Development of Lamotrigine Solid Dispersion for the Formulation and Evaluation of Fast Dissolving Tablets

 

Pooja Yadav, Amit Alexander,  Hemlata Thapa, Tripti Banjare, Palak Agrawal, Akansha Bhandarkar, Aditi Bhatt, Swapnil Gupta, Hemlata Sahu, Shradha Devi Diwedi, Pankaj Sahu, Siddharth Kumar Sahu, Kailash Sahu, Deeksha Dewangan, Deepika,

Mukesh Sharma, D. K. Tripathi, Ajazuddin*

Rungta College of  Pharmaceutical Sciences and Research, Kohka-kurud Road, Bhilai, Chhattisgarh, 4900024

 

ABSTRACT:

Lamotrigine is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorders. Its acts primarily by obstructing voltage dependent sodium channel hence a decreased level of excitatory neurotransmitter. Solid dispersion is a newer technique of enhancing the solubility of poorly soluble drugs using suitable polymer. Moreover, for obtaining better drug absorption, faster onset of action and safety regarding its administration fast dissolving tablets are becoming standards. These upon administration into mouth gets rapidly dissolve due to presence of saliva without any need of water. Lamotrigine solid dispersion was prepared using PEG 6000 as polymer in the ratio (1:1). Fast dissolving tablet of lamotrigine was formulated using 3 different superdisintegrants (crosscarmellose, kollidon, sodium starch glycolate (SSG)) in different ratios. The formulated tablets were then evaluated for its different parameters. The result of invitro dissolution study showed that formulation F5 is most successful as it dissolved in a very short period containing combination of kollidon and SSG in the ratio (1:3). An increased disintegration time was noted with combination of crosscarmellose and SSG (1:1) ratio.

 

 

 

INTRODUCTION:

Lamotrigine acts as anticonvulsant drug, which is used for the treatment of partial seizures. It is considered as a first line drug for treating tonic–clonic seizures.⁽¹⁾ It not only inhibits the voltage dependent sodium channels but also act as a mood stabilizer. As such, Lamotrigine is rapidly and completely absorbed through oral route with a good absolute bioavailability (98%) but inspite of its good bioavalbility, it shows a delayed onset of action because of its low aqueous solubility (0.17g/L).^(2,3) The solubility of  lamotrigine can be improved by formation of solid dispersion using suitable carrier. Hydrophilic polymers are widely used as carrier materials for solid dispersion like Poly ethylene glycol (PEG), Polyvinyl pyyrolidine K30 (PVP K30), Urea etc.⁽⁴⁾

 

Although, there is enormous development in drug delivery but still oral route is the most preferred route because of its low cost, ease of administration and a better patient compliance.⁽⁵⁾  Recent advances in oral drug delivery system provides a wide opportunity to achieve maximum therapeutic efficacy, among which fast dissolving tablets are one such approach.⁽⁶⁾ The use of superdisintegrants in fast dissolving tablets help in enhancing drug disintegration and dissolution. They primarily act by promoting the wettability and dispersibilty of the formulation.The primary objective of the present investigation was to formulate solid dispersion of Lamotrigine using PEG6000 as carrier and was evaluated for its increased solubility. Furthermore, the prepared solid dispersions were formulated into fast dissolving tabet using 3 different superdisintegrants (cross carmellose, kollidon, sodium starch glycolate) in varying ratio.^(7,8)

 

 

MATERIAL AND METHOD:⁽⁹⁾

Lamotrigine API, PEG 6000, crosscarmellose, kollidon, sodium starch glycolate and all other excipients were obtained from pharmaceutics laboratory of RCPSR, Kohka Kurud Road, bhilai.

 

Equipment Used:

UV-Visible Spectrophotometer (SHIMADZU UV-1800), Tablet Compression machine (SHAKTI), Dissolution apparatus (ELECTROLAB TDT- 08L)

 

Preparation of calibration curve of Lamotrigine in 0.1 N HCl:

Preparation of 0.1N HCL solution:

To make 0.1N HCL solution, 8.9ml of concentrated HCl was taken in a 1000ml volumetric flask and then distilled water was added to make up the volume to 1000ml.

 

Preparation of standard stock solution:

Standard drug solution of Lamotrigine was prepared by dissolving 5mg pure drug in 0.5ml of methanol and further diluted with  50.00ml 0.1 N HCL, a concentration of 100μg/ml was obtained, from which desired concentration solutions were prepared.

 

Determination of λmax:

10μg/ml solution of  Lamotrigine was prepared and scanned in UV range 200-400nm and spectrum was obtained. The λmax was found to be 264nm.

 

Preparation of calibration curve:

From the stock solution of Lamotrigine , a series of dilutions ranging from 5-25μg/ml were prepared. Absorbance of these solutions was measured at 264nm wavelength and calibration curve was plotted between concentration and absorbance.

 

Preparation of solid dispersion by melting method:

PEG 6000 was heated in a china dish on hot plate at 50-60˚C. Measured amount of drug was added to the melted PEG6000 and mixed eventually for few minutes. The molten mixture was then immediately cooled by placing it in an ice bath and solidified. The hardened mixture was powdered, sieved through an 44 –mesh screen, packed and stored in dessicator.

 

Solubility studies of prepared solid dispersion of Lamotrigine:

Into a volumetric flask containing 10ml of water, an excess amount of solid dispersion was added. The content of the flask were equilibrated by shaking for 24 hours in a thermostatically controlled water bath at 37±0.1˚C. After 24 hours, the solution was filtered and its solubility was determined.

 

Dissolution studies:

The prepared solid dispersion was subjected to dissolution studies using USP paddle type II apparatus. The dissolution medium used was 0.1 N HCL (pH 1.2) temperature 37°C ± 0.5°C and paddles rotated at 50 rpm. Sample of 150 mg  SD equivalent to 75 mg of drug were filled inside muslin cloth pouches and dropped inside 900 ml of dissolution medium. A volume of 1ml of samples were withdrawn every 10 min, and diluted to 10ml with the dissolution medium and analyzed at 264 nm for Lamotrigine.

 

Preparation of Lamotrigine fast dissolving tablet by direct compression method: ^(10,11)

The fast dissolving tablets of Lamotrigine were prepared by direct compression method. Six different formulations were prepared for Lamotrigine fast dissolving tablet with different composition of superdisintegrants.

 

All the ingredients (except magnesium stearate and talc) were passed through sieve # 40. The powder blend were then dried in hot air oven at 50°C for 20-30min, before punching the powder were lubricated with magnesium stearate and talc, then punched in a multi tooling lab based punching machine (SHAKTI) in a slow and steady speed with high compression power to avoid capping and evaluated for parameters such as hardness, friability, disintegration time, wetting time, weight variation and drug content.

 

Evaluations of Powder blends: ^(12,13)

Powders were evaluated for all pre-compression parameters like angle of repose, bulk density, tapped density, Hausner’s ratio and compressibility index. The evaluations were done using all the methods as per specified in pharmacopoeias.

Table 1: Formulation Table:

Ingredients	F1	F2	F3	F4	F5	F6
Solid dispersion equivalent to 25mg of lamotrigine	50mg	50mg	50mg	50mg	50mg	50mg
Avicel PH102	108mg	108mg	108mg	108mg	108mg	108mg
Cross carmellose	6mg	18mg	12mg	1.5mg	1.5mg	1.5mg
Kollidon	1.5mg	1.5mg	1.5mg	18mg	6mg	18mg
Sodium starch glycolate	18mg	6mg	12mg	6mg	18mg	18mg
Magnesium stearate	1.5mg	1.5mg	1.5mg	1.5mg	1.5mg	1.5mg
Talc	1.5mg	1.5mg	1.5mg	1.5mg	1.5mg	1.5mg
sucrose	13.5mg	13.5mg	13.5mg	13.5mg	13.5mg	13.5mg

 

Angle of repose:

It is defined as “the maximum angle between surface of the pile and horizontal plane”. It is measured using fixed funnel method. The funnel is kept vertically attacked to a stand at a specific height, below which a paper is kept on a horizontal surface. The funnel is first filled with the powder and then opened to release the same in a form of conical heap, the height of heap is measured with scale and then angle of repose is calculated using formula below:

 

θ = tan^-1 h/r

Where

h = height of heap,

r = radius of heap

 

Tapped density: ^(14,15)

It was determined by placing the powder in a measuring cylinder and tapping it 100times, the total mass of powder was determined and density was calculated using the formula:

 

Tapped density = Vb/Vf

Where

Vb = initial volume,

Vf = tapped volume

 

Bulk density:

A known quantity of powder blend is putted into a measuring cylinder and levelled, note the bulk volume and calculate the bulk density using formula below:

 

Bulk density = m/Vo

Where

m = unsettled,

Vo = apparent volume

 

Compressibility index:

It was calculated using measured values of bulk and tapped density as:

 

Carr’s index = [(Vt-Vb)/Vt] x 100

Where

Vt = tapped volume and

Vb = bulk volume

 

Hausner’s ratio:

It is also calculated from using measured values of bulk and tapped density as:

 

Hausner’s ratio = Dt/Do

Where

Dt = tapped density,

Do = bulk density

 

 

Evaluation of tablets:

Prepared tablets were evaluated for certain properties like tablet weight variation, assay, hardness, friability, dissolution study, etc.

 

Assay:

Tablets containing 25mg Lamotrigine were weighted; powdered and average weight was calculated. Powder equivalent to 10mg of Lamotrigine was dissolved in 30ml of 0.1N HCL solution . This was further diluted up to the mark with same solvent. The solution was filtered and first 5ml of filtrate was discarded. This solution was further diluted to obtain 10μg/ml solution with same solvent and subjected for UV analysis.

 

Tablet weight variation: ⁽¹⁶⁾

Every individual tablet in a batch should be in uniform weight and weight variation within permissible limits. Twenty tablets were randomly selected and accurately weighted using an electronic balance. The results are expressed as mean values of 20 determinations.

 

Hardness:

The hardness of tablets is defined as “the force required in breaking a tablet” and it is determined using Monsanto hardness testing apparatus. The tablet is placed vertically in the tester and the force required to break the tablet is measured in kg/cm²

 

Friability:

The friability of tablets was measured in a Roche friabilator. 20 tablets of known weight (Wo)were taken in a drum for 4 minutes(100 revolutions) and weight (W) again. Percentage friability was calculated from the loss in weight as given in equation below. The weight loss should not be more than 1% w/w.

% friability = (Wo-W)/Wo X 100

 

Dissolution studies of prepared formulations:^(17,18)

The  prepared tablet  were  subjected to dissolution studies using USP Paddle Type II apparatus. The dissolution medium used was stimulatory salivary solution (pH 6.6). A volume of 10 ml of samples were withdrawn after every 1 min and analyzed at 264 nm for Lamotrgine.

 

RESULT AND DISCUSSION:

Table 2: Calibration curve data of Lamotrigine in O.1N HCl

Concentration	Absorbance
5	0.142
10	0.291
15	0.411
20	0.565
25	0.708

 

Figure 1: Standard calibration curve of Lamotrigine in 0.1N HCL

 

Calibration curve of Lamotrigine was prepared in0.1N HCL. The slope of the graph was found to be 0.028 and intercept with + 0.001 with regression coefficient R² = 0.998.

 

 

Table 2: Evaluation of powder blends of different compositions of Lamotrigine tablet:

Formulation	Angle of repose (θ) in ° (degree)	Bulk density (gm/ml)	Tapped density (gm/ml)	Carr’s index (%)	Hausner’s ratio
F1	26	0.40	0.45	12.34	1.17
F2	28	0.41	0.49	13.54	1.15
F3	30	0.29	0.42	17.78	1.21
F4	29	0.32	0.42	20.13	1.18
F5	32	0.40	0.52	15.54	1.17
F6	27	0.33	0.42	19.56	1.12

 

Table 3: % drug release of lamotrigine from solid dispersion

Sample time (min)	Absorbance	Concentration	Amount	% drug release
10	0.074	2.64	23.76	47.52
20	0.083	2.9	26.1	52.2
30	0.095	3.35	30.15	60.3
40	0.104	3.67	33.03	66.06
50	0.114	4.03	36.27	72.54

 

 

 

 

Table 4: Evaluation of different formulations of Lamotrigine fast dissolving tablet

Formulation	Weight variation(%)	Hardness	Friability	Disintegration time(sec.)	Wetting time (sec)	%drug content
F1	5.5	3.5	0.6	67	48	93.3%
F2	4.3	3.7	0.4	65	22	94.7%
F3	5.6	3.5	0.5	72	31	96.8%
F4	4.6	3.2	0.8	61	28	95.5%
F5	3.9	3.7	0.3	54	17	98.9%
F6	4.8	3.4	0.5	62	25	96.6%

 

Table 5: Comparative invitro dissolution study of different formulations of Lamotrigine fast dissolving tablet

TIME (in min)	5	10	15	20	25	30
F1	34.15	47.54	58.21	67.23	73.54	86.34
F2	34.18	42.33	58.32	67.43	74.16	85.56
F3	34.19	47.87	58.32	67.43	74.16	85.56
F4	34.19	47.87	58.76	67.56	74.23	87.45
F5	35.95	48.64	59.33	70.01	74.32	89.56
F6	33.45	47.32	59.23	66.98	73.33	83.67

 

 

Figure 2: Comparative invitro dissolution study of different test formulations of Lamotrigine fast dissolving tablets.

DISCUSSION:

Fast dissolving tablet of Lamotrigine was formulated using different ratios of superdisintegrants (crosscarmellose, kollidon, sodium starch glycolate). Solid dispersion of  Lamotrigine was prepared  by fusion method using PEG6000 as a carrier material. The ratio (1:1) of Lamotrigine and PEG6000 was suited for the preparation as it released 72.5% of drug (Table 3). Interestingly, it was found that the prepared solid dispersion increased the solubility from 1.7mg/ml to 8.5mg/ml that is 20% increase in the solubility. The prepared solid dispersion with other ingredients were subjected to various preformulation studies before compression (Table 2). The angle of repose for formulation F1 to F6 varied from 25-35 howing good flow properties. The tapped density (0.45-0.55) and bulk density (0.32-0.40) also confirmed good flow characteristic of the granules. In addition to this, carrs’s index and hausner’s ratio ranged between 12.34-20.13 and 1.15-1.20 respectively which confirmed good flowability. The compressed tablets of different formulations were also subjected to several evaluation parameters (table 4). The weight of all the tablets were within the permissible limit as specified in different pharmacopoeias. Hardness of the tablet varied within 3.5-3.7 which indicates good mechanical strength. Friability of all the tablets were within 0.3-0.6 showing resistance to mechanical stress. The wetting time for formulation F5 was very less (17sec.). Moreover , it disintegrated very fastly (54 sec.) as compared to other formulations. The percent drug content of tablets was within permissible limit i.e. 96.6%- 98.9%. The drug release profile of all the formulation was given in table 5 and figure 2. Among all the formulations formulation F5 was found to have better release profile when compared to others. The formulation F5 showed NLT 89.56% release in 30 min. An increase in release kinetic was observed on increasing concentration of super disintegrant. The ratio of kollidon and sodium starch glycolate (1:3) was known to be best suited for fast disintegration and drug release.

 

CONCLUSION:

The present study was done to formulate and evaluate fast dissolving tablet of Lamotrigine. The tablets were formulated by direct compression technique. Solid dispersion of lamotrigine using PEG6000 revealed better solubility of lamotrigine.(8.5mg/ml). All the formulation showed acceptable release among which F5 was best selected out. The study revealed that kollidon and sodium starch glycolate can be used in different ratio for better drug disintegration and drug release.

 

ACKNOWLEDGMENT:

Authors want to acknowledge the facilities provided by the Rungta College of Pharmaceutical Sciences and Research, Kohka, Kurud Road, Bhilai, Chhattisgarh, India. The authors also wants to acknowledge Chhattisgarh Council of Science and Technology (CGCOST) for providing financial assistance under mini research project (MRP) vide letter no. 1124/CCOST/MRP/2015; Dated: September 4, 2015 and 1115/CCOST/MRP/2015; Dated: September 4, 2015.

 

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Accepted on 18.10.2017        © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(6): 2468-2472.