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Research Paper Development of Fast Dissolving Carbamazepine Tablets: Effect of Functionality of Superdisintegrants

N. G. Raghavendra Rao1*, Tarun Patel2 and Rathan Kumar3 1Luqman College of Pharmacy, Gulbarga, India. 2APMC College of Pharmaceutical Education and Research, Himatngar, India. 3N.E.T. College of Pharmacy, Raichur, India.

ABSTRACT: Carbamazepine, a dibenzapine derivative with structure resembling that of tricyclic antidepressants, is used in the treatment of epilepsy. The major problem of this drug is very low solubility in biological fluids and poor bioavailability after oral administration. Carbamazepine fast dissolving tablets (FDT) have been prepared by direct compression method. Effects of superdisintegrants (such as croscarmellose sodium, crospovidone and sodium starch glycolate) on wetting time, disintegrating time, drug content, in vitro release, and stability parameters have been studied. The prepared tablets were characterized by DSC and FTIR Studies. No chemical interaction between drug and excipients was confirmed by DSC and FTIR studies. Disintegration time and dissolution parameters (t50% and t90%) decreased with increase in the level of croscarmellose sodium and crosspovidone, whereas disintegration time and dissolution parameters increased with increase in the level of the sodium starch glycolate in tablets. Among all formulations f8 was considered best. The results concluded that fast dissolving tablets of poorly soluble drug carbamazepine, showing enhanced dissolution, will lead to improved bioavailability, improved effectiveness and hence better patient compliance.

KEYWORDS: Fast dissolving tablets; Carbamazepine; croscarmellose sodium; crospovidone and sodium starch glycolate

Introduction Carbamazepine, a dibenzapine derivative with structure resembling the tricyclic antidepressants, is used in the treatment of epilepsy. One of the major problems with this drug is its very low solubility in biological fluids and its biological half-life between 18 to 65 hrs that results into poor bioavailability after oral administration (Reynolds JEF, 1993; Mc Naman JO, 1996). It shows erratic dissolution profile in gastric and intestinal fluid due to its poor water solubility. The peak plasma concentration C max and the time taken to reach C max (t max) depend upon extent and rate of dissolution of drug, respectively. The rate of dissolution can be increased by increasing the surface area of available drug by various methods (micronization, complexation and solid dispersion) (Martin A, 1993). The dissolution of a drug can also be influenced by disintegration time of the tablets. Faster disintegration of tablets delivers a fine suspension of drug particles resulting in a higher surface area and faster dissolution (Setty CM, 2008).

Of all the orally administered dosage forms, tablet is most preferred because of ease of administration, compactness and flexibility in manufacturing. Due to changes in various physiological functions associated with aging including difficulty in swallowing, administration of intact tablet may lead to poor patient compliance and ineffective therapy. The pediatric and geriatrics patients are of particular concern. To overcome this, dispersible tablets (Schiermeier S, 2002) and fast-disintegrating tablets (Mizumoto T, 2005) have been developed. Most commonly used methods to prepare these tablets are; freeze-drying/Lyophilization (Virley P, 1990), tablet molding (Dobetti L, 2000) and direct-compression methods (Bi Y, 1996). Lyophilized tablets show a very porous structure, which causes quick penetration of saliva into the pores when placed in oral cavity (Virley P, 1990; Patrick K, 1997). The main disadvantages of tablets produced are, in addition to the cost intensive production process, a lack of physical resistance in standard blister packs and their limited ability to incorporate higher concentrations of active drug’ can be rearranged in a better way (Schiermeier S, 2002). Moulded tablets dissolve completely and rapidly. However, lack of strength and taste masking are of great concern (Dobetti L, 2000; Chang RK, 2000). The main advantages of direct compression are low manufacturing cost and high mechanical integrity of the tablets (Bi Y,

International Journal of Pharmaceutical Sciences and Nanotechnology

Volume 3 • Issue 1 • April – June 2010

* For correspondence: N.G. Raghavendra Rao,

E-mail: [email protected]

824

N.G. Raghavendra Rao et al. : Development of Fast Dissolving Carbamazepine Tablets: Effect of… 825

1996; Takao M, 1996). Therefore, direct-compression appears to be a better option for manufacturing of tablets. The fast disintegrating tablets prepared by direct compression method, in general, are based on the action established by superdisintegrants such as croscarmellose sodium, crospovidone and sodium starch glycolate. The effect of functionality differences of the superdisintegrants on tablet disintegration has been studied (Zhao N, 2005). The objective of the this work was to develop carbamazepine fast dissolving tablets by using croscarmellose sodium, crospovidone and sodium starch glycolate as superdisintegrants. A total 12 formulations were prepared by direct compression method, compositions of which are given in [Table 1].

Material and Methods Carbamazepine drug was procured as gift sample from Cadila Health Care, Ahmedabad, Gujarat. Superdisintegrants like croscarmellose sodium, crosspovidone and sodium starch glycolate were procured as a gift sample from Maruthi Chem. Ahmedabad, Gujarat. Aspartame as received as a gift sample from Aan Pharma Pvt Ltd., Rakanpur-Gujarat. Sodium lauryl sulphate, D.C. mannitol, microcrystalline cellulose, talc, and magnesium stearate were purchased from S.D. fine chem., Mumbai.

Preparation of blends and tablets Carbamazepine tablets were prepared by direct compression method. The composition of each tablet is shown in [Table 1]. The drug, diluents, superdisintegrant and sweetener were passed through sieve # 40. All the above ingredients were properly mixed together (in a poly-bag). Talc and magnesium stearate were passed through mesh # 80, mixed, and blended with initial mixture in a poly-bag. The powder blend was compressed into tablets on a 10 station rotary punch tableting machine (Rimek Mini Press-1) using 8 mm punch set.

Evaluation of Carbamazepine tablets The prepared tablets were evaluated for weight variation, hardness, friability, disintegration time, wetting time, drug content, and stability studies. In weight variation test twenty tablets were selected randomly and the average weight was calculated. Then individual tablets were weight was calculated. Then individual tablets were weighed and the weight was compared with an average weight. The Pfizer hardness tester was used for the determination of the hardness of tablets. Tablet was placed in contact between the plungers, and the handle was pressed, the force of the fracture was recorded. The friability of tablets was determined using Roche friabilator (Cambel Electronics, Mumbai, India). Six tablets were tested from each formulation. In the Disintegration time (Rockville, MD, USP, 2004) study tablet was put into 100 ml distilled water

at 37 ± 2°C. Time required for complete dispersion of a tablet was measured with the help of digital tablet disintegration test apparatus. To measure wetting time of tablet (Sunada H, 2002), a piece of tissue paper folded twice was placed in a small petri dish (internal diameter = 6.5cm) containing 5 ml of distilled water. A tablet was placed on the paper, and the time for complete wetting of the tablet was measured in seconds. The solubility studies of carbamazepine in different solvents/buffer solutions were carried out to know the solubility and the appropriate dissolution medium was decided. Table 2 shows the solubility data of carbamazepine in solvent/buffer solutions. In this study, 1% SLS was used as dissolution media because it can maintain perfect sink conditions. For the determination of drug content (Younxia B, 1999) atleast three tablets from each formulation were weighed individually, pulverized, and diluted to 259 ml with sufficient amount of 1% sodium lauryl sulphate solution. After that an aliquot of the filtrate was diluted and analyzed spectrophotometrically at 287nm. The stability study of the tablets was carried out according to International Conference on Harmonization guidelines for zone III and IV. The formulations were stored at 40 ± 2oC / 75 ± 5 %RH for 4 weeks by storing the samples in stability chamber (Lab-Care, Mumbai).

In vitro release studies (Indian Pharmacopoeia, 1996), was carried out in the USP dissolution test apparatus (Electrolab TDT - 08 L Dissolution tester USP) type 2 (paddle). 900 ml of the dissolution medium (1% sodium lauryl sulphate solution) was taken in covered vessel and the temperature was maintained at 37 ± 0.5oC. The speed of the paddle was set at 75 rpm. Sampling was done at every one min interval. For each sample 5 ml of the dissolution medium was withdrawn and the same amount of dissolution medium at 37oC was replenished to the dissolution medium. The sample was withdrawn and diluted with 1% sodium lauryl sulphate solution and analyzed in the UV spectrophotometer at 287 nm. All the studies were performed in triplicate.

Characterization of Carbamazepine tablets FTIR Studies: IR spectra for drug, and powdered tablets were recorded in a Fourier transform infrared spectrophotometer (FTIR 1615, Perkin Elmer, USA) with KBr pellets.

DSC Studies: DSC scans of about 10mg, using an automatic thermal analyzer system were performed with accurately weighed Carbamazepine and formulation (Mettler Toledo, USA). Sealed and perforated aluminium pans were used in the experiments for all the samples. Temperature calibrations were performed using indium as standard. An empty pan sealed in the same way as the sample was used as a reference. The entire samples were run at a scanning rate of 10°C/min from 50-300C°.

826 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 • Issue 1 • April - June 2010

Results and Discussion The values of pre-compression parameters evaluated were within prescribed limits and indicated good free flowing

property. The data obtained from post-compression parameters such as weight variation, hardness, friability, wetting time, drug content and in vitro disintegration are shown in [Table 3].

Table 1 Composition of carbamazepine fast dissolving tablets.

Ingredients (mg) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

Carbamazepine 100 100 100 100 100 100 100 100 100 100 100 100 Sodium starch glycolate 2.5 5 7.5 10 -- -- -- -- -- -- -- -- Croscarmellose sodium -- -- -- -- 2.5 5 7.5 10 -- -- -- -- Crospovidone -- -- -- -- -- -- -- -- 2.5 5 7.5 10 Micro crystalline cellulose 40 40 40 40 40 40 40 40 40 40 40 40 DC-Mannitol 42.5 40 37.5 35 42.5 40 37.5 35 42.5 40 37.5 35 Aspartame 10 10 10 10 10 10 10 10 10 10 10 10 Talc 3 3 3 3 3 3 3 3 3 3 3 3 Magnesium Stearate 2 2 2 2 2 2 2 2 2 2 2 2

Table 2 Solubility study data of carbamazepine in various solvents and buffers.

Sl. No Name of the solvent Concentration (mg/ml) (± SD), n = 3

1 Phosphate buffer pH 6.8 2.18 ± 0.002



4 1% sodium lauryl sulphate 6.58 ± 0.008

5 2% sodium lauryl sulphate 5.42 ± 0.050

6 0.1N Hydrochloric acid 0.528 ± 0.004

Table 3 Results of post compression parameters.

Formulation Hardness

Kg/cm2

(± SD), n=3

Friability (%) (± SD), n=6

Drug content (mg %)

(± SD), n=10

Wetting time (sec) (± SD),

n=3

Weight variation (mg) (± SD), n=20

F 1 3.2 ± 0.13 0.66 ± 0.8 99.86 ± 0.4 32.14 ± 1.6 201.58 ± 1.7

F 2 3.2 ± 0.12 0.58 ± 0.14 99.28 ± 0.2 62.07 ± 1.4 200.64 ± 1.1

F 3 3.2 ± 0.12 0.64 ± 0.4 99.49 ± 0.9 74.04 ± 1.1 200.45 ± 0.8 F 4 3.3 ± 0.13 0.57 ± 0.5 99.51 ± 0.7 88.11 ± 1.8 199.68 ± 0.4 F 5 3.3 ± 0.14 0.61 ± 0.2 99.22 ± 10 51.16 ± 1.4 200.48 ± 1.5 F 6 3.5 ± 0.11 0.65 ± 0.05 99.92 ± 0.8 48.21 ± 1.2 201.64 ± 1.9 F 7 3.2 ± 0.14 0.62 ± 0.18 99.52 ± 0.4 41.23 ± 1.6 200.55 ± 2.1 F 8 3.1 ± 0.15 0.59 ± 0.24 99.34 ± 1.1 38.31 ± 1.2 201.48 ± 1.1 F 9 3.4 ± 0.14 0.55 ± 0.16 99.64 ± 0.9 22.11 ± 1.1 202.51 ± 1.8

F 10 3.2 ± 0.11 0.61 ± 0.09 99.41 ± 0.6 18.10 ± 1.8 200.66 ± 1.2 F 11 3.2 ± 0.14 0.63 ± 0.4 99.28 ± 0.4 14.10 ± 1.3 201.45 ± 1.8 F 12 3.1 ± 0.11 0.59 ± 0.3 99.44 ± 1.1 12.18 ± 1.4 200.68 ± 0.9

Note: Values in parenthesis are standard deviation (±SD)


In all the formulations, hardness test indicated good mechanical strength, friability is less than 1% which indicated that tablets had a good mechanical resistance. Drug content was found to be high (≥99.1%) and uniform in all the tablet formulations.

The tablets were subjected for evaluation of in vitro disintegration time. The in vitro disintegration time for all the formulations varies from 09.13 ± 0.6 to 53.20 ± 2.2 sec. Figure 1 depicts the disintegration behavior of the tablets. It was observed that when crospovidone is used as disintegrant, the tablet disintegrates rapidly in a short time due to easy swelling ability of crospovidone when compared to other tablets prepared by using croscarmellose sodium and sodium starch glycolate. Comparatively, disintegration times of the tablets containing Crospovidone > Croscarmellose sodium > Sodium starch glycolate. It is observed that the disintegration time of the tablets decreased with increase in the level of croscarmellose sodium and crospovidone. However, disintegration time increased with increase in the level of sodium starch glycolate in the tablets. It indicates that increase in the level of sodium starch glycolate had a negative effect on the disintegration of the tablets. At higher levels, formation of a viscous gel layer by sodium starch glycolate (Bolhuis GK, 1997) might have formed a thick barrier to stop the further penetration of the disintegration medium and hindered the disintegration or leakage of tablet contents. Thus, tablet disintegration is retarded to some extent with tablets containing sodium starch glycolate. Thus, these results suggest that the disintegration times can be decreased by using wicking type of disintegrants (crospovidone). Results are shown in [Table 3].

Since the dissolution process of a tablet depends upon the wetting followed by disintegration of the tablet, the measurement of wetting time may be used as another confirmative test for the evaluation of fast dissolving tablets. In wetting time study, the wetting time was rapid in crospovidone followed by croscarmellose sodium and sodium starch glycolate. It was observed that as concentration of croscarmellose sodium and crospovidone increased, the time taken for wetting was reduced. However as in case of sodium starch glycolate as concentration was increased time taken for wetting was also increased. The wetting time results are mentioned in [Table 3].

The influence of superdisintegrants on the dissolution of carbamazepine from the tablets is shown in [Figure 2-4 and Table 4]. The t 50% and t 90% (time for 50% and 90% of release) values decreased with increase in the level of croscarmellose sodium and crospovidone. However, t 50% and t 90% values increased with increase in the level of sodium starch glycolate. These results indicated that dissolution parameter values of croscarmellose sodium and sodium starch glycolate containing tablets are in consistent with the disintegration time values observed. However,

disintegration time values observed with crospovidone tablets are not predictable of dissolution of the drug. The rapid increase in dissolution of carbamazepine with the increase in croscarmellose sodium may be attributed to rapid swelling and disintegration (Rowe RC, 2003) of tablet into apparently primary particles (Zhao N, 2005). While, tablets prepared with sodium starch glycolate, disintegrate due to rapid uptake of water, followed by rapid and enormous swelling (Rowe RC, 2003) into primary particle but more slowly (Zhao N, 2005) due to the formation of a viscous gel layer by sodium starch glycolate (Bolhuis GK et al., 1997). Crospovidone exhibits high capillary activity and pronounced hydration with a little tendency to gel formation (Rowe RC, 2003) and disintegrates the tablets rapidly but into larger masses of aggregated particles (Zhao N, 2005). Thus, the differences in the size distribution generated and differences in surface area exposed to the dissolution medium with different superdisintegrants rather than speed of disintegration of tablets may be attributed to the differences in the t 50% and t

90% values with the same amount of superdisintegrants in the tablets. The [Figure 7] showing the photographs of tablet disintegration at 30, 60, and 90 sec of different formulations. Thus, although the disintegration times were lower in crospovidone containing tablets than that of croscarmellose sodium containing tablet, comparatively higher t 50% and t 90% values were observed due to larger masses of aggregates. Among all formulations studied, formulation f8 showed 99.47% drug release in 3 min.

The stability study for tablets was carried out at 40 ± 2oC (75 ± 5% RH for 4 weeks) by storing the sample in stability chamber. No appreciable change in physical characteristics hardness, disintegration time and drug content was observed even after the evaluation for 4 weeks. The stability studies results are shown in [Table 5].

IR spectra of carbamazepine and formulation f8 are shown in [Figure 5]. Pure drug showed characteristic absorption bands at 3467 (NH Stretching of NH2), 3080 (Aromatic CH stretching), 1678 (C=O stretching of CO NH2), 1605, 1489 (C = C ring stretching) and the formulation F8 showed characteristic absorption band at 3465 (NH Stretching of NH2), 3080 (Aromatic CH stretching), 1681 (C=O stretching of CO NH2), 1605, 1489 (C = C ring stretching). The IR spectra of pure carbamazepine and formulation revealed that there is no appreciable changes in the position of absorption band. This revealed that there was no chemical interaction between drug and the polymer.

Thermograms of pure drug carbamazepine and the formulation f8 revealed that the pure drug has a sharp endotherm at 193.91oC. However the drug and its formulation showed characteristic changes in the appearance of the thermogram. It is observed that in f8 the nature of thermogram is totally changed and the sharp peaks are shifted to lower range around 167.61oC and the


peaks of pure drug have changed to broad peaks with reduction of the height of each peak [Figure 6]. This change indicate the dehydration of pure drug and change in

the particle size giving more amorphous type of the product which may help in increasing the fast release of tablets.

0

20

40

60

80

100

0.00% 2.00% 4.00% 6.00% 8.00% 10.00% 12.00%

Concentartion of superdisintegrants

Tim

e (s

ec.)

Fig. 1 Effect of concentration of superdisintegrants on disintegration time (■ = sodium starch glycolate;

▲ = croscarmellose sodium; ● = crospovidone, ♦ = Indion-414) and wetting time (□ = sodium starch glycolate; ∆ = croscarmellose sodium; ○ = crospovidone, ◊ = Indion-414) of various formulations prepared by direct

compression technique.

0

20

40

60

80

100

120

0 2 4 6 8 10 12Time (min.)

% D

rug

rele

ase

f-1 ssg (2.5%) f-2 ssg (5%) f-3 ssg (7.5%) f-4 ssg (10%)

Fig. 2 Dissolution profiles of different sodium starch glycolate formulations.

Concentration of superdisintegrants


0

20

40

60

80

100

120

0 2 4 6 8Time (min.)

% D

rug

rele

ase

f-5 ccs(2.5%) f-6 ccs(5%) f-7 ccs(7.5%) f-8 ccs(10%)

Fig. 3 Dissolution profiles of different croscarmellose sodium formulations.

0

20

40

60

80

100

120

0 2 4 6 8Time (min.)

% D

rug

rele

ase

f-9 cp (2.5%) f-10 cp (5%)f-11 cp(7.5%) f-12 cp(10%)

Fig. 4 Dissolution profiles of different crospovidone formulations.

% D

rug

rele

ase

% D

rug

rele

ase


Table 4 Dissolution parameters (t50% and t90%) and disintegration time of tablets prepared by direct compression technique.

Formulation t50% (min)

(± SD), n=4 t90% (min)

(± SD), n=4 Disintegration Time

(sec) (± SD), n=6

F1 0.90 ± 0.7 5.80 ± 0.2 21.18 ± 1.2

F2 0.96 ± 0.4 6.70 ± 0.4 28.21 ± 0.9

F3 1.96 ± 1.2 7.00 ± 0.7 42.39 ± 0.5

F4 2.60 ± 0.5 9.50 ± 0.5 53.20 ± 2.2

F5 0.80 ± 0.4 5.68 ± 1.1 14.22 ± 0.8

F6 0.73 ± 0.8 3.95 ± 1.8 13.21 ± 0.6

F7 0.70 ± 0.5 3.60 ± 0.4 12.80 ± 0.9

F8 0.66 ± 0.7 2.70 ± 1.2 12.50 ± 0.8

F9 0.87 ± 1.1 5.86 ± 0.7 14.18 ± 0.9

F10 0.78 ± 0.4 4.00 ± 0.6 10.30 ± 0.7

F11 0.74 ± 1.5 3.63 ± 1.6 9.32 ± 0.5

F12 0.60 ± 0.5 3.60 ± 0.5 9.13 ± 0.6


Table 5 Results of stability study.

Formulation Disintegration time

(sec) (± SD), n=6 Hardness Kg/cm2

(± SD), n=3 Drug content (mg %)

(± SD), n=5

F 1 21.14 ± 1.3 3.2 ± 0.5 99.41 ± 0.2

F 2 28.25 ± 1.0 3.2 ± 0.9 99.18 ± 0.6

F 3 42.29 ± 1.5 3.1 ± 0.22 99.24 ± 1.1

F 4 53.31 ± 2.1 3.2 ± 0.11 99.21 ± 0.8

F 5 15.23 ± 0.6 3.2 ± 0.24 99.16 ± 1.2

F 6 13.11 ± 1.6 3.4 ± 0.16 99.81 ± 0.5

F 7 12.91 ± 1.8 3.1 ± 0.11 99.41 ± 0.8

F 8 12.70 ± 0.9 3.1 ± 0.8 99.28 ± 1.3

F 9 14.20 ± 0.4 3.3 ± 0.11 99.44 ± 1.1

F 10 10.32 ± 0.3 3.1 ± 0.13 99.26 ± 0.9

F 11 9.33 ± 0.2 3.2 ± 0.4 99.29 ± 0.6

F 12 9.18 ± 1.5 3.1 ± 0.10 99.11 ± 1.2



Fig. 5 (A) IR spectrum of carbamazepine, (B) IR spectrum of formulation f 8.

Fig. 6 DSC thermograms of carbamazepine (A), formulation f 8 (B).


F 1 (SSG – 2.5%) 30 sec

F 1 (SSG – 2.5%) 60 sec

F 1 (SSG – 2.5%) 90 sec

F 8 (CCS 10%) 30 sec

F 8 (CCS 10%) 60 sec

F 8 (CCS 10%) 90 sec

F 12 (CP – 10%) 30 Sec

F 12 (CP – 10%) 60 Sec

F 12 (CP – 10%) 90 Sec

Fig. 7 Photographs showing disintegration of tablets in water after 30, 60 and 90 Sec.

Conclusion The major problem of carbamazepine is that it is erratically absorbed from GIT, its limited aqueous solubility which may hinder dissolution may decrease bioavailability. The

above results demonstrate that, although functionality differences existed between the superdisintegrants, the fast dissolving carbamazepine tablets could be prepared by using any of the superdisintegrants used. Overall results indicates that formulation f8 which contain 10%


Croscarmellose sodium was the better one and satisfies all the criteria as fast dissolving tablet. Carbamazepine showing enhanced dissolution will lead to improved bioavailability, effectiveness and hence better patient compliance. Fast dissolving tablets prepared with superdisintegrants must be protected from atmospheric moisture. The dissolution rate of carbamazepine fast dissolving tablets could be enhanced by superdisintegrants.

Acknowledgements Authors thank Cadila Health Care Ltd. Ahmedabad for providing a gift sample of carbamazepine and Maruti Chemicals for superdisintegrants. The authors are thankful to Mr. S. R. Reddy, Chairman, Navodaya Education Trust, Raichur for his support and facilities.

The authors are also grateful to Dr. R. H. Udupi, professor, N.E.T. Pharmacy College, Raichur, and Dr. M. G. Purohith, Emeritus Professor, Luqman College of Pharmacy, Gulbarga for their valuable suggestions.

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