Formulation of Rapidly Disintegrating Fast Dissolving Diazepam Tablets Using Solid Dispersions through a Statistical Approach

 

Tapan Kumar Giri and Biswanath Sa*

Centre for Advanced Research in Pharmaceutical Sciences, Department of Pharmaceutical Technology, Jadavpur University, Kolkata-700032, India.

*Corresponding Author E-mail: biswanathsa2003@yahoo.com

 

ABSTRACT:

This study present development of diazepam tablet, which can provide rapid disintegration of the tablet as well as rapid release of the drug in the oral cavity. The tablets were prepared by direct compression method using solid dispersion of the drug with polyethylene glycol and/or sodium lauryl sulphate as solid dispersion to increase aqueous solubility and dissolution of drug. A 23 factorial design was used to limit the number of experimental trials and to optimize the formulations which disintegrate rapidly and release the drug immediately. Out of the eight formulations five formulations complied the criteria of rapidly disintegrating fast dissolving tablets. The optimum formulation was found to disintegrate in 26.12 seconds and released 85% of the drug in 10.13 minutes. This study indicates that rapidly disintegrating fast dissolving tablet can be prepared by the conventional direct compression method utilizing the existing infrastructure of tablet manufacturing and could provide rapid absorption of drug by quick disintegration of the tablet and rapid release of the drug in the oral cavity for emergency treatment of seizure.

 

KEYWORDS: Diazepam, Rapidly disintegrating, Solid dispersion, Factorial design.

 


INTRODUCTION:

Development of new drug delivery systems has been one of the major thrust areas of pharmaceutical research for the last few decades. In more recent years, increasing attention has been paid in formulating not only fast dissolving and/or disintegrating tablets that are swallowed, but also orally disintegrating tablets that are intended to dissolve rapidly in the mouth1-3. These tablets are convenient for young children, elderly and patients with swallowing difficulties, and in situations where potable liquids are not available. Small volume of saliva is usually sufficient to result in disintegration of such tablets in the oral cavity.

 

Because the oral mucosa is highly vascularized4, drugs that are absorbed through the oral mucosa directly enter into the systemic circulation, bypassing the gastrointestinal tract (GIT) and first-pass metabolism in the liver. This result in a rapid onset of action5 and higher bioavailability of drug than those observed from conventional tablet dosage form6.

 

Diazepam is widely used as sedative, anxiolytic and anticonvulsant agent7-9. It is also very useful in suppressing epileptic convulsion and anxiety during preoperative anesthesia. However after oral administration, peak blood level reaches between 1-2 hours10.

 

If treatment of epileptic seizure is delayed beyond 15 minutes, it may cause serious damage to the patient11. Rapid absorption of a drug requires rapid dissolution, which in turn depends on higher aqueous solubility. The solid dispersion approach has been widely and successfully applied to improve the solubility, dissolution rate, and consequently, the bioavailability of poorly water soluble drugs12-14.

 

Very limited reports are available for enhancing the solubility of diazepam in binary solid dispersion system15,16. However, the solubilization efficiency of binary solid dispersion system is frequently low and, thus relatively large amounts of carrier are needed to solubilize small amounts of a given drug. Therefore, this study was carried out to modify the solubility and dissolution characteristics of the drug using SLS as a third component in the ternary system.

 

The objective of this study was to use a combined system consisting of a hydrophilic carrier like PEG and a surfactant like SLS for the development of diazepam tablets that can provide rapid drug dissolution without prolonging the disintegration time of the tablet. Traditionally these formulations are developed by comparing the effects produced by the change of one variable at a time. The method is time consuming, requires a lot of efforts and may not reflect the joint effects of independent variables. Therefore a 23 randomized full factorial design was used to study the effects of formulation variables on the performance of these tablets.

 

MATERIALS AND METHODS:

Materials:

Diazepam (East India Pharmaceutical Works Ltd., Kolkata, India), Saccharin-Na [Dey’s Medical Stores (Mfg.) Ltd., Kolkata, India], Aerolac (Pharmaceutical Coating Pvt. Ltd., Mumbai, India) were obtained as gift samples. Polyethylene glycol-6000(PEG-6000) (Qualigens, Mumbai, India), Sodium lauryl sulfate (SLS) (Loba Chemie, Bombay, India), Mannitol (Merck, Mumbai, India), Magnesium stearate and all other ingredients were obtained commercially and used as received.

 

Preparation of Solid dispersion:

The solid dispersions of diazepam with PEG 6000 and SLS were prepared at different ratio (Drug: PEG: SLS = 1:3:1, 1:3:2, 1:10:1 and 1:10:2) by melting method .Required amount of PEG 6000 was melted in a glass container at 700C.Required amount of diazepam was then added to the molten PEG 6000 and mixed thoroughly with a glass rod until a homogeneous system was obtained. In dispersions incorporating surfactant, the surfactant was dissolved in the melted carrier prior to the addition of diazepam. The molten mixture was cooled rapidly by placing the glass container in an ice bath for about 5 minutes until solidified. The dispersions were stored 48 hr. in a vacuum desiccators at room temperature. The hardened mixture was powdered in a mortar, sieved through British Standard sieve No.44, and stored in a screw-cap vial at room temperature until further use.

 

Phase Solubility Study:

Solubility studies of diazepam were carried out by adding  excess amounts of drug to 10 ml of USP phosphate buffer solution (pH-5.8) containing increasing concentrations of PEG 6000 (0-10% w/v), SLS(0-1.5%w/v),and a mixture of PEG 6000(0-10%w/v) and 1.5%w/v SLS in stoppered conical flasks. The flasks were shaken at 50 revolutions per minute in shaking incubator (Model KMC 8480 SL, Vision Scientific Company Ltd., Seol, South Korea) at 37±0.50C until equilibrium (about 90hr) was reached. The resulting mixtures were filtered and aliquots, following suitable dilutions, were analyzed using Spectrophotometer (Genesis, 10 UV, Thermo Electron Corporation, Wisconsin, USA.) at 230 nm to determine solubilities of diazepam in different media. Each experiment was performed three times.

 

Thermal Analysis:

Differential thermal analysis of diazepam, PEG-6000, SLS and their solid dispersions were carried out using Perkin-Elmer instrument (Pyris Diamond TG/DTA,Singapore). About 4 mg samples were kept in aluminum pans and scanned at a rate of 5°C/min between 30°-210°C under nitrogen atmosphere.

 

X-ray Diffraction study:

X-ray powder diffraction patterns of diazepam, PEG-6000, SLS and their solid dispersions were carried out with a X-ray powder diffractometer (Rigaku-MiniFlax,Tokyo,Japan.) using a copper Kα target with a nickel filter at 30 kV voltage,15 mA current. The scanning rate was 10/min over a 2θ range of 5°-60°.

 

Factorial design:

A 23 full factorial design was carried out using Statgraphics Plus 3.0® software. In this design three factors were evaluated each at two levels and experimental trials were performed at all eight possible combinations. The levels of the three factors were selected on the basis on the preliminary experiments carried out before constructing the factorial design. All other formulation and manufacturing variables were kept constant throughout the study. The amount of SLS(X1), PEG 6000(X2), and Mannitol (X3) were selected as independent variable. The DT and t85% were selected as dependent variables.

 

Preparation of tablet by direct Compression:

Drug (as such or in solid dispersion), mannitol and aerolac were mixed for 10 minutes. The resulting mixture was further mixed with magnesium stearate for 5 minutes. The final powder mixture was then directly compressed into tablets using concave punches (approx.9.5 mm diameter) in a 10 station mini press tablet machine (Rimek, Karnavati Engineering Ltd. Gujrat, India).

 

Disintegration Test:

Disintegration times were measured using a modified disintegration test method17. 10ml of water was taken in a petridish (10 cm diameter) and a tablet was carefully placed in the centre and agitated mildly. Time for the tablet to completely disintegrate into fine particles was noted.

 

Dissolution Test:

Dissolution profiles of the diazepam tablets were determined in USP phosphate buffer solution (500 ml, pH 5.8, 37±0.5oC )using USP II dissolution test apparatus(model TDP 06P, Electrolab, Mumbai, India).At appropriate time intervals, 10ml samples were withdrawn and was replenished with the same volume of fresh medium. The aliquots, following suitable dilution, were analyzed spectrophotometrically at 230 nm. Each test was performed in triplicate (C.V < 3%).

 

RESULTS AND DISCUSSION:

Rapidly disintegrating fast dissolving tablets of diazepam having 5 mg potency were prepared by direct compression method using solid dispersion of diazepam with PEG-6000 and SLS. The compositions of the tablets have been represented in Table-1. The hardness (measured using Monsanto hardness tester) of the tablet was adjusted 2 Kg/Cm2 by varying the thickness of the tablet. The friability (determined using Friabilator, Veego, Mumbai, India) of the tablets was found to be confined within the range of 0.02 to 0.55%. The potency of the tablets as determined following the method of Indian Pharmacopoeia(1996) was found to be 5.04±0.06 mg. 8 formulations were prepared based on 23 full factorial design(Table-2).Fitting a multiple linear regression model to the factorial design gave a predictor equation which was a first order polynomial,  having the form:

Y= b0+b1X1+b2X2+b3X3+b12X1X2+b13X1X3+b23X2X3+b 123X1X2X3                                                                           (1)

Where, Y = level of a given response (dependent variable)

b = regression coefficients for the first order polynomial.

X = level of the independent variable.

 

Table 1: Composition of diazepam tablets (300mg)

Ingredient

Quantity(mg)

Diazepam

5 mg

PEG-6000

15 to 50 mg

SLS

5 to 10 mg

Manitol

6 to 30 mg

Magnesium stearate

1 mg

Saccharin sodium

3 mg

Aerolac

Quantity sufficient to 300 mg

 

Disintegration time of 8 formulations prepared according to the factorial design were measured and put in equation 1, and a full model polynomial (equation 2) was generated.

DT =121.38 +22.87 X1+62.79 X2 – 11.53 X3 + 2.64 X1X2 – 13.79 X2X3 + 6.23 X3X1 – 8.28 X1X2X3                     (2)

 

The results of multiple linear regression analysis and analysis of variance (ANOVA) have been represented in Table-3. Since all the coefficients were significant at 95% confidence level (p<0.05), they were retained in the full model.

 

The positive sign of the coefficients b1 and b2 indicates that increase in the amount of SLS and PEG-6000 will increase DT and negative sign of the coefficient b3 indicate that increase in the amount of mannitol will decrease DT.Table-2 shows that increasing in the amount of PEG-6000 from 15 mg to 50 mg increased the DT and also increasing in the amount of SLS from 5 mg to 10 mg increased the DT. Further increasing in the amount of manitol from 6 mg to 30 mg decreased the DT. One of the 8 formulations containing 15 mg PEG-6000, 5 mg SLS and 30 mg mannitol showed least DT of 26.12 seconds. The increased DT of tablets prepared by solid dispersions could be related to the soft and waxy nature of PEG-6000.Such carrier essentially acts as strong binders within tablets.

 

Table 2: Composition and Responses for a 23 Factorial Design

Batch Code

Variable Levels*

DT(seconds)

Mean ±SD, n=3

t85%(minutes)

Mean ±SD, n=3

X1

X2

X3

F1

-1

-1

-1

50.60±1.66

20.32±1.05

F2

+1

-1

-1

62.04±2.44

17.31±0.85

F3

-1

+1

-1

181.93±4.05

9.87±0.96

F4

+1

+1

-1

237.05±3.45

9.80±0.99

F5

-1

-1

+1

26.12±1.66

10.13±0.25

F6

+1

-1

+1

95.58±0.93

9.07±0.39

F7

-1

+1

+1

135.39±0.78

7.83±0.25

F8

+1

+1

+1

182.30±1.59

7.11±0.21

Translation of coded levels in actual units

Coded level                   -1                +1

X1: SLS (mg)                 5                  10

X2: PEG 6000(mg)       15               50

X3: Mannitol (mg)       6                  30

 

During compression the carrier could plasticize, soften or melt, filling the pores within tablets and subsequently increase the DT of the tablet18. The decreased DT of tablets observed by the incorporation of manitol could be reduction of viscosity of PEG-6000 in the solid dispersion. In addition mannitol dissolves in order producing pores in the tablet and enhances penetration of water to facilitate disintegration.

 

The relationship between the dependent and independent variables was further elucidated using contour and response surface plots. The effect of X1 and X2 and their interaction on disintegration time at two fixed level (-1 and + 1) of X3 (6 mg and 30 mg) are given in Figures 1-4

 

Figure 1 : Response surface plot (3D)  showing  the effect of the amount of SLS (X1) and PEG-6000(X2) added on the response disintegration time at fixed level of X3 ( 6 mg).

 

Figure 2: Contour plot showing the effect of the amount of SLS (X1) and PEG-6000 (X2) added on the response disintegration time at fixed level of X3 ( 6 mg).

 

Figure 3 : Response surface plot (3D) showiong the effect of the amount of SLS (X1) and PEG-6000(X2) added on the response disintegration time at fixed level of X3 (30 mg).

 

Figure 4: Contour plot showing the effect of the amount of SLS (X1) and PEG-6000 (X2) added on the response disintegration time at fixed level of X3 ( 30 mg).


Table 3: Summary of results of Regression Analysis and ANOVA for measured Response*

Response (DT)

b0

b1

b2

b3

b12

b23

b31

b123

FM

121.38

22.87

62.79

11.53

2.64

13.79

6.22

8.28

P value

0

0

0

0

0

0

0

0

 

 

DF

SS

MS

F

 

R2

 

Regression

FM

7

117673

16810.5

3063.22

 

0.999

 

Error

FM

16

87.8056

5.4878

-

 

-

 

Response(t85%)

b0

b1

b2

b3

b12

b23

b31

b123

FM

11.43

0.61

2.78

2.89

0.41

1.71

0.16

0.33

P value

0

0.007

0

0

0.0125

0

0.2823

0.0392

RD

11.43

0.61

2.78

2.89

0.41

1.71

-

0.33

P value

0

0.007

0

0

0.0125

0

-

0.0395

 

 

DF

SS

MS

F

 

R2

 

Regression

FM

7

472.618

67.5169

132.57

 

0.983

 

 

RM

6

471.987

78.6646

152.32

 

0.981

 

Error

FM

16

8.1489

0.5093

-

 

-

 

 

RM

17

8.7794

0.5164

-

 

-

 

*FM indicates full model; RM, reduced model; p value, the significance level; DF, degrees of freedom; SS, sum of squares; F, Fischer’s ratio; R2, regression coefficient.

 


At low level of X3(6 mg), disintegration time increased 186.45 seconds when the amount of X1 and X2 were increased from low level (5 mg and 15 mg) to high level (10 and 50 mg). Similarly at high level of X3 (30 mg), disintegration time increased 156.18 seconds when the amount of X1 and X2 were  increased from low level (5 and 15 mg) to high level ( 10 and 50 mg).

 

Dissolution properties of all eight formulations required by the experimental design are shown in figure-5.

 

Figure 5: Dissolution profiles of tablets of 8 formulations prepared as per 23 Factorial Design. The results are expressed as the mean ± SD(n=3).

 

t85% of 8 formulations prepared according to the factorial design were measured from dissolution data and put in equation 1 to generate a full model polynomial equation (equation 3).

 

t85% = 11.43 – 0.61 X1 – 2.78 X2 – 2.89 X3 + 0.41X1X2 + 1.71 X2X3 + 0.16 X3X1 -0.33 X1X2X3                         (3)

 

The results of multiple linear regression analysis and analysis of variance (ANOVA) have been represented in Table-3. Since the significance level of the coefficients b13 was p = 0.282(p>0.05), they were omitted from the full model and a reduced model (equation 4) was generated.

t85% = 11.43 – 0.61 X1 – 2.78 X2 – 2.89 X3 + 0.41 X1X2 + 1.71 X2X3 -0.33 X1X2X3                                                 (4)

 

The positive sign of b1, b2 and b3 indicate that increase in the concentration of either PEG-6000 or SLS or mannitol will decrease the t85% of tablet. Improved dissolution of a drug from a solid dispersion has been ascribed to several factors like amorphization of drug, increased wetability, reduced aggregation and/or agglomeration, increased effective surface area and solubilization of drug in the carrier system19.

 

Table-2 shows that by increasing PEG-6000 concentration from 15 mg (F1) to 50 mg (F3) drastically reduced t85% from 20.32 minutes to 9.80 minutes when other two independent variables in terms of the amount of SLS and the amount of mannitol were kept constant at lowest concentration. It was further noted that by increasing SLS concentration from 5 mg (F3) to 10 mg (F4) reduced t85% from 9.87 minutes to 9.80 minutes when amount of PEG-6000 was kept constant at high level and amount of manitol was kept constant at low level.

 

The role of added SLS (X1) and its interaction with X2 (amount of PEG-6000 added ) on t85% at fixed level of X3 (amount of Mannitol added) can be discussed with the help of Figures 6-9.

 

Figure 6 : Response surface plot (3D) showiong the effect of the amount of SLS (X1) and PEG-6000(X2) added on the response t85% at fixed level of X3 ( 30 mg).

 

Figure 7: Contour plot showing the effect of the amount of SLS (X1) and PEG-6000 (X2) added on the response t85% at fixed level of X3 ( 30 mg).

 

Figure 8 : Response surface plot (3D) showiong the effect of the amount of SLS (X1) and PEG-6000(X2) added on the response t85% at fixed level of X3 ( 6 mg).

 

Figure 9: Contour plot showing the effect of the amount of SLS (X1) and PEG-6000 (X2) added on the response t85% at fixed level of X3 ( 6 mg).

 

As shown in the figure 6 and 7, at high levels of X3(30 mg), t85% decreased 3.02 minutes when the amount of X1 and X2 were increased from low level (5 mg and 15 mg) to high level (10 and 50 mg) .Similarly from the figures 8 and 9 it is evident that at low level of X3 (6 mg), t85% decreased 10.52 minutes when the amount of X1 and X2 were increased from low level (5 and 15 mg) to high level (10 and 50 mg).

 

These findings indicated that the simultaneous presence of surfactant and hydrophilic polymer gave rise to a synergistic effect of their solubilizing and wetting properties towards the drug. The occurrence of micellar solubilization by the employed surfactants can be ruled out, since the final surfactant concentration in the dissolution medium (0.002% w/v for the highest surfactant amount) was in all cases below their respective critical micelle concentration, for example, between 0.1 and 0.2 % w/v for SLS20. Therefore, the favorable effect obtained can be attributed mainly to the improved drug wettability and decrease of aggregation phenomena as a consequence of a reduced interfacial tension between drug particles and dissolution medium. Phase solubility study revealed that aqueous solubility of diazepam increased linearly as the concentration of PEG 6000 and SLS were increased from 0 to 10% and 0 to 1.5%. At 10% concentration of PEG 6000 and 1.5% concentration of SLS, aqueous solubility of the drug increased by 2.27 and 19.77 times respectively as compared to the aqueous solubility(57.65 mg/L) of pure diazepam at 37oC. Physicochemical state of solid dispersion, studies using DSC, X-ray diffraction indicated absence of formation of solid solution instead a partial transformation of crystalline drug to amorphous state was noted. From figure 10 it was noted that the intensity of crystalline peaks of diazepam in the solid dispersions was significantly less than of intact diazepam, indicating lower crystallinity of diazepam in the ternary solid dispersion system. The thermal curves of pure components and solid dispersions are shown in figure 11. Solid dispersion system displayed only one endothermal peak, corresponding to the polymer fusion, whereas drug and surfactant endothermal effects were not detected. The disappearance of the drug melting peak was due to its dissolution in the melted carrier. The decrease in peak melting temperature of PEG due to the presence of drug or both drug and surfactant. Partial amorphization together with improved wetting of drug and solubilization of drug by the carrier could be responsible for improvement in solubility and consequent dissolution of the drug. Further it was observed that by increasing the concentration of manitol from 6 mg (F4) to 30 mg (F8) reduced t85% from 9.80 minutes to 7.11 minutes when other two independent variables remained constant at high level. During dissolution, the interfacial layer between the dissolving front and the dissolution bulk medium became rich of carrier, another barrier for the drug to diffuse prior to release into the bulk phase. Mannitol may reduce the viscosity of this barrier resulting in an increase in the release of the drug.

 

Figure 10:  X-ray diffraction patterns of diazepam, PEG-6000, SLS, and their solid dispersion.

 

Figure 11:  DSC patterns of diazepam, PEG-6000, SLS, and their solid dispersion.

 

Two principal criteria appear to be important for developing rapid disintegrating fast dissolving tablet:

1) Tablet disintegration which should be preferably < 3 minutes21 and 2) Rapid drug dissolution: time required for 85% dissolution (t85%) should be less than 30 minutes22. Examination of the results (Table 2) revealed that although t85% of all the tablets was less than 30 minutes, DT of F3, F4 and F8 tablets were greater than 3 minutes. It was also noted that the amountof PEG 6000 in these tablets were present in the highest amount (50 mg) and that was responsible for the protracted disintegration of the tablets. Among the other tablets which complied the above two criteria, F5 tablets exhibited a DT of 26.12 seconds and t85% of 10.13 minutes.

 

CONCLUSION:

Rapidly disintegrating fast dissolving tablet of diazepam can be prepared by the existing direct compression method using solid dispersion of the drug using a hydrophilic carrier PEG and a surfactant SLS instead of the drug as such. Suitable statistical approach can reduce the number of experimental runs and provide several formulation options with the desired disintegration time of tablet and dissolution time of drug contained therein. In the present study, it was revealed that several combinations of PEG 6000 and SLS can produce tablets that provide less than 3 minutes DT and less than 30 minutes t85%. However, tablets prepared using lowest level of PEG and SLS and highest level of mannitol provided the faster tablet disintegration and reasonably quick drug dissolution (26.12 seconds and10.13 minutes).Such tablets could be used in emergency treatment of anxiety disorder and epileptic seizure.

 

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Received on 07.06.2010       Modified on 23.06.2010

Accepted on 06.07.2010      © RJPT All right reserved

Research J. Pharm. and Tech.3 (4): Oct.-Dec.2010; Page 1246-1251