Synthesis of Natural Salicylic Acid as a Cosmetic Ingredient Using Green Chemistry Methods

Abstract

Objective: Salicylic acid (SA) is a keratinolytic agent also used as preservative in cosmetic products. Green chemistry, known as sustainable chemistry, is the design of products and processes eliminating the use of chemicals. It is applicable throughout a chemical product's life cycle, including its design, manufacture, use, and final disposal. The aim of this study was to synthesize SA with green chemistry methods using different amounts of wintergreen oil and to optimize the relevant steps in this path.
Materials and Methods: The SA was synthesized from natural wintergreen oil using green chemistry methods. First laboratory-scale synthesis was developed and 15 laboratory-scale synthesis trial patterns, using reaction temperature, wintergreen oil-sodium hydroxide molar ratio, sodium hydroxide-water weight ratio, reaction time and pH were performed. Purity was analysed with gas chromatography- mass spectrometry (GC-MS) and moisture analysis was performed.
Results and Conclusion: As a result of pilot production run with 1 kg, 5 kg, and three batches of 20 kg of wintergreen oil, SA was produced with a yield range of 91.06-93.92 %. The resulting SA batches had a purity of approximately 99%. This is a sufficient degree of purity for SA to be used as a raw material in cosmetics products. Filtering the SA solution using a filter press reduced crystal drying time and brought down the total production time to eight days.

Full text

Experimed 2022; 12(1): 12-7 ORIGINAL ARTICLE
DOI: 10.26650/experimed.2022.1068934
Synthesis of Natural Salicylic Acid as a Cosmetic
Ingredient Using Green Chemistry Methods
Gökhan Özokan1 , Tuğba Sağır1 , Ebru Emekl-Alturfan2
1BioArge Laboratories, Yıldız Technical University Technocity, Ikitelli, Istanbul, Turkiye
2Department of Basic Medical Sciences, Faculty of Dentistry, Marmara University, Istanbul, Turkiye
ORCID ID: G.Ö. 0000-0003-1140-1996; T.S. 0000-0002-3717-8828; E.E.A. 0000-0003-2419-8587
Cite this article as: Ozokan G, Sagir T, Emekli-Alturfan E. Synthesis of natural salicylic acid as a cosmetic ingredient using green chemistry
methods. Experimed 2022; 12(1): 12-7.
ABSTRACT
Objective: Salicylic acid (SA) is a keratinolytic agent also used as preservative in cosmetic products. Green chemistry, known as sustainable
chemistry, is the design of products and processes eliminating the use of chemicals. It is applicable throughout a chemical product's life
cycle, including its design, manufacture, use, and final disposal. The aim of this study was to synthesize SA with green chemistry methods
using different amounts of wintergreen oil and to optimize the relevant steps in this path.
Materials and Methods: The SA was synthesized from natural wintergreen oil using green chemistry methods. First laboratory-scale
synthesis was developed and 15 laboratory-scale synthesis trial patterns, using reaction temperature, wintergreen oil-sodium hydroxide
molar ratio, sodium hydroxide-water weight ratio, reaction time and pH were performed. Purity was analysed with gas chromatography-
mass spectrometry (GC-MS) and moisture analysis was performed.
Results and Conclusion: As a result of pilot production run with 1 kg, 5 kg, and three batches of 20 kg of wintergreen oil, SA was produced
with a yield range of 91.06-93.92 %. The resulting SA batches had a purity of approximately 99%. This is a sufficient degree of purity for SA
to be used as a raw material in cosmetics products. Filtering the SA solution using a filter press reduced crystal drying time and brought
down the total production time to eight days.
Keywords: Salicylic acid, green chemistry, wintergreen oil, cosmetic
Corresponding Author: Ebru Emekli-Alturfan E-mail: eiemekli@marmara.edu.tr
Submitted: 07.02.2022 Revision Requested: 02.03.2022 Last Revision Received: 31.03.2022 Accepted: 31.03.2022
Content of this journal is licensed under a Creative Commons
Attribution-NonCommercial 4.0 International License.
12
INTRODUCTION
Salicylic acid (SA) is a beta-hydroxy acid, and its name orig-
inates from the Latin word salix, which means “willow tree.”
As an ingredient in Aspirin, SA has numerous health bene-
fits. It has a therapeutic effect on various skin conditions,
such as acne and eczema (1). It is used in the production of
cosmetic care products, such as creams, masks, shampoos
and tonics (2). Moreover, SA has an exfoliating effect on
skin, which helps to remove dead cells (3).
As a raw material, it is used in the production of food and
textiles, as well as pharmaceuticals and cosmetic products
(4). Although it has been widely used in cosmetic products
in recent years due to its protective properties and derma-
tological effects, the SA contained in these products has
been produced via industrial synthesis. In this method,
phenol (which is a highly toxic chemical) is used as a raw
material. The synthesis reaction of SA is presented in Figure
1. Industrial SA synthesis creates certain impurities in the
end product which have toxic effects as indicated in the
pharmacopeia. In contrast, the natural synthesis method
uses the oil of wintergreen, which has a methyl salicylate
Figure 1. Industrial synthesis of SA.

13
Experimed 2022; 12(1): 12-7
Özokan et al.
Salicylic Acid Synthesis Using Green Chemistry
content of over 99%. Oil of wintergreen is first hydrolysed with
sodium hydroxide and then further hydrolysed with hydro-
chloric acid to obtain crystal SA free from toxic impurities (5).
SA and its derivatives have long been recognized as important
pharmacological agents. Salicin, the active ingredient in willow
bark, was isolated in 1828. Hippocrates, the father of medicine,
prescribed willow bark to reduce fever and pain during child-
birth in the fifth century B.C. Salicylate levels have been found
to be high in a variety of plant species other than willow. An-
other medicinal derivative known as wintergreen oil also con-
tains methyl salicylate. Medicinal plants high in salicylates have
been used by various cultures around the world for thousands
of years and continue to be used today (6).
Chemical peeling is a technique used to improve, smooth, and
revitalize the skin through controlled removal of epidermis/
dermis, enabling healthy skin formation (7). The aim of chemi-
cal peeling is to cause damage to skin layers up to the desired
depth, in order to treat various skin lesions and conditions by
leveraging the increased collagen and elastin production trig-
gered by wound healing (8). The most common chemical peel-
ing agents are alpha-hydroxy acids (AHA) (lactic acid, glycolic
acid, and fruit acids), trichloroacetic acid (TCA), beta-hydroxy
acids (BHA, SA), Jessner solution, and their combinations (9).
SA affects the epidermis and is generally used in the treatment
of acne, acne scars, blackheads, and photo-aging, as well as in
the secondary treatment of skin spots. It penetrates into the
pores of the skin, preventing sebum build-up and balancing
skin tone. Marczyk et al. compared the effects of 50% pyruvic
acid and 30% SA peels on skin lipids and found that SA had a
greater sebumetric impact than pyruvic acid (10). In the 1860s,
it was discovered that SA could soften and exfoliate the stra-
tum corneum. With its comedolytic properties, SA works to
dissolve dead skin cells, and has an anti-inflammatory effect
in lower concentrations, which helps to treat acne and reduce
acne scars (11). SA is also a desmolytic agent because it disrupts
cellular junctions rather than breaking intercellular keratin fila-
ments (12). Imayama et al. concluded that peeling with SA can
cause changes in the underlying dermal tissue without directly
wounding the skin (13, 14). Its anti-inflammatory and anti-irri-
tant properties enable SA to be well-tolerated by all skin types
(15). It also soothes painful acne and sensitive skin (16).
Acne vulgaris is a common condition that can cause both
physical and psychological problems, such as redness after
acne, hyperpigmentation after inflammation, acne scars, and
affects the quality of life. SA acts on normal keratinization, re-
duces inflammation, and regulates sebum production with a
comedolytic action. The SA concentration used to treat acne
is 0.5–5% (17). SA has been shown to reduce the lipid content
of the sebocytes cell line (SEB-1) to suppress the inflammatory
response in SEB-1 by inhibiting the NF-kB pathway (16). SA is
also effective in the treatment of dandruff, caused by keratino-
cyte hyper-proliferation as it loosens the bonds between the
corneocytes, allowing them to be washed away (18, 19).
Green chemistry is a novel method in chemistry that aims to
minimize the environmental impact during the production and
use of chemicals (20). It is based on ecological concerns and
takes into account economic and technological factors. It fa-
vours the most ecologically-economically advantageous solu-
tion of existing alternatives (21).
The foundation of this philosophy was laid with the enactment
of the Environmental Protection Act in the United States (US)
in 1990. This act focused on the prevention of polluting waste
and was followed by the establishment of the Office of Pollu-
tion Prevention and Toxics within US Environmental Protec-
tion Agency (EPA) (22). The twelve green chemistry principles
were presented as the first guidebook on green chemistry by
Anastas, a US EPA representative, and Warner (23). The history
of green chemistry was initiated by the pollution prevention
movement in 1990. Then it was formalized with the establish-
ment of EPA in 1991“Presidential Green Chemistry” awards
were given for the first time in 1996. The “Green Chemistry and
Engineering” conference was first held in 1997 (24).
The goals of green chemistry are schematized in Figure 2. To
achieve these goals, the principles of green chemistry include
preventing waste, maintaining atom economy and synthesis
of less toxic chemicals, and developing safer chemicals, safer
solvents, and auxiliaries. Energy efficiency should also be main-
tained through the use of renewable feedstocks. Derivatization
is aimed to be reduced, minimized, or avoided, as these steps re-
quire additional reagents and can cause waste. Chemical prod-
ucts should be designed so that when they reach the end of
their useful life, they degrade into harmless degradation prod-
ucts and do not persist in the environment. Analytical meth-
odologies that enable real-time, in-process monitoring and
control prior to the formation of hazardous substances must be
developed further. Finally substances used in a chemical pro-
cess should be selected to reduce the likelihood of chemical
accidents such as releases, explosions, and fires (24, 25).
Figure 2. Goals of green chemistry.

Experimed 2022; 12(1): 12-7
Özokan et al.
Salicylic Acid Synthesis Using Green Chemistry
14
In the light of this information, the aim of our study was to
synthesize SA with green chemistry methods using different
amounts of wintergreen oil and to optimize the relevant steps
in this path.
MATERIALS AND METHODS
Salicylic Acid Synthesis using Green Chemistry
Developing Laboratory-Scale Synthesis
SA was synthesized from natural wintergreen oil using organic
synthesis and green chemistry methods. First, sodium salic-
ylate was synthesized and then it is crystallized as described
below. The main synthesis steps were schematized in Figure 3.
Sodium Salicylate Synthesis
Sodium hydroxide solution (5M) was slowly added to winter-
green oil over 10-15 minutes. White precipitates formed. Reflux
was commenced by turning on the heater and stirrer. A homo-
geneous solution was formed within one hour; heating contin-
ued for a further two hours for three hours of total reflux. After
three hours, the solution was left to cool at room temperature.
The reflux equipment system is shown in Figure 4.
Crystallization of Salicylic Acid
At room temperature, to the reaction solution the HCl solution
(6M) was slowly added over 30 minutes to reduce its pH to be-
tween 2 and 1.5. The addition of HCl created an exothermic re-
action. The solution was cooled continuously while the HCl was
added. The solution was left overnight to allow precipitates to
form. Then it was washed and filtered under vacuum. The crys-
tals were washed using water and dried at 40oC for 3-4 days.
The filtration equipment is shown in Figure 5 (26, 27).
Laboratory-Scale Synthesis Trial Pattern
In our studies a total of 15 trials were made, using the parame-
ters in Table 1. The optimum parameters with the highest reac-
Figure 3. The main steps of SA synthesis.
Figure 4. Reflux equipment system.
Figure 5. Filtration equipment.
Table 1. Laboratory-Scale Synthesis Trial Pattern of SA.
Parameter 1 Reaction Temperature 80oC, 90oC, 100oC
Parameter 2 Wintergreen oil-sodium hydroxide molar ratio 1:3, 1:5, 1:7
Parameter 3 Sodium hydroxide-water weight ratio 1:5, 1:7, 1:10
Parameter 4 Reaction Time 2 hours, 3 hours, 4 hours
Parameter 5 pH (HCl precipitation) 1.5, 1.7, 2.0

15
Experimed 2022; 12(1): 12-7
Özokan et al.
Salicylic Acid Synthesis Using Green Chemistry
tion yield were reaction temperature: 90oC; 1:7 wintergreen oil-
sodium hydroxide molar ratio; 1:5 sodium hydroxide - water
weight ratio; reaction time of 3 hours, and pH of 1.5. The result-
ing SA was analysed for purity using gas chromatography-mass
spectrometry (GC-MS), which revealed a purity of 99%.
GC-MS Analysis
For the GC-MS analysis a HP-5ms ultra inert, 30 m x 250 µm x
0.25 µm column was used. Temperature program was arranged
as follows: beginning: 60oC, final 260oC, and the temperature
increase rate was 3oC per minute. Inlet temperature was 250oC
and the MS detector temperature was 230oC. Analysis duration
was 66.6 minutes. Helium flow rate and the split ratio were 1.1
ml/minute and 20:1, respectively.
Sample Preparation
5 mg of SA was dissolved in 1.5 ml of methanol. Injection volume
was 1µl and SA retention time was 20.3 minutes. SA MS peaks
were determined as 138, 120, 92, 64, 53 in molecular weight.
Moisture Analysis
The samples were placed in moisture analyser at 95oC, and it
was observed that samples that were dried at 40oC for four days
had a moisture content of under 0.5%.
Pilot-Scale Synthesis Optimization
Pilot-scale production was optimized by gradually increasing
wintergreen oil amounts (1 kg, 5 kg, 20 kg). Synthesis param-
eters (caustic ratio, acid amount, drying time) were taken into
account to obtain laboratory-scale synthesis data. Yield and
impurity analyses were performed after each batch. The Pi-
lot-Scale synthesis trial pattern of SA is given in Table 2.
Yield and Purity Analysis Criteria for Pilot-Scale Salicylic
Acid Production
The criteria include the fulfilment of the following criteria: a
yield of a minimum 80% raw material input, a minimum 95%
purity as analysed by GC-MS and a maximum loss of 0.5 % on
drying analysis through moisture analyser.
RESULTS
Results of Salicylic Acid Synthesis from 1 kg of Wintergreen
Oil
At the end of sodium salicylate synthesis and crystallization
steps, the product was dried for 14 days at 40oC to obtain 0.84
kg of SA with a yield of 92.47%. The resulting SA was analysed
for purity using GC-MS, which revealed a purity of 98.25%. The
product’s moisture content was analysed at 95oC, showing that
samples that were dried at 40oC for 14 days had a moisture con-
tent of under 0.5%.
Results of Salicylic Acid Synthesis from 5 kg of Wintergreen
Oil
4.18 kg of SA with a yield of 91.96% was obtained. The resulting
SA was analysed for purity using GC-MS, which revealed a pu-
rity of 97.95%. Moisture analysis revealed that samples dried at
45oC for 10 days had a moisture content of under 0.5%.
Results of Salicylic Acid Synthesis from 20 kg of Winter-
green Oil (20 kg batch)
For the first batch, 17.07 kg of SA with a yield of 93.92% was
obtained. The resulting SA was analysed for purity using GC-
MS, which revealed a purity of 99.16%. The product’s moisture
content was analysed at 95oC, showing that samples that were
dried at 50oC for 14 days had a moisture content of under 0.5%.
For the second batch, 16.93 kg of SA with a yield of 93.19%
was obtained. The resulting SA was analysed for purity using
GC-MS, which revealed a purity of 99%. Moisture content was
analysed at 95oC, showing that samples that were dried at 50oC
for 7 days had a moisture content of under 0.5%.
For the third batch, 16.96 kg of SA with a yield of 93.34% was
obtained. The resulting SA was analysed for purity using GC-
MS, which revealed a purity of 99%. Moisture content was ana-
lysed at 95oC, showing that samples that were dried at 45oC for
7 days had a moisture content of under 0.5%. The pilot produc-
tion results are given in Table 3.
Table 2. Pilot-Scale Synthesis Trial Pattern of SA.
Parameter 1 Amount of wintergreen oil 1kg, 5 kg, 20 kg
Parameter 2 SA drying temperature 40oC, 45oC, 50oC
Parameter 3 SA drying time 7 days, 10 days, 14 days
Table 3. Pilot Production Results of SA.
1 kg batch Total production time 15 days Yield 92.47%, purity 98.25%
5 kg batch Total production time 15 days Yield 91.96%, purity 97.95%
First 20 kg batch Total production time 15 days Yield 93.92%, purity 99.16%
Second 20 kg batch (press filtered) Total production time 8 days Yield 93.19%, purity 99%
Third 20 kg batch (press filtered) Total production time 8 days Yield 93.34%, purity 99%

Experimed 2022; 12(1): 12-7
Özokan et al.
Salicylic Acid Synthesis Using Green Chemistry
16
Pilot production runs with 1 kg, 5 kg and three batches of 20
kg of wintergreen oil produced SA with a yield range of 91.06-
93.92% using green chemistry methods. The resulting SA
batches had a purity of approximately 99%. This is a sufficient
degree of purity for the SA to be used as a raw material in cos-
metics products. Filtering the SA solution via a filter press had
a reduced crystal drying time and brought down total produc-
tion time to eight days.
DISCUSSION
SA is one of the most common active ingredients used in cos-
metic products. It is an organic compound. It is a colourless
crystal found naturally in various plants, such as willow bark or
wintergreen. SA used in skin care products can be either natu-
ral or synthetic.
According to a report by the Regional Network Coordinating Or-
ganizations (RNCOs), which is an Indian based market research
company, the world cosmetics market was valued at $233 billion
in 2012, and is projected to reach $ 480,4 billion by 2030, with a
compound annual growth rate of 4.6% (28, 29). In response to
such anticipated growth, cosmetic brands are expected to keep
abreast of customer needs and develop innovative products if
they want to maintain their position in the market (28).
In 2012, global SA consumption was at 79,725 tonnes, and this
figure is expected to climb to 149,652 tonnes in 2023. This indi-
cates a compound annual growth rate of 6.5%. Total global sale
revenue of SA was $239.5 million in 2012, and this is expected
to rise to $546.8 million in 2023. This indicates a compound an-
nual growth rate of 8.6%. The regional breakdown of the SA
market for the year 2013 was as follows: North America 27.9%,
Europe 34.9%, Asia-Pacific 25.3%, and other regions 11.9%.
Natural cosmetic products account for around 1% of global
cosmetics market (28, 30).
In addition to skin care products, SA is also included in hair care
formulations to treat excessive oil and dandruff (31). It cleanses
the scalp. It is used as an anti-dandruff agent in hair products
(conditioners, shampoos) and in baby shampoos to prevent
cradle cap. It is also used as a preservative to extend the shelf
life of products (32). It inhibits the growth of various types of
bacteria. SA is considered safe when used as a preservative in
cosmetic products at a concentration of 0.5%, according to the
Scientific Committee on Consumer Safety. SA has a strong an-
tifungal effect. SA produced protein leakage into the medium,
significant lipid degradation, and intracellular disarray in the
pathogen. Having keratolytic effect and dissolving the super-
ficial layers of the epidermis, SA has an important therapeutic
effect on oily and problematic skin. It is also used in medicine
for its analgesic and anti-inflammatory properties (33).
Using alternative solvents, reducing waste, increasing the effi-
ciency of the different processes, improving economy in energy,
and using safe chemicals are the main concepts of green chem-
istry. Solvents are required in these reactions to dissolve solids,
enable transfer of material (extraction), stabilize transition states
and to facilitate precipitation. Non-toxicity alone does not indi-
cate that a certain product is compatible with green chemistry.
Solvent reclamation, solubility, lack of toxic formations, atom ef-
ficiency, separation of product and solvent and ineffectiveness
of solvent on end product are required factors to be compatible
with green chemistry. Water as a molecular solvent offers high
solubility with polar compounds besides being clean, cheap
and having low reactivity. On the other hand, organic solvents
are toxic, costly and flammable. 15 million kg of organic solvent
is used globally every year. The primary mission of green chem-
istry is to find alternatives to these solvents.
Different from our study, Molleti and Yadav (34) prepared a new
sulphated Fe2O3–ZrO2 catalyst with altered iron loadings using
the combustion technique and utilized in methyl salicylate
preparation from SA and dimethyl carbonate. The methyl salic-
ylate produced was reported to be widely useable in food and
pharma industries. They also evaluated the effect of different
kinetic parameters on the esterification rate of SA. They report-
ed that optimum conditions for the 99% conversion of SA with
the 100% selectivity to be 120°C after 150 min at a molar ratio
of 1:10, SA to dimethyl carbonate.
In our study, filtering the SA solution via a filter press led to a re-
duced crystal drying time, and brought down total production
time to eight days. As the SA production size increases (from 1
kg to 20 kg), one of the biggest problems is getting more moist
solids after filtration. The filter press device is a special filtering
device. During filtration, air is applied to the crystals, resulting
in drier solids. In this way, the drying time of the solid is signifi-
cantly reduced. Accordingly one of the most important param-
eters of green chemistry is to shorten the process time.
To obtain a marketable product, it is essential to create the
necessary conditions for pilot production. Data obtained from
laboratory-scale synthesis is used to increase production grad-
ually to factory-scale. For this purpose, in our study, different
batches of (1 kg, 5 kg, 20 kg) oil of wintergreen was prepared
for the production of SA. Our results revealed a sufficient de-
gree of purity for the SA to be used as a raw material in cos-
metics products. Accordingly evaluation of production purity
with GC-MS stands out as an important feature to support the
results of our study.
Ethics Committee Approval: Ethics committee approval is not re-
quired because of no material or experimental animal that would re-
quire permission.
Peer-review: Externally peer-reviewed.
Author Contributions: Conception/Design of Study - G.Ö., T.S.; Data
Acquisition - G.Ö., T.S.; Data Analysis/Interpretation - G.Ö., T.S.; Drafting
Manuscript - G.Ö., T.S.; Critical Revision of Manuscript - E.E.A.; Final Ap-
proval and Accountability - G.Ö., T.S., E.E.A.
Conflict of Interest: The authors have no conflict of interest to declare.
Financial Disclosure: The authors declare that this study has received
no financial support.

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Experimed 2022; 12(1): 12-7
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Salicylic Acid Synthesis Using Green Chemistry
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