Optimization of Pulsatile Compression Coated Floated tablets of Tramadol HCL for Chronopharmacotherapy of Rheumatoid Arthritic pain using 2³ Factorial Design

 

Pasam Jyothirmayi¹*, Dr. G. Devalarao², Mandava Venkata Basaveswara Rao³

¹Research Scholar, Krishna University, Krishna District, Andhra Pradesh, India.

²Department of Pharmaceutical Analysis, K.V. S. R Siddhartha College of Pharmaceutical Sciences, Vijayawada, Andhra Pradesh, India.

³Department of Chemistry, Krishna University, Krishna District, Andhra Pradesh, India.

 

ABSTRACT:

Objective: The main aim of study is to develop modified oral compression coated floated tablets for pulsatile delayed release of Tramadol HCL by applying design of experiments (DOE). Pulsatile release systems are generally formulated to undergo a lag-time of predetermined span of time of no release, followed by a rapid and complete release of loaded drugs. Methods: These systems consist of three steps in formulation. In the first step burst release core tablets of Tramadol HCL were prepared with superdisintegrants such as Cross Povidone, Sodium Starch Glycolate and Cross Carmellose Sodium. In second step, these core tablets were compression coated with polymers HPMC K4M, HPMC K15M, Ispaghula gum and Tamarindus gum to assign suitable lag time to formulation. In third step, top buoyant layer was compressed using suitable polymers such as HPMC K100M, Ispaghula gum and their combination. Results: In the preliminary two steps, immediate release core tablets were optimized with formulation CF2 which contains sodium starch Glycolate 8% as immediate release agent. Then in compression coated formulation CCF8 was optimized. Among complete coated floated formulation BF4 and BF8 shows significant lag time of 5hr and drug release for a period of 12 hrs. Conclusion: A modified oral compression coated floated tablets for pulsatile delayed release of Tramadol HCL was made possible with BF4 and BF8 which shows better drug release with suitable lag time and drug release and fulfilled my objective of work.

 

 

 

INTRODUCTION:

RA is an autoimmune disorder involving the migration of inflammatory cells into the synovium that surrounds the joints, causing cytokines, the chemicals of inflammation, to be secreted and inflammation to occur within joints and soft tissues (swelling, pain and loss of function).⁽¹⁾ Morning stiffness is a characteristic feature and occurs in many patients. Pain, functional disability, and stiffness show 24-hour rhythms in many patients with RA, with a peak in the early morning.^(2,3)

 

The drug management of patients with RA has two objectives: symptom control, and disease modification and complete suppression of progressive inflammation. Combinations of analgesics and DMARDs are often needed to achieve both of these aims, especially in the early stages of the disease, because most DMARDs are slow to take effect. Pain control drugs include analgesics as well as NSAIDs for general pain. NSAIDs are drugs that can reduce pain, fever, and inflammation. Inflammation is the body's protective response to irritation or injury and is recognized by redness, warmth, swelling, and pain. These medications inhibit Cyclooxygenases (COXs) enzymes, which are rate-determining enzymes for prostaglandins and other prostanoids synthesis, such as thromboxanes.^(4,5) Tramadol is a centrally acting analgesic having the aminocyclohexanol group, which has a strong analgesic action similar to opioid profile. The mode of action is not clear, even though the parent and M1 metabolite of Tramadol binds to μ- opioid receptors and results in weak inhibition and reuptake of norepinephrine and serotonin.⁽⁶⁾

 

Chronomodulated systems are gaining interest now a days as these systems deliver the drugs on specified time period as per pathological need resulting in improved therapeutic efficacy and patient compliance.⁽⁷⁾ Chronomodulated systems or sigmoidal systems or pulsatile drug delivery systems are the systems that releases the drug at the fast or controlled rate with a programable lag time. These systems are useful for the drugs having chronopharmacological behavior (where night time dosing is required), first pass effect and having specific site of absorption in gastrointestinal tract (GIT).⁽⁸⁾

 

Compression coating or press coating technique is a simple and unique approach of a pulsatile drug delivery systems. Reservoir system with rupturable polymeric compression coating is provided with buoyant layer. Thick coating can be applied rapidly and no special coating solvent or coating equipment is required for manufacturing of the tablet.⁽⁹⁾ It has been used to protect hygroscopic, light sensitive, oxygen labile or acid labile drug, to combine and separate different therapeutic drugs, and to modify a drug release pattern (delayed pulsatile and programmable release of different drugs in one tablet).⁽¹⁰⁾ Compression coated floated tablets are composed of an inner core immediate release tablet surrounded by an outer barrier hydrophilic/hydrophobic polymer layer and upper buyont layer. Buyont layer helps in floating, the outer polymer layer can erode or rupture or dissolve after a certain lag time, after which the drug is released from core tablet. The rupturing of the barrier is obtained by an expanding core on water penetration through the barrier coating such as swelling agents.⁽¹¹⁾ Hydroxypropylmethyl cellulose (HPMC) is a synthetic released retardant that is widely used as an extended release agent in pharmaceutical industry.⁽¹²⁾ Pulsstile floated drug delivery system of Tramadol HCL is better option for these patients and is optimized by using factorial design.

 

MATERIALS AND METHODS:

The drug Tramadol HCL was obtained from Hetero drugs, Hyderabad. Tamarindus gum and Ispaghula gum were isolated by suitable procedures. Ingredients such as Sodium Starch Glycolate, Cross Povidone, Cross Carmellose sodium, HPMCK15M, Methocel K100, Sodium bicarbonate and citric acid were also obtained from yarrow chem. Products. All the remaining ingredients micro crystalline cellulose, talc, magnesium stearate and lactose are of from analytical grade.

Compatibility study by FTIR:

Drug-exciepients compatibility was studied by taking pure drug and its formulation with exciepients especially with Ispaghula gum by FTIR spectral analysis. This was established by conducting one month compatibility at 40^◦C and 75% relative humidity by using potassium bromide pellet method employed by using shimadzu FTIR spectrometer. FTIR spectra of pure drug and formulation were shown in fig 1 A and B respectively.

 

Fig 1: FTIR spectra of A. Tramadol HCL and B. Tramadol HCL Formulation with ispaghula

 

Calibration curve of Tramadol HCL:

100mg of Tramadol HCL was taken in a 100mL volumetric flask and dissolved with 100mL of 0.1 N HCL to give the concentration of 1000mg/mL. From the above stock solution, aliquots of concentrations 40 to 300mg/mL were prepared for pH 1.2 buffer. When this solution was scanned in the UV range i.e. from 200nm to 800nm l_max was found to be 271nm for Tramadol HCL. The absorbance of these solutions was measured at 271 nm and a graph of concentration versus absorbance was plotted.

 

Isolation of Tamarindus gum:

Take the tamarind seeds and peel out the outer cover and obtain the white part of seeds and crush them. The crushed seeds of Tamarindus were soaked in water for about 24 h, then take this soaked crushed seeds into a muslin cloth and press them for the release of gum. The marc was removed from the gum and to the extracted gum equal quantity of absolute ethyl alcohol was added to precipitate the gum and it was separated by filtration. The marc was for multiple extractions with decreasing quantity of extracting solvent i.e., water with the increase of the number of extractions. The isolation process was continued until the material was free of gum. The separated gum was dried in a hot air oven at temperature 40ºC. Then the extracted dried gum was powdered and stored in an airtight container at room temperature.^(13,14) Both the peeled tamarindus seeds and extracted gum were shown in fig 2(a).

 

Isolation of Ispaghula gum:

Seeds from Plantago ovate were collected and soaked in distilled water for 48 h, boiled for 10-20 min until the mucilage was released into water. This extracted mucilage was passed through muslin cloth, to the obtained filtrate acetone was added to precipitate the mucilage. This precipitated mucilage was separated and dried in an oven 40⁰C, passed through sieve no #80 and stored in desiccators. The collected Ispaghula seeds and extracted gum powder images were shown in fig 2 (b).

 

Fig 2: (a) Peel off seeds and powdered gum of Tamarindus, (b) Ispaghula seeds and gum powder

 

Development of Formulation:

At first Rapid release core tablets were formulated by using super disintegrants such as Sodium Starch Glycolate, Cross Povidone, Cross Carmellose Sodium by direct compression method. These formulations were represented in table 2 as CF1 to CF6. These tablets were compression coated with both natural and synthetic polymers (HPMC K4M, HPMCK15M and isolated Tamarindus, Ispaghula gum). These polymers according to the calculated amounts in the given table no 2 as CCF1 to CCF8 were blended together, 2/3 rd portion of blended mixture was introduced in die cavity, then place the core tablet and add remaining 1/3^rd portion, then compress using 8mm punch. In last step buoyant composition in table no 2 along with combination of Ispaghula gum and Methocel K100M as major polymers for delayed floating were blended together and compressed over the prepared above compression coated tablet by using 9mm punch to obtain coated floated tablet of Tramadol HCL and represented as BF1 to BF8. ⁽¹⁵⁾

 

Table 1: 2³ Factorial Design for buoyant layer

Independent Variables	Low (-)	High (+)
Methocel K 100 (X1)	80	100
Ispaghula gum (X2)	20	40
Sodium bicarbonate (X3)	60	80
Dependent Variables
Y1 = Floating Lag Time (FLT)
Y2 = Total floating time (TFT)
Y3= % Swelling index (SI)
Y4 = Drug Release at 10th hr (DR10h)

 

 

Table 2: Composition of core tablet

Composition of core tablet
S. No	Formulation Ingredients	Formulation code (mg)
		CF1	CF2	CF3	CF4	CF5	CF6
1	Tramadol HCL	100	100	100	100	100	100
2	SSG	4	8	-	-	-	-
3	CP	-	-	4	8	-	-
4	CCS	-	-	-	-	4	8
5	MCC	42	38	42	38	42	38
6	Talc	2	2	2	2	2	2
7	Magnesium stearate	2	2	2	2	2	2
Total weight		150	150	150	150	150	150
Composition of compression coat
		CCF1	CCF2	CCF3	CCF4	CCF5	CCF6	CCF7	CCF8
1	HPMC K4	150	-	-	-	150	-	120	-
2	HPMC K15	-	150	-	-	-	150	-	120
3	Ispaghula Gum	-	-	200	-	-	-	40	40
3	Tamarindus Gum	-	-	-	200	50	50	40	40
4	MCC	10	10	10	10	10	10	10	10
Total weight		160	210	210	210	210		210	210
Composition of buoyant layer
		BF1	BF2	BF3	BF4	BF5	BF6	BF7	BF8
1	Methocel K100	80	100	80	100	80	100	80	100
2	Ispaghula gum	20	20	40	40	20	20	40	40
3	Sodium bicarbonate	60	60	60	60	80	80	80	80
4	Citric acid	20	20	20	20	20	20	20	20
5	Lactose	20	-	20	-	20	-	20	-
6	Talc	5	5	5	5	5	5	5	5
7	Magnesium stearate	5	5	5	5	5	5	5	5
Total weight		550	550	550	550	550	550	550	550

Formulation Design:

For 2³ factorial design, by using formulation design expert 12.0 software (stat-ease) demo version 3 factors were evaluated each at 2 levels and were represented in table 1. In these formulations, independent variables selected are amounts of Methocel K 100(X1), Ispaghula gum (X2) and ratio of sodium bicarbonate: citric acid (X3), whereas Floating Lag Time (FLT), Total floating time (TFT) and Drug Release at 10^th hr (DR_10h) were selected as dependent variables. In this statistical model, 8 interactive terms were used, then responses were evaluated. The main effects (X1, X2, and X3) represent the average result of changing 1 factor at a time from its low to high value. The interaction terms (X1X2, X2X3 and X1X3) show how the response changes when 1 or more factors are simultaneously changed.^(16,17)

 

Preformulation studies: The drug and polymers were selected and identified:

Physicochemical characterization of gum:

The separated ispaghula mucilage powder was evaluated for solubility, swelling index, density, compressibility index and angle of repose.

 

Phytochemical Examination:

Phytochemical tests such as Molisch’s test, Ninhydrin test, Ferric chloride test, Wagner’s test, Keller-Killani test, Fehling’s test, Shinoda test, ruthenium red test were performed for both the gums and were reported in table 3.⁽¹⁸⁾

 

Evaluation parameters of tablets:

The compressed coated and coated floated tablets were evaluated for various parameters such as weight variation, hardness, friability, thickness, disintegration time and drug content were represented in table 4.^(19,20)

 

In-vitro buyonacy time:

In vitro buoyancy studies were performed for all the formulations. The randomly selected tablets from each formulation were kept in a 100ml beaker containing simulated gastric fluid, pH1.2 as per USP. The time taken for the tablet to rise to the surface and float was taken as Floating Lag Time (FLT). The duration of time the dosage form constantly remained on the surface of medium was determined as the Total Floating Time (TFT).

 

In-vitro swelling studies:

The swelling index of tablets was determined by placing the tablets in the basket of dissolution apparatus using dissolution medium pH 1.2 buffers at 37±0.5ºC. After 0.5, one, two, three, four, five, six, seven, and up to twelve hours, each dissolution basket containing tablet was withdrawn and blotted with tissue paper to remove the excess water and weighed on the analytical balance. The experiment was done in triplicate for each time point, swelling index was calculated.⁽²¹⁾

                Wet weight of tablet – Dry weight of Tablet

Swelling index = ---------------------------------- x 100

                                 Dry weight of Tablet

 

In-vitro dissolution study:

The release rate of Tramadol Hydrochloride from floating tablets was determined using United States Pharmacopoeia (USP) Dissolution Testing Apparatus 2 (paddle method). The dissolution test was performed using 900ml of 0.1N HCL for 12 hrs. A sample (5ml) of the solution was withdrawn from the dissolution apparatus hourly and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45μ membrane filter and diluted to a suitable concentration with 0.1N HCL for 12 hrs. Absorbance of these solutions was measured at 271nm using a UV/ Visible spectrophotometer.

 

Drug release kinetics:

Tramadol hydrochloride tablets made with Hydroxy Propyl Methyl Cellulose K 100 and Ispaghula were subjected to various kinetic studies like zero order (Cumulative percentage drug released vs. Time), first order (Log cumulative percentage of drug unreleased vs. Time), Higuchi equation (Cumulative percentage of drug unreleased vs. Square root of time) and Korsemeyer’s (Log cumulative percentage released vs. Log time)

 

Stability studies:

Accelerated stability study was carried out for optimized batch (F8) at 40 ± 2^∘C/75 ± 5% RH over 3-month period according to ICH guidelines in stability chamber (Thermolab India). At the end of the 3 months, the tablets were examined for physical characteristics, drug content, in vitro drug release (lag time), and floating lag time.^(22,23)

 

RESULTS AND DISCUSSION:

Properties of gums:

The isolated gums were physico chemically evaluated and these parameters are represented in table 3. Among them tamarindus gum is soluble in hot water and swells in cold water whereas Ispaghula gum is soluble in various solvents as shown in table 3. Particle size of tamarindus gum is slightly more than Ispaghula gum is 0.13mm on average. pH values are 6.2 and 2.1 respectively. Both the gums show good flow properties. Proteins and alkaloids were additionally present in tamarindus gum along with Carbohydrates and glycosides while reducing sugars were specially present in Ispaghula gum powder. Both gums produce mucilage and shows positive results for ruthenium red test. With this extracted gum powders have shown that they are suitable for producing formulation. The swelling property of these gums is responsible for considering them as one of the excipients or polymers with special properties and is represented in table 5.

 

Table 3: Physicochemical and Phytochemical screening of Tamarindus gum and Ispaghula gum:

Parameters	Tamarindus gum	Ispaghula gum
Solubility	Soluble in hot water	Soluble in water, Dimethyl Sulfoxide and in NaOH (2.5%)
Swelling index in water (0.1 g gum)	Forms gel in cold water	Not less than 38
Loss on drying (1g of powder at 100-1050C for 2 h.)	Not more than 10%	Not more than 13%
pH	6.2	2.1
Mean particle size	0.165mm	0.136mm
Compressibility index	15.68	16.74
Hausner ratio	1.15	1.14
Angle of repose	22.42	21.45
Carbohydrates (Molisch’s test)	+	+
Tannins (Ferric Chloride test)	-	-
Proteins (Ninhydrin test)	+	-
Alkaloids (Wagner’s test)	+	-
Glycosides (Kellar-Kellani test)	+	-
Mucilage (Ruthenium red test)	+	+
Flavonoids (Shinoda test)	-	-
Reducing sugars (Felhing’s test)	-	+

 

Evaluation of tablets:

All the tablet powder blends are having acceptable good density and flow properties. Compression properties of core, coat and coated floated tablets were represented in table 4. Weight variation for all the mentioned formulations were within the range of 97 to 101%, hardness values varies from 4.65 to 6.4 kg/cm², friability values ranges from 0.65 to 0.75 and all the values were within specified limits. Content uniformity in the core tablets ranges from. Disintegration time of core tablets varies from 1.5 to 3.1 min. drug content uniformity in core tablets ranges from 97.68 to 101.1%.

 

Table 4: Characterization of prepared tablets

Formulation code	Weight variation	Hardness (kg/cm2)	Friability (%)	Thickness (mm)	Content uniformity	Disintegration Time (min)
CF1	101	6.4	0.72	2.6	99.28	3.1
CF2	97	6.3	0.68	2.6	99.66	2.6
CF3	98	5.8	0.69	2.7	101.1	2.4
CF4	99	5.6	0.66	2.75	97.68	2.7
CF5	98	5.7	0.68	2.6	99.41	2.3
CF6	99	6.4	0.65	2.62	98.19	1.4
Physical characteristics of coated formulations
CCF1	98	5.8±0.3	0.68	5.88±0.05	98.64
CCF2	97	5.3±0.2	0.56	6.0±0.04	101.31
CCF3	96	5.6±0.1	0.87	6.13±0.02	99.94
CCF4	96	5.4±0.3	0.72	6.28±0.05	99.83
CCF5	98	5.6±0.18	0.88	5.94±0.06	101.49
CCF6	101	5.5±0.33	0.83	6.07±0.01	101.27
CCF7	98	6.1±0.15	0.98	6.18±0.05	101.17
CCF8	96	5.8±0.33	0.84	6.15±0.06	99.86
Physical characteristics of pulsatile floating formulations
Formulation code	Hardness (kg/cm2)		Weight variation	Friability	Floating lag time (sec)(FLT)	Total floating time (h)
	core	total
BF1	6.4	4.8	101	0.68	132	>8
BF2	6.3	4.7	97	0.75	126	>8
BF3	5.8	4.72	98	0.72	160	>10
BF4	5.6	5.1	99	0.68	155	>9
BF5	5.7	4.68	98	0.69	126	>7
BF6	6.4	4.74	99	0.66	130	>7
BF7	5.7	4.81	98	0.68	155	>8
BF8	5.8	4.65	99	0.65	162	>10

 

In-vitro buoyancy time:

In-vitro buoyancy time is denoted by both floating lag time (FLT) and total floating time (TFT). Their results are based on composition of polymer, gum and sodium bicarbonate in the above formulations. Based on the obtained values BF3 and BF8 shows better results and it is noted that Ispaghula gum has shown synergistic effect when combined with sodium bicarbonate. In the total formulations FLT values ranges from 126 to 162 sec. while that of TFT ranges from 7 to 10 hrs. This floating behavior of formulated tablets was photographically shown in fig.3

 

In-vitro swelling studies:

From the results swelling study was represented as % SI and it was concluded that as polymer gradually absorbs water swelling increases with respect to time, this is because of hydrophilic nature of polymer as well as gums. Among all BF8 shows maximum swelling index of 97.33% and which may be due to the presence of Methocel K100 and Ispaghula gum at their maximum concentrations. All the remaining formulations also shows characteristic SI% as per their compositions.

 

Fig. 3: Floating at initial hrs, after 5hrs, after 8hrs, after 10hrs

 

In-vitro dissolution study:

The drug release from compressed tablets were graphically shown in fig.4 The formulation which consists of SSG at its high concentration releases the drug within 45 min. From the pulsatile floating formulations BF4 and BF8 both shows the drug release up to 11h with lag period of 4 h. Methocel K100 with Ispaghula gum and sodium bicarbonate helps in buoyant behavior of formulations.

 

Fig. 4: Percentage drug release of pulsatile floating formulations

 

Table 5: Optimization data analysis and ANOVA table

Formulation code	Floating lag time (sec) [FLT]	% Swelling index [SI %]		Total floating time (h) [TFT]	% Drug release at the end of 10h [DR10h]
BF1	132	91.86		8	98.84
BF2	126	92.22		7	95.56
BF3	160	93.82		7	98.61
BF4	155	94.62		9	96.62
BF5	126	92.84		8	91.16
BF6	130	91.66		10	98.26
BF7	155	95.22		8	92.62
BF8	162	97.33		10	90.84
ANOVA table
RESPONSE	Sum of squares	df	Mean of squares	F value	P value	P<0.05
FLT
Regression	1766.50	4	441.62	33.97	0.0078	Significant
Residual	39.00	3	13.00
SI
Regression	24.07	3	8.02	11.63	0.0191	Significant
Residual	2.76	4	0.6896
TFT
Regression	9.38	3	3.13	25.00	0.0047	Significant
Residual	0.5000	4	0.1250
Invitro drug release at 10 th hr (DR10h)
Regression	70.90	2	35.45	24.04	0.0027	significant
Residual	7.37	5	1.47

 

Fig 5: Contour plots for compressed coated formulations (BF1-BF8)

 

Optimization data analysis:

Observed responses of nine formulations were fitted to various models using Design‑Expert software trial version 12.0 (Stat-Ease, Inc., USA, trail version). It was seen that the quadratic models were best‑fitted to study the responses, that was, floating lag time (FLT), total floating time (TFT), % Swelling Index (SI) and % drug release at 10 th hr (DR_10h). The polynomial equations generated for responses were given as:

 

POLYNOMIAL EQUATION:

FLT = 143.25 + -1 * X₁ + -7.11494 * X₂ + 1.5 * X₃ + 14.75 * X₁X₃

SI % =93.6963 + 0.70625 * X1 + 0.41625 * X2 + 0.32125 * X3 + 1.55125 * X1X3 + 0.06125 * X2X3

 

TFT = 8.375 + -0.125 * X₁ + 0.875 * X₂ + 0.625 * X₃ + -0.125 * X₁X₂ + 0.125 * X₂X₃

 

DR_10h = 95.3138 + -2.76875 * X₁ + -1.09375 * X₂ + -0.17375 * X₃ + -0.45125 * X₁X₂ + -0.64125 * X₁X₃ + 0.50375 * X₂X₃ + 0.15125 * X₁X₂X₃

 

Where X1, X2 and X3 were coded values and were represented in table1. The positive value of a factor in the above equations point outs the enhancement of that response and vice versa. All values of the correlation coefficient (R²), standard deviation, % coefficient of variation, and results of ANOVA are shown in Tables 5. A value of R² and results of ANOVA for the dependent variables confirmed that the model was significant for observed response variables. Response surface methodology has been used as experimental design to determine the effect of independent variables on all possible dependent variables. Fraction of design space (FDS) evaluation helps experimenter’s size constrained response surface (RSM) and mixture designs, for which the normal power calculations lose relevance. Supply the “signal” and the “noise” and the graph will show the amount of the design region that can estimate with that precision. An FDS >80% is generally acceptable to ensure that the majority of the design space is precise enough for your purpose. Experimental design Based on the preliminary experiments and our previous studies, three factors (polymer, gum and bicarbonate compositions) were identified key factors responsible for obtained responses. The polymer Methocel K100 was chosen because it decreases the release of drug from the tablet at optimum concentration. Ispaghula gum in floating layer serves as excellent source for the floating benefit of formulation. The polymer caused a coarse covering, likely due to drug’s residue that has not been surrounded by polymer, thoroughly. When increasing the concentration of polymer, it forms stiff layer over the drugs, and this hindered the release of drug from the tablet surface.

 

Drug release kinetics:

The release kinetics profile of Tramadol hydrochloride tablets was fitted to various mathematical models such as Higuchi, Korsmeer Peppas, Zero order and First order. The drug release was found to obey zero order kinetics (R² as 0.982) and Korsmeyer Peppas (R² as 0.997).

 

Stability studies:

Accelerated stability study indicated that the optimized formulation BF8 was physically as well as chemically stable after 3 months.

 

CONCLUSION:

In this work formulation of modified oral coated floated tablet for chronotherapy based release of Tramadol HCL was successfully developed. Optimized BF8 showed lag time of 4 h and 162 ± 2 sec floating lag time along with maximum drug release (98.96±2%). The increase in gastric residence time is due to effervescent agents sodium bicarbonate along with Methocel K100 and Ispaghula gum. The optimized BF8 may be used for the administration at bed time which will release Tramadol HCL in the early morning which will relieve the elevated pain. However, there is further need of investigation for clinical acceptance of this novel drug delivery system.

 

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Received on 18.01.2020           Modified on 07.03.2020

Accepted on 07.05.2020         © RJPT All right reserved