Formulation and Evaluation of Mouth Dissolving Tablets of Clozapine by Direct Compression Method

 

N. Sravanthi¹*, Alekhya¹, I. Vikram Reddy²

¹Pulla Reddy Institute of Pharmacy, Gummadidala, Domadugu,

²Dr. Reddy’s Laboratories Ltd, Bachupally, Hyderabad

 

ABSTRACT:

Mouth dissolving tablets overcomes the problem of swallowing, have faster onset of action. The present work focuses on preparation of Clozapine mouth dissolving tablets by direct compression method using various superdisintegrants and subliming agents. Six formulations were prepared and evaluated for Pre compression and post compression parameters. Effect of super disintegrant Crosspovidone and Explotab on wetting time, disintegration time, and drug content and in vitro release have been studied. values were found to be as16.76,23.09 . Comparative evaluation showed direct compression method a better alternative to sublimation method and rapidly disintegrate in oral cavity. Prepared by direct compression with Explotab superdisintegrants shows 99.79 while sublimation method using camphor 93.58 release in 12 min. Kinetic studies indicated that all the formulations followed first order release with fickian diffusion mechanism. 

 

 

 

INTRODUCTION:

The oral route of administration is considered as the most widely accepted route. But the most evident drawback of the commonly used oral dosage forms like tablets and capsules is difficulty in swallowing, leading to patients incompliance particularly in case of pediatric and geriatricpatients1.Thus, a new delivery system known as oral fast dissolving/disintegrating (FDDS) /melt-in-mouth tablets gaining importance. These oral dosage forms dissolve rapidly in saliva and can be swallowed without the need of drinking water2. Elimination of bitterness is an important criterion in product formulation of mouth dissolving tablets3.

 

Superdisintegrants added in the formulation increase the dissolution characteristics thus increasing the bioavailability of drug4. Clozapine, an antipsychotic agent has been found to be an ideal candidate for mouth dissolving tablets5. Clozapine is used to suppress both positive and negative symptoms of schizophrenia and many neuroleptic responses. Compared with the atypical antipsychotics, and be effective for residual positive symptoms in the treatment of refractory patients6.

 

MATERIALS AND METHODS:

MATERIALS:

Clozapine was obtained from Sun pharma, Avicel(MCC) from Signet chemical, Ac-di-sol (Crosscarmellose) from FMC biopolymer, Cellosol (Crosscarmellose) from Microwax Ltd, Indore, PolyplasdoneXL (Crosspovidone) from Sun pharma, Explotab (SSG) from Forum bioscience, Camphor from Fine Chem Ltd., India, all other excipients used were of analytical grade.

 

METHODS:

Preparation of mouth dissolving tablets of Clozapine using direct compression method:⁷

All the ingredients were passed through sieve no. 60. Drug, mannitol, MCC and sodium saccharin were triturated in a glass mortar. To this Superdisintegrants were incorporated and finally magnesium stearate and talc were added as lubricant, followed by compression.

 

Preparation of mouth dissolving tablets of Clozapine by Sublimation method⁸

Accurately weighed quantities of Clozapine, volatilizable component, mannitol and sodium saccharine were mixed and passed through sieve # 45. Finally magnesium stearate and Talc were added and subjected to compression. After compression the tablets were heated in hot air oven at 60⁰c until constant weight was obtain to ensure the complete removal of volatilizable component.

 

Evaluation of tablets:

Pre compression parameters:

Before compression the blend was evaluated for Angle of repose, Bulk density, tapped density and compressibility index. Results of all the formulation were shown in Table 3 and the values obtained lies within the acceptable range.

 

Post-compression Parameters:

Appearance:

Examination of tablets from each batch showed flat circular shape with no cracks and having pale yellow color.

 

Thickness test:

The thickness of the tablets from each formulation was measured by using dial caliper by picking the three tablets randomly.

 

Hardness Test:

Hardness test was performed by Monsanto tester. Hardness was maintained to be within 2.38 kg/cm² to 4.16 kg/cm².

 

Friability Test:

Friability was performed using Roche friabilator.

 

Weight Variation Test:

To study weight variation, 20 tablets of each formulation were weighed using an electronic balance and the test was performed according to the official method.

 

Drug Content Uniformity:

Tablet containing 50mg of drug is dissolved in 100ml of 0.1N HCl taken in volumetric flask. The drug is allowed to dissolve in the solvent. The solution was filtered, 1ml of filtrate was taken in 50ml of volumetric flask and diluted up to mark with 0.1N HCl and analyzed spectrophotometrically at 209nm. The concentration of Clozapine in mg/ml was obtained by using standard calibration curve of the drug graphically shown in Fig.1.

 

In vitro Dispersion Time:

Tablet was placed in 10 ml phosphate buffer solution, pH 6.8±0.5^oC. Time required for complete dispersion of a tablet was measured.

 

Wetting Time:

The tablet was placed in a petridish of 6.5 cm in diameter, containing 10 ml of water at room temperature, and the time for complete wetting was recorded. To check for reproducibility, the measurements were carried out six times and the mean value calculated.

 

Wetting absorption ratio:

A piece of tissue paper folded twice was placed in a small petridish containing 6ml of distilled water. A tablet was put on the paper and time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio, R, was determined using equation:

                   (Wa – Wb)

R =  10  x   ----------------

                          Wb

Where,

Wb = weight of the tablet before water absorption

Wa = weight of the tablet after water absorption

 

Three tablets from each formulation were analyzed performed and standard deviation was also determined. Results were tabulated in Table 5.

 

In vitro Disintegration Time:

Place one tablet in each of the 6 tubes of the basket.  Add a disc to each tube and run the apparatus using pH 6.8 (simulated saliva fluid) maintained at 37⁰±2⁰C as the immersion liquid.  The assembly should be raised and lowered between 30 cycles per minute. The time in seconds taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured and recorded.

 

In vitro Dissolution Studies:

All the six formulations were subjected for in vitro dissolution studies using tablet dissolution tester USP XXIII using 0.1N HCl as dissolution medium. The samples were withdrawn at different time intervals and analyzed at 209nm. Cumulative drug release was tabulated in Tablem6.

 

 

Comparative evaluation of formulations with marketed formulation:

The promising formulation (F3 and F4) as found by evaluation studies was compared with marketed product innovator (50mg). The evaluation parameters tested and compared were drug content uniformity and in-vitro dissolution profile. The values obtained for in vitro dissolution study were recorded in Table 7.

 

Scanning Electron Microscopy:

This is done to examine the surface topography, texture of the formulations, morphology of fractured or sectioned surfaces, this provide important information about the porosity of the device in the matrix of the formulations by subjecting the formulations to SEM in dry state at the magnification X150 using a JEOL JSM-T330A Scanning Microscope as shown in Fig:13-18.

 

Curve fitting analysis:

The results of dissolution data fitted to various drug release kinetic equations. The correlation coefficient and slope values obtained are shown in Table 8. Next, the model fitting of the release profiles were performed using PCP DISSO-V2 software to observe the mechanism. The correlation coefficient values obtained for all five models are tabulated in Table 9.

 

Stability Studies:

The formulations F3, F6 were selected for stability studies on the basis of their high cumulative % drug release, in vitro disintegration time and in vitro dispersion studies. The stability studies were carried out at 25⁰C/60% RH and 40⁰C/75% RH for all the selected formulations up to 30 days. The results obtained are tabulated in Table 10 and Table 11.

 

RESULT AND DISCUSSION:

The results of thickness, hardness, friability, weight variation, drug content uniformity, Invitro dispersion time and Invitro disintegration time were tabulated in Table 4. All the formulations showed angle of repose within the limits which indicates good flow. The formulated tablets were elegant and almost uniform thickness. The weight loss after friability test was found well within the approved range (<1%) in all the formulation, indicates the tablets possess good mechanical strength. In case of formulation F4, F5 and F6, the tablets were worn out at their edges with more % friability. Formulation F1 to F3 possesses good mechanical strength. All the tablets passed weight variation test as the % weight variation was within the pharmacopoeias limits of ±7.5%. All formulations showed quick wetting, this may be due to ability of swelling and also capacity of absorption of water. All superdisintegrants have high water absorption capacity and cause swelling. In vitro dispersion time was measured by the time taken to undergo uniform dispersion. Rapid dispersion within seconds has been observed in all the formulations. Formulation F1, F2 and F3 prepared by direct compression method show better dispersion within seconds than sublimation method F4, F5 and F6. This in vitro dispersion time gives direct information regarding super disintegration nature of disintegrants used. All formulations showed disintegration time less than 30 seconds. Formulation F1 and F3 showed fast disintegration compared to formulation F4 to F6. The drug content of the tablets were found between 49.53±0.55 mg to 49.90±0.68 mg of Clozapine. F3 prepared by direct compression and F6 by sublimation method showed good drug release than other formulations. Graphical representation is shown in Fig.2.

 

Direct compression method gives better results in all parameter than the sublimation method, but sublimation method hardness is not so good as compared to direct compression method. But it is in the acceptable range. The friability results is less because of evaporation of subliming material which results in porosity of the tablets so tablets have low strength. Direct compression method showed better disintegration as compared to sublimation method which is shown in Table 4. The mean value of drug content uniformity observed was 99.28%. The marketed product gave 92.38% of drug release in 12 minutes of dissolution study. In-vitro dissolution profiles of marketed product in comparison to the formulated batches were shown graphically in Fig.4 and showed that the formulation F2 with 89.4% of drug release has better release of drug in comparison to marketed product. After examination the photographic results obtained from SEM, it was observed that formulation F1 to F3 have smoothed, plane and less porous surface than F4 to F6. The porous surface may be because of sublimation of camphor, ammonium bicarbonate and ammonium carbonate. The results were found to be linear for first order release. It is concluded that release of drug from formulations F1 to F6 followed first order. The plots are shown in Fig.3. The formulations F1, F4 and F6 show First order and formulation F2 and F3 show Peppas model and F5 shows Hixson Crowell. From the values obtained, it is proved that formulations F1, F4 and F6 dissolution (release) of the drugs follows first order, may be due to rapid diffusion or the porous nature. The 'n' value indicates release mechanism and in the present study 'n' value range within 0.0889 to 0.4995 for all six batches. So the drug release follows Fickian diffusion mechanism. From these results it was concluded that, formulations F3 and F6 are stable and retained their original properties.

 

Table 1: Composition of Mouth Dissolving Tablets of Clozapine

 

Table 2: Standard Calibration Curve of Clozapine at 209 nm in 0.1N HCl

 

 

Fig.1 calibration curve Correlation (r) = 0.998

 

Table 3: Pre compression parameters

Formulation Code	Angle of Repose (q)	Loose Bulk Density (gm/cm3)	Tapped Bulk Density (gm/cm3)	% Compressibility
F1	29.32	0.57	0.68	16.18
F2	31.01	0.55	0.71	22.53
F3	29.73	0.59	0.69	14.5
F4	28.20	0.57	0.65	12.3
F5	29.30	0.58	0.66	12.12
F6	26.65	0.62	0.72	13.89

 

Table 4: Evaluation of Tablet Parameters^{9, 10}

Formulation Code	Uniformity of Thickness  (mm)	Hardness  (kg/cm3)	Friability %	Weight Variation  (mg)	Drug Content Uniformity  (mg)	In vitro Disintegration Time (min)	In vitro Dispersion Time (min)
F1	2.98	3.88	0.93	300.2	49.89	13.67	18.67
F2	3.16	3.50	0.88	299.6	49.65	10.4	15.22
F3	2.88	4.16	0.71	298.6	49.75	14.61	18.00
F4	3.05	3.38	2.34	239.6	49.53	30.41	35.3
F5	3.48	3.48	1.67	239.8	49.90	24.2	27.93
F6	2.85	2.38	1.54	241.3	49.82	16.81	21.47

 

Table 5: Wetting Time, Water Absorption Ratio

Formulation Code	Wetting Time	Water Absorption Ratio
F1	25.50	19.45
F2	18.01	24.89
F3	16.76	23.09
F4	29.58	33.56
F5	27.60	23.84
F6	23.58	27.08

 

Table 6: In vitro Dissolution Profile of the Formulations F1 to F6

Formulation code	Time (min)	Absorbance at 283nm	Cum. Drug Released (mg)	Cum. % Drug Released	Cum. % Drug Retained	Log Cum. % Drug Retained
F1	2 4 6 8 10 12	0.303 0.338 0.358 0.388 0.406 0.431	30.38 34.62 36.85 40.11 42.17 44.94	61.77 69.24 73.7 80.23 84.33 89.89	38.23 30.76 26.3 19.77 15.67 10.11	1.582 1.488 1.42 1.296 1.195 1.004
F2	2 4 6 8 10 12	0.228 0.308 0.344 0.368 0.398 0.411	23.24 31.52 35.36 38.01 41.27 42.82	46.48 63.04 70.73 76.01 82.55 85.65	53.52 36.96 29.27 23.99 17.45 14.35	1.73 1.57 1.47 1.38 1.24 1.17
F3	2 4 6 8 10 12	0.372 0.385 0.417 0.440 0.463 0.485	37.92 39.45 42.93 45.51 48.11 48.72	75.83 78.90 85.86 91.02 96.21 99.79	24.17 21.1 14.14 8.98 3.79 0.21	1.38 1.32 1.15 0.95 0.58 -0.68
F4	2 4 6 8 10 12	0.151 0.381 0.414 0.430 0.439 0.449	15.39 38.92 42.50 44.36 45.52 46.79	30.78 77.84 85.00 88.73 91.05 93.58	69.22 22.16 15.00 11.27 08.95 6.42	1.79 1.34 1.18 1.05 0.95 0.81
F5	2 4 6 8 10 12	0.322 0.347 0.365 0.398 0.420 0.441	32.82 35.55 37.58 41.15 43.62 46.00	65.64 71.10 75.16 82.30 87.24 92.00	34.36 28.90 24.84 17.70 12.76 8.00	1.54 1.46 1.39 1.25 1.10 0.90
F6	2 4 6 8 10 12	0.411 0.437 0.450 0.459 0.465 0.470	41.89 44.77 46.35 47.52 48.39 49.16	83.78 89.55 92.69 95.04 96.78 98.33	16.22 10.45 07.31 04.96 3.22 1.67	1.21 1.02 0.86 0.69 0.51 -0.19

 

Table 7: Comparison with marketed product

Time (min.)	Cumulative % Drug Released
	F3	F4	Marketed product
2	75.83	30.78	10.60
4	78.90	77.84	19.42
6	85.86	85.00	28.09
8	91.02	88.73	36.61
10	96.21	91.05	40.89
12	99.79	93.58	46.61

 

Table 8:  Slope and Correlation (r) Values

Formulation Code	Cum. % Drug Released V/s. Time			Log Cumulative % Drug Retained V/s Time
	Correlation coefficient	Slope	Rate constant k	Correlation coefficient	Slope	Rate constant k
F1	0.997	2.75	-6.33	0.987	0.0556	-0.12805
F2	0.963	3.71	-8.54	0.995	0.0554	-0.12759
F3	0.995	2.53	-5.82	0.962	0.0985	-0.22685
F4	0.806	5.10	- 1.85	0.953	0.0886	-0.20405
F5	0.980	2.67	- 2.25	0.982	0.0631	-0.14532
F6	0.966	1.38	- 2.22	0.999	0.086	-0.19806

Table 9: Model fitting of the Release Profile using Five Different Models (r-value)

Formulation Code	Mathematical Models (Kinetics)
	Zero Order	First Order	Higuchi Matrix	Peppas	Hixson Crowell	‘n’ values	Order of release
F1	0.987	0.997	0.980	0.989	0.995	0.2052	First Order
F2	0.963	0.995	0.992	0.998	0.989	0.3371	First order
F3	0.985	0.962	0.963	0.995	0.970	0.1595	First order
F4	0.806	0.953	0.923	0.888	0.901	0.4995	First order
F5	0.980	0.982	0.964	0.975	0.990	0.1887	First order
F6	0.966	0.999	0.999	0.999	0.998	0.0889	First Order

 

Table 10: F3 and F4 Stability data stored at 25⁰C/60% RH¹¹

Formulation Code	Tested after time (in days)	Hardness (kg/cm2)	Drug content uniformity	Friability %	Disintegration time (sec)
F3	10	4.16	49.817	0.79	14.32
	20	4.28	49.75	0.76	14.67
	30	4.34	49.75	0.72	14.67
F4	10	3.38	49.53	2.36	30.41
	20	3.34	49.34	2.60	30.43
	30	3.35	49.64	2.00	30.46

 

Table 11: F3 and F4 Stability data stored at 40⁰C/75% RH¹¹

Formulation Code	Tested after time (in days)	Hardness (kg/cm2)	Drug content uniformity	Friability %	Disintegration time (sec)
F3	10	4.11	49.88	0.71	14.36
	20	4.27	49.79	0.75	14.4
	30	4.33	49.61	0.76	14.6
F4	10	3.34	49.34	2.00	30.46
	20	3.36	49.83	2.65	30.42
	30	3.38	49.49	2.13	30.4

 

 

Fig:2 In vitro % cumulative drug release VS time

 

Fig: 3 first order rate release for the formulations

 

Fig.4comparision of invitro drug release profile of F3, F4 and marketed products

 

Fig: 5 UV spectrum of Clozapine

 

Fig: 6 I.R spectrum of Clozapine

 

Fig: 7 IR Spectrum of Formulation F1

 

Fig: 8 IR Spectrum of Formulation F2

 

Fig: 9 IR Spectrum of Formulation F3 

 

Fig: 10 IR Spectrum of Formulation F4

 

Fig:11 IR Spectrum of Formulation F5

 

Fig:12 IR Spectrum of Formulation F6

 

 

Scanning electron microscopy of all the formulations Fig: 13-18

 

 

SUMMARY:

An attempt to develop mouth dissolving tablets of Clozapine was achieved with view to improve bioavailability. The IR spectra’s revealed that, polymers and excipients used were compatible with drug. The formulated tablets showed compliance for various physiochemical parameters viz. tablet dimensions, hardness friability, weight variation, content uniformity and disintegration. In vitro disintegration time, in vitro dispersion time and wetting time showed good results in both methods. Water absorption ratio indicates good absorptivity in all formulations. In vitro release studies revealed that 90% of drug releases from all the formulations were within 12 minutes. Formulation F3 showed faster drug release in comparison to the marketed formulation of Clozapine. Stability studies on formulation F3 and F4 indicated that the most suitable storage temperature was 25°C to 40°C for a period of 30 days. Overall, in both the method direct compression showed good results and formulations F3 and F6 tablets disintegrated rapidly with good results.

 

ACKNOWLEDGMENT:

Authors are thankful to Prof. C.P. Sastry Industrial Guide, P.V. Narsaraju (Pangea Pharma Ltd.), Prof S. Punitha , Prist University, Tanjavur  for providing all the facilities for this research work.

 

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