Development and Evaluation of Clonazepam Fast Disintigrating Tablets Using Superdisintigrates and Solid Dispersion Technique

Bhalerao AV¹*, Deshkar SS¹, Shirolkar SV¹, Gharge VG² and Deshpande AD¹

¹Dept. of Pharmaceutics, Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune-411018

²Emcure Pharmaceuticals Ltd. Pune-411018.

*Corresponding Author E-mail: aparnavb@rediffmail.com

ABSTRACT

Recent developments in mouth dissolving/disintegrating tablets have brought convenience in dosing to elderly and children who have trouble in swallowing tablets. The objective of the present study was to prepare the mouth disintegrating tablet of clonazepam (antiepileptic). As precision of dosing and patient's compliance become important prerequisite for a long term antiepileptic treatment, there is a need to develop a formulation for this drug which overcomes problems such as difficulty in swallowing, inconvenience in administration while travelling and patient's acceptability. Hence, the present investigation was undertaken with a view to develop a fast disintegrating tablet of clonazepam which offers a new range of product having desired characteristics and intended benefits. The drug is poorly water soluble therefore to enhance the solubility and release of drug, solid dispersion of drug and PVP K30 was prepared by solvent evaporation method. Different combinations of superdisintegrants such as crosscarmellose sodium, sodium starch glycolate, crospovidone were used. Directly compressible mannitol, and aspartame were used to enhance the mouth feel and taste. Lactose was used as diluents. The tablets were prepared by direct compression technique on rotary tablet machine. The tablets were evaluated for hardness, friability, weight variation, wetting time, dispersion time and uniformity of content. Optimized formulations were evaluated by in vitro dissolution test. All the tablets had hardness 3-3.5 kg/cm² and friability of all formulations was less than 1, weight variation and drug content were within official limit. Amongst all formulations, formulation F10 prepared by drug:PVPK30 (1:4:)ratio and  combination of 5% w/w crosscarmellose sodium  and  5% w/w of sodium starch glycolate showed least dispersion  time of 8s and faster dissolution.

KEYWORDS: Clonazepam, superdisintegrants, solid dispersion, mouth disintegrating tablets.

INTRDUCTION:

Recent developments in technology have presented viable dosage alternatives for pediatric, geriatric, bedridden, nauseous or non compliant patients. Traditional tablets and capsules administered with 250 ml of water may be inconvenient or impractical for such patients. The concept of mouth dissolving/disintegrating tablets emerged from the desire to provide patient with more conventional means of taking their medication when drinking water is not available¹. Most of the technologies for the manufacture of mouth dissolve tablets use superdisintegrants so that the tablet disintegrates in saliva. Many superdisintegrants are employed such as crosscarmellose sodium, sodium starch glycolate and crospovidone². Clonazepam is an antiepileptic drug and useful in the treatment of petit mal, myoclonic seizures and infantile spasms.

Mouth dissolving tablets of clonazeapm were prepared by solid dispersion of drug with PVP K30 by solvent evaporation method³. Lactose was used as diluent and crosscarmellose sodium, sodium starch glycolate and crospovidone as superdisintegrants and the effectiveness of superdisintegrants has been investigated⁴. The present investigation deals with the development of an effective and stable fast disintegrating of clonazepam having adequate hardness, low disintegration time and pleasant taste. Its insolubility in water and bland taste makes it an ideal candidate for fast disintegrating tablets with regards to palatability. Since epileptic patients have to strictly follow dosage regimen for preventing sub therapeutic concentration, fast disintegrating tablets will avoid missing out of dose even during travelling or other situations where there is no access to water.

MATERIAL AND METHODS:

Clonazepam was obtained as gift sample from Cipla, Mumbai. Crosscarmallose sodium, sodium starch glycolate, Crospovidone was obtained from Signet

Table 1:- Composition of fast disintegrating tablets of clonazepam

Ingredients	Formulations (mg/Tablet)
	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12
Drug*	4	4	4	4	4	4	4	4	4	4	4	4
PVP K30*	4	4	4	8	8	8	12	12	12	16	16	16
Aspartame	1	1	1	1	1	1	1	1	1	1	1	1
Mannitol	5	5	5	5	5	5	5	5	5	5	5	5
Lactose	56	56	56	52	52	52	48	48	48	44	44	44
Talc	1	1	1	1	1	1	1	1	1	1	1	1
Magnesium stearate	1	1	1	1	1	1	1	1	1	1	1	1
Croscarmellose Sodium	4	-	4	4	-	4	4	-	4	4	-	4
Sodium starch glycolate	4	4	-	4	4	-	4	4	-	4	4	-
Crospovidone	-	4	4	-	4	4	-	4	4	-	4	4

*S.D. = Solid Dispersion.

Table 2:- Evaluation of fast disintegrating tablets of clonazepam

Parameter

Batch code

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

F11

F12

Weight variation** (mg/tablet)

80.8± 0.52

80.9± 0.62

80.± 0.14

80.3± 0.31

80.5± 0.41

80.1± 0.51

80.5± 0.23

80.6± 0.34

80± 0.61

80± 0.32

80.2± 0.61

79.8± 0.42

Hardness (kg/cm2) *

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

Friability**(%)

0.31

0.43

0.56

0.83

0.77

0.60

0.65

0.43

0.71

0.89

0.33

0.61

Dispersion time(sec) *

15± 1.15

45± 1.0

28± 1.23

12± 1.56

40± 1.45

25± 1.12

10± 1.20

38± 1.45

20± 1.0

8± 1.25

32± 1.56

15± 1.6

Uniformity of    content*   (%)

97.5± 0.20

98.4± 0.31

98.8± 0.35

98.5± 0.52

97.6± 1.0

98.8± 0.36

97.6± 0.89

98.2± 0.87

98.1± 0.54

98.2± 0.3

98.6± 0.25

98.5± 0.25

* (n=5), ** (n=20)

Chemical Corporation, Mumbai. Polivinyl pyrrolidone (PVPK-30), Mannitol, Lactose were obtained from Loba Chemicals Mumbai. While purified talc and magnesium state were purchased from S.D. Fine Chemicals Mumbai. All other chemicals and reagents were of analytical grade.

Experimental:

Tablets were prepared by direct compression method. All excipients were screened through 44# sieve and weighed individually. The drug was mixed thoroughly with solution of PVP K30 (5-20%w/v) in methanol and methanol was evaporated to get solid dispersion. The solid dispersion of drug and excipients were weighed and mixed thoroughly with superdisintegrants and lubricated with talc and magnesium stearate. The weighed powder was compressed into a tablet by using 6 mm standard concave punches. The theoretical tablet weight was fixed at 80 mg. Table No-1 gives formulations of tablets.

Evaluation of Tablets:

The tablets were evaluated for hardness, friability⁵, weight variation⁶, uniformity of content⁷, wetting time⁸ and in vitro dispersion time⁹. The crushing strength of the tablets was measured using a Monsanto hardness tester (Sheetal Scientific Industries, Mumbai, India).

The friability of a sample of 20 tablets was measured using a Roche Friabilator (Electrolab). Twenty pre weighed tablets were rotated at 25 rpm for 4 minutes. The tablets were then reweighed after removal of fines (using no. 60 mesh screen), and the percentage of weight loss was calculated.

The wetting time of the tablets was measured using a simple procedure. Five circular tissue papers of 10-cm diameter were placed in a petri dish with a 10-cm diameter. Ten milliliters of water containing methylene blue, a water-soluble dye, was added to the petri dish. A tablet was carefully placed on the surface of tissue paper. The time required for water to reach the upper surface of the tablets was noted as the wetting time.

The dispersion time was measured using a modified method (n = 5). For this purpose, a petri dish (10-cm diameter) was filled with 10 ml of water. The tablet was carefully put in the center of the petri dish and the time for the tablet to completely disintegrate into fine particles was noted.

Uniformity of content was determined by triturating 5 tablets in mortar and then by dissolving quantity equivalent to one tablet in 100ml Methanol. An aliquot of 2 ml was withdrawn filter through whatman filter paper no.41 and diluted to 10 ml and analyzed by UV Spectrophotometer at 272nm against blank prepared by using dummy tablets treated in a similar manner. The results of all evaluation parameters are shown in Table 2.

Figure No-1 Dissolution profiles of clonazepam tablets containing different ratio of Drug: PVPK 30.

Drug release was carried out using USPXXVI Type II (Paddle Type) apparatus in 500ml 0.1N HCL at 37+ 0.5⁰C and with 50 rpm speed. Aliquots of 5ml were withdrawn at various intervals within a period of 40 min. and analyzed using UV/VIS Spectrophotometer at wavelength 272nm. The drug release of tablets was also compared with that of tablet prepared with drug and lactose.

RESULTS AND DISCUSSION:

Water insoluble diluents such as microcrystalline cellulose and dicalcium phosphate were omitted from the study as they are expected to cause an unacceptable feeling of grittiness in the mouth. Among the soluble diluents, lactose was selected as a model soluble diluent considering its advantages in terms of easy availability, cost-effectiveness, and relative moisture insensitivity. The sweetener combination aspartame and mannitol gives long lasting sweet taste to the formulation. Mannitol because of its negative heat of solution give cooling sensation and mask after bitter taste of aspartame.

Formulations tested for all the official test of tablet and were found to be within limits. Tablets were found to disintegrate fast, showing dispersion time less than one minute. The formulation, F10 was found to have the minimum dispersion time of 8s containing Drug: PVPK30 (1:4) ratio and combination of crosscarmallose sodium and sodium starch glycolate as superdisintegrants. The tablets with combination of superdisintegrants other than crosscarmellose sodium and sodium starch glycolate showed more dispersion time. Tablets of F1, F4, F7and F10 which showed lesser dispersion time are further subjected to dissolution testing. All tablets showed 100% drug release within 30 min. While plane drug tablet contain lactose showed 90 % drug release within 40 min.(Fig-1). Out of four formulations, formulation F10 showed faster release. The Drug: PVPK30 (1:4) ratio helps to increase the solubility of clonazepam, and superdisintegrants help to disintegrate the tablet hence both effects showed fast dissolving of tablet. Thus, it can be concluded that effective mouth dissolving tablet of clonazepam can be prepared.

CONCLUSION:

Fast disintegrating tablet is a promising approach with a view of obtaining faster action of the drug and would be advantageous in comparison to currently available conventional forms. The dosage form had a good balance over disintegration time and mechanical strength. Amongst all formulations, formulation F10 prepared by drug:PVPK30 (1:4:)ratio and  combination of 5% w/w crosscarmellose sodium  and  5% w/w of sodium starch glycolate showed least dispersion  time of 8s and faster dissolution. Thus it can be concludes that combination of solid dispersion and superdisintegrants is a promising approach to prepare fast disintegrating tablet of poorly water soluble antiepileptic drug clonazepam.

ACKNOWLEDGEMENT:

The authors express their graditude to Cipla, Mumbai for the generous gift of clonazepam,  Signet Chemicals for providing superdisintegratant Crosscarmallose sodium, sodium starch glycolate, and Crospovidone,  and also to Loba Chemicals Mumbai for providing gift sample of Polivinyl pyrrolidone (PVPK-30), Mannitol, and Lactose.

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Received on 06.12.2008  Modified on 13.05.2009

Accepted on 22.05.2009  © RJPT All right reserved

Research J. Pharm. and Tech.2(2): April.-June.2009,;Page 375-377