Singh et al: Formulation and Evaluation of Orally Disintegrating Tablets of Lamotrigine 2881 

Research Paper

Formulation and Evaluation of Orally Disintegrating Tablets of Lamotrigine Sudarshan Singh*, S.S. Shyale and P. Karade Department of Pharmaceutics, HSBPVT’s, College of Pharmacy, Kashti, Ahmednagar 414701, Maharastra, India. Received February 28, 2015; accepted March 31, 2015

ABSTRACT

The aim of this study was to design orally disintegrating tablet (ODT) of Lamotrigine. It is an Antiepileptic drug which is widely used in epilepsy. It is also used in simple and complex partial seizures and secondary generalized tonic-clonic seizures. It is poorly water soluble drug (0.46 mg/ml). Thus, an attempt was made to enhance the water solubility by complexation with β-cyclodextrin (1:1 molar ratios). The orally disintegrating tablet of lamotrigine was prepared by direct compression method using different concentration of superdisintegrants such as Sodium starch glycollate, croscarmellose sodium by sublimating agent such as camphor. The formulations were evaluated for weight variation, hardness, friability, drug content, wetting time, in vitro disintegration time and in vitro dissolution studies. The prepared tablets were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry. The disintegration time for the complexed tablets prepared

by different concentration of superdisintegrants was found to be in range of 32.54 0.50 to 55.12 0.57 sec and wetting time of the formulations was found to be in range of 28.47 0.67 to 52.19 0.72 sec. All the formulation showed almost 100 percent of drug release within 15 min. Among all the formulation F6 and F7 prepared with 18% croscarmellose sodium and camphor shows faster drug release, respectively 10 min, F6 gives good result for disintegration time, drug release, wetting time and friability. Further formulations were subjected to stability testing for 30 days at temperature of 40 ± 5 ºC/75 ± 5 %RH. Tablets showed no appreciable changes with respect to physical appearance, drug content, disintegration time and dissolution profiles. Results were statistically analyzed by one-way ANOVA at a p < 0.05. It was found that, the data at any point of time are significant at p < 0.05.

KEYWORDS: Lamotrigine; β-Cyclodextrin; Sodium starch glycollate; Croscarmellose.

Introduction

ODTs are designed to disintegrate or dissolve rapidly on contact with saliva, thus eliminating the need for chewing the tablet, swallowing an intact tablet, or taking the tablet with water. Although no water is needed to allow the drug to disperse quickly and efficiently, most technologies utilize the body's own salivation. This mode of administration was initially expected to be beneficial to paediatric and geriatric patients, to people with conditions related to impaired swallowing and for treatment of some patients when compliance may be difficult (Reddy et.al., 2009). ODT has previously been distinguished as a separate dosage form because of the specific, intended performance characteristics of such products, which are rapid oral disintegration in saliva with no need for chewing or drinking liquids to ingest these products (Thakur and Mridul, 2011).

Most benefits of ODT are for paediatric, geriatric and bedridden or developmentally disabled patients. Patients with persistent nausea who are travelling or who have little or no access to water can also benefit from ODTs. In the near future, other patient populations will also be targeted (Devi et. al., 2010). The ease of administration of orally disintegrating tablet, along with its pleasant

taste, may encourage a patient to adhere to a daily medication regimen (Bhandari et. al., 2008).

Lamotrigine is an antiepileptic drug widely used in epilepsy. The major problem with Lamotrigine is its very low solubility in GI fluids which result in to poor bioavailability after oral administration. Therefore there is a strong need to formulate solubility enhanced Lamotrigine in suitable dosage form like orally disintegrating tablets to achieve reliable bioavailability and enhance patient compliance (Martindale, 2007; Kundu and Sahoo, 2008). Hence this investigation was carried out for enhance dissolution through complexation, formulating the complex in orally disintegrating tablet by using sublimating agent testing phase solubility study of drug with β-cyclodextrin and preparation of inclusion complex of lamotrigine with β-cyclodextrin by employing different method.

Materials and Methods

Materials

Lamotrigine was received as a gift sample from Abott pharma pvt. Ltd., Goa. Crosscarmellosesodium and sodium starch glycollate was received as a gift sample from Signet Chemical Co Ltd, Bandra Kurla Complex,

 

International Journal of Pharmaceutical Sciences and NanotechnologyVolume 8Issue 2 April – June 2015

MS ID: IJPSN-2-28-15-SINGH

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Mumbai β-Cyclodextrin was and other materials used were of analytical grade and procured from commercial sources.

Methods

Solubility enhancement by using β-cyclodextrin: Different molar ratios of lamotrigine with β-cyclodextrin (1:1, 1:1.5, 1:1.75, 1:2) was prepared by kneading method for solubility enhancement. β-Cyclodextrin was slowly added to the mortar, small quantity of distilled water was added while triturating to obtain a homogenous paste. The drug was slowly added to the paste and mixture triturated for one hour. During the process, the water content of the paste was empirically adjusted to maintain the consistency of the paste. The paste was dried at 40 oC for 24 hr, pulverized by passing through sieve no. 85 and stored in a desiccator till further use(Alexanderet.al., 2010).

Drug excipients compatibility studies: The FT-IR spectrum of Lamotrigine and Physical mixture of Lamotrigine with croscarmellose sodium and sodium starch glycollate were analyzed to verify the compatibility between the pure drug and polymers using FT-IR (Make Varian carry, Model-510) by KBr disc method(Meyers, 2000).DSC thermogram of the Lamotrigine and Physical mixture of Lamotrigine, crosscarmellose sodium and sodium starch glycollate were obtained from Shimadzu DSC-60 (Shimadzu Limited Japan) by heating at a scanning rate of 10 °C/ min over a temperature range 50 °C -300 °C under nitrogen environment. DSC thermogram of pure Lamotrigine and formulation were obtained to verify chemical interaction between drug and excipients. Formulation of orally disintegrating tablets: Lamotrigine Orally disintegrating tablets were prepared by direct compression method according to formula given in the Table 1. All the ingredients were sieved through 60‐mesh sieve separately and collected. The drug and the ingredients were weighed and mixed in geometrical order and direct compressed to acquire tablets of 175 mg weight using 6 mm flat punch on 10 station compression machine (Cemach R and D Tablet press). The compressed tablets were subjected to drying in hot air oven at 60 oC

for 6 hours to facilitate the sublimation of camphor during drying (Sawarikar et.al., 2010). Pre-compression evaluation parameter: The powder bed was evaluated for the blend property such as Bulk density, Tapped density, Carr’s index, Hausner’s ratio and Angle of repose (Velmurugan and Sundar, 2010). Evaluation of orally disintegrating tablets: The thickness of individual tablets was measured with a micrometer, which permits accurate measurement and provides information on the variation between tablets. Hardness requires a certain amount of strength, or hardness and resistance to friability, withstand mechanical shock. Tablet hardness is also called as crushing strength. Monsanto hardness tester was used to check the hardness of the tablets (Khinchi et. al., 2010). The friability of twenty tablets was measured using a USP type Roche Friabilator Pre-weighed tablets were placed in a plastic chambered Friabilator attached to a motor revolving at a speed of 25 rpm for 4 min. The tablets were then dusted, reweighed and percentage weight loss (friability) was calculated (Rampure et. al., 2010).

Wetting time: A Petri dish containing 6 ml of 6.8 phosphate buffer was used. A tissue paper folded twice was kept in the dish and a tablet was placed on it. A small quantity of Amaranth red colour was put on the upper surface of the tablet. Time required for the upper surface of the tablet to become red was noted as the wetting time of the tablet (Sudarshan and Dhaval, 2010).

Disintegration test: Disintegration of rapidly disintegrating oral tablets is achieved in the mouth owing to the action of saliva; however amount of saliva in the mouth is limited. A modified method was used to determine disintegration time of the tablets. A cylindrical vessel was used in which 10 mesh a screen was placed in such a way that only 2 ml of disintegrating medium would be placed below the sieve. To determine disintegration time, 6 ml of phosphate buffer (pH 6.8), was placed inside the vessel in such a way that 4 ml of the media was below the sieve and 2 ml above the sieve. Tablet was placed on the sieve and the whole assembly was then placed on a shaker. The time at which all the particles pass through the sieve was taken as a disintegration time of the tablet (Abdul and Hamed, 2011).

TABLE 1

Composition of Lamotrigine orally disintegrating tablets.

Ingredients(in mg) F1 F2 F3 F4 F5 F6 F7 F8 F9

Drug complex (eq. to 25 mg) 135.8 135.8 135.8 135.8 135.8 135.8 135.8 135.8 135.8

Sodium starch glycollate (12%, 15%, 18% w/w)

21 26.25 31.5 - - - - - -

Croscarmellose Sodium (12%, 15%, 18% w/w)

- - - 21 26.25 31.5 31.5 31.5 31.5

Direct compressible lactose 10.7 5.45 0.2 10.7 5.45 0.2 0.7 7.2 7.7

Camphor 7 7 7 7 7 7 7 - -

Aerosil 0.5 0.5 0.5 0.5 0.5 0.5 - 0.5 -

Total weight (mg) 175 175 175 175 175 175 175 175 175

Singh et al: Formulation and Evaluation of Orally Disintegrating Tablets of Lamotrigine 2883 

In vitro drug release: The release from rapidly oral disintegrating tablets of Lamotrigine was determined using USP dissolution testing apparatus 2 (paddle method). The dissolution test was performed using 900 ml of acidic buffer, pH 1.2 at 37 ± 0.5 °C and 50 rpm. A sample (5 ml) of the solution was withdrawn from the dissolution apparatus at different time intervals and the samples were replaced with fresh dissolution medium. Later the withdrawn sample was diluted to suitably with acidic buffer, pH 1.2. Absorbance of these solutions was measured at 267 nm using a UV Visible double beam spectrophotometer (Jasco v-630). Cumulative percentage drug release was calculated using an equation obtained from a standard curve (Indian Pharmacopoeia, 2007).

Statistical analysis: Results obtained for above disintegration time, wetting time and in vitro dissolution studies measurement are expressed as mean SEM and subjected to one-way analysis of variance (ANOVA) with P < 0.05 were considered to be statistically significant.

Stability Study: To assess the drug and formulation stability, stability studies was performed according to ICH guideline. Optimized orally disintegrating tablets were sealed in aluminium packing and kept in humidity chamber maintained at 40 °C and 75% RH for one month. Samples were analyzed for the disintegration time, wetting time, in vitro drug release study and other physicochemical properties at regular intervals (ICH, 2003).

Results and Discussion Solubility enhancement of lamotrigine: A complex of

lamotrigine and β-cyclodextrin in different molar ratios (1:1, 1:1.5, 1:1.75, and 1:2) were prepared. The solubility of lamotrigine-β-cyclodextrin was studied and presented in Figure 1. Solubility of Lamotrigine is increases with 1:1.75 molar ratios.

Drug excipients compatibility studies: The spectrum of FTIR is shown in Figure 2. The characteristic peaks of

Lamotrigine N-H stretch at 3812.80–3665.53 cm-1, C-H stretch at 2960.25–2876.42 cm–1, C=C stretch at 1947.97–1816.43 cm–1 and C-N stretch at 1643.80–1409.92 cm–1

C-Cl stretch at 791.60 cm-1 based on these value the sample of Lamotrigine is comparable with literature value. FTIR spectra of optimized formulation are shown in Figure 3. the characteristic peaks of Sodium starch glycollate and crosscarmellose sodium, N-H stretch at 3665.32–3643.22 cm–1, C-H stretch at 3468.25–3126.29 cm–1, C=C stretch at 2713.94–2511.74 cm–1 and C-N stretch at 1643.85–1414.62 cm–1 C-Cl stretch at 792.84 cm–1

were not affected. It was found that Lamotrigine is complies with all excipient blend.

Fig. 1. Solubility enhancements of drug by kneading method in various solvents.

DSC thermograms (Figure 4) showed that Lamotrigine melt at 219.52 °C and this result collaborates with the result of experiment on melting point 220 oC and the literature value of 218 °C. There is no shift, or change in magnitude and intensity of endothermic peak in Figure 5 indicating that the drug does not interact with any of the excipients used in the study.

Fig. 2. FTIR spectrum of the Lamotrigine.

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Fig. 4. DSC thermogram of Lamotri-gine.

Pre-compression evaluation parameter The results of pre-compression parameters are

presented in Table 2. Bulk density and Tapped density were found in acceptable limit which indicating that the packing properties required during compression are adequate in all formulations. Carr’s index indicating good compressibility. Hausner’s ratio and Angle of repose were found inacceptable limit which implies good flow property.

Physical characteristic of the tablets Tablets of all batches were evaluated for weight

variation, hardness, diameter thickness and friability results were tabulated in Table 3. All batches pass

weight variation test and found to be within range which is 173.78 2.20 to 175.85 1.14 as given in Table 3. The hardness is within the range of 3 to 3.4 kg/cm2, it indicates that tablet have good mechanical strength (Alexanderet al., 2010). The mean thickness of all formulation was found to be in the range of 5.02 to 5.07 mm. The tablet mean diameter of all formulation was found to be in the range of 6.01 to 6.05 mm as given in Table 3. For all formulation percentage friability were found to be in the range of 0.23 to 0.89 %. The friability were less than 1% in all the formulations ensuring that the tablet were mechanically stable(Alexander et al., 2010).

Fig. 3. FTIR Spectrum of Lamotrigine with all excipients blend. 

Singh et al: Formulation and Evaluation of Orally Disintegrating Tablets of Lamotrigine 2885 

TABLE 2

Evaluation of pre-compression parameters of tablet blends F1 to F9 (n = 3)

Batch code

Bulk density (gm/ml) ± SD

Tapped density (gm/ml) ± SD

Carr’s index % ± SD

Hausner’s ratio ± SD

Angle of repose (0) ± SD

F1 0.5263 0.03 0.6566 0.01 14.05 0.23 1.2635 0.01 28.36 0.61 F2 0.5555 0.04 0.7143 0.01 13.12 0.25 1.2857 0.01 29.21 0.54

F3 0.4761 0.01 0.5882 0.03 16.04 0.18 1.2353 0.02 27.58 0.85

F4 0.5263 0.02 0.6250 0.01 14.78 0.14 1.1875 0.01 28.86 0.20 F5 0.5555 0.01 0.7143 0.04 13.02 0.25 1.2857 0.04 29.82 0.83

F6 0.4761 0.03 0.5545 0.02 14.29 0.13 1.167 0.03 27.96 0.39 F7 0.4592 0.02 0.6245 0.03 12.34 0.16 1.235 0.05 28.24 0.35

F8 0.5317 0.01 0.5689 0.03 14.87 0.17 1.154 0.04 29.98 0.49

F9 0.4681 0.04 0.7215 0.03 16.35 0.15 1.257 0.02 30.46 0.28

Note: Values are mean of three observation (n = 3) and Values in parenthesis are Standard Deviation (± SD)

TABLE 3

Post compression properties of tablets F1 to F9 (n = 20)

Batch code

Average weight of Tablet (mg) ± SD

Hardness (kg/cm2) ± SD

Diameter (mm) ± SD

Thickness (mm) ± SD

Friability ± SD %

F1 174.25 1.29 3.25 0.28 6.037 0.05 5.02 0.03 0.63 0.02

F2 173.96 1.44 3.2 0.90 6.010 0.03 5.05 0.08 0.52 0.02 F3 173.94 2.10 3.0 0.26 6.020 0.04 5.06 0.02 0.73 0.01

F4 175.20 2.0 3.1 0.13 6.010 0.03 5.05 0.02 0.89 0.02

F5 174.25 2.26 3.2 0.58 6.033 0.06 5.02 0.05 0.75 0.03 F6 173.78 2.20 3.0 0.10 6.027 0.03 5.07 0.06 0.45 0.02

F7 175.85 1.14 3.1 0.13 6.021 0.05 5.03 0.05 0.54 0.04 F8 174.56 1.56 3.2 0.65 6.035 0.01 5.05 0.03 0.78 0.02

F9 173.89 2.15 3.2 0.26 6.015 0.02 5.04 0.02 0.83 0.03

Note: Values are mean of three observation (n = 3) and Values in parenthesis are Standard Deviation (± SD)

Disintegrationtime The results of Disintegration time is presented in

Table 4. The formulations F1, F2 and F3 were prepared with 12 % w/w, 15 % w/w and 18 % w/w of Sodium starch glycollate which show disintegration time 55.12, 51.36 and 47.78 sec respectively. The results suggest that, as the content of Sodium starch glycollate is increased disintegration time decreases. The formulations F4, F5 and F6 were prepared with 12 % w/w, 15 % w/w and 18 % w/w of crosscarmellose sodium which shows disinte-gration time 45.14, 40.78 and 32.54 sec respectively. The results suggest that, as the content of croscarmellose sodium is increased disintegration time decreased. The formulations F7, F8 and F9 were prepared with 18 % w/w respectively of crosscarmellose sodium to assess the effect of aerosil and camphor on disintegration time. Formulation was prepared coded as F7 with camphor and CCS, The F7 showed a disintegration time of 33.17 sec. Further F8 was developed with Aerosil and CCS, which showed disintegration time of 53.13 sec. and later F9 was prepared with 18 % w/w CCS alone. F9 showed disintegration time of 53.73 sec. The above results of F7, F8 and F9 suggest that, camphor decreases the disintegration time and whereas Aerosil has no effect on disintegration time. Statistically the data was analyzed by one-way ANOVA at a p < 0.05. It was found that, the data at any point of time are significant at p < 0.05.

Wetting time The results of wetting time are presented in Table 4.

The formulations F1, F2 and F3 were prepared with 12 % w/w, 15 % w/w and 18 % w/w of Sodium starch glycollate which shows wetting time 45.36, 40.47 and 37.23 sec respectively. The results suggest that, as the content of Sodium starch glycollate is increased wetting time decreases. The formulations F4, F5 and F6 were prepared with 12 % w/w, 15 % w/w and 18 % w/w of crosscarmellose sodium which shows wetting time 38.69, 35.12 and 28.47 sec respectively. The result suggests that, as the content of CCS increased wetting time decreases. The formulations F7, F8 and F9 were prepared with 18 % w/w respectively of croscarmellose sodium to assess the effect of Aerosil and camphor on wetting time. Formulation was prepared coded as F7 with camphor and CCS, The F7 showed a wetting time of 31.87 sec. Further F8 was developed with aerosil and CCS, which showed wetting time of 50.63 sec and later F9 was prepared with 18 % w/w CCS alone. F9 showed wetting time of 52.19 sec. The above results of F7, F8 and F9 suggest that, camphor decreases the wetting time and whereas Aerosil has no effect on wetting time. The result of wetting time for optimized batch is presented in Figure 6. Statistically the data was analyzed by one-way ANOVA at a p < 0.05. It was found that, the data at any point of time are significant at p < 0.05.

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TABLE 4

Post compression parameters of tablets F1 to F9 (n = 3)

Batch Code

Disintegration time (s) ± SD

Wetting Time (s) ± SD

F1 55.12 0.57 45.36 0.66 F2 51.36 0.43 40.47 0.55 F3 47.78 0.61 37.23 0.46 F4 45.14 0.35 38.69 0.67 F5 40.78 0.49 35.12 0.60 F6 32.54 0.50 28.47 0.67 F7 33.17 0.48 31.78 0.59 F8 53.13 0.62 50.63 0.85 F9 53.73 0.61 52.19 0.72

Note: Values are mean of three observation (n = 3) and Values in parenthesis are Standard Deviation (± SD)

In vitro drug release The result of in vitro drug release study is presented in

Figure 7. The comparative study of dissolution profile of formulations F1, F2 and F3 were prepared with 12 % w/w, 15 % w/w and 18 % w/w of Sodium starch glycollate as super disintegrating agent. Each of the tablets in all the formulations contains 25 mg of Lamotrigine and camphor as sublimating agent. The percentage release of drug from F1, F2 and F3 were found to be 92.89 %, 95.89 and 99.04 % in 15 min study respectively. The slope values of release data suggest that, as the concentration of Sodium starch glycollate increased rate of release of drug gradually

increases. The comparative study of dissolution profile of formulations F4, F5 and F6 were prepared with 12 % w/w, 15 % w/w and 18 % w/w of croscarmellose sodium as super disintegrating agent. Each of the tablets in all the formulations contains 25 mg of Lamotrigine and camphor as sublimating agent. The percentage release of drug from F4, F5 and F6 were found to be 99.85 %, 99.65 % and 93.49 % in 16, 16, 10 min study respectively. The slope values of release data suggest that, as the concentration of croscarmellose sodium is increased rate of release of drug gradually increases. The comparative study of dissolution profile of formulations F7, F8 and F9 were prepared with 18 % w/w respectively of croscarmellose sodium as super disintegrating agent. Each of the tablet in F7 formulations contain 25 mg of Lamotrigine and camphor as sublimating agent and absence of aerosil which does not affect on in vitro drug release. Batch F8 camphor was absent which showed affect on in vitro drug release. Batch F9 both Aerosil and camphor was absent which also showed affect on in vitro drug release. The percentage release of drug from F7, F8 and F9 were found to be 99.80 %, 97.91 % and 94.45 % in 10, 16 and 16 min respectively. The slope values of release data suggest that, as the absence of camphor in batch F8, Aerosil and camphor in batch F9 showed great effect on in vitro drug release.

Fig. 5. DSC thermogram of Lamotrigine with powder mixture of excipients.

Tablet wetting initial Tablet wetting after 28.47 sec

Fig. 6. Wetting time of orally disinte-grating tablet of Lamotrigine.

Singh et al: Formulation and Evaluation of Orally Disintegrating Tablets of Lamotrigine 2887 

Fig. 7. Comparative dissolution profile of batches F-1 to F-9.

Stability studies The tablets were studied for short term stability at

40 °C 2 °C and 75% 5 % RH conditions for the period of 30 days. Statistically the data was analyzed by one-way ANOVA at a p < 0.05. It was found that, the data at any point of time are significant at p < 0.05.

Conclusions

Orally disintegrating tablet of Lamotrigine was formulated by using various superdisintegrants such as croscarmellose sodium and Sodium starch glycollate in different proportions by sublimating agent like camphor. The solubility of Lamotrigine is enhanced by inclusion complexes with β-CD as a drug carrier. Then the prepared inclusion complexes was characterized and evaluated by DSC and FT-IR. The disintegration time of formulation F6 was found to 32.54 seconds. Wetting time studies showed that wetting time was rapid in formulations containing camphor followed by CCS and SSG. It was found that as the concentration of CCS and SSG was increases, then wetting time was reduces. The wetting time of F6 formulation was found to be 28.47seconds.Invitro disintegration of batch F-6 gives rapid disintegration time and wetting time. Drug content was found to be 101.23%. Results of in-vitro dissolution data showed that from formulation F1-F9, F-6 gives the drug release up to 99.65% within 10 min. So F6 was considered as a best formulation. As a result of this study, it may be concluded that the inclusion complexation technique may be useful to enhance solubility, dissolution rate and subsequently bioavailability of poorly soluble drug. The concept of formulating high porous orally disintegrating tablets of Lamotrigine inclusion complexes using superdisintegrants by sublimation technique offers a suitable and practical approach in serving desired objectives of faster disintegration and dissolution characteristics. Accelerated stability study was carried out for optimized formulation F6 which showed no

significant difference in the drug content, disintegration time, hardness, friability and in vitro dissolution studies which confirms the stability of the product. Results were statistically analyzed by one-way ANOVA at a p < 0.05. It was found that, the data at any point of time are significant at p < 0.05.

Acknowledgements

Express my most cardial and humble thanks to management of Hon. Shri. Babanrao Pachpute Vichardhara Trust Group of Institutions, College of Pharmacy, for necessary help and facilitate the use of the necessary instruments and materials required during the entire course of this research work. I am also grateful to Abott pharma pvt. Ltd, Goa And Signet Chemical Co Ltd, Bandra Kurla Complex, Mumbaifor providing me gift samples of Drug and Polymers.

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Address correspondence to:  Dr. Sudarshan Singh, Assistant Professor, Department of Pharmaceutics, H.S.B.P.V.T, Group of Institutions, College of Pharmacy, Kashti, Ahmednagar-414701, Maharashtra. Mob: +91-9765593639; E-mail: sudarshansingh83@hotmail.com