b). pH testing:

The pH of the preparation was determined using a universal pH indicator. The pH paper dipped in the sample of the scrub preparation is shaken within 10 seconds, then the changes that occur on the pH paper are compared in color with the standard on the pH indicator.

c). Viscosity testing:

he viscosity test was performed using a Brookfield viscometer with a size 03 spindle with a rotation of 30 rpm.

d). Sedimentation testing:

The whipped scrub preparation was poured into a 10 ml volumetric flask for the sedimentation test, which was then left to stand for 4 weeks without being stirred. Every week, the effects of sedimentation were seen and triple-recorded¹⁴.

e). Redispersion testing:

The redispersion test involved placing the whipped scrub formulation in a 10ml volumetric flask and leaving it untouched for one week. After this period, the flask was manually rotated 180° by hand, and the time required for the formulation to fully disperse was recorded¹⁵. This procedure was repeated three times.

f). Hedonic testing:

The parameters used are the level of panelists' liking for the color, aroma, taste on the skin and dosage form of the whipped scrub preparation. The required panelists are 30 people. The test scale range is 1-5 (1 = very dislike, 2 = dislike, 3 = quite like, 4 = like, 5 = very like).

Antioxidant activity test by DPPH method:^16,17,18,19

2ml of DPPH was mixed with 1 ml of ascorbic acid, avocado seed extract, and the whipped scrub preparation series solution. The mixture was incubated in a dark environment for 30 minutes, after which the absorbance was measured at the maximum wavelength (λ max). The following method was used to figure out the percentage value of DPPH inhibition:

Antioxidant percentage or percent inhibition = (A-B)/A x 100%

This time, B stands for the sample's absorbance value and A for the control's absorbance value. After determining the percentage of antioxidant activity, a graph will be created to plot the percentage of free radical scavenging against the concentration in ppm, along with the % inhibition results. A linear regression equation is used to find the IC50 number, which tells us the concentration needed to stop 50% of the DPPH free radicals. Here, y is set to 50, and x represents the concentration of the test solution capable of inhibiting 50% of the free radicals.

RESULTS AND DISCUSSION:

Drug-likeness:

To identify compounds with high antioxidant activity that are safe for skin application, a method is required to evaluate these compounds before synthesis and clinical testing. Computational chemistry prediction offers such an approach, enabling the prediction of the physicochemical properties of compounds using computer models. This technique supports the development of more effective and safer pharmaceutical formulations.

The parameters used in the ADMETlab 2.0 application in assessing the drug-likeness of compounds are SAscore and Npscrore²⁰. SAscore (synthetic accessibility score) indicates the potential of a compound to be synthesized. NPscore (natural product-likeness) is used in determining the part in the compound structure that has bioactivity²¹. The compounds used as prediction materials are several antioxidant compounds contained in avocado seeds²².

Table 2: Eight antioxidant compounds that are widely contained in avocado seeds

Compound	SMILES	Structure
Ferulic acid	C1C(C(OC₂=CC(=CC(=C₂₁)O)O)C₃=CC(=C(C=C₃)O)O)O
Lutein	CC1=C(C(CC(C1)O)(C)C)C=CC(=CC=CC(=CC=CC=C(C)C=CC=C(C)C=CC2C(=CC(CC₂(C)C)O)C)C)C
Chlorogenic acid	C1C(C(C(CC1(C(=O)O)O)OC(=O)C=CC₂=CC(=C(C=C₂)O)O)O)O
Rutin	CC1C(C(C(C(O1)OCC₂C(C(C(C(O2)OC₃=C(OC₄=CC(=CC(=C₄C₃=O)O)O)C5=CC(=C(C=C₅)O)O)O)O)O)O)O)O
Phlorizin	C1=CC(=CC=C1CCC(=O)C₂=C(C=C(C=C₂OC₃C(C(C(C(O₃)CO)O)O)O)O)O)O
Vanilic acid	COC1=C(C=CC(=C1)C(=O)O)O
Isoquercitrin	C1=CC(=C(C=C1C₂=C(C(=O)C₃=C(C=C(C=C₃O₂)O)O)OC4C(C(C(C(O₄)CO)O)O)O)O)O
Quercetin	C1=CC(=C(C=C1C₂=C(C(=O)C₃=C(C=C(C=C₃O₂)O)O)O)O)O

Based on data from ADMETlab 2.0, eight compounds are widely contained in avocados and have high antioxidant activity.

Table 3. Drug-likeness evaluation of antioxidant compounds in avocado seeds based on ADMETlab 2.0

Compound	Synthesis Score (SAscore)	Natural Product Score (NPscore)
Ferulic Acid	3.344	2.304
Lutein	4.960	2.115
Chlorogenic Acid	3.871	2.246
Rutin	4.783	2.015
Phlorizin	3.785	1.802
Vanillic Acid	1.542	0.524
Isoquercitrin	4.008	2.160
Quercetin	2.545	1.701

The synthetic accessibility score (SAscore) estimates how easily drug-like molecules can be synthesized by evaluating their fragment contributions and complexity. A high SA score (≥ 6) indicates that the compound is challenging to synthesize, whereas a low score (< 6) suggests it is easier to synthesize²³. Thus, it can be concluded that the eight antioxidant compounds found in avocado seeds are relatively easy to synthesize.

The natural product similarity score (NPscore) is useful for identifying bioactive regions within compound fragments. This score typically ranges from -5 to 5, with higher values indicating a greater likelihood that the molecule is a natural product²⁴. According to the table results, all eight compounds are classified as natural products.

Skin Permeability:

Skin permeability is a crucial factor in ensuring product efficacy, particularly in the development of transdermal drug delivery systems. This predictor is based on a database of compounds that have been tested for human skin permeability in vitro. The results of these predictions are expressed as skin permeability constants (log Kp).

Table 4. Skin permeability prediction results using pkCSM and SwissADME

Compound	Skin Permeability (Log Kp)
Compound	pkCSM (cm/s)	SwissADME (cm/s)
Ferulic acid	-2.735	-6.41
Lutein	-2.741	-1.95
Chlorogenic acid	-2.735	-8.76
Rutin	-2.735	-10.26
Phlorizin	-2.728	-8.58
Vanilic acid	-2.726	-6.31
Isoquercitrin	-2.735	-8.88
Quercetin	-2.735	-7.05

If a compound's logKp is greater than -2.5, the pkCSM predicts that it has low skin permeability. Based on the results in table 4, all compounds are classified as low in skin permeability²⁵. According to Potts RO. and Guy RH, the more negative the logKp, the fewer molecules penetrate the skin. So it can be concluded in the Swiss ADME results that the antioxidant compound lutein is the compound that has the highest permeability and rutin is the lowest, so the possibility of rutin antioxidant compounds to penetrate into the skin is very small²⁶.

Toxicity:

Skin irritation may occur as a possible reaction from productsthat are applied to the skin, so it is necessary to identify compounds that can cause allergies when in direct contact with the skin. This prediction is useful to evaluate the ability and safety of compounds in inducing skin sensitization.

In the prediction using SwissADME, compounds are declared to have toxic potential when they are positive, the more, the higher the toxicity value²⁷. Based on table 5, compounds such as Ferulic Acid, Lutein, and Quercetin have the potential to have high toxic potential on skin sensitization. Then Ferulic Acid, Vanilic Acid, and Quercetin also have the potential to irritate the eyes. Unlike the pkCSM prediction results, the parameter in stating the safety of a compound is yes/no²⁸, so based on the above results, all eight compounds are considered safe when applied to the skin.

Ferulic acid has low toxic effects and has been used in skin care products as a photoprotective, skin lightening component and plays a role in delaying skin photoaging. However, its use should be limited as it tends to oxidize rapidly²⁹. Lutein accumulates in large amounts in the retina which plays a role in protecting the retina, but is also found in the skin, breast, brain and cervix. At high doses, it causes yellow coloration of the skin and eyes although it does not have toxic effects and still requires further in vivo research³⁰. Research related to the toxic effects of quersetin in vivo is still limited to the liver and kidneys at levels greater than 16g/kg³¹. While the benefits of quersetin to prevent poisoning due to heavy metals, pesticides, mycotoxins and protect cells from damage and the effect of inhibiting various toxic diseases³². Vanilic acid was tested for subacute oral toxicity in rats to determine whether long-term use had the effect of lowering serum sodium levels but was not considered a major toxic effect³³. Avocado seed powder is macerated using 95% ethanol solvent which is a common solvent used in the extraction of anthocyanin compounds because the polarity of ethanol is almost the same as anthocyanin so that anthocyanins will be dissolved completely³⁴. Avocado seed ethanol extract produces a weight of 71.57g, thus obtaining a yield of 12.13%. The phytochemical screening of avocado seed ethanol extract reveals the presence of positive for alkaloid, flavonoid, steroid, phenol and saponin compounds.

pH testing:

The purpose of the pH measurement is to ensure that the whipped scrub has a suitable pH level that is safe for the skin.

Fig.1 pH Test Result

The highest pH was observed in F0, while the lowest was found in F3. This occurs because an increase in the amount of extract leads to a reduction in pH, as avocado seed extract contains acidic flavonoid compounds³⁶. According to SNI 16-4399-1996, the recommended pH for a topical formulation aligns with the skin's optimal pH range, which is between 4.5 and 8³⁷. Skin pH plays a crucial role in maintaining skin homeostasis. Therefore, it can be concluded that this preparation meets the appropriate pH requirements. A formulation with a pH that is too alkaline may lead to dry and rough skin, while a pH that is too acidic can cause skin irritation³⁸.

he data were evaluated with the Shapiro-Wilk test, revealing that they were not normally distributed. Therefore, the Kruskal-Wallis test was used for further analysis. The pH of the whipped scrub showed a Sig. value of 0.005, and since Sig. < 0.05, H0 was rejected, indicating a significant difference between formula 0 and formulas 1, 2, and 3.

Viscosity Testing:

Viscosity testing aims to determine the consistency of the preparation. The higher the viscosity value of a preparation, the more difficult it will be for the preparation to be poured and the preparation is difficult to re-disperse, and vice versa³⁹.

Fig 2. Viscosity Test Results

Factors that affect viscosity or increase viscosity values are due to the high amylose content of 40% and amylopectin content of 60% in brown rice⁴⁰. Amylose is amorphous or absorbs water at a high rate so that the water absorption capacity of brown rice flour is high⁴¹. The increase in viscosity is because brown rice has hydroxyl groups that can cause its ability to absorb water to be very large, where initially the water is outside the granule then the water absorbs into the granule in the future⁴².

The viscosity value increases as more avocado seed extract is added to the whipped scrub. With a higher concentration of the extract, the water content in the scrub reduces, resulting in a thicker consistency. The viscosity value affects the flow properties of the preparation, the higher the viscosity value, the greater the resistance to flow so that the preparation is difficult to flow and difficult to apply⁴³.

In this study, the results of the viscosity test showed an increase every time, The data obtained were analyzed with the Shapiro-wilk statistical test, the data were normally distributed and the Levene homogeneity test was homogeneous, so further tests using the ANOVA test showed the Sig. value of the viscosity of the whipped scrub was 0.001 then Sig. <0.05 so that H₀ is rejected there is a significant difference between groups of formula 0 with formulas 1, 2 and 3.

Sedimentation Testing:

The purpose of sedimentation testing is to measure the extent of particle settling in the preparation over a specified period⁴⁴. The results obtained from testing the whipped scrub preparation from the 4 formulas, for 4 weeks the sedimentation volume was allowed to stand without stirring then measured every week and calculated the equation. The sedimentation volume equation can be measured using the formula F (sedimentation volume), Vu is the final volume of sediment that settles divided by Vo is the initial volume of suspension before settling as much as 10ml. The sedimentation test results formed between 0.79-0.88, which is less than 1 and can be said that the suspension of whipped scrub meets the requirements. A good suspension sedimentation volume test has a value price of 1 or close to 1⁴⁵. ANOVA test shows the Sig. value of whipped scrub sedimentation is 0.733 then Sig. > 0.05 so that H0 is accepted there is no significant difference between groups of formula 0 with formulas 1, 2 and 3.

Redispersion Testing:

Redispersion testing is conducted to assess how well the suspension can be re-mixed through shaking, ensuring that the active ingredients are evenly dispersed throughout the formulation. This test simulates the motion of hand stirring, mimicking what happens when the product is shaken before use, ensuring it can be poured easily. The redispersion test results ranged from 11.33 to 22.67 seconds, indicating that the whipped scrub suspension meets the criteria for good redispersibility. Redispersion is closely related to viscosity; the higher the viscosity of a product, the more challenging it becomes to pour and redisperse the product, and vice versa⁴⁶. A suspension's redispersion is considered good if it is fully re-dispersed after being shaken by hand within a maximum of 30 seconds⁴⁷. The ANOVA test showed a Sig. value of 0.001 for the redispersion of the whipped scrub, leading to the rejection of H0 since Sig. < 0.05, indicating significant differences between formula 0 and formulas 1, 2, and 3.

Antioxidant Testing:

DPPH is a commonly used synthetic purple radical in antioxidant assays. Antioxidants interact with DPPH by donating hydrogen atoms, converting it to DPPH-H, which results in a color change from purple to yellow⁴⁸. Changes in purple to yellow color intensity occur due to the hydrogen released by the compound molecules in the extract that form the compound 2,2 diphenyl-I-picrylhydrazin.

Table 6. Average % Inhibition Results and IC₅₀ Value

Sample	Concentration (ppm)	% inhibition	Linear Regression Equations	IC ₅₀(ppm) ±SD
Ascorbic Acid	2	7.6790	y = 5.0489x – 3.4991	10.5961± 2.07
	4	16.0502
	6	25.4807
	8	37.1370
	10	47.6247
Avocado Seed Extract	10	18.6456	y = 1.6265x + 4.3326	28.0770± 0.81
	20	37.0655
	30	55.5138
	40	71.8225
	50	82.5928
F1	600	17.5670	y = 0.0308x – 0.9440	1,654.02± 250.81
	700	20.3917
	800	23.9218
	900	27.0897
	1000	29.6335
F2	600	33.8672	y = 0.0503x + 3.5124	924.2060± 184.04
	700	38.6305
	800	44.2090
	900	47.7377
	1000	54.4844
F 3	600	41.6376	y = 0.0711x – 1.6208	726.03± 12,14
	700	48.2735
	800	54.3659
	900	61.6096
	1000	70.5353

Ascorbic acid has an IC₅₀ value of 10.596 ppm, so it can be said that vitamin C has strong antioxidants. Avocado seed extract has an IC₅₀ value of 28.077 ppm, so avocado seed extract can be said to contain very strong antioxidant compounds⁴⁹. While the IC₅₀ value of whipped scrub preparation F1 produces a value of 1,654.02ppm, F2 produces a value of 924.206ppm and F3 produces a value of 726.03ppm. It can be said that the whipped scrub preparation has a very weak antioxidant. This occurs because the base material added to the whipped scrub formulation enhances each compound's capacity to donate electrons to DPPH. An increase in electron donation to DPPH leads to a reduction in absorbance value, an increase in percent inhibition, and a decrease in the IC50 value⁵⁰. Additional substances in the whipped scrub formula preparation such as methyl paraben, propyl paraben, TEA and glycerin. The hydroxy group will undergo an oxide reduction reaction with unstable electrons from DPPH⁴⁷. The Kruskal-Walis test which showed the Sig. value of antioxidants was 0.047, then Sig. <0.05 As a result, H0 is rejected, indicating a significant difference between the antioxidant test groups of the extracts with vitamin C and formula 1; formula 2 with formula 1; and formula 3 with ascorbic acid and formula 1.

CONCLUSION:

1. Drug-Likeness evaluation resulted in ferulic acid, lutein, cholorogenic acid, rutin, phlorizin, vanillic acid, isoquercitrin and quersetin compounds. have relatively low skin permeability with logKp >-2.5. Ferulic Acid, Lutein, and Quercetin have high toxic potential in skin sensitization, Ferulic Acid, Vanilic Acid, and Quercetin compounds also have the potential to irritate the eyes. In contrast to the pkCSM prediction results, the parameters in stating the eight compounds are safe when applied to the skin.

2. The antioxidant value in F1 with a concentration of 2.5% avocado seed extract produces an IC₅₀ value of 1,654.02ppm, the IC₅₀ value in F2 with a concentration of 5% produces an IC₅₀ value of 924.206ppm, and in F3 with a concentration of 7% produces an IC₅₀ value of 726.03ppm. The whipped scrub preparation is classified as a rather low-potency antioxidant.

CONFLICT OF INTEREST:

Regarding this investigation, there are no conflicts of interest involving the authors.

ACKNOWLEDGMENTS:

The researcher would like to thank Obat Inovasi for funding this research and Faculty of Pharmacy Sekolah Tinggi Ilmu Kesehatan Samarinda.

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Received on 13.04.2024 Revised on 21.08.2024

Accepted on 24.10.2024 Published on 10.04.2025

Available online from April 12, 2025

Research J. Pharmacy and Technology. 2025;18(4):1773-1780.

DOI: 10.52711/0974-360X.2025.00254

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Material	Concentration (%)		Material Function
Material	F 0	F 1	F 2	F 3
Avocado seed extract	-	2.5	5	7.5	Active ingredients / active substances
Brown rice flour	-	10	10	10	Scrub / peeling
Hydroxylpropyl methylcellulose	1.5	1.5	1.5	1.5	Suspending agent
Xanthan gum	1	1	1	1	Suspending agent
Tween 80	5	5	5	5	Wetting agent
Glycerin	1	1	1	1	Wetting agent
Triethanolamine	0.1	0.1	0.1	0.1	pH Adjustment
Methyl paraben	0.1	0.1	0.1	0.1	Preservative
Propyl paraben	0.05	0.05	0.05	0.05	Preservative
Fragrance Oil	qs	qs	qs	qs	Fragrance
Ethanol	2	2	2	2	Preservative
Aquadest	ad 100	ad 100	ad 100	ad 100	Solvent

Compound	ADMET Lab 2.0			pkCSM
Compound	Skin Sensitization	Eye Irritation	Respiratory Toxicity	Skin Sensitisation
Ferulic acid	+++	+++	--	No
Lutein	+++	---	---	No
Chlorogenic acid	--	---	---	No
Rutin	---	---	---	No
Phlorizin	--	---	---	No
Vanilic acid	--	+++	--	No
Isoquercitrin	--	---	---	No
Quercetin	+++	+++	--	No