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Vol 2: 10 (2012) IJPIs Journal of Pharmaceutics and Cosmetology

Bhise Sucheta D. et al Page 10

1. INTRODUCTION

Disintegrants are substances or group of substances added to the formulations that facilitate the breakup or

disintegration of tablets into smaller particles that dissolve more rapidly than in the absence of disintegrants.

Disintegrant have the major function to oppose the efficiency of tablet binder and physical forces that act under

compression to form the tablets. Tablet disintegration has been considered as the rate limiting step in faster drugrelease. Disintegrants are substances that are added to formulations to dissolve more rapidly in aqueous environment.

Mucilages have been used as disintegrants due to their swelling properties. They can display good binding property;

both of these properties depend upon the concentration of mucilage in formulation. Generally in the 1 to 10%

concentration of total tablet weight mucilages can act as disintegrant. This is an important parameter to determine the

application of mucilage in particular formulation. (1,2)

Mucilages are used as disintegrant in solid pharmaceutical formulations. Many of them are already evaluated

for its disintegrant properties and others are in process. Disintegrants are an essential component to tablet formulations.

The ability to interact strongly with water is essential to disintegrant function. Combinations of swelling and/or

wicking and/or deformation are the mechanisms of disintegrant action. In a direct compression process, drug is blended

with a variety of excipients, subsequently lubricated and directly compressed into a tablet. A disintegrant used in this

type of formulation, simply has to break the tablet apart to expose the drug substance for dissolution [3, 4]. Most

common tablets are those intended to be swallowed whole and to disintegrate and release their medicaments rapidly in

the gastrointestinal tract (GIT).

The proper choice of disintegrant and its consistency of performance are of critical importance to the

formulation development of such tablets. In more recent years, increasing attention has been paid to formulating not

only fast dissolving and/or disintegrating tablets that are swallowed, but also orally disintegrating tablets that are

intended to dissolve and/or disintegrate rapidly in the mouth. Most prior studies have focused on the function related

properties of superdisintegrants with special emphasis on correlating these functional properties to disintegrant

efficiency and drug release rate. Water penetration rate and rate of disintegration force development are generally

positively related to disintegrant efficiency in nonsoluble matrices.

Natural Superdisintegrants:

Disintegrating agents are substances routinely included in the tablet formulations to aid in the breakup of the

compacted mass when it is put into a fluid environment. They promote moisture penetration and dispersion of the tablet

matrix. In recent years, several newer agents have been developed known as Superdisintegrants. These newer

substances are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength.

On contact with water the superdisintegrants swell, hydrate, change volume or form and produce a disruptive change in

the tablet. Effective superdisintegrants provide improved compressibility, compatibility and have no negative impact

on the mechanical strength of formulations containing high-dose drugs. The natural superdisintegrants involve various

natural substances like gums, mucilages, and other substances of natural origin which are more effective at lower

concentrations with greater disintegrating efficiency and mechanical strength. Some natural substances like gum

karaya, modified starch and agar have been used in the formulation of MDTs. Mucilage of natural origin is preferredover semisynthetic and synthetic substances because they are comparatively cheaper, abundantly available, non

irritating and nontoxic in nature. Some natural polymer provides the fast disintegration as synthetic superdisintegrants.

Recently some gums and mucilages have been investigated to improve the disintegration processes.

Rapidly disintegrating tablets (RDT) are solid single-unit dosage forms that are placed in the mouth, allowed to

disperse/dissolve in the saliva and then swallowed without the need for water (1). Decline in swallowing of

conventional tablets, capsules or powders have consequently, attracted the development of RDT has among

pharmaceutical industry but also academia.(2).Commercially available rapidly dissolving or disintegrating tablets are

obtained by several methods. Rapidly disintegrating tablets were developed by compression methods using dry & wet

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powders containing drugs. The preparation processes for wet granulation usually as follows: after blending the

excipient with the drug, the powder mixture is moistened with solvent. The resultant wet powder will then be molded

or compressed under low compression force, and after drying in ambient air or an oven, the desired tablets will be

obtained. The most commonly used solvent is aqueous alcohol, although other volatile solvents such as acetone and

hydrocarbons have also been used. To increase the hardness and reduce erosion of the edges of the tablets during

handling, binding agents such as glucose, sucrose, acacia, or povidone are usually added to the solvent mixture (3) .

When a solid dosage form is orally applied, the drug substance has to be dissolved first so that it can be

absorbed. If the particle surface of the drug is hydrophobic, the effective surface actually involved in the dissolution

process is smaller than the geometric particle surface (4), because wetting is restricted by hydrophobic surfaces.

Dissolution therefore is delayed fast dissolving preparations are especially applied in acute disease situations are

designed, therefore, in such a manner that the optimum of the effective surface area is quickly generated. The

generation of the effective surface is an influential process that begins immediately after the dosage form and solvent

have come into contact and controls the drug liberation during the starting phase. Researchers have suggested mixing

of hydrophilic substances with disintegration property may yield for rapid generation of effective surface especially of

hydrophobic drugs(5). An attempt is made in the present study to investigate the property of dried isabgol mucilage as

hydrophilic superdisintegrant

(6)

and also to study of effect on surface properties. For that purpose diclofenac,hydrophobic drug having anti-inflammatory action was compressed as tablets with dried isabgol mucilage. Tablets

were investigated with respect to wetting, water uptake, disintegration dissolution and other parameters. The excipients

which are generally a mixture of several substances are involved in a complex series of processes that begin when the

solvent contacts the solid and penetrate the matrix.

Now a day fast dissolving technology has a nice applicability in case of patient care. Because this type of

formulation can disintegrate within few seconds and release their active ingredient very fast and onset of action can be

achieved in few minutes. Mostly superdisintegrants are added to the formulations to break up the tablet into small

particle that can rapidly dissolve. Many synthetic substances like Sodium Starch Glycolate, Ac-di-Sol, Crossprovidone

, and Kyron T314 have been used as a disintegrating agent in the tablet formulation.1 Mucilage and gums have been

used since ancient times for their medicinal uses. In the modern era also they are widely used in the pharmaceutical

industries as thickeners, water retention agents, and emulsion stabilizers, suspending agents, binders and film formers.

Apart from its use in finished medicines, newer uses have been found in the preparation of cosmetics, textiles, and

paint paper. Mucilage of natural origin is preferred over synthetic and semisynthetic agent because they are cheaper,

abundantly available, nontoxic and nonirritating in nature. Lepidium sativum (family: Cruciferae) is known as asaliyo

and widely used as herbal medicine in India. Its seeds contain higher amount of mucilage, which has various

characteristic like binding, disintegrating, gelling etc. Hence using similar technique, in the present study, a method is

developed to isolate the mucilage from seeds of Plantago Ovata and it was used to develop the mouth dissolving

tablets of antihypertensive drug Telmisartan. The disintegration property of MDTs was compared with widely used

superdisintegrants like Sodium starch glycolate (SSG), and Microcrystalline cellulose (MCC)(7, 8).

2. MATERIAL AND METHODS

2.1 Material:

Telmisartan was obtained as a gift sample from Unichem Laboratories, Nasik, Maharashtra and all other

chemicals of AR grade were obtained from New Neeta Chemicals, Pune, Maharashtra, India.

2.2 Method:

2.2.1 Methodology for extraction of mucilage(9)

Plantago ovata: Mucilage was isolated by soaking seeds ofPlantago ovata in water (20-30 times) for at least 48 hrs,

boiled for 2 hrs subsequently mucilage was released into the water completely. With the help of the muslin cloth the

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mucilage was squeezed out and separated from seeds. The mucilage collected and precipitated using 3 times of 95%

ethanol. Collected mucilage was dried in the oven at 50-55. Dried mucilage was scraped and powdered using pestle

and mortar. Powder was sieved using mesh no.60.

2.2.2 Physicochemical characterization of mucil age:

(a) Weight loss on drying

Weight loss on drying was determined for an appropriate quantity of mucilage at 105 C for 2 hour and percentage loss

of moisture on drying was calculated using the formula:

LOD (%) = (Weight of water in sample/Weight of dry sample) 100

(b) Particle size

The particle size of the dried-powder mucilage was determined by the microscopic method and the study was carried

out in triplicate

(c) pH of solution

The PH of the 0.5% solution was measured with a pH meter.

(d)Charring

A few milligrams of dried mucilage were placed in a melting-point apparatus. The temperature was taken and recorded

when the material started to char.(e) Swelling ratio

The study was carried out using a 100 ml stoppard graduated cylinder. The initial bulk volume of 1 gm of dried

mucilage was recorded. Water was added in sufficient quantity to yield 100 ml of a uniform dispersion. The sediment

volume of the swollen mass was measured after 24 hour, stored at room temperature. The swelling ratio was calculated

by taking the ratio of the swollen volume to the initial bulk volume.

(f) Bulk and tapped density

A preweighted, presieved quantity of dried mucilage was poured into a graduated cylinder, and the volume recorded.

The cylinder was tapped until the powder-bed volume reached a minimum value, and the tapped volume was recorded.

The bulk and tapped densities were calculated.

Bulk density = Mass/Bulk volume

Tapped density = Mass/Tapped volume

(g) Compressibility Index

Compressibility index gives the important property of granules. It is also known as Carrs index. It can be calculated by

following equation:

Compressibility Index= (T B) x 100

T

(h) Viscosity

Rheological studies of dried mucilage were carried out using varying concentrations (0.1 0.5% w/v) prepared in

distilled water. The viscosities were measured using a Brookfield viscometer.

(i) Angle of Repose

The fixed funnel and free-standing cone methods employ a funnel that is secured with its tip at given height, H, whichwas kept 2 cm, above graph paper that is placed on a flat horizontal surface. With r, being the radius of base of conical

pile,

tan = h / r

2.3 Analysis of Telmisartan:

2.3.1 Construction of Cal ibration Curve of Telmisartan in 0.1N HCl(10)

10 mg of Telmisartan was transferred to 10 ml volumetric flask containing 10 ml ethanol. From this stock

solution 1 ml of aliquot was diluted to 10 ml using distilled water to give a solution of concentration of 100g/ml. This

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standard stock solution was then appropriately diluted with distilled water to obtain series of Telmisartan solutions in

the range of 2-20g/ml.The absorbance of all the solutions was measured against blank as distilled water at 293 nm

using double beam spectrophotometer. A standard plot of absorbance v/s concentration of drug was plotted.

2.3.2 Characteri zation of Telmi sartan

(a) Melti ng Point Determination:The melting point was determined by using Digital Melting Point Apparatus.

(b) Solubil ity determination of Telmisartan:

i. Aqueous solubility determination:

The solubility was determined in distilled water. The procedure is detailed as follows:

In 250ml conical flasks, 25 ml of distilled water was transferred. Excess quantity of drug was added to each flask. Then

the flask was kept in rotary mechanical shaker for 48 hours. Mixtures in flasks were filtered. The filtrate were diluted

with appropriate medium and analyzed by using UV spectrophotometer at 293nm.

ii. pH dependent solubility determination:

pH solubility of Telmisartan was obtained in the buffers of pH 1.2,4.6,6.8 and 7.4.Excess quantity of drug was

added to 250 ml conical flasks containing 25 ml of buffers. Then flasks were shaken on rotary mechanical shaker for

48 hours. Mixtures in flasks were filtered. The filtrates were diluted with appropriate medium and analyzed by using

spectrophotometer at 290 nm.

2.4 Preparation of Fast dissolving Telmisartan Tablets using Sodium Starch Glycolate (synthetic),

Microcrystalline cellulose (synthetic) and Plantago ovatamucilage (herbal) superdisintegrants:(11, 12)

Different fast dissolving tablets formulations were prepared by direct compression method. All the powders

were passed through 80 mesh sieve to decrease the particle size. Required quantity of drug and excipients mixed

thoroughly. The blend was compressed using single punch tablet punching machine. Each tablet contained 05 mg of

Telmisartan and other pharmaceutical ingredients.

2.5 Formulation for optimization of Sodium Starch Glycolate as a disintegrating agent:

Composition for optimization of sodium starch glycolate as a solubilizing agent for fast dissolving formulation

is shown in Table 1.

Table 1: Formulation for optimization of sodium starch glycolate as a disintegrating agent

Ingredients A1 A2 A3 A4 A5

Telmisartan 05 05 05 05 05

SSG 7.2 9.4 12.5 14.6 18

Mannitol 84.4 82.2 79.1 77 73.6Magnesium stearate 2.16 2.16 2.16 2.16 2.16

Talc 1.24 1.24 1.24 1.24 1.24

Total weight 100 mg 100 mg 100 mg 100 mg 100 mg

* All quantity in mg

Same studies were conducted for MCC as superdisintegrant but the results were not as good as SSG hence

SSG was considered for further studies.

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2.6 Formulation of preliminary trial batches to check the activity of mucilage as disintegrating agent:

Composition of preliminary trials batches to check the activity of mucilage as disintegrating agent is as shown

in Table 2.

Table 2: Two trial batches to check the activity of mucilage as disintegrating agent

Ingredients Sodium starch glycolate Mucilage

Telmisartan 05 05

MCC 65.20 65.20

SSG 05% -

Mucilage - 05%

Magnesium stearate 1.8 1.8

Talc 03 03

Mannitol 15 15

Total weight 100 mg 100 mg

2.7 Optimization of mucilage concentrations as dissolution and disintegration enhancing agent:Composition for optimization of mucilage as a disintegrating agent for fast dissolving formulation is shown in

Table 3

Table 3: Optimization of mucilage concentration as dissolution and disintegration time enhancing agent

Ingredients M1 M2 M3 M4 M5

Telmisartan 05 05 05 05 05

MCC 74.66 72 69.33 66.66 64

Mucilage (%) 2 4 6 8 10

Magnesium stearate 6.5 3 3 3 3

Talc 8.5 5 5 5 5

Total wt 100 100 100 100 100

* All quantity in mg

2.8 Formulation of Mouth Dissolving Tablets for comparison of mucilage with SSG as super disintegrants:

Comparison of mucilage with SSG for its superdisnitegrant activity was performed as per formula given in

Table 4.

Table 4: Comparison of mucilage with SSG as a disintegrating agent

Ingredients Sodium Starch Glycolate Mucilage

Telmisartan 05 05MCC 76.8 80.6

SSG 10 -

Mucilage - 10

Magnesium stearate 2.4 1.2

Talc 4 2

Total weight 100 mg 100 mg

* All quantities in mg

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2.9 Evaluation of MDTs of Telmisartan: (13)

Prepared tablets were evaluated for certain physical properties like uniformity of weight, hardness, friability

and dissolution study.

2.9.1 Uni formi ty of weight

Every individual tablet in a batch should be in uniform weight and weight variation in within permissible

limits. The weights were determined to within 1 mg by using electronic balance. Weight control is based on a sample

of 20 tablets. Determinations were made in triplicate.

2.9.2 Hardness

The hardness of the tablets was determined by diametric compression using a Hardness testing apparatus

(Monsanto Type). A tablet hardness of about 4-5 kg is considered adequate for mechanical stability. Determinations

were made in triplicate. Determinations were made in triplicate.

2.9.3 Fr iabili ty

The friability of the tablets was measured in a Roche friabilator (Camp-bell Electronics, Mumbai). Tablets of a

known weight (W0) or a sample of 20 tablets are dedusted in a drum for a fixed time and weighed (W) again.

Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not

be more than 1 %.% Friability: W0W / W0 * 100

2.9.4 I n-vitr o disin tegration test(14)

The test was carried out on 6 tablets using Tablet disintegration tester in distilled water at 37C 2C as a

disintegration media and the time in second taken for complete disintegration of the tablet with no palable mass

remaining in the apparatus was measured in seconds.

2.9.5 Wetting time(17)

The wetting time of the tablets can be measured using a simple procedure. Five circular tissue papers of 10 cm

diameter are placed in a petridish with a 10 cm diameter. Ten millimeters of water-containing Eosin, a water-soluble

dye, is added to petridish. A tablet is carefully placed on the surface of the tissue paper. The time required for water to

reach upper surface of the tablet is noted as a wetting time.

2.9.6 In-vitr o dissoluti on profi le of prepared MDTs of Telmisartan (15)

The release rate Telmisartan from fast dissolving tablets was determined using United State Pharmacopoeia

(USP) XXIV dissolution testing apparatus II (paddle method). The dissolution test was performed using 900 ml of

0.1N HCl 4) at 370C and 50 rpm. A sample (10 ml) of the solution was withdrawn from the dissolution apparatus at 2,

5, 10, 15, 20, 25 and 30 min. The samples were replaced with fresh dissolution medium of same quantity. The samples

were filtered through a 0.45 m membrane filter. Absorbance of these solutions was measured at 293 nm using a

Shimadzu UV- 1601 UV/Vis spectrophotometer.

Cumulative percentage of drug release was calculated using an equation obtained from a standard curve.

3. RESULT AND DISCUSSION

Characterization of mucilage:

Chemical characterization of Plantago Ovatamucilage:(16, 18)

The presence of mucilage in extracted material was confirmed using Molisch's test and by treatment with

ruthenium red. Both tests were positive for the presence of mucilage.

Physiochemical characterization of Plantago Ovatamucilage:

The results of other investigations (percentage yield, particle size, pH of solution, loss on drying) are shown

below:

Percentage yield: 22%

pH: 6.2

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Particle size: 150- 200 m

Loss on drying

The weight loss on drying indicates the amount of moisture present in the material available to interact with

other material. For dried mucilage, the loss on drying was 18.25%.

Swell ing rati o

The swelling ratio of mucilage, determined in distilled water, was 2.9. There was a significant change in

swelling by the end of the study, which indicated that the mucilage had excellent swelling properties.

Viscosity

The viscosity of the extracted dried mucilage was 9.12cps for 0.5 % solution. It can be concluded that mucilage

has a viscosity of such type that is suitable for fast dissolving drug delivery.

Table 5: Rheological data of dried mucilage Plantago ovata

Concentration Viscosity:

0.1% 1.45 cps

0.2 % 2.89 cps

0.3 % 5.47 cps

0.4 % 8.19 cps

0.5 % 9.89 cps

Flow property

The flow properties and compressibility of the dried mucilage, including bulk and tapped density, Carr's index,

the Hausners ratio, and the Angle of repose are shown in Table 6. It can be concluded that the dried mucilage has a

good flow properties which is suitable for a direct-compression formulation.

Table 6: Flow properties of dried mucilage

Bulk density (g/ml) 0.35

Tapped density (g/ml) 0.64

Carrs index (%) 40.44

Hausner ratio 1.56

Angle of repose (0) 37.91

Analysis of Telmisartan:

Melti ng Point Determination

Melting point of pure Telmisartan was found to be 248.5C which was obtained by using open capillary tube

method.

Solubi li ty determination of Telmi sartan

The solubility of Telmisartan in water at 37C was found to be 85.9g/ml,therefore Telmisartan can be

considered as practically insoluble drug as per IP.According to IP poorly soluble drugs are those that have solubility

less than 1 part per 10000 parts of water.

pH solubil ity profil e

To find out influence of pH on the solubility, the pH dependent solubility studies were carried out using buffers

in the range of pH 1.2 to pH 7.4.The solubility data for Telmisartan at different pH values is given in the Table

7.Telmisartan has pH dependent solubility.

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Table 7: pH solubility profile of Telmisartan

Media Solubility (g/ml)

pH 1.2 88.2

pH 4.6 84.9

pH 6.8 36.2

pH 7.4 28.6

Figure 1: FT-IR Spectra of Telmisartan

Spectroscopic Studies:

Construction of Calibration Curve of Telmisartan

Figure 2: Depicts the Calibration curve of Telmisartan in 0.1N HCl

Characterization of prepared tablet:

Optimization of Sodium starch glycolate as a disintegrati ng agent

In preliminary study, different batches were prepared as per the composition given in Table 1. Different other

evaluation parameters were also studied. Considering release profile, batches A1- A4 shows drug release with slight

variations. From all batches, it was found that Batch A2 gives desirable fast release action. Moreover, hardness,

disintegration time of tablet were found 40.2 kg/Cm2, 40 sec, it gives 68.35% release of drug with in 30 minute.

Therefore, the sodium starch glycolate concentration 10% was selected for further work.

30

150

50

100

4000 400100020003000

%T

Wavenumber[cm-1]

y = 0.055x - 0.019

R = 0.9989

0

0.1

0.2

0.3

0.4

0.5

0.6

2 4 6 8 10 12 14 16 18 20

Absorbance

Concentration (g/ml)

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Table 8: Evaluation parameters of Telmisartan fast dissolving tablet

Batch

Code

Hardness (n=3)

kg/cm2

DT time

(Sec)

Wetting time

(Sec)%Friability

Weight

Variation

A1 4.181.2 45 52 0.47 245 2.50

A2 4.340.8 40 49 0.49 248 2.00A3 4.071.1 44 47 0.44 251 2.74

A4 5.021.12 47 50 0.51 249 2.15

A5 4.491.04 51 45 0.52 252 2.54

Figure 3: Comparison of dissolution profile of Sodium Starch Glycolate containing MDTs in 0.1 N HCl as

dissolution media

Preliminary trails batches to check the activity of mucilage as disintegrating agent:

In present investigation attempt was made to prepare Fast Dissolving tablet formulation of Telmisartan using

mucilage as a disintegrating agent in one batch and in another batch SSG batch tablets were prepared by direct

compression method. In preliminary study, different batches were prepared as per the composition given in Table 2.

From the obtained result, it was found that 10 % mucilage batch gives desirable fast release action compared to 10 %

SSG (Figure 4).

Figure 4: Comparative cumulative drug release profile for mucilage and SSG

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Optimization of mucilage concentration as a super disintegrating agent:

In preliminary study, different batches were prepared as per given in Table 3 and evaluated for in-vitro

dissolution study (Figure 5) and other evaluation parameters (Table 9). From all batches, it was found that Batch M5

(Table 9) gives desirable fast release action. Moreover, hardness, disintegration time of tablet were found 40.2

kg/cm2, 17 sec, it gives 79.90% release of drug with in 30 minute. Therefore, the mucilage concentration 10% was

selected for further work.

Table 9: Evaluation parameters for Telmisartan MDTs containing mucilage

Batch

Code

Hardness (n=3)

kg/cm2

DT time

(Sec)

Wetting

time

(Sec)

%Friability

(n=3)

Weight

Variation

(n=3)

M1 4.06 1.17 37 40 0.43 249 2.48

M2 4.11 0.78 34 37 0.46 250 1.00

M3 4.02 0.49 31 35 0.45 251 1.64

M4 4.14 0.75 24 27 0.43 249 1.15

M5 4.00 0.20 17 19 0.47 250 1.45

Figure 5: Dissolution profiles for mucilage containing MDTs in 0.1N HCl

Table 10: Comparison of evaluation parameters of Telmisartan MDTs optimized batches containing Mucilage

and SSG

Batch CodeHardness (n=3)

kg/cm2

DT

time

(Sec)

Wetting

time

(Sec)

%Friability

(n=3)

Weight

Variation

(n=3)

A2 SSG 4.340.8 40 49 0.47 248 2.00

M5 Mucilage 4.00 0.20 17 19 0.39 2321.45

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4. CONCLUSION

In the all above formulation mucilage was incorporated as a disintegrating agent to reduce the disintegration

time and sodium starch glycolate was incorporated to increase the solubility of mucilage. Based on result, it was

concluded that higher dissolution of tablet could be obtained when mucilage concentration is 10% and also the sodium

starch glycolate concentration was 10%. Promising batch (M5) exhibited better drug dissolution (79.9%) after 30 minthan the other tablets. The disintegration and mean dissolution time for batch M5 was 17 seconds and 5.27 seconds

respectively, is better than other tablet prepared from other synthetic disintegrating agent. From the obtain result, it was

found that mucilage batch gives desirable fast release action as compared to SSG. (16, 17, 18)

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