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FORMULATION AND
STABILITY OF CREAM
PREPARATIONS
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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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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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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).
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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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
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.
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.
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.
13.
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Concentration
(mg /ml)
10
Solvent
Water
30
93.0
50
Water
100
60
84.0
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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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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