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CHAPTER III

FORMULATION AND
STABILITY OF CREAM
PREPARATIONS

3.1 FORMULATION OF CREAM PREPARATIONS


Traditionally, emulsions have been defined as dispersions of macroscopic droplets
of one liquid in another liquid, with a droplet diameter approximately in the range of 0.5100 m (Becher, 1965). According to the definition of International Union of Pure and
Applied Chemistry (IUPAC) (1971), In an emulsion liquid droplets and / or liquid
crystals are dispersed in a liquid.
Creams are semisolid emulsions intended for external applications. They are often
composed of two phases. Oil-in-water (o/w) emulsions are most useful as water-washable
bases, whereas water-in-oil (w/o) emulsions are emollient and cleansing agents. The
active ingredient is often dissolved in one or both phases, thus creating a three-phase
system. Patients often prefer a w/o cream to an ointment because the cream spreads more
readily, is less greasy, and the evaporating water soothes the inflamed tissue. O/W creams
(vanishing creams) rub into the skin; the continuous phase evaporates and increases the
concentration of a water-soluble drug in the adhering film. The concentration gradient for
drug across the stratum corneum therefore increases, promoting percutaneous absorption
(Barry, 2002; Betageri and Prabhu, 2002).
The various factors involved in the formulation of emulsions and topical products
have been discussed by Block (1996), Barry (2002) and Jain et al., (2006) and are briefly
presented in the following sections.
3.1.1 Choice of Emulsion Type
Oil-in-water emulsions are used for the topical application of water-soluble drugs,
mainly for local effect. They do not have the greasy texture associated with oily bases
and are therefore pleasant to use and easily washed from skin surfaces. Moisturizing

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creams, designed to prevent moisture loss from the skin and thus inhibit drying of the
stratum corneum, are more efficient if formulated as o/w emulsions, which produce a
coherent, water-repellent film.
3.1.2 Choice of Oil Phase
Many emulsions for external use contain oils that are present as carriers for the
active ingredient. It must be realized that the type of oil used may also have an effect both
on the viscosity of the product and on the transport of the drug into the skin (Barry,
2002). One of the most widely used oils for this type of preparation is liquid paraffin.
This is one of a series of hydrocarbons, which also includes hard paraffin, soft paraffin
and light liquid paraffin. They can be used individually or in combination with each other
to control emulsion consistency. This will ensure that the product can be spread easily but
will be sufficiently viscous to form a coherent film over the skin. The film-forming
capabilities of the emulsion can be further modified by the inclusion of various waxes,
such as bees wax, carnauba wax or higher fatty alcohols.
3.1.3 Emulsion Consistency
A consideration of the texture or feel of a product intended for external use is
important. A w/o preparation will have a greasy texture and often exhibits a higher
apparent viscosity than o/w emulsions. This fact imparts a feeling of richness to many
cosmetic formulations. Oil-in-water emulsions will, however, feel less greasy or sticky on
application to the skin, will be absorbed more readily because of their lower oil content,
and can be more easily washed from skin surface. Ideally emulsions should exhibit the
rheological properties of plasticity / pseudoplasticity and thixotropy. Emulsions of high
apparent viscosity for external use (cream) are of a semisolid consistency. There are

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several methods by which the rheological properties of an emulsion can be controlled


(Billany, 2002).
3.1.4 Choice of Emulsifying Agent
The choice of emulgent to be used would depend on factors such as its
emulsifying ability, route of administration and toxicity. Most of the non-ionic emulgents
are less irritant and less toxic than their anionic and cationic counter parts. Some
emulgents, such as the ionic alkali soaps, often have a high pH and are thus unsuitable for
application to broken skin. Even in normal intact skin with a pH of 5.5, the application of
such alkaline materials can cause irritation. Some emulsifiers, in particular, wool fat can
cause sensitizing reactions in susceptible people. The details of various types of
emulsifying agents are available in the literature (Betageri and Prabhu, 2002; Billany,
2002; Swarbrick et al., 2006).
3.1.5 Formulation by the HLB Method
The physically stable emulsions are best achieved by the presence of a condensed
layer of emulgent at the oil water interface, and the complex interfacial films formed by a
blend of an oil-soluble emulsifying agent with a water-soluble one produces the most
satisfactory emulsions.
It is possible to calculate the relative quantities of the emulgents necessary to
produce the most physically stable emulsions for a particular formulation with water
combination. This approach is called the hydrophilic-lipophilic balance (HLB) method.
Each surfactant is allocated an HLB number representing the relative properties of the
lipophilic and hydrophilic parts of the molecule. High numbers (up to a theoretical
number of 20), therefore, indicates a surfactant exhibiting mainly hydrophilic or polar

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properties, whereas low numbers represent lipophilic or non-polar characteristics. Each


type of oil requires an emulgent of a particular HLB number in order to ensure a stable
product. For an o/w emulsion, the more polar the oil phase the more polar must be the
emulgent system (Billany, 2002; Im-Emsap et al., 2002; Swarbrick et al., 2006).
3.1.6 Concept of Relative Polarity Index
In the ingredient selection in cosmetic formulations, a new concept of relative
polarity index (RPI) has been presented (Wiechers, 2005). The physicochemical
characteristics of the ingredients determine their skin delivery to a greater extent than the
formulation type. The cosmetic formulation cannot change the chemistry of the active
molecule that needs to penetrate to a specific site within the skin. However, the
formulation type can be selected based on the polarity of the active ingredient and the
desired site of action for the active ingredient. For optimum skin delivery the solubility of
the active ingredient needs to be as high as possible (to create a large concentration
gradient) and as small as possible (to create a large partition coefficient). To achieve this,
it is necessary to determine the following parameters.


The total amount dissolved in the formulation that is available for skin penetration;
the higher this amount, the more will penetrate until a solution concentration is
reached in the skin, therefore a high absolute solubility in the formulation is required.

The polarity of the formulation relative to that of the stratum corneum; if an active
ingredient dissolves better in the stratum corneum than in the formulation, then the
partition of the active ingredient will favour the stratum corneum, therefore a low
(relative to that in the stratum corneum) solubility in the formulation is required
(Wiechers, 2005).

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These requirements can be met by considering the concept of RPI (Wiechers,


2003, 2005). In this systematic approach, it is essential to consider the stratum corneum
as another solvent with its own polarity. The stratum corneum appears to behave very
similarly to and in a more polar fashion than butanol with respect to its solubilizing
ability for active ingredients (Scheuplein and Blank, 1973). The polarity of stratum
corneum, as expressed by its octanol / water partition coefficient, is 6.3.
The relative polarity index may be used to compare the polarity of an active
ingredient with both that of the skin, and that of the oil phase of a cosmetic formulation
predominantly consisting of emollients. It may be visualized as a vertical line with a high
polarity at the top and a high lipophilicity at the bottom. The polarity is expressed as the
log10 of the octanol / water coefficient. For example, the relative polarity index values of
glycerin and isostearyl isostearate are -1.76 and 26.98, respectively (Wiechers, 2005). In
order to use the concept of the relative polarity index, three numbers (on log10 scale) are
required.


The polarity of the stratum corneum is set at 0.8. However, in reality this value will
change with the hydration state of the stratum corneum that is determined, in part, by
the external relative humidity (Bonwstra et al., 2003).

The polarity of the active molecule.

The polarity of the formulation.

For multiphase or multipolarity systems like emulsions, the active ingredient is dissolved
in the phase. For example, in an o/w emulsion where a lipophilic active ingredient is
dissolved in the oil phase, it is the polarity of the homogenous mixture of the lipophilic
active ingredient and internal oil. For the same lipophilic active in a w/o emulsion, it is

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the polarity of the homogenous mixture of the lipophilic active ingredients and external
oil. For water-soluble active ingredients, it is the polarity of the homogenous mixture of
the hydrophilic active ingredient and the aqueous phase, regardless whether it is internal
(w/o emulsions) or external (o/w emulsions).
Once the active ingredient and the formulation type have been chosen, it is
necessary to create the delivery system that will effectively deliver the molecule. The
concept of relative polarity index allows the formulator to select the polarity of the phase
in which the active ingredient is incorporated on the basis of its own properties and those
of the stratum corneum. In order to achieve maximum delivery, the polarity of the active
ingredient and the stratum corneum need to be considered. In order to improve the skin
delivery of active ingredients, the first step involves selecting a primary emollient with a
polarity close to that of the active ingredient in which it will have a high solubility. The
second step is to reduce the solubility of the active ingredient in the primary emollient via
the addition of a secondary emollient with a different polarity and therefore lower
solubility for the active ingredient. This approach has shown a 3-4 fold increase in skin
penetration with out increasing the amount of active ingredients in the formulation
(Wiechers, 2005).
3.2 FORMULATION OF ASCORBIC ACID CREAMS
Ascorbic acid is a water-soluble material and is included frequently in skin care
formulations to restore skin health. It is very unstable and is easily oxidized in aqueous
solution. This vitamin is known to be a reducing agent in biological systems and causes
the reduction of both oxygen- and nitrogen- based free radicals (Higdon and Frei, 2002).
It can also act as a co-antioxidant with the tocopheroxyl radical to regenerate alpha-

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tocopherol (Packer et al., 1979, Buettner, 1993; Peyrat-Maillard et al., 2001). In this
reaction the two vitamins act synergistically. Alpha-tocopherol first functions as the
primary antioxidant that reacts with an organic free radical. Thereafter, ascorbic acid
reacts with the free radical tocopheroxyl to general alpha-tocopherol. In physiological
conditions, the ascorbyl radical formed by regenerating tocopherol is then converted back
to ascorbate by the redox cycle (Davies et al., 1991). The interaction of ascorbic acid
with a redox partner such as alpha-tocopherol has been found useful to slow its oxidation
and prolong its action.
The instability of ascorbic acid makes this antioxidant active ingredient a
formulation challenge to deliver to the skin and retain its effective form. In addition to its
use in combination with alpha-tocopherol in cream formulations, the stability of ascorbic
acid may be improved by its use in the form of a fatty acid ester such as ascorbyl
palmitate. Ascorbyl palmitate has been used in thixogel formulations, and is typically
incorporated into the mineral oil phase. Preliminary experiments have shown that it could
be slowly released from the starch-oil emulsion matrix and act as an antioxidant (Wille,
2005).
Various physical and chemical factors involved in the formulation of cream
preparations have been discussed in the above sections. For polar and air / light sensitive
compounds such as ascorbic acid it is important to consider factors such as the choice of
formulation ingredients, polar character of formulation, HLB value, pH, viscosity etc. to
achieve stability.

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3.3 STABILITY OF CREAMS


3.3.1 Physical Stability
The most important consideration with respect to pharmaceutical and cosmetic
emulsions (creams) is the stability of the finished product. The stability of a
pharmaceutical emulsion is characterized by the absence of coalescence of the internal
phase, absence of creaming, and maintenance of elegance with respect to appearance,
odor, color and other physical properties. An emulsion is a dynamic system, however,
any flocculation and resultant creaming represent potential steps towards complete
coalescence of the internal phase. In pharmaceutical emulsions creaming results as a lack
of uniformity of drug distribution and poses a problem to the pharmaceutical
compounder. Another important factor in the stabilization of emulsions is phase inversion
which involves the change of emulsion type from o/w to w/o or vice versa and is
considered as a case of instability. The four major phenomena associated with the
physical instability of emulsions are flocculation, creaming, coalescence and breaking.
These have been discussed by Garti and Aserin (1996), Im-Emsap et al. (2002) and Sinko
(2006).
3.3.2 Chemical Stability
The instability of a drug may lead to the loss of its concentration through a
chemical reaction under normal or stress conditions. This results in a reduction of the
potency and is a well-recognized cause of poor product quality. The degradation of the
drug may make the product esthetically unacceptable if significant changes in color or
odor have occurred. The degradation product may also be a toxic substance. The various
pathways of chemical degradation of a drug depend on the structural characteristics of the

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drug and may involve hydrolysis, dehydration, isomerization and racemization,


decarboxylation and elimination, oxidation, photodegradation, drug-excipients and drugdrug interactions. Factors determining the chemical stability of drug substances include
intrinsic factors such as molecular structure of the drug itself and environmental factors
such as temperature, light, pH, buffer species, ionic strength, oxygen, moisture, additives
and excipients. The application of well-established kinetic principles may throw light on
the role of each variable in altering the kinetics of degradation and to provide valuable
insight into the mechanism of degradation (Baertschi and Alsante, 2005; Yoshioka and
Stella, 2002; Lachman et al., 1986). The chemical stability of individual components
within an emulsion system may be very different from their stability after incorporation
into other formulation types. For example, many unsaturated oils, are prone to oxidation
and their degree of exposure to oxygen may be influenced by factors that affect the extent
of molecular dispersion (e.g. droplet size). This could be particularly troublesome in
emulsions because emulsification may introduce air into the product and because of the
high interfacial contact area between the phases (Barry, 2002). The use of antioxidants
retards oxidation of unsaturated oils, minimizes changes in color and texture and prevents
rancidity in the formulation. Moreover, they can retard the degradation of certain active
ingredients such as vitamin C (Vimaladevi, 2005). The stability problems of dispersed
systems and the factors leading to these stability problems have been discussed by
Weiner (1996) and Lu and Flynn (2009).
3.3.3 Microbial Stability
Topical bases often contain aqueous and oily phases, together with carbohydrates
and proteins and are susceptible to bacterial and fungal attack. Microbial growth spoils

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the formulation and is a potential toxic hazard. Therefore, topical formulations need
appropriate preservatives to prevent microbial growth and to maintain their quality and
shelf-life (Barry, 2002; Arger et al., 1996). Cream formulations may contain fats and oils
with high percentage of unsaturated linkages that are susceptible to oxidation degradation
and development of rancidity. The addition of antioxidants retards oxidation of fats and
oils, minimizes changes in color and texture and prevents rancidity in the formulation.
Moreover, they can retard the degradation of certain active ingredients such as vitamin C.
These aspects in relation to dermatological formulations have been discussed by Barry
(1983, 2002) and Vimaladevi, 2005).
3.3.4 Stability of Ascorbic Acid in Liquid Formulations
Ascorbic acid is very unstable in aqueous solution. Different workers have studied
the stability of ascorbic acid in liquid formulations (Connors et al., 1986; Austria et al.,
1997). Its shelf-life can be prolonged by appropriate choice of vehicle and control of
other variables such as pH, stabilizers, temperature, light, and oxygen (Table 3).
Similarly, the stability of various concentrations of ascorbic acid in solution form may
vary depending upon the type of solvent used (Table 4) (Connors et al., 1986; Satoh et
al., 2000; Lee et al., 2004; Zeng et al., 2005).
3.3.5 Stability of Ascorbic Acid in Emulsions and Creams
Ascorbic acid exerts several functions on skin such as collagen synthesis,
depigmentation, and antioxidant activity. Ultraviolet radiation generates reactive oxygen
species (ROS) which produce some harmful effects on the skin including photocarcinoma
and photoaging. In order to combat these problems, ascorbic acid as an antioxidant has

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Table 3. Effect of vehicles on the stability of ascorbic acid (% ascorbic acid remaining in
solutions after storage at room temperature) (Connors et al., 1986).
No. Vehicle
1.

Corn Syrup

30
96.5

60
92.5

Storage Time (days)


90
120
180
92.0
92.0
90.0

2.

Sorbitol

99.0

99.0

99.0

97.0

96.0

92.5

89.0

3.

4% Carboxymethyl

84.0

68.0

56.5

38.0

240
86.0

360
76.0

Cellulose
4.

Glycerin

100

100

99.0

99.0

97.0

93.5

92.0

5.

Propylene glycol

99.5

99.0

98.0

94.5

92.0

90.0

90.0

6.

Syrup USP

100

100

98.0

98.0

93.0

90.0

88.0

7.

Syrup 212 g/L

88.0

81.0

77.5

74.5

64.5

59.0

44.0

8.

2.5% Tragacanth

78.5

62.0

51.0

32.0

9.

Saturated solution of

99.0

93.5

87.5

80.0

64.0

58.0

51.0

Dextrose
10.

Distilled Water

90.0

81.5

74.5

67.5

40.5

18.5

11.

50% Propylene glycol +

98.0

96.0

93.3

95.5

95.4

94.2

93.0

98.2

98.4

97.8

91.4

50% Glycerin
12.

25% Distilled Water +


75% Sorbo (70% solution
of Sorbitol)

13.

50% Glycerin + 50%


Sorbo

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Table 4. Stability of various concentrations of ascorbic acid in water, propylene glycol,


and USP syrup at room temperature (% of ascorbic acid remaining in solution)
(Connors et al., 1986).

Concentration
(mg /ml)
10

Solvent
Water

30
93.0

50

Water

100

60
84.0

Storage Time (days)


90
120
180
240
82.0 67.0 51.5 41.0

360

94.0

92.0

88.0

79.5

60.5

59.0

30.0

Water

97.0

93.0

91.0

83.5

70.5

68.0

59.0

10

Propylene glycol

100

98.5

98.0

97.5

96.0

92.0

86.0

50

Propylene glycol

100

97.0

98.0

98.0

98.0

96.5

93.5

100

Propylene glycol

100

100

100

100

99.0

100

92.5

10

Syrup

100

100

98.0

99.0

97.0

96.0

84.0

50

Syrup

100

100

100

100

99.0

100

96.0

100

Syrup

100

100

100

100

100

100

99.5

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been used in various dosage forms and in different concentrations (Darr et al., 1996;
Gallarate et al., 1999; Zhang et al., 1999; Pinnell et al., 2001; Lee et al., 2004; Raschke
et al., 2004; Elmore, 2005; Farahmand et al., 2006; Maia et al., 2006). Ascorbic acid has
good photoprotective ability against UVA-mediated phototoxicity (Darr et al., 1996). A
variety of formulations containing ascorbic acid or its derivatives have been studied in
order to evaluate their stability and delivery through the skin (Gallarate et al., 1999;
Zhang et al., 1999; Ozer et al., 2000; Pinnell et al., 2001; Lee et al., 2004; Raschke et al.,
2004; Farahmand et al., 2006). Formulations containing derivatives of ascorbic acid are
found to be more stable than ascorbic acid but they do not produce the same effect as that
of the parent compound probably due to the lack of redox properties (Heber et al., 2006).
Effective delivery of ascorbic acid through topical preparations is a major factor that
should be critically evaluated as it may be dependent upon the nature or type of the
formulation (Gallarate et al., 1999; Pinnell et al., 2001). The pH of the formulation
should be on the acidic side (~ pH 3.5) for effective penetration of the vitamin in the skin
(Pinnell et al., 2001) and for its stabilization in the formulation (Gallarate et al., 1999).
Some other antioxidants such as alpha-tocopherol, ferulic acid and sodium metabisulphite
have also been used in combination with ascorbic acid for the purpose of its stabilization
in topical formulations and to produce some synergistic effects (Darr et al., 1996; Lin et
al., 2005; Maia et al., 2006; Tournas et al., 2006). Effect of some rheological properties
such as viscosity and dielectric constant on the stability of ascorbic acid in emulsions has
also been investigated (Connors et al., 1986). Viscosity of the medium is an important
factor that should be considered for the purpose of ascorbic acid stability as higher
viscosity formulations have shown some degree of protection (Ozer et al., 2000;

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Szymula, 2005). Along with other factors formulation type also plays an important role in
the stability of ascorbic acid. It is reported that ascorbic acid is more stable in emulsified
system as compared to aqueous solutions (Gallarate et al., 1999; Lee et al., 2004). In
multiemulsions, ascorbic acid is reported to be more stable as compared to simple
emulsions (Gallarate et al., 1999; Ozer et al., 2000; Lee et al., 2004; Farahmand et al.,
2006).
Ascorbic acid and its derivatives have been used in a variety of cosmetic
formulations as an antioxidant, pH adjuster, anti-aging and photoprotectant (Elmore,
2005). The control of instability of ascorbic acid poses a significant challenge in the
development of cosmetic formulations. It is also reported that certain metal ions or
enzyme systems effectively convert ascorbic acids antioxidant action to pro-oxidant
activity (Elmore, 2005). Therefore, utilization of an effective antioxidant system is
required to maintain the stability of vitamin C in various preparations (Zhang et al., 1999;
Pinnell et al., 2001; Maia et al., 2006). The chemical stability of ascorbic acid has been
studied in emulsions and creams by several workers (Darr et al., 1996; Gallarate et al.,
1999; Lee et al., 2004; Raschke et al., 2004; Elmore, 2005; Farahmand et al., 2006),
however there is a lack of information on the photostability of ascorbic acid in cream
formulations.
3.3.6 Stability Testing of Emulsions
The stability testing of emulsions (creams) may be carried out by performing the
following tests (Billany, 2002):

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3.3.6.1 Macroscopic examination


The assessment of the physical stability of an emulsion is made by an
examination of the degree of creaming or coalescence occurring over a period of time.
This involves the calculation of the ratio of the volume of the creamed or separated part
of the emulsion and the total volume. A comparison of these values can be made for
different products.
3.3.6.2 Globule size analysis
An increase in mean globule size with time (coupled with a decrease in globule
numbers), indicates that coalescence is the cause of this behavior. This can be used to
compare the rates of coalescence for a variety of emulsion formulations. For this purpose,
microscopic examination or electronic particle counting devices (coulter counter), or
laser diffraction sizing are widely used.
3.3.6.3 Change in viscosity
Many factors may influence the viscosity of emulsions. A change in apparent
viscosity may result from any variation in globule size or number, or in the orientation or
migration of emulsifier over a period of time.
3.2.6.4 Accelerated stability tests
In order to compare the relative stabilities of a range of similar products it is
necessary to speed up the processes of creaming and coalescence by storage at elevated
temperatures and then carrying out the tests described in the above sections.
3.3.7 FDA guidelines for semisolid preparations
According to FDA draft guidelines to the industry (Shah, 1997), semisolid
preparations (e.g. creams) should be evaluated for appearance, clarity, color,

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homogencity, odour, pH, consistency, viscosity, particle size distribution (when feasible),
assay, degradation products, preservative and antioxidant content (if present), microbial
limits / sterility, and weight loss when appropriate. Additionally, samples from
production lot or approved products are retained for stability testing in case of product
failure in the field. Retained samples can be tested along with returned samples to
ascertain if the problem was manufacturing or storage related. Appropriate stability data
should be provided for products supplied in closed-end tubes to support the maximum
anticipated use period, during patient use, and after the seal is punctured allowing product
contact with the cap / cap lever. Creams in large containers including tubes should be
assayed by sampling at the surface, top, middle, and bottom of the container. In addition,
tubes should be sampled near the crimp. The objective of stability testing is to determine
whether the product has adequate shelf-life under market and use conditions.

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