CHAPTER III

FORMULATION AND

STABILITY OF CREAM

PREPARATIONS

32

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 0.5-

100 µm (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

34

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

35

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

37

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-

38

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.

39

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

40

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

decarboxylation and elimination, oxidation, photodegradation, drug-excipients and drug-

drug 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

41

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).

Storage Time (days) No. Vehicle

30 60 90 120 180 240 360

1. Corn Syrup 96.5 92.5 92.0 92.0 90.0 86.0 76.0

2. Sorbitol 99.0 99.0 99.0 97.0 96.0 92.5 89.0

3. 4% Carboxymethyl

Cellulose

84.0 68.0 56.5 38.0 – – –

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

Dextrose

99.0 93.5 87.5 80.0 64.0 58.0 51.0

10. Distilled Water 90.0 81.5 74.5 67.5 40.5 18.5 –

11. 50% Propylene glycol +

50% Glycerin

98.0 – 96.0 – 93.3 – –

12. 25% Distilled Water +

75% Sorbo (70% solution

of Sorbitol)

95.5 95.4 – 94.2 93.0 – –

13. 50% Glycerin + 50%

Sorbo

98.2 98.4 97.8 – – 91.4 –

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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).

Storage Time (days) Concentration

(mg /ml)

Solvent

30 60 90 120 180 240 360

10 Water 93.0 84.0 82.0 67.0 51.5 41.0 –

50 Water 94.0 92.0 88.0 79.5 60.5 59.0 30.0

100 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;

45

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 acid’s 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,

47

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.