Stability and Stabilization of Ascorbic Acid

Abstract

Ascorbic acid (vitamin C) is extensively used in a variety of formulations including creams. It is an ingredient of anti-aging cosmetic products alone or along with alpha-tocopherol (vitamin E). In solutions and creams, ascorbic acid is susceptible to air and light and undergoes oxidative degradation to dehydroascorbic acid and further to inactive products. The degradation is influenced by oxygen, temperature, viscosity and pH of the medium and is also catalyzed by metal ions, particularly Cu2+, Fe2+, and Zn2+. This review highlights the stability and modes of stabilization of ascorbic acid in both the cosmetic and pharmaceutical preparations. A number of approaches involved in the stabilization of the vitamin such as the use of antioxidants, stabilizers, synergists, other vitamins, and formulation of multiple emulsions, nanosuspensions, microencapsulation, etc. have been discussed

(16) Stability and Stabilization of Ascorbic Acid. Available from: https://www.researchgate.net/publication/321148774_Stability_and_Stabilization_of_Ascorbic_Acid [accessed Jan 28 2018].

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KEYWORDS: Ascorbic acid; stability; stabilization, cosmetic and pharmaceutical preparations.
AbstractAscorbic acid (vitamin C) is extensively used in a variety of formulations including creams. It is an
ingredient of anti-aging cosmetic products alone or along with alpha-tocopherol (vitamin E). In
solutions and creams, ascorbic acid is susceptible to air and light and undergoes oxidative degradation to dehydroascorbic
acid and further to inactive products. The degradation is influenced by oxygen, temperature, viscosity and pH of the medium
and is also catalyzed by metal ions, particularly Cu2+, Fe2+, and Zn2+. This review highlights the stability and modes of stabilization
of ascorbic acid in both the cosmetic and pharmaceutical preparations. A number of approaches involved in the stabilization of
the vitamin such as the use of antioxidants, stabilizers, synergists, other vitamins, and formulation of multiple emulsions,
nanosuspensions, microencapsulation, etc. have been discussed.
Stability and Stabilization of Ascorbic Acid
A Review
INTRODUCTION
Ascorbic acid (AA) is known to play an important role as
an antioxidant due to its presence in the body  uids (1). It
causes an increase in the rate of absorption of iron, calcium
and folic acid and hence reduces allergic reactions,
boosts the immune system, stimulates the formation of bile
in the gallbladder and facilitates the excretion of various
steroids (2). In the body AA plays an essential role in the
production of collagen tissue around bones, teeth, cartilage,
skin and damaged tissue (3). It has shown a prominent
pharmacological effect in a number of disease conditions
such as scurvy, common cold, osteoarthritis, hypertension,
heart diseases, cancer, diabetes mellitus, asthma, wound
healing, pregnancy, gout and eye diseases (4). Because
of all these favourable effects, AA has been used in a
variety of cosmetic and pharmaceutical formulations (5). It
is highly soluble in water and alcohol, and is easily oxidised
to dehydroascorbic acid in its solubilised form (1). The rapid
degradation of AA in aqueous media is still a major factor
in the formulation of its products. It is also reported that AA
oxidation occurs rapidly in an alkaline environment especially
at higher temperatures (>50°C) (6) and its reaction with
oxygen is strongly catalysed by metal ions, particularly cupric
and ferric ions (7, 8). The degradation of AA proceeds both by
aerobic and anaerobic pathways and depends upon many
factors such as oxygen, temperature, light, pH and storage
conditions (1, 3, 9–12).
STABILITY OF AA
The stability of a pharmaceutical formulation, particularly,
the semisolid dosage form depends on its formulation
characteristics and the nature of the active ingredients.
These characteristics are in uenced by the nature and
amount of the excipients to be added and their sensitivity to
the environmental factors to which these dosage forms are
exposed. In the semisolid dosage forms a careful selection
of bases including oil-in-water (o/w) and water-in-oil (w/o)
emulsifying agents, humectants, emollients, etc. would
provide physical stability to the formulation and enhance the
shelf-life of the product. In the selection of these ingredients
the formulator has to take into consideration the nature of
the active ingredient and the possible effect of formulation
ingredients on its stability pro le. The stability of AA and
various modes of its stabilization are discussed in the following
sections:
Vegetables and Fruits
AA is a white crystalline organic compound and can be
synthesized from glucose or extracted from certain natural
sources such as fruits and vegetables to meet the nutrient
requirements of a healthy diet. Plants and most animals
synthesize their own AA but humans lack this ability due to the
de ciency of an enzyme known as L-gulono-gamma-lactone
oxidase (13).
AA along with its derivatives is added to foods and fruit
FORMULATION
MUHAMMAD ALI SHERAZ*, MARIUM FATIMA KHAN, SOFIA AHMED, SADIA HAFEEZ KAZI, IQBAL AHMAD
*Corresponding author
Baqai Institute of Pharmaceutical Sciences, Baqai Medical University, 51, Deh Tor, Toll Plaza,
Super Highway, Gadap Road, Karachi-74600, Pakistan
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the studies
related to the
stabilization of
AA.
STABILIZATION OF
AA
In order to
achieve maximum
stability of AA in
various foods,
cosmetics and
pharmaceutical
formulations, different strategies have been employed, some
of which are briey described below:
Use of Other Vitamins in Combination with AA
AA is known to be one of the important members of the
water-soluble vitamin group. It has been reported that AA
acts synergistically with other water- and fat-soluble vitamins
including alpha-tocopherol (vitamin E) (TP) (31). In recent
years, AA has been successfully used in a number of cosmetic
and dermatological formulations along with TP. They are
specically indicated for topical applications such as skin
depigmentation and ability to take part in proline and lysine
hydroxylation in collagen biosynthesis (3). The stabilizing
effect of TP on the photodegradation of AA has been studied
using UV spectrometry. Similarly, the stability of AA in o/w
creams in the presence of vitamins including riboavin (RF),
nicotinamide (NA) and TP has been investigated by Ahmed
et al. (31), Jung et al. (37), Kim et al. (38) and the results
showed the highest stability of AA with TP.
Use of Stabilizers / Preservatives / Synergists
The photosensitivity of AA makes it highly unstable for use
in cosmetic (9) and pharmaceutical preparations (26) and
hence it requires the use of appropriate stabilizing agents. As
mentioned above, TP acts as a synergist with AA, by acting as
an electron donor to restore the tocopheroxyl radical (7, 39).
TP rst functions as the primary antioxidant that reacts with
an organic free ascorbyl radical in the physiological system
and is then converted back to ascorbate through the redox
cycle (40). The interaction of AA with a redox partner such as
TP has been found to be useful to slow down its oxidation and
prolong its physiological action (3, 41, 42).
The instability of AA in various formulations also leads to the
use of stabilizers or preservatives such as citric acid (CT),
boric acid (BA) or tartaric acid (TA). A study was designed
to determine the effects of CT, TA and BA on the stabilization
of AA in various o/w cream formulations in the light and
in the dark. The results indicated a marked decrease in
the rate of degradation of AA by these stabilizers both
in the light and in the dark. The order of stabilization was
found as CT>TA>BA (20). Similarly, a decrease in the rate
of degradation of AA in w/o creams has been observed
in the presence of CT indicating that the change of phase
does not affect the efcacy of the stabilizer (21). In the AA
formulations, these agents act simultaneously as antioxidants
(29, 43, 44), preservatives or synergists (45) that may lead to
the stabilization of the formulations. CT has been found to
be a naturally occurring antioxidant in carcinogenesis (46)
and lipid peroxidation (47) whereas BA acts as a complexing
agent for hydroxyl compounds including AA (9, 20, 48–52)
juices for the improvement of nutritional quality (14, 15).
The degradation of AA in orange, grape, pomegranate
juices and sour cherry nectar with or without the addition of
hydrogen peroxide (H2O2) has been studied at 20, 30 and
40°C (16). In another stability study for the determination of
the retention of AA in homogenized raw fruits and vegetables
stored under routine conditions, raw collard greens (Brassica
oleracea var. viridis), clementine (Citrus clementina hort. ex
Tanaka) and potatoes (Solanum tuberosum) were selected
as the representatives of foods to be sampled in a USDA’s
National Food and Nutrient Analysis Program (NFNAP) (17).
The retention of AA was also studied in dried guava during
storage at 30, 40 and 50°C and with different water activity
values that resulted in the degradation of AA by a pseudo-rst
order reaction (18).
Cosmetic and Pharmaceutical Formulations
AA has found wide applications in the eld of cosmetics
and pharmacy. In cosmetic preparations AA is used for its
anti-ageing, depigmentation (19) and antioxidant properties
(20–22) along with its ability to reduce wrinkles by promoting
collagen synthesis (23). Because of these favourable effects,
AA has long been used in cosmetic preparations (5, 24).
AA is sensitive to light (9, 25–30) and is degraded to form
dehydroascorbic acid and 2,3-diketogulonic acid on UV
irradiation by photooxidation and subsequent hydrolysis (27)
(Figure 1).
Similarly, chemical oxidation has also been found as a
major cause of AA degradation in the dark (9, 20, 21,
31) thus making it difficult to be used in cosmetics and
pharmaceutical formulations. The contact of AA with
metals in solution form has been reported to form free
radicals which are then converted to molecular oxygen
that oxidizes AA in solution. The rate of oxidation has
been found to increase with pH, oxygen content and
concentration of metal ions in the solution (32, 33). In
an attempt to study the stability of AA in pure water
solutions (without buffers), it has been observed that the
rate of oxidation is pH dependent, showing a minimum
at pH 2.5 to 3.0 and a maximum at pH 4.0. The pH
adjustment is necessary to preserve the physical, chemical
and therapeutic properties of AA because fruit juices
containing this vitamin have pH values ranging from 2.5 to
5.0 (34).
A number of derivatives of AA such as sodium ascorbate
and ascorbyl palmitate are used as antioxidants in
cosmetics and pharmaceutical preparations (29, 35).
However, they lack the biological activity similar to that of
AA (5, 36); therefore, this review particularly emphasizes
Figure 1. Degradation of ascorbic acid (AA) upon UV irradiation by photooxidation and subsequent hydrolysis.
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to use the latter in dermocosmetic products (71). It has
been stated that the stability of AA may be achieved by
preparing a solid-in-oil-nanosuspension (SONS) having
medium chain triglycerides such as sucrose erucate (i.e.
lipophilic surfactant) and sucrose monolaureate (i.e.
hydrophilic surfactant) stored at 25°C, protected from light.
A lipase-based enzymatic technique has been used to
degrade a formulation phase making it easier for AA to be
extracted. The results showed that the entire encapsulated
AA (95.3%) has been successfully extracted from the SONS
with the addition of a medium-chain triglyceride. Hence
the SONS showed increased stability of AA due to low
moisture contents (65).
Use of Solvents
In aqueous solution AA undergoes rapid oxidation (1)
but its stability is increased in acidic and weakly alkaline
media upon the addition of acetonitrile. It has been
observed that acetonitrile decreases the rate of AA
degradation to four fold at a concentration of 0.2%
while at a concentration of 2.0% the rate of reaction
reaches to the least value and remains unchanged upon
further addition of acetonitrile (58). This may be due to
a change in the polarity of the medium to inhibit the
rate of degradation of ionized AA. The effect of ethanol
on the stabilization of AA was also studied and the
results indicated a markedly lower effect of this solvent
compared to acetonitrile (58).
Effect of Viscosity, Dielectric Constant and pH
The rate of a chemical reaction may be affected by a
number of factors including the pH, viscosity and dielectric
constant of the medium which can greatly influence the
stability of oxidisable substances (72, 73). A study has been
performed to determine the effect of different humectants
such as ethylene glycol, propylene glycol and glycerine
in cream formulations containing AA. The humectants
showed stabilizing effect on the degradation of AA,
depending upon their viscosity, in the order of ethylene
glycol>propylene glycol>glycerine (9). A study of the rate
of photolysis of AA in aqueous and organic solvents has
been carried out using UV irradiation. It has been observed
that there is a linear relation between the rate of photolysis
and the solvent dielectric constant or the reciprocal
of viscosity. Hence an increase in the solvent dielectric
constant or a decrease in solvent viscosity leads to an
increase in the rate of photolysis. This should be taken into
consideration during the formulation of pharmaceutical
preparations containing AA (50). As stated earlier the rate
of photolysis of AA in cream formulations is also affected
by pH and redox potential of AA (e.g. E° at pH 5.0 = +0.127
V and at pH 7.0 = +0.058 V) and is due to the change in
the ionization of AA. An increase in the viscosity of creams
is also known to affect the physical stability of AA in cream
formulations. It has been reported that the higher the
viscosity of the medium the lower will be the degradation
of AA. Therefore, a careful selection of excipients including
emollients and humectants is of utmost importance to
improve the stability of AA (21).
Microencapsulation
Microencapsulation and emulsification are the widely
used techniques for the stabilization of AA in formulations
particularly at a concentration of 1–5% (18, 69, 74).
and enhances its level in plasma (53). Stabilization of AA
is also achieved by using other antioxidants such as DL-
methionine, mannitol, sorbitol, sucrose, dextrose, sodium
thiosulphate, halide salts, triplet quenchers, metal-
complexing agents and various viscosity enhancing agents
(54, 55). For the maximum stability of AA in solutions the
use of metaphosphoric acid is also reported (56, 57) with
greater efficacy than that of CT, perchloric, acetic, and
orthophosphoric acids (57, 58). In another study palmitic
acid (PA), an emulsifier, has been observed to exert a
greater stabilizing effect against the degradation of
AA in creams than the myristic and stearic acid (9). The
drugs prepared in the form of extruded granules with low
substituted hydroxyl propyl cellulose (L-HPC) and water
have been investigated using AA and thiamine nitrate
(TN) as model drugs. D-Mannitol is used as the control
additive for a comparison with L-HPC. The percentage of
AA remaining after a storage period of 14 days at 60°C in
a closed glass bottle was 57% in D-mannitol granules and
89% in L-HPC granules, showing higher stability of AA in
L-HPC granules (33).
Formulation of Multiple Emulsions
Multiple w/o/w emulsions are vesicular systems in which small
water droplets are entrapped within oil drops, and then
dispersed in the aqueous phase (59). They may be used as
a potent drug and cosmetic vehicles to prolong the action
after administration (60–63). The w/o emulsions containing
AA complexed with surfactants have been reported
(64–66). In a separate formulation, AA is added into the
inner aqueous phase of the w/o/w emulsion using parafn
oil at a concentration of 1% and a two step method for the
preparation of the emulsion. Stability studies on AA have been
performed at different temperatures, such as 8°C (refrigerator),
25°C (oven) and 40°C (oven) at 75% RH (stability cabin) for a
period of 28 days to foresee the changes in these formulations.
Different parameters, such as pH, globule size, electrical
conductivity and effect of centrifugation (simulating gravity)
have been evaluated during the stability studies. Multiple
emulsion formulations have been found to be stable at lower
temperatures (i.e. 8° and 25°C) during the study period with
no phase separation in all the samples (67). Another study has
been conducted using a high concentration of AA up to 30%
in the dispersed phase of w/o emulsions, with their continuous
phase containing rened soybean oil or Moringa oleifera oil
and a food-grade hydrophobic emulsier. All the w/o emulsions
appeared stable for more than 30 days at 4°C or 25°C with
slight increase in the average droplet diameter and without
any phase separation. AA retention ratio of these emulsions
followed rst-order kinetics showing good stability (68).
In order to study the effect of composition on AA
formulations such as surfactant/co-surfactant associations
and the use of different oils on the physicochemical
characteristics of the system, a polyglycoside
microemulsion has been developed which showed
good stability. It can protect AA from degradation with
enhanced penetration ability into the skin for topical
application. The study also revealed that the control of
pH and electrolyte concentration is necessary for the
stabilization of AA in the formulations (69, 70).
Formulation of Nanosuspensions
Since AA is not as stable as its derivatives such as tetra-
isopalmitoyl ascorbic acid (IPAA), it is often, recommended
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Both w/o and w/o/w emulsification methods have
been used for encapsulation of AA (3, 67–69, 74–76). In
order to improve AA microencapsulation by complex
coacervation, both gelatine and gum arabic have
been used as encapsulating agents. In a w/o emulsion
using corn oil, a 30% solution of AA and polyglycerol
polyricinoleate (PGPR 90) as surfactant has been made for
making coacervation of a hydrophilic core material. The
encapsulation was carried out successfully in the double
emulsion with the complex coacervation thus confining
AA to a more stable microcapsule form rather than in
solution. It suggests the option of controlled release
under specific conditions and masking the acidic taste
of AA (77). Microencapsulated AA is also reported to
be more stable to colour change (18). Starch and beta-
cyclodextrin encapsulated AA delays its degradation
during storage at a temperature of 38°C and relative
humidity of 84% (18).
CONCLUSION
The stability of air sensitive drugs such as AA has always
been a problem for the formulator. Various approaches
have been adopted to achieve stabilization of AA in
cosmetic preparations. These include the use of stabilizers,
antioxidants, preservatives, synergists, emulsifiers etc. The
techniques of entrapment of AA in multiple emulsions and
encapsulation in nanosuspensions have shown significant
improvement in the stabilization of AA. The control of
medium pH, polarity and viscosity also prolong the shelf-life
of AA in cosmetic preparations.
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