INTRODUCTION:

Endemic plants are plants that only grow in certain areas, so they are not spread in all areas. One of the endemic plants of the island of Sulawesi Indonesia is the Dengen plant (Dillenia serrata)¹. This plant is one of the plants that has many benefits in society. In general, the people of Sulawesi use the fruit as a substitute for tamarind for cooking. In addition, other plant parts have the potential to be used as medicine^2,3,4

One part of the plant that is claimed by the community as a treatment for vomiting blood is the bark⁵. Based on Santi Sinala's research⁶ that Dengen stem bark extract (EKBD) originating from Luwu Regency has a polyphenol content of 445.02mg/g gallic acid, at a concentration of 100ppm with an SPF value of 5 has moderate protective strength and antioxidant activity of stem bark with an IC50 value of 48.33ppm⁷.

In the manufacture of pharmaceutical preparations, both in the form of drugs and cosmetic preparations, the ingredients for these preparations must be standardized⁸. No exception for an extract as an active ingredient. The extract of a plant must be standardized because the extract is not a single preparation. Many complex active substances contained in an extract. In addition, because the extract comes from a plant, in which a plant grows there are many factors that affect the compound content in the extract. For example metal contamination from soil, air, water; bacterial contamination; aflatoxin, etc. Standardization of this extract will guarantee the quality and safety of these pharmaceutical preparations, so that these preparations are safe for users⁹.

Based on the research results, Dengen stem bark extract (EKBD) has been standardized. The results obtained on organoleptic examination were brownish red color, characteristic odor, thick texture, and astringent taste. Content of compounds that dissolve in water is 6.16± 0.125%, content of compounds that dissolve in ethanol is 44.61±0.15%, contains flavonoids, saponins and tannins, ash content is 4.17±0.0285%, ash content is insoluble acid 0.024±0.03%, moisture content 21.08± 0.209%, specific gravity 0.8256±0.002 (5%), 0.8248± 0.005 (10%), total bacterial and mold/yeast contamination <1.0 x 10¹with negative mold/yeast culture, heavy metal content (mercury-Hg) 0.3335µg/g, Copper-Cu <0.01µg/g, Lead-Pb 0.094µg/g. Based on the results of the study, the ethanol extract of dengen (Dillenia serrata ) stem bark met the applicable extract standardization requirements which included specific and non-specific parameters as raw material for medicine¹⁰.

If an extract has been standardized, then the extract can be processed into pharmaceutical dosage forms, both drugs and cosmetics. Based on the results of the research above, dengen stem bark contains high antioxidant compoundsand has potential as a sunscreen, so it can be made into cosmetic preparations in the form of emulgels. Emulgel is a preparation that combines the principle of a gel with an emulsion¹¹. Topical preparations like creams, ointments have many limitations such as less spreading coefficient, less penetration through the stratum corneum, less patient compliance due to stickiness or need to be applied by rubbing etc¹². Similarly, gels have limitations in delivering hydrophobic drugs. Compared to gel and emulsion preparations, emulgel preparations are thixotropic, non-greasy, easy to spread, easy to remove, emollient, environmentally friendly, transparent, and can be used as a cosmetic base¹³. Emulgel also has good skin penetration and a long shelf life. All of this makes emulgels an advantageous topical drug delivery system^14,15.

The formulation of the problem in this research is how the stability of an emulgel product containing EKBD has been standardized using two variations of gelling agents so that a stable emulgel preparation product containing dengen stem bark extract (Dillenia serrata) can be obtained which is standardized. The purpose of this study was to observe the effect of the addition of KBD extract on the physical quality of emulgel preparations and to obtain a stable emulgel product containing standardized dengen (Dillenia serrata) stem bark extract with accelerated storage.

MATERIALS AND METHODS:

Materials:

The material is the Dengen steam bark (Dillenia serrata) originating from Luwu Regenc, South Sulawesi, Indonesia; ethanol 96%, ingredients for emulsions and gels (Carbopol 940 and CMC sodium). The tools used in this study were glassware, climatic chambers, pH meters and viscometers.

Making Dengen Extract:

Dengen stem bark simplicia was extracted by maceration using 96% ethanol solvent. Soaking was carried out for 5 x 24 hours while stirring. After 5 times 24hours, the extraction results are accompanied. The residue is then soaked again until the solvent is colorless again. The results of soaking were concentrated by means of a rotary evaporator to obtain a concentrated extract. Then the yield of the extract is calculated

Total Exctract

Extract yield = -------------------------- x 100%

Simplicia Weight

Making Emulgel:

a. Formula Design:

Table 1: Formula I using Carbopol 940 as gelling agent

Ingredient		Concentration (%)
Ingredient		F1	F2	F3
Active Ingredients	EKBD	1	1	1
Gel Base	Carbopol 940	0.25	0.5	1
Gel Base	TEA	0.25	0.5	1

Table 2: Formula II using CMC Sodium as gelling agent

Ingredient			Concentration (%)
			F1	F2	F3
Active Ingredients		EKBD	1	1	1
Gel Base		CMC sodium	1	2	3
Ingredient			Concentration (%)
			F1	F2	F3
Emulsion Base
	lanolin		3	3	3
	Liquid Paraffin		5	5	5
	Stearic Acid		1	1	1
	Cetyl Alcohol		1	1	1
	Propylene glycol		5	5	5
	Tweens 60		3	3	3
	Span 60
	Nipagin		0.03	0.03	0.03
	Nipasol		0.01	0.01	0.01
	Tokoferol		0.05	0.05	0.05
	Aquadest		add 100	add 100	add 100

Making Emulgel:

Each base according to the concentration is made using hot water until it swells and forms a homogeneous gel base. Meanwhile, the base emulsion is prepared by mixing the oil phase and the water phase which have been heated to a temperature of 70^◦C using intermittent shaking to form an emulsion corpus. A total of 50grams of gel base and 50grams of emulsion base were mixed together to form an emulgel preparation. Furthermore, EKBD was added and stirred until homogeneous. Lastly, tocopherolare added.

Accelerated Storage:

This test was carried out based on the effect of temperature stress (freeze thaw) where the preparations were stored at 4°C for the first 12 hours and 40°C for the next 12hours for 10 cycles¹⁶.

Evaluation of Physical Stability:

Tests carried out on emulgel preparations are as follows:

1. Organoleptic:

Organoleptic observations include: shape, smell and color. Inspections are carried out before and after accelerated storage.

2. Homogeneity:

The homogeneity test was carried out by smearing 0.1 gram of sample on a glass object and then observing it. The materials used in the manufacture of emulgel must be evenly dispersed. The preparation must show a homogeneous arrangement and no coarse particle grains can be seen . Inspections are carried out before and after accelerated storage.

3. pH check:

The pH test was carried out by taking 0.5 grams of emulgel and then diluting it with 5 mL of distilled water, then checking the pH using a pH meter. Normal skin pH value according to SNI standard no. 06-2588 ie 4.5 - 6.5. Inspections are carried out before and after accelerated storage.

4. Viscosity:

Viscosity test was determined using a Brookfield viscometer RV type, all formulas were determined for viscosity at room temperature (25-28⁰C) using 0.3rpm and 63 spindle. Inspection was carried out before and after accelerated storage.

5. Spreadability Test:

as much as 0.5gram is placed carefully on a transparent glass that rests on graph paper, let the preparation spread at a certain diameter. Then covered with transparent glass and given a load (50g, 100g, 150g, 200g and 250 g). Then measured the increase in area after being given a load¹⁷. Inspections are carried out before and after accelerated storage.

6. Stickiness Test:

The adhesion test was carried out by using an adhesive test tool. The sample is leveled on one glass object, then covered with another glass object. After that it was pressed with a load of 250g for 5 minutes. Attach the object glass and then mount it on the stickiness tester and the stopwatch is turned on. Time is calculated from the load and stopped when the object glass is released.

7. Emulsion Type Test:

Emulsion type test was carried out using the color solubility test method. Where, staining was carried out on emulgel preparations using methylene blue. If the preparation is mixed homogeneously with methylene blue then the preparation is of the oil-in-water type and if it does not mix, it is of the water-in-oil type.

RESULTS:

Table 3. Extract Yield

Dry simplicia weight (g)	Extract Weight (g)	Extract Rendering (%)
500g	83.15	16.63

Organoleptic Test and Homogeneity:

Table 4. Organoleptic Observations of Carpobol Based Emulgel Preparations Before and After the Accelerated Stability Test

S. No	Organoleptic
	Before Testing			After Testing
	Form	Color	Smell	Form	Color	Smell
Base F1	Homogeneous	White	Odorless	Homogeneous	White	Odorless
F1	Homogeneous, slightly diluted	Chocolate	Odorless	Homogeneous, slightly diluted	Chocolate	Odorless
Base F2	Homogeneous	White	Odorless	Homogeneous	White	Odorless
F2	Homogeneous	Chocolate	Odorless	Homogeneous	Chocolate	Odorless
Base F3	Homogeneous	White	Odorless	Homogeneous	White	Odorless
F3	Homogeneous	Chocolate	Odorless	Homogeneous	Chocolate	Odorless

Source: Primary Data 2022

Table 5: Organoleptic Observation Results of Emulgel Preparations CMC Sodium Base Before and After the Accelerated Stability Test

No	Organoleptic
	Before Testing			After Testing
	Form	Color	Smell	Form	Color	Smell
Base F1	Not Homogeneous, Dilute	White	Odorless	Not Homogeneous, Dilute	White	Odorless
F1	Not Homogeneous, Dilute	Chocolate	Odorless	Not Homogeneous, Dilute	Chocolate	Odorless
Base F2	Homogeneous	White	Odorless	Homogeneous	White	Odorless
F2	Homogeneous	Chocolate	Odorless	Homogeneous	Chocolate	Odorless
Base	Homogeneous	White	Odorless	Homogeneous	White	Odorless
F3.1	Homogeneous	Chocolate	Odorless	Homogeneous	Chocolate	Odorless

Source: Primary Data 2022

Note: F1 Base = Formula 1 Base without Extract

F1 = Formula 1, Base+Extract

F2 Base = Formula 2 Base without Extract

F2 = Formula 2, Base+Extract

F3 Base = Formula 3 Base without Extract

F3 = Formula 3, Base+Extract

pH Test:

Figure 1: Carbopol Base pH diagram before and after accelerated storage

Figure 2: Na-base pH diagram. CMC before and After Accelerated Storage

Viscosity Test:

Figure 3: Carbopol Base Viscosity Diagram before and After Accelerated Storage

Figure 4: Viscosity Chart of CMC Sodium Base before and After Accelerated Storage

Spreadability Test:

Figure 5: Carbopol Base Spreadability Test Diagram before and after Accelerated Storage

Figure 6: CMC Sodium Base Spreadability Test Diagram before and After Accelerated Storage

Stickiness Test:

Figure 7: Chart of Stickiness Test on Carbopol Base before and after Accelerated Storage

Figure 8: Diagram of Stickiness Test of CMC Sodium Base Before and After Accelerated Storage

Emulsion Type Determination:

Table 6. Results of Emulsion Type Tests for Emulgel Preparations Before and After the Accelerated Stability Test

Formulas	Carbopol Base		CMC Base
Formulas	Before	After	Before	After
Base F1	o/w	o/w	o/w	o/w
F1	o/w	o/w	o/w	o/w
Base F2	o/w	o/w	o/w	o/w
F2	o/w	o/w	o/w	o/w
Base F3	o/w	o/w	o/w	o/w
F3	o/w	o/w	o/w	o/w

Source :Primary Data 2022

DISCUSSION:

1. Effect of Extract Addition on Base:

Basically, the addition of extracts to the base of a preparation can affect the consistency of the final preparation. Some of the possible changes that occur when the extract is added to the base are:

· The base can be diluted by the addition of an ethanol-containing extract

· The base can get thicker with more extract concentrations

· Base color changes based on the amount of extract

· The presence of an odor from the preparation comes from the odor of the added extract.

· Changes in the pH of the preparation.

a. pH

Based on observations on carpobol-based formulas, base pH compared to base + extract, for the three formulas experienced an increase in value. Whereas in the CMC sodium-based formula, all three formulas experienced a decrease in pH value. This illustrates that the addition of extracts has an effect on the pH of the preparation.

Figure 9: Carbopol Base pH diagram with the addition of extracts

Changes in the pH of the increasing Carbopol base were probably due to the ethanol extract of KBD, which had a pH of 8, thus increasing the basicity of Carbopol, so that the pH of the base+extract was getting towards an alkaline pH value. Statistically, the Independent Sample T Test T test showed that the three formulas differed between base and base + extract (p <0.05).

Meanwhile, on CMC sodium base, the three formulas experienced a decrease in pH value. In F1 and F2 statistically, it has a p value <0.05 so there is a difference between the base formula and the base+extract. Whereas in the F3 formula, statistically it has a value of p> 0.05 (0.319) which means that the base and the base + extract have no significant difference.

Figure 10: CMC Sodium Base pH diagram with the addition of extracts

The addition of both Carbopol and CMC sodium concentrations will also increase the pH of the preparation. This can be seen on the base without extracts F1, F2 and F3 which respectively experienced an increase in pH value. Carbopol is a gelling agent which when dissolved in water has a pH of 3.4 – 4.3, which is an acidic pH. This is because carpobol has the chemical structure of carboxylic acid (COOH)¹⁸. With the addition of TEA which is alkaline, it will ionize this group and change it to the pH of the skin. Meanwhile, sodium CMC is a polymer with a pH of 6-10¹⁹.

b. VISCOSITY:

Observations of the viscosity for both bases increased with the addition of base concentration as seen from the viscosity of the base without extract, respectively F1, F2 and F3, the value of the viscosity increased. The increase in the viscosity of emulgel preparations was affected by the increase in the concentration of the gelling agent Carbopol and CMC sodium²⁰. The viscosity of gel preparations depends on the structure and molecular weight of the gelling agent or gel base used. Carbopol is a high molecular weight acrylic acid polymer, which when neutralized with TEA has the ability to absorb and retain water, resulting in a viscous gel²¹. CMC sodium is a polymer derived from cellulose²². In polymer dispersions derived from cellulose, polymer molecules enter into the cavity formed by water molecules causing hydrogen bonds to occur between the hydroxyl groups (OH) of the polymer and water molecules. These hydrogen bonds play a role in hydration during the swelling process of a polymer, so that an increase in CMC sodium concentration causes more hydroxyl groups to bind so that the viscosity of the preparation increases^23,24.

However, in this formula, the viscosity value decreased for all formulas from the base after the addition of KBD extract. This can also be seen in the organoleptic test, where in the F1 formula both bases show a watery preparation. This is probably due to the alcohol content in the extract can reduce the viscosity of the gel and emulsion systems. Alcohol can break down the emulsion and affect the crosslink bonds of the polymer. In addition to CMC sodium base at a pH of less than 3, the viscosity of CMC increases due to the formation of a slightly soluble gel, while at a pH above 10 the viscosity of CMC slightly decreases²⁵. Based on this, the addition of extracts with a pH of 8 can affect the viscosity of the CMC polymer. Statistically using the Independent Sample T Test on the Carbopol basis, both F1, F2 and F3, there is a significant difference in the viscosity value of the base and the viscosity value of the base+extract with a value of p<0.05. Meanwhile, CMC sodium base formula, F1 and F2 formulas have p>0.05, so that there is no difference in viscosity between base and base+extract. For F3, the value of p <0.05, so that the basis + extract is significantly different.

Figure 11: Carbopol Base Viscosity Diagram with the Addition of Extracts

Figure 12: CMC Sodium Base Viscosity Diagram with the Addition of Extracts

2. Accelerated Storage Effects:

A pharmaceutical preparation before being marketed must have stability that meets the requirements. Emulgel preparations are no exception, because this preparation contains an emulsion which is basically a preparation that is easily damaged in storage because it consists of two heterogeneous phases, so the possibility of separating into each phase has a great opportunity. If phase separation occurs, the preparation can be said to be unstable and will be damaged. Therefore, it is necessary to test the stability of the preparation.

One test to determine the stability of a product is an accelerated stability test (Accelerated Stability Test). This study uses storage conditions that exceed general conditions, this is done to increase the speed of physical and chemical degradation so that the process of observing degradation reactions and predicting shelf life can be carried out more quickly²⁶. Accelerated stability tests for dispersed systems in semisolid dosage forms include shaking tests, centrifugal tests, Freeze-thaw tests, and elevated temperature tests. Storage conditions for both physical and chemical stability studies for semisolid preparations were at 40 ^oC with a storage time of 3 months²⁷.

The test carried out in this study was the Freeze-thaw test, in which the preparation was placed at 40±2°C/75 ±5% RH for 10 cycles. This situation is found in a tool called the Climatic Chamber.

a. Organoleptic Test:

Based on observations, before and after accelerated storage on Carbopol based emulgel and CMC sodium base after storage, shape, odor and color did not change.

b. pH test:

The pH test aims to determine the acidity and alkalinity of a preparation, especially topical preparations. Ideally topical preparations have a pH value that is the same as the pH of the skin. This is because preparations that are too acidic will cause irritation to the skin and will give a burning feeling, while preparations that are too alkaline will make the skin dry and itchy²⁸. Cosmetic preparations made must be close to the physiological pH of the skin or equal to that pH, namely 4.5-6.5.

Based on the diagram above, the pH of the preparations for both the base formulas F1, F2 and F3 and the formula + extracts F1, F2 and F3 decreased after accelerated storage.

Statistically on the Carbopol base formula, F1 has a p value <0.05, so the pH value before and after storage is different. While F2 and F3 there was no difference in pH value before and after storage (p>0.05). For CMC sodium base, F1 and F2 there was no difference in pH value (p>0.05), while for F3 there was a difference in pH value before and after storage (p<0.05).

If it is adjusted to the range of physiological pH requirements of the skin, then F3 does not meet the requirements, because its pH value is above the physiological pH of the skin. This is because the concentration of carpobol and sodium CMC used is a large concentration. This decrease in pH value may be caused by a chemical reaction that may occur in the preparation during the storage process.

c. Viscosity Test:

Viscosity testing aims to determine the value of the viscosity of a substance. The higher the viscosity value, the higher the level of viscosity of the substance.

In the emulgel viscosity test, it was found that the emulgel viscosity values for all formulas on both bases before and after the accelerated storage test decreased. This viscosity value decreases during storage, because temperature affects the viscosity of a substance. In an aqueous solution, the higher the temperature, the lower the viscosity, in other words, the thinner the water.

Viscosity changes during storage in emulgel preparations refer to their physical stability. The smaller the change in the viscosity of an emulgel, the more stable the emulgel will be. The change in the viscosity of the emulgel before and after accelerated storage had no significant difference.

A preparation must be able to maintain its stability during storage time. The stability of a preparation can be seen from the shift in viscosity during storage. Preparations are considered to have good stability if they have a percentage shift in viscosity of less than 10%²⁹. The formula for calculating the viscosity shift is:

b - a

Viscosity Shift Value = ----------- x 100%

Description: a = viscosity value Ho

b = viscosity value during storage time

Table 7: Viscosity Change Shift Value

Carpobol Base	Before	After	% Shift
Base F1	6186	5114	20.96
F1	2707	2368	14.32
Base F2	14463	14421	0.29
F2	13164	12493	5.37
Base F3	19868	19431	2.25
F3	18884	17649	7.00
CMC Base	Before	After	%Shift
Base F1	1714	1672	2.51
F1	1693	1633	3.67
Base F2	12261	11688	4.90
F2	10971	10544	4.05
Base F3	18220	17685	3.03
F3	17278	16993	1.68

Based on the above results, it can be seen that each formula has a different viscosity shift value. In the carpobol base formula, F1 has a value above 10% so that it can be said that the preparation is unstable during storage. While F2 and F3 have values below 10%. CMC sodium base formula shows all formula below 10%. The smaller the viscosity of a preparation, the more unstable it will be during storage. A preparation if the viscosity is high, the preparation will be more stable during storage because the movement of the particles will tend to be more difficult the thicker the preparation²⁹.

Statistically, for both Carbopol and sodium CMC bases, the viscosity of F1 before and after storage was significantly different (p<0.05). The formulas F2 and F3 have a value of p>0.05, so there is no difference in the viscosity before and after storage.

According to SNI 16-4399-1996³⁰, the standard viscosity value for emulgel preparations is 6,000-50,000 cP. Based on this requirement, F1 in the Carbopol and sodium CMC base formulas does not meet the requirements because the viscosity value of F1 for both bases is less than 6000 cP.

d. Spreadability Test:

Spreadability test aims to determine the spreading power of the gel on the skin and determine the softness of the gel preparation on the skin. Good gel spreadability is between 5-7 cm³¹. If the spreading power is too small, it will be relatively difficult to spread when applied to the skin, whereas if the spreading power is too large, it will tend to spread quickly when applied so that it will cause an uncomfortable feeling to the user. Good spreadability is an indicator that the gel preparation is easy to spread.

Based on the table above, before storage, it was observed that the spreading power values of F1, F2 and F3 decreased for both carpobol based and sodium CMC based emulsions. This is because the viscosity value of F1 is more dilute than F2 and F2 is more dilute than F3. The more viscous the spreading power decreases.

In testing the spreadability of the emulgel after accelerated storage in the two basic formulas, it showed an increase in the spreadability. This is due to a decrease in the emulgel viscosity value after storage because the viscosity value is inversely proportional to the spreadability value.

Statistically, all formulas F1, F2 and F3 on both bases showed a value of p>0.05, which means there was no significant difference in the spreadability values before storage and after accelerated storage.

Based on the spreadability requirements with a range of 5-7cm, the F2 formula for both formulas, both Carbopol and sodium CMC bases, meets the requirements, while F1 is above the upper limit, which is 7cm, and F3 is below the lower limit, which is 5cm.

e. Stickiness Test:

The adhesion test was carried out to determine how long the preparation adhered to the skin before cleaning the preparation. According to Puspitasari and Setyowati in 2018, that the longer the ability of a gel to adhere to the skin, the more likely the amount of active substance released from the base or basic ingredients to penetrate into the skin layers is also greater, but too strong an adhesive force will block the skin pores. Meanwhile, if it is too weak, the therapeutic effect will not be achieved.

The adhesion of a preparation is directly proportional to its viscosity. The higher the viscosity, the higher the sticking power. The adhesion of topical preparations is not less than 4 seconds³².

In the emulgel adhesion test, it was found that the emulgel adhesion value after accelerated storage underwent a change, namely a decrease in adhesion to all formulas. This is proportional to the decreased viscosity value because the adhesive power is directly proportional to the viscosity.

Statistically, on the basis of Carbopol, F1 and F2, there was no significant difference in the values of adhesion before and after storage (p>0.05), whereas in F3 there was a value of P<0.05, so there were differences in the values of adhesion before and after storage. For CMC sodium base, all formulas, both F1, F2 and F3, had no difference (p>0.05).

Based on the requirement of not less than 4 seconds, the Carbopol base formula (F1, F1, F3 base after storage) and the CMC sodium base formula (F1 after storage) are not included in the range of requirements because the value is less than 4 seconds.

f. Emulsion Type Test:

Emulsion type testing is one of the standards in determining the stability of an emulsion preparation because if the emulsion type changes during storage, it can be stated that the preparation is unstable because it cannot pay attention to the dosage form. In addition, changes in the type of emulsion can lead to the phenomenon of creaming, namely the process of separating the oil phase and the water phase so that in the end the emulsion will break and be damaged. In this emulgel preparation, an emulsion type determination test was carried out because emulgel contains emulsion preparations.

Based on the test results, the emulsion type of all formulas, both Carbopol base and CMC sodium base, after accelerated storage, did not change the emulsion type, namely the o/w emulsion type.

CONCLUSION:

Based on the results of the research, the conclusions that can be drawn from this research are there is an effect of adding extract to the pH value and viscosity of the emulgel preparation and the ethanol extract of dengen stem bark ( Dillenia serrata ) can be formulated in the form of an emulgel. The formula that meets the test requirements is the CMC sodium base F2 formula with a concentration of 2%.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation

ACKNOWLEDGMENTS:

The authors would like to thank Poltekkes Ministry of Health Makassar (Poltekkes Kemenkes Makassar) for their kind support in finance for this research.

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Received on 27.12.2022 Modified on 14.06.2023

Research J. Pharm. and Tech 2024; 17(1):188-196.

DOI: 10.52711/0974-360X.2024.00030