INTRODUCTION:

Over the past three decades Mouth Dissolving Tablets (MDTs) have gained much attention as a preferred alternative to conventional oral dosage forms such as tablets and capsules. An MDT is a solid dosage form that disintegrates and dissolves in the mouth (either on or beneath the tongue or in the buccal cavity) without water within 60 seconds or less and absorption is systemic without first pass metabolism. For people who are having the problem in the swallowing or chewing can take it easily as the disintegrated mass can slide down smoothly with the help of saliva. An MDT is formulated as a bioequivalent line extension of an existing oral dosage form. Superdisintigrants are used for the rapid dissolution and sublimating agents are used to increase porosity.^[1-5]

The application of an optimization technique consisting of statistical design to pharmaceutical formulation development would provide an efficient and economical method to acquire the necessary information to understand the relationship between controllable (independent) variables and performance or response (dependent) variables^[6-9]. Olanzapine chemically is 2-methyl-4-(4-methylpiperazin-1-yl)-5H-thieno[3,2- c][1,5]benzodiazepine, which is the atypical antipsychotic agent, selected due to is poor water solubility and less bioavailability due to first pass metabolism.^[10-11]The purpose of the study was to formulate and evaluate mouth dissolving tablets of Olanzapine. With the application of A 3² full factorial design and Response Surface Methodology (RSM) effect of formulation variables on the performance of these tablets were studied.

MATERIALS AND METHODS:

Materials:

Olanzapine was obtained as a gift sample from Aventis Pharmaceuticals (Goa), Polacrilin Potassium (PK) was gifted by Themax, Pune,(M.S), Microcrystalline Cellulose (MCC), Camphor, Sodium Lauryl Sulphate (SLS), Magnesium Stearate and Lactose were procured from Lobachemie, Mumbai. Other reagents and organic solvents used were of analytical grade. Buffer and its dilutions were prepared with double-distilled water.

Methods:

Preparation of olanzapine MDT Tablets:

The tablets were prepared as follow according to the proportion given in the table 1. The raw materials were passed through a no. 120 sieve. All materials mixed in polybag for 20 min and then mixture was lubricated by magnesium stearate before compression. The tablets were compressed using six station rotary tablet compression machine (JM-6, JMC)equipped with 8 mm punch. The tablet weight was adjusted to 150 mg. Sublimation of camphor was done at 60⁰c.

Table 1: Composition of Mouth Dissolving Tablets

INGREDIENTS	AMOUNT (mg)
Olanzapine	10.0
Polacrilin Potassium	7.5-12.5
Camphor	10-30
MCC	45
Magnesium Stearate	1.5
Lactose q.s.	150

Table2: Design Matrix as per 3² Factorial Designs

Run	Coded Level		Actual Value
Run	X₁	X₂	PK (mg)	Camphor(mg)
O₁	-1	-1	7.5	10
O₂	-1	0	7.5	15
O₃	-1	+1	7.5	30
O₄	0	-1	10	10
O₅	0	0	10	15
O₆	0	+1	10	30
O₇	+1	-1	12.5	10
O₈	+1`	0	12.5	15
O₉	+1	+1	12.5	30

Full Factorial Design^[12-15]:

A3² randomized full factorial design was used in the present study. In this design 2 Factors are evaluated, each at 3 levels, and experimental trials are performed at all 9 possible combinations. The amount of superdisintegrant, Polacrilin Potassium (X1), and the amount of subliming agent, camphor (X2), were selected as independent variables. The design matrix and coded levels are mentioned in actual values as shown in table 2 and 3.The disintegration time and percentage friability were selected as dependent Variables. As shown in equation (1), a statistical model incorporating interactive and polynomial terms was used to evaluate the responses.

Y = β₀– β₁ X₁ - β₂ X₁²- β₃ X₂+ β₄ X₂² + β₅ X₁ X₂- β₆ X₁² X₂+ β₇ X₁ X₂²+ β₈ X₁²X₂²-----(1)

Where, Y are the dependent variables, namely, disintegration time (Y₁) and percentage friability (Y₂); b₀ is the arithmetic mean response of the 9 runs; and b₁andb₈ are the estimated coefficients for the factors X₁ and X₂, respectively. The main effects (X₁ and X₂) represent the average result of changing one factor at a time from its low to high value. The interaction term (X₁X₂) shows how the response changes when 2 factors are simultaneously changed. The polynomial terms (X₁₂ and X₂₂) are included to investigate nonlinearity. The simplified models were then utilized to produce three-dimensional response surface plots and contour plots to analyze the influence of disintegration time and percentage friability.

Table.3: Coded and actual values of formulations as per 3² Factorial Design

Independent Variable
X1	Polacrilin Potassium (Superdisintegrant
X2	Camphor (Subliming Agent)
Levels	Low	Medium	High
Coded Levels	-1	0	+1
Dependent Variable (Response Variable)
Y1	Disintegration Time (Sec)
Y2	Percentage Friability (%)

Evaluation of Tablet Properties ^16,17:

Thickness and Crushing strength:

The thickness of the tablet was measured using Vernier caliper and the crushing strength of the tablets was measured using a Monsanto hardness tester.

Friability test:

The friability of a sample of 20 tablets was measured using a Roche Friabilator (Jashbin). 10 preweighed 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.

Disintegration test:

The disintegration time was measured using a disintegration apparatus (META LAB) using 900 ml in pH 1.2 without disk at 37 ⁰C.

Dissolution Studies:

Dissolution experiments were performed in triplicate with a dissolution tester (make- Electrolab) in pH 1.2 a simulated gastric fluid (SGF) at 37⁰C using the USP XXV paddle method (Type II) at a rotation speed of 50 rpm. At appropriate time intervals, 10 ml of the mixture was withdrawn and filtered. The removed samples were analyzed at 260 nm by UV-Vis spectrophotometer (UV 530 JASCO)

RESULTS AND DISCUSSION:

On the basis of the results obtained in the preliminary screening studies, the batch containing PK showed the fastest disintegration. Hence, it was selected for further studies. Table 4 includes the value of (Mean±SD) of weights, hardness and thickness of 9 formulations prepared using the various polymers along with values of their assay and friability. Tablet weights in all 9 batches of polymer blends between 150.33 mg and 151.86 mg, diameter between 8mm and 8.1mm, thickness between 1.7mm to 1.8mm, tablet hardness between 4.8 to 5.4 Kg /cm2 and tablet friability between 0.016% to 0.34%. Thus all physical parameters of the compressed tablets were quite within control. In the present study, all the tablets disintegrated in ≤ 31 sec fulfilling the official requirements (3 min) for dispersible tablets. It is observed that tablets containing high concentration of Polacrilin potassium and camphor were disintegrated immediately. Different superdisintgrants containing tablets were disintegrated in following manner as shown in Table 5.

Table 4 : Physical evaluation parameters of formulations O1-O9.

FORMULATIONS	WEIGHT VARIATION (mg). MEAN ± S.D	HARDNESS(kg). MEAN±S.D.	THICKNESS (mm) MEAN ±S.D.	FRIABILITY(%) MEAN ± S.D
O₁	150.62±1.1	5.2 ± 0.29	1.7 ± 0.05	0.34±0,02
O₂	150.83±2.32	4.8 ± 0.52	1.8± 0.00	0.29±0,03
O₃	151.32±1.47	5.4 ± 0.29	1.7± 0.02	0.28±0,02
O₄	151.39±1.11	4.9 ± 0.52	1.7± 0.02	0.25±0,04
O₅	150.89±1.46	4.9 ± 0.59	1.8± 0.00	0.21±0,02
O₆	150.33±1.82	5.3 ± 0.76	1.8± 0.03	0.215±0,02
O₇	151.26±1.20	5.3 ± 0.72	1.8± 0.01	0.195±0,02
O₈	151.86±1.43	5.3 ± 0.53	1.7± 0.00	0.185±0,02
O₉	150.63±1.36	5.3 ± 0.53	1.8± 0.02	0.16±0,03

Table 5: Disintegration Time of Mouth Dissolving Tablets (O1-O9)

FORMULATIONS	DISINTEGRATION TIME (SEC)
O₁	31±3
O₂	26±2
O₃	22±3
O₄	18±3
O₅	16±2
O₆	11±2
O₇	9±2
O₈	7±2
O₉	5±2

In order to investigate the factors systematically, a factorial design was employed. The disintegration time and percentage friability for the O₁ to O₉ showed a wide variation from 30 to 10 Sec. , 0.34 to 0.16 % losses respectively the data indicates that the loss is clearly depends on the selected independent variables. The polynomial equations can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (positive or negative).The polynomial equations can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (positive or negative).The polynomial equation for response variables are shown below

Y1 (DT) = +107.67 –57.83 X1 -6.50 X1 ²-22.50 X2+2.50 X2 ² + 0.75 X1 X2

Y2 (%F) =+0.21 +0.078 X1+0.028 X1 ²-0.065X2+0.042 X2²- 0.032X1X2

Concerning disintegration time, the results of multiple linear regression analysis showed that both the coefficients b₁and b₂ bear a negative sign. Therefore, increasing the concentration of either camphor or PK is expected to decrease the disintegration time. when high percentage of camphor is used then high porosity is expected and water uptake is increased with decrease the disintegration time, also the friability of the tablet was get increased because the coefficient b₁bears a positive sign.

It means that high conc. Of the camphor leads to the porous tablet with less mechanical strength As indicated by negative sign of the coefficient b₂when there is increase of the PK the friability get decreased. Three-dimensional response surface plots and Two-dimensional contour plots are presented in Figs1, 1a and 2, 2a of plots are useful in study of the effects of two factors on the response at one time and third factor is kept constant. Relationship between these factor is nonlinear. The cumulative % of drug release from various formulations are shown in Figure 3 and 3a.

Fig.1: Response Surface Plot of Y1 (DT)

Fig. 1a: Contour Plot of Y1 (DT)

Fig.2: Contour Plot of Y2 (%F)

Fig.2a: Contour Plot of Y2 (%F)

Figure- 3 Release profiles of O1-O5 Tablets

Figure-3a Release profiles of O6-O9 Tablets

CONCLUSION:

The results of a 3²full factorial design revealed that the amount of polacrilin potassium and camphor significantly affect the dependent variables, disintegration time, and percentage friability. The significant effects of the interaction and polynomial variables on the investigated characteristics of Olanzapine mouth dissolving tablets were verified. It is thus concluded that by adopting a systematic formulation approach, an optimum point can be reached in the shortest time with minimum efforts. Conclusively, the current study attained that, successful development of Olanzapine, which improve the bioavalability of drug by providing an alternative to parenteral and other drug delivery of Olanzapine.

ACKNOWLEDGEMENT:

The authors are grateful to Aventis Pharmaceuticals (Goa), for providing gift samples.

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Received on 14.03.2011 Modified on 18.04.2011

Research J. Pharm. and Tech. 4(8): August 2011; Page 1265-1268