­
ble to any industry in which sanitary procedures
must be followed. The Sanitary Design Princi­
ples are in the form of a checklist covering many
details, such as the construction of the manufac­
turing plant, processing and packaging equip­
ment, floors, walls and ceilings, plant services,
and the relative ease of cleaning both equipment
and the environment. 41
If the bacterial count in the finished product
is high despite precautions taken to prevent con­
tamination in the raw materials, including the
water supply, then the pipelines, filling equip­
ment, and containers must be checked for
sources of contamination or interference with
the activity of the preservatives. For example,
some filling equipment may still contain some of
the semisolid after rinsing or flushing of the
equipment during the cleaning operation. In
such cases, complete disassembly and thor�mgh
cleaning are mandatory.
The container may contribute to contamina­
tion by harboring bacterial spores, or by sorption
or chemical interaction with the preservative,
which thereby lowers its concentration in the
preparation. Plastic containers, rubber seals,
and closures have been shown to . react with
some preservatives. 42 Reduced preservative
concentration also can occur through chemical
complexation with the surfactant or gum as
shown in Table 18-5.
In the presence of 5% polysorbate 80, 80% of
the total methylparaben present in the aqueous
phase is inactive. 44 Such inactivation also oc­
curs with benzalkonium chloride, benzoic acid,
cetylpyridinium chloride, dehydroacetic acid,
and sorbic acid. The partial inactivation of the
TABLE 18-5. Degree of Binding of p-Hydroxy­
benzoate Esters by Various Macramolecules
Macromolecule Unbound Unbound
2% wlv Methylparaben % Propylparaben %
Gelatin 92
Methylcellulose 91
Carbowax 4000 84
PVP 78
Myrj 52 55
Tween 20 43
Tween 80 43
From Barkley, E. L.: Am. Perf. Aromat., 73:33, 1959.
552 • The Theory and Practice of Industrial Pharmacy
T
preservative can be overcome by an excess of
the same preservative, by the substitution of a
noncomplexing preservative, or by the substitu­
tion of a noncomplexing emulsifier system.
The antibacterial or bacteriostatic activity of
the preservative depends also on its partition
coefficient. The preservative may partition be­
tween the oil and the aqueous phase, and if the
preservative is more soluble in one phase than
another, an additional quantity of the preserva­
tive must be added so that both phases are pro­
tected from microbial spoilage. Hence, methyl­
paraben and propylparaben are frequently used
in semisolids because of their better solubility in
aqueous and oil phases, respectively.
Many of the preservative studies reported in
the literature are performed in simple aqueous
systems. It is comforting to know that the pre­
servatives appear to be more effective in the fin­
ished formulations than indicated in the com­
plexation studies. The interactions occurring in
a complex emulsion sptem in a semisolid ap­
parently do not apply. 4 However, in view of the
fact that interaction of preserv�ives with macro­
molecules does occur, the finished formulation
should be tested microbiologically for'preserva-
. a dequacy.
tive
The p-hydroxybenzoate esters are used in
combination with one another because of their
synergistic action. In general, they are employed ·
at a concentration level approaching their maxi­
mum solubility in water. The solubilities of some
commonly used preservatives are given in Table
18-6. The propyl or butyl ester is usually dis­
solved in the fat phase and should be increased
for vehicles with a high fat content. Satisfactory
protection of the emulsion against microbial
growth may possibly be attained with sorbic
acid, in which the p-hydroxybenzoate esters
prove to be ineffective. 45
The paraben esters of p-hydroxybenzoic acid
are still popular as preservatives because their
toxicity is low, they are odorless, they do not dis­
color, and they are nonirritating to the skin. On
the negative side, the parabens have a low solu­
bility in water and are less effective against
gram-negative bacteria than molds and yeasts.
Combining the parabens with phenoxy­
ethanol, 47 or with imidazolidinyl urea (Germall
II),48 improves their activity against bacteria,
89 yeast, and molds. The supplier* claims that the
87 combination system retains activity against
81 yeast and mold even when paraben activity has
64 been diminished by interaction with nonionics
16
or other substances in the formulation, or has
14
10
*Sutton Laboratories, Inc., Chatham, NJ
J
TABLE 18-6. Solubilities of Same Preservatives in g/100 ml Solvent at 25°C
Bithional
Butyl-p hydroxybenzoate
p-Chloro-m-xylenol
Dehydroacetic acid
Ethyl paraben
Methyl-p-hydroxybenzoate
Propyl-p-hydroxybenzoate
Sorbic acid
S = soluble; SS = slightly soluble; • = in glycerin. These descriptive terms are approximate solubilities as defined in USP XX.
migrated into the oil phase. Germall II is used in
concentrations of 0.1 to 0.5% alone or in combi­
nation with the parabens. It should be added to
the product below 60°C.
The solid parabens may be difficult to incorpo­
rate into some formulations because of their low
water solubility. A 50% by weight oil-in-water
emulsion (Liqua Par*) has been marketed. The
oil phase is a mixture of p-hydroxybenzoic acid
esters: n-butyl, isobutyl and isopropyl. The aque­
ous portion contains water with emulsion stabi­
lizers. The solubility of the active ingredients in
water at 25°C is 0.06 g/100 g and is freely misci­
ble with propylene glycol. The preservative
should be added to the aqueous phase at a tem­
perature not exceeding 70 to 75°C and stirred
until thoroughly dissolved before the_ prepara­
tion of the emulsion. Paraben hydrolysis may
occur if the temperatures exceed 80°C. The sup­
plier recommends the use of a concentration
ranging from 0.05 to 0.3% active ingredient.
Another preservative that is available is
Dowicil 200t, which is described as a broad­
spectrum antimicrobial effective against bacte­
ria, yeast, and molds at concentrations of 0.02 to
0.3% weight. It is not inactivated by nonionic,
anionic, or cationic formulation ingredients. The
substance is extremely soluble in water but is
virtually insoluble in oils and organic solvents.
Chemically, it is the cis isomer 1-(3-chloroallyl)-
3,5,7-triaza-1-azoniaadamantane chloride. The
preservative should not be heated above 50°C
and is unstable in solution below pH 4 and above
pH 10. Discoloring of this material may occur,
but can be prevented by the addition of sodium
sulfite. Strong oxidizing or reducing agents
should be avoided since these may adversely af­
fect the antimicrobial efficacy.
Newer preservatives are being marketed, but
all of these substances must be thoroughly eval-
*Mallinckrodt, Inc., St. Louis, MO.
tDow Chemical, U.S.A., Midland, MI.
Mineral Propylene
Water Oil Glycol
0.0004 1.0 0.5
0.02 s 110
0.0025 ss 1.5*
0.10 0.01 1.7
0.075
0.25 0.03 22
0.06 26
0.2 5.5
uated for their effectiveness in the product, and
their effect on the physicochemical stability of
the product. As with all new dermatologicals
under development, patch testing must be con­
ducted to eliminate any possibility of skin irrita­
tion or sensitivity with the products containing
these substances.
Rapid determination of preservative efficacy
in semisolids can be done in 48 hours for bacte­
ria and 7 days for molds.49 The method utilizes
the so-called D-value, or decimal reduction time,
which is calculated from a plot of the log number
of surviving organisms per gram against time of
inoculation of the product with specific orga­
nisms. The D-value is a numerical value of rate
of destruction of a particular organism in a Spe­
cific product. Since it is a quantitative expres­
sion, it can be used to compare the rate of inacti­
vation of different organisms in one or more
products. The D-value permits the calculation of
the time required for the complete destruction of
any size population of organisms.
The method consists of inoculating the prod­
uct with known amounts of the test organisms.
The products are then sampled periodically to
record the population of each test organism, and
the log of the surviving organisms at each sam­
ple time is plotted. The slope of the line is deter­
mined by linear regression, and the negative
reciprocal of the slope represents the D-value.
The time predicted for complete destruction of
the test organism in a product is calculated by
linear estimate of the x-intercept. Figure 18-2
shows the effect of different concentrations of
parabens on the death rate of Staphylococcus
aureus in a cream.
The D-values for the control, the cream with
the lower, and the cream with the higher con­
centrations of parabens were 18, 4, and 0.6 hr,
respectively. The times predicted for the com­
plete destruction of S. aureus in these samples
were 63, 19, and 3 hr for the control, low­
paraben-content cream, and high-paraben-
SEMISOLIDS • 553

6
5 irritancy, potency,-compatibility, odor, discolora­
0 tion to chelate trace quantities of metals.
z 3
01
0
...J
2 Pilot plant or small-scale production equip­
0 2 3 4 5 technique or formula. Mixing and stirring opera­
Hours
FIG. 18-2. Survivor curves showing the effects of different
concentrations of parabens on the rate of death of Staphy­
lococcus aureus {n a cream. Symbols: •-•, cream with no
parabens (control): ■-■, cream with 0.12% methyl- and
0.08% propyl-paraben; and .i.-.i., cream with 0.2%
methyl- and 0.1% pmpyl-paraben. (From Orth, D. S.:
]. Soc. Cosm. Chem., 30:321, 1979.)
content cream, respectively. The time required
for the complete destruction of a specific organ­
ism of known population in a particular product
may be predicted from the D-value. If the mean
D-value for S. aureus in a product is 2.5 hr, the
time for 106 S. aureus per milliliter to be totally
inactivated is given by the product of the log
number of the organisms per milliliter multi­
plied by the D-value, or 6 x 2.5 hr= 15 hr.
Table 18-7 shows the composition of the vehi­
cles of several corticosteroid creams. It is de­
signed to show how currently marketed semisol­
ids utilize the principles described in the
previous sections, namely, the different physio­
logically innocuous fatty materials used in the
fat phase, the emulsifier systems, and the
humectants, preservatives, antioxidants, and
chelating agents.
554 • The Theory and Practice of Industrial Pharmacy
Antioxidant�
Antioxidants are added to semisolids when­
ever oxidative deterioration is anticipated. The
antioxidant system is determined by the com­
ponents of the formuiation, and the selection
depends on several factors, such as toxicity,
tion, solubility, and stability. Often, two antioxi­
dants are wsed, since the combination is often
synergistic. Listed in Table 18-8 are some physi­
cal and chemical properties of antioxidants in
common use. Acids such as citric, maleic, phos­
phoric, or tartaric may be added to the combina­
Industrial Processing
ment is essential in developing a manufacturing
procedure for a production-size batch. The prep­
aration of many batches, ranging in size from
2.5 to 25.0 or more kilograms, for product evalu­
ation and clinical testing provides opportunity to
observe, correct, or improve the effects of minor
but important variations in the manufacturing
tions are critical in the preparation of emulsions,
and in the laboratory these operations can be
carefully controlled in 0.5- or 1.0-kg, batches of
finished product.
The electrically operated propeller-type mixer
can be manually adjusted and positioned in the
laboratory mixing vessel to achieve maximum
turbulence. The angle of entry of the propeller
shaft and the depth of the propeller can be easily
varied in the laboratory to prevent aeration. A
metal spatula can be held or positioned in the
beaker during mixing to serve as a baffle to in­
crease turbulence without entrainment of air.
Similar maneuverability and control of the mix­
ing action is more limited with larger stationary
equipment used for the manufacture of semisol­
ids. High-speed agitation may introduce air into
the product, and slow mixing may not form a
satisfactory emulsion.
Such problems occur in large-scale manufac­
ture, but would not be apparent in small 1- or
2-kg batches for which a beaker and a laboratory
mixer are used. Small-scale equipment similar
to the production models can approximate pro­
duction conditions. It may not be possible to pre­
dict the exact mixing time and rotational speed
of the agitator, but the overall processing charac­
teristics can be ascertained if identical mixers
are used.
Aeration of the semisolid should be avoided,
since it may lead to emulsion instability and var­
iation in density within a batch, resulting in
weight variation of the ointment or cream in its
container. Entrainment of air can occur during
the mixing, homogenizing, or milling stage, dur­
ing the transfer of the product to storage and/or
filling equipment, and during the filling or pack­
aging operation.
Aeration may be prevented at the primary
emulsion step if one phase is introduced into the
other in such a manner that splashing and
streaming are avoided. The incoming liquid
should enter the mixing kettle below the surface
of the other liquid. Vortexing and splashing are
overcome by careful adjustment of the mixing
conditions and liquid flow pattern.
Completely enclosed kettles are available for
the manufacture of semisolids, which tend to
aerate excessively. The sealed vessels can be
operated under vacuum; mixing and emulsifica­
tion can then be performed without entrainment
of air. Loss of moisture and volatile substances
may present problems, however, because of the
vacuum.
A closed system prevents aeration of the prod­
uct during homogenization or milling, and when
the material is transferred to the storage tanks,
vessels, or hoppers of the filling machines.
When an auger device or a wormdrive is used in
the hopper to deliver the material to the tube or
jar at the filling outlet, the hopper must be kept
full of product, or the rotation of the auger will
drive air into the semisolid.
Rheologic Changes. Homogenization fre­
quently increases the consistency of a semisolid
emulsion because it increases the number of
emulsified particles. It can also have the oppo­
site effect, that of decreasing the viscosity of the
product owing to an electrolyte effect. Some
products retain their viscosity if they are not
homogenized. Consistency also is affected by
the number of passes through the homogenizer,
the pressures used for homogenization with the
valve-type homogenizer, or the clearance be­
tween the rotor and stator if a colloid mill is
used.
Some commercial creams are sensitive to agi­
tation and stress. The continuous rotation of an
auger in the hopper of the filling machine may
cause a cream to liquefy. Such creams may be
made more resistant to agitation by a formula
change; however, the soft and easy spreading
properties of the cream on the skin may then be
lost. The replacement of the auger by another,
gentler feeding device is of value.
Fusion Method. Anhydrous ointments are
manufactured by the fusion process. The active
substance is dissolved in the melted fats and
waxes, or in one of the components of the vehi­
cle, and then mixed with the base. The melted
mass must be mixed while cooling because the
fatty alcohols, fatty acids, and waxes do not form
true solutions with petrolatum and mineral oil,
but crystallize from the melt as the temperature
falls.
Manufacture of Emulsions. Time, temper­
ature, and mechanical work are the three varia­
bles in the manufacture of emulsified semisol­
ids. The three factors are interrelated and must
be carefully controlled if the same high-quality
batches are to be manufactured repeatedly.
Equipment is available for automatically con­
trolling many aspects of emulsion manufacture,
such as the complete control of the temperature
in the jacket and regulation of the mixing time
and rate of agitation: If the volume warrants the
cost, the entire operation can be automated. The
kettles must be thoroughly cleaned before re-use
becctus_e the presence of small quantities of for­
eign contaminants or the residue from a previ­
ous batch may have an adverse effect on the sta­
bility and quality of the emulsion.
Preparation of Oil and Aqueous
Phases
The components of the oil or fat mixture are
placed into a stainless steel steam-jacketed ket­
tle, melted, and mixed.
Some of the solid components (e.g., stearic
acid, cetyl alcohol) are available in many differ­
ent forms: cakes, flakes, or powder. The flakes
are preferable because of the convenience of
handling. The powder may have occasional fine
metal contaminants from the pulverizing equip­
ment. Petrolatum is inconvenient to handle un­
less it is melted and transferred by pumping or
pouring from its drum. Transfer of large quanti­
ties of petrolatum is expedited by heating the
petrolatum in the steel drum in which it is re­
ceived from the supplier by means of immersion
heaters, or by placing the drums in a hot room
(60 to 62°C) until the petrolatum is fluid. The
liquefied petrolatum can then be transferred to
the mixing kettle by metering pump through
metal-reinforced inert plastic hoses and insu­
lated pipes. The oil phase is then strained
through several layers of cheese cloth to remove
any foreign matter. Alternatively, the petrolatum
can be passed through a filter medium, particu­
larly for an ophthalmic preparation. The oil
phase is transferred by gravity or pump to the
emulsion mixing kettle whose walls have been
SEMISOLIDS • 555
f

�
�
�
� TABLE 18-7. Components of Some Typical Corticosteroid Cream Bases
',:,
� Synalar
Q. Cordran Kenalog Lidex Locorten Aristocort Oxylone Synalar Emollient Valisone
�- Cream Cream Cream Cream Cream Cream Cream Cream Cream
£;,
;;- Emulsifiers

i Sorbitan monostearate X X X

[ Sorbitan monooleate X
Sodium lauryl sulfate X
Polyoxyethylene sorbitan X X X
monostearate
Polyoxy 40 stearate X
Polyethylene glycol 100 X
monocetyl ether
Polysorbate 80 X

Fat Phase Components

Glyceryl monostearate X X X
Cetyl alcohol X X X X
Spermaceti X X X
Stearyl alcohol X X X
Stearic· acid X X
Petrolatum X
Liquid petrolatum X X X
Cetostearyl alcohol X
Isopropyl palmitate X
Squalane X

�-------�

Polyols
Glycerin X
Propyiene glycol X X X X X

Polyethylene glycol 400 X

Polyethylene glycol 6000 X

1,2,6 Hexanetriol X
Sorbitol solution X

Antimicrobial agents
Methylparaben X X X X

Propylparaben X X X

Ethylparaben X
Butylparaben X
X
4-chloro-m-cresol
X
Thimerosol
Sorbic acid X

Potassium sorbate X

Buffering agents
X X X
Citric acid
X
Phosphoric acid
X
Monobasic sodium phosphate
Purified water X X x X X X X X

�
§
TABLE 18-8. Commercial Antioxidants
Common name BHA
Chemical name (Butylated hydroxyanisole)
3-t-butyl-4-hydroxyanisole
2-t-butyl-4-methoxyphenol
Melting point 55° -60° C
Solubility at 25°
in % [approx.]
Propylene glycol 70
Peanut oil 40
Modified from Rosenwald, R.H.: Am Perf. Cos., 78:41, 1963.
heated to the temperature of the oil phase to pre­
vent some of its higher-melting components
from congealing. The components of the aque­
ous phase are dissolved in the purified water
and filtered. A soluble drug may be added to the
aqueous phase at this time, provided the high
temperature does not degrade the active sub­
stance or the emulsion is not adversely affected;
otherwise, the soluble drug may be added in so­
lution after the emulsion has formed and has
cooled.
Mixing of Phases. The phases are usually
mixed at a temperature of 70 to 72°C, because at
this temperature intimate mixing of the liquid
phases can occur. The phase mixing tempera­
ture can be lowered a few degrees if the melting
point of the fat phase is low enough to prevent
the premature crystallization or congealing of its
components. Decreasing the temperature at
which the phases are mixed decreases the cool­
ing time, which is a significant factor when the
batch size is large. The properties of some emul­
sions (borax-beeswax type) 9-epend on the tem­
perature at which the phases are mixed. The ini­
tial mixing temperature must be raised above 70
to 72°C, because intimate mixing of the compo­
nents at monolayer levels cannot occur, since
the emulsion that forms immediately has a high
viscosity. The phases can be mixed in one of
three ways: (1) simultaneous blending of the
phases, (2) addition of the discontinuous phase
to the continuous phase, and (3) addition of the
continuous phase to the discontinuous phase.
The simultaneous blending of the phases re- -
quires the use of a proportioning pump and a
continuous mixer. This method of emulsifica­
tion is satisfactory for continuous or large-batch
operation. The second method may be used for
emulsion systems that have a low volume of dis­
persed phase. The third process is preferred for
many emulsion systems, since the emulsions
undergo an inversion of the emulsion type dur­
ing the addition of the continuous phase, which
results in a finer dispersed phase globule. The
558 • The Theory and Practice of Industrial Pharmacy
BHT propyl gallate
(Butylated hydroxyto!uene)
3,5-di-5-butyl-4-hydroxytoluene alkyl gallate
2,6-di-t-butyl-4-methylphenol
70°C 150°C
insoluble 55
30 0.5
disperse or aqueous phase in an oil-in-water
emulsion is added slowly to the inner phase with
agitation. The initial low concentration of water
in relation to the concentration of oil results in
the formation of a water-in-oil emulsion. The
viscosity of the emulsion continues to increase
as more water is added, and the volume of the oil
phase also increases up to a point of its maxi­
mum expansion. Beyond this point, the viscosity
decreases, and emulsion inversion is said to
occur. The phases reverse themselves, and the
inner phase is finely dispersed.
Batch sizes are on a weight basis, which is
independent of variations in temperature and
density. To measure the weight in a kettle, load
cells are placed onto the bases of the manufac­
turing kettle. The kettle exerts a pressure on the
cell, which is transmitted by means of a hydrau­
lic force exerted by a layer of oil seated on a dia­
phragm and can be read on a dial or recorded.
Figure 18-3 is a schematic presentation of a load
cell. Figure 18-4 is a photograph of a manufac­
turing kettle resting on a load cell.
Cooling the Semisolid Emulsion. Follow­
ing the addition of the phases, the rate of cooling
is generally slow to allow for adequate mixing
while the emulsion is still liquid. The tempera­
ture of the cooling medium in the kettle jacket
should be decreased gradually and at a rate con­
sistent with the mixing of the emulsion and
scraping of the kettle walls to prevent formation
of congealed masses of the ointment or cream,
especially when the semisolid contains a large
percentage of high-melting substances. Figure
18-5 is a photograph of a manufacturing kettle
showing agitator and sweep blades. Aeration
may occur if the semisolid thickens considerably
upon cooling, and steps should be taken to pre­
vent this. If perfume is to be added to an oil-in­
water emulsion, it is best done while the mix­
ture is at a temperature of 43 to 45°C to avoid _
chilling the emulsion and to facilitate dissolu­
tion of the perfume oil in the still incompletely
congealed oil phase. The perfume may be added

STAYPLATE
....
j"'
..,
C
z ences in the size of the fat and wax crystals and
::;
>­
u the dispersed globules.
FIG. 18-3. Schematic diagram of a cross-section of a hy­
draulic :oad cell. The hydraulic load cell is a frictionless
piston.and cylinder assembly with a fixed acting·area. It is
specifically designed for the conversion of force or weight
into a proportional hydraulic pressure. This pressure may
be connected to a dial indicator, a recorder, a controller, or
transducers. (Courtesy of the A. H. Emery Company, New
Canaan, CT.)
near room temperature to a water-in-oil emul­
sion, since dissolution of the perfume oils is to
occur in the outer phase of the system.
The drug is added in solution form, if not al­
ready incorporated, or as crystals, provided it is
soluble in the external phase. An insoluble pow­
der should be dispersed in the continuous phase
FIG. 18-4. Photograph of a load cell set under one of the legs of a manufacturing kettle. (Permission of Ciba-Geigy Corp.)
prior to removing the semisolid from the kettle
for homogenization and/or storage. Figure 18-6
shows a Gifford-Wood homomixer after it has
been withdrawn from a kettle used for dispers­
ing solids. The cooling of the semisolid stored in
a large covered vessel is not uniform, since cool­
ing is more rapid at the surface or the walls of
the container. Hence, variation in physical prop­
erties of the semisolid may occur, such as differ­
Adjustment of the final water content of a
water-in-oil emulsion is not easy once the emul­
sion has been formed. Several batch runs help to
determine the amount of water lost on heating
in the particular process, and this lost water
should be added to the required amount at the
start of manufacture. The oil film surrounding
each emulsified water droplet in a water-in-oil
emulsion tends to retard evaporation, so that
water loss is not excessive following this type of
emulsification.
Low-Energy Emulsification
The high cost of energy has prompted re­
evaluation of manufacturing procedures in an
attempt to limit the amount of thermal and me­
chanical energy expended in the production of
emulsions. It has been shown that the use of a
minimum amount of the emulsion phase in the
SEMISOLIDS • 559
FIG. 18-5. Stainless steel jacketed mixing kettle equipped 1nth a slml'-spced. anchor-type .,weep blade agitator which
takes the material from the side wall and swirls it around tlie secondary, har-type mixer. The bar-type mixer rotates at a
higher speed and directs the flow of material downu·ard for tlwrouqh aq1tat/lm. ! Permission of C1ha-Gcigy Corp.)

emulsification stage can result in a considerable
reduction in energy requirements and process­
ing time without compromising the quality of
the product. The major cost saving is achieved
by heating both the oil phase and a portion of
water or external phase to the required tempera­
ture to form a concentrated emulsion. The bal­
ance of the aqueous phase is added at room tem­
perature during the cooling state. Thus, the
energy used to heat the aqueous phase and the
mechanical energy of mixing during the cooling
stage are reduced.
Figure 18-7 illustrates the usual method of
emulsion manufacture. The internal phase of an
oil-in-water emulsion usually consists of fats,
waxes, preservative, and perhaps an emulsifier.
The external phase contains the water-soluble
substances. Both are heated to a high tempera­
ture and then mixed to form an emulsion. The
emulsion is then cooled. The low-energy
method, illustrated in Figure 18-8, shows that a
major portion of the aqueous phase, which may
be as much as 70%, can be added at the cool
dilution stage. The savings in energy could be
considerable.
The quality, stability. rheologic properties,
and the particle size distribution of the internal
phase of the finished product prepared by this
process depend on several variables. These in­
clude the temperature required for forming the
concentrated emulsion, the ratio of the external
phase to the internal phase forming the concen­
trated emulsion, the phase inversion tempera­
ture, the type and intensity of mixing, and the
rate of addition of the external phase. 50•51
Homogenization. The creams or ointments
that require further treatment are then trans­
ferred or pumped to the proper homogenizer, the
selection of which is governed by the degree and
rate of shear stress required. The choices in­
clude a low-shear gear pump, a roller mill, ·a col­
loid mill, a valve-type homogenizer, and a suita­
ble sonic homogenizer. Uniform dispersion of an
insoluble drug in a semisolid, as well as reduc­
tion of the size of the fatty aggregates can be
attained by the passage of the warm (30 to 40°C)

560 • The Theory and Practice of Industrial Phannacy

FIG. 18-6. The high shear Homo-Mixer is attached to an electrically driven lift mechanism for raising or lawering it into
the jacketed kettle used for dispersing solids in liquids. (Permission of Ciba-Geigy Corp.)

ointment or cream through a homogenizer or
mill.
Storage of Semisolids. Unless rapid in­
process methods of analysis are developed, it is
the usual practice to store the semisolid until the
specified quality control tests have been com­
pleted before packaging into appropriate con­
tainers: tubes, jars, or single-dose packets. A
product is considered to be "in-process" until it
has been packaged. These preliminary quality
control tests are time-consuming and delay the
packaging process; however, it is less costly to
wait for the assay and to store the material until
it can be scheduled for filling than to package
and then perhaps be compelled to empty the
containers to recover the material, should the
semisolid fail to meet the established specifica­
tions for the product. Some semisolids have a

SEMISOLIDS • 561

INTERNAL EXTERNAL
PHASE PHASE
,,,
FINISHED
EMULSION
FIG. 18-7. Conventional emulsion processing. (Modified
from Lin, T.J.:]. Soc. Cosm. Chem., 29:745, 1978.)
tendency to "set up" or exhibit an increase of
viscosity on storage, and such products cannot
be stored for any length of time. The industrial
pharmacist must be aware of the delays caused
by quality control requirements and packaging
schedules, so that he can develop formulations
that tolerate storage in bulk without undergoing
marked changes in consistency which might
cause filling problems. The active substance in
the cream or ointment may react with the stor­
age container unless a highly resistant #316,
stainless steel, is used for bulk storage. Evapora­
tion of water from a cream must be retarded; this
can be effectively accomplished by placing non­
reactive plastic sheeting in direct contact with
the cream, as well as covering the storage con­
tainer with a tight-fitting stainless steel lid.
Transfer of Material For Packaging. The
semisolid may be gravity fed, if it is a two-level
EXTERNAL
INTERNAL PHASE
PHASE PART (1)
',I
CONCENTRATED
EMULSION
FIG. 18-8. Law-energy emulsion processing. (Modified from Lin, T.].: ]. Soc. Cosm. Chem., 29:745, 1978).
562 • The Theory and Practice of Industrial Phannacy
operation, or pumped to the filling equipment. It
must be able to resist the shear stress developed
in the transfer of the product, as well as that due
to the mechanical action of the filling equip­
ment.
Once a formal manufacturing procedure has
been established, there should be no deviation
from it. If a change is necessary, however, the
problem should be carefully re-evaluated, first in
the research and development laboratory and
then at the pilot plant and manufacturing level.
Although the design and the evaluation of
semisolids usually does not include the equip­
ment cleaning operation following the manufac­
ture and filling of the product, it is mandatory
that the cleaning operation be thorough to avoid
any contamination between batches. Cleaning
of large-scale equipment is facilitated and labor
costs and downtime of equipment can be re­
duced through the use of high-pressure (up to
1000 psi), low-volume pump systems now avail­
able. The cutting force of high-pressure hot
water that may contain detergent can be applied
like a knife edge to clean difficult-to-reach tight
spots inside kettles and· tanks and a variety of
manufacturing and processing equipment, elim­
inating old-fashioned manual scrubbing.
Homogenizers, pumps, and filling equipment
that have areas wherein pockets of water or
product may accumulate and that are ordinarily
inacessible must be completely disassembled,
cleaned, sanitized, and dried before reassembly.
Ball valves and sanitary (Ladish) type or sanitary
threaded piping should be used throughout. The
packing material used as lubricant for the shafts
of mixers should also be replaced during the
cleanup process if there is any possibility that
they may harbor microorganisms. The manufac-
EXTERNAL
PHASE
PART (2)
FINISHED
EMULSION
turing and packaging equipment should be sani­
tized following thorough cleaning with deter­
gents. They should be flushed with chlorinated
water, formalin, or other suitable sterilant fol­
lowed by a bacteria-free water rinse. Water and
swab samples should be taken to verify micro­
bial elimination.
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SEMISOLIDS • 563