INTRODUCTION:

The present study outlines approach for design and evaluation of quetiapine fumarate to enhance the gastric retention time by developing once a day floating controlled release drug delivery¹. Quetiapine fumarate (QF) is a dibenzothiazepine Class anti-psychotropic agent. It is used in the treatment of bipolar 1 disorder and schizophrenia. Quetiapine has short half-life and pH-dependent solubility, showing low solubility with increasing pH leading to variable oral bioavailability^2,3. To overcome these problems, once a day buoyant tablets were prepared by using gas generating system^4,5.

The absorption window of the drug is at duodenum making it suitable to be delivered as floating drug delivery system⁶. The effect of various diluents and other excipients was also taken into consideration while evaluating the release of the drug from the dosage form^7,8.

MATERIALS:

Quetiapine fumarate was gifted by Aurobindo Pharma Ltd, Hyderabad, All grades of HPMC were gifted by Dr. Reddy’s laboratories, Hyderabad, Sodium bicarbonate, Lactose, Microcrystalline cellulose (MCC), Magnesium stearate and talc were obtained from S.D. Fine chemical Pvt Ltd, Mumbai, Hydrochloric Acid Merck specialties Pvt Ltd, Mumbai, Pharmatose was gifted by DMV-Fonterra Excipients GmbH Co KG, Germany, Lactopress was gifted by DFE Pharma, Germany.

METHODS:

Preparation of floating tablets:

The tablets were prepared by direct compression using Cadmach 18 Stage Rotary machine after blending all the ingredients uniformly at various ratios as shown in table 1, 2 and 3.

Table 1. Formulas for preparing buoyant quetiapine fumarate tablets by using gas generating system

Formulation Code	Drug (mg)	HPMC K4M (mg)	HPMC K15M (mg)	HPMC E4M (mg)	HPMC K100LV (mg)	Sodium bicarbonate (mg)	Magnesium Stearate (mg)	Talc (mg)	Directly Compressible Lactose (mg)
F1	60	-	60	-	-	80	6	6	188
F2	60	20	-	-	5	45	6	6	258
F3	60	80	-	-	60	32	6	6	156
F4	60	-	68	-	60	32	6	6	168
F5	60	-	72	-	60	32	6	6	164
F6	60	-	80	-	40	32	6	6	176
F7	60	-	80	-	60	32	6	6	156
F8	60	-	-	80	60	32	6	6	156

Table 2. Composition of F7 formulation with different diluents

Formulation Code	Drug (mg)	HPMC K15M (mg)	HPMC K100LV (mg)	Sodium bicarbonate (mg)	Magnesium Stearate (mg)	Talc (mg)	Directly Compressible Lactose (mg)	Pharmatose (mg)	Lactopress (mg)	MCC (mg)
F7	60	80	60	32	6	6	156	-	-	-
F7a	60	80	60	32	6	6	-	156	-	-
F7b	60	80	60	32	6	6	-	-	156	-
F7c	60	80	60	32	6	6	-	-	-	156

Table 3. Composition of F8 formulation with different diluents

Formulation Code	Drug (mg)	HPMC E4M (mg)	HPMC K100LV (mg)	Sodium bicarbonate (mg)	Magnesium Stearate (mg)	Talc (mg)	Directly Compressible Lactose (mg)	Pharmatose (mg)	Lactopress (mg)	MCC (mg)
F8	60	80	60	32	6	6	156	-	-	-
F8a	60	80	60	32	6	6	-	156	-	-
F8b	60	80	60	32	6	6	-	-	156	-
F8c	60	80	60	32	6	6	-	-	-	156

Characterization of Floating Tablets:

Weight variation:

Ten tablets from each batch were individually weighed in grams on an analytical balance. The average weight and standard deviation were calculated and the results were expressed as compliance or non-compliance of set limits⁹.

Hardness of the tablets:

Six tablets were measured in the hardness examination. Tablet hardness was measured using a Pfizer hardness tester. The crushing strength of the 6 tablets with known weight and thickness of each was recorded in kg/cm²and the average hardness and standard deviation was reported¹⁰.

Friability of the tablets:

Six tablets of the formulation were weighed and measured in a Roche type friabilator. The tablets were rotated at 25rpm for 4min, and the samples were then reweighed. The percentage friability was calculated using the equation

W₁ – W₂

F% = ------------------- X 100

W₁

Where, F% represents the percentage weight loss, and W1 and W2 are the initial and final tablets weights, respectively¹¹.

Content uniformity:

Ten tablets were weighed and triturated to get fine powder. Weight equivalent to 10mg of quetiapine fumarate was dissolved in 10ml of 0.1 N HCl and agitated for 15 min, the volume was adjusted to 100ml using 0.1 N HCl with continuous agitation for 5min. The solution was filtered and suitable dilutions were prepared with 0.1 N HCl. Same concentration of the standard solution was also prepared. The drug content was estimated by recording the absorbance at 301nm by using UV-Visible spectrophotometer¹².

The floating lag time and the total floating time:

This test was characterized by floating lag time and total floating time. The test was performed using USP XXIII type II paddle apparatus using 900ml of 0.1 N HCl at paddle rotation of 50rpm at 37±0.5^oC. The time required for tablet to rise to surface of dissolution medium and duration of time the tablet constantly float on dissolution medium was noted as floating lag time and total floating time¹³.

Drugexcipients interaction studies:

In order to evaluate the integrity and compatibility of the drug in the formulation, drug–excipient interaction studies were performed. The infrared spectra of pure drug, physical mixture of drug and excipients, polymer and formulation were recorded between 4000 to 400cm^-1on FTIR. The IR spectra for the test samples were obtained using KBr disk method using an FTIR spectrometer¹⁴.

In vitro dissolution Study of tablets:

The tablet was placed inside the Dissolution test apparatus type 2 apparatus (Paddle method). 5ml of sample were withdrawn at time intervals of 0.5, 1, 2, 3, 4, 6, 8, 10 and 12h. The volume of dissolution fluid adjusted to 900ml by replacing 5ml of dissolution medium (0.1N Hydrochloric acid) after each sampling. The release studies were conducted with 3 tablets, and the mean values were plotted versus time. Each sample was analyzed at 301nm using double beam UV and Visible Spectrophotometer against reagent blank. The drug concentration was calculated using standard calibration curve¹⁵.

Mechanism of drug release:

The different mathematical models may be applied for describing the kinetics of the drug release process from tablets; the most suited being the one which best fits to the experimental results. The kinetics of quetiapine fumarate release from tablets formulations were determined by finding the best fit of the release data to zero order, first order, matrix, Hixson-Crowell, Higuchi, and Korsmeyer-Peppas plots¹⁶.

RESULTS AND DISCUSSION:

Solubility of drug:

Figure1. Quetiapine fumarate quantitative solubility chart in various media.

The drug quetiapine fumarate is more soluble in 0.1 N HCl, and its quantitative solubility was 32.6mg/ml. As pH increased, solubility decreased significantly as shown in figure 1 i.e. pH 4.5 acetate buffer (5.6mg /ml), pH 6.8 phosphate buffer (2.2 mg/ml), water (2mg/ml) and pH 7.4 phosphate buffer (1.5mg/ml). It showed pH dependent solubility, highly soluble in acidic pH but poorly soluble in alkaline pH.

Table 4. Evaluation of quetiapine floating tablets

Formulation	Weight variation(mg)	Hardness(kg/cm)	Thickness (mm)	% Friability	Drug content (mg)	Floating lagtime (seconds)	Total Floating time(h)
F1	405.1 ± 2.08	4.7 ± 0.2	3.73 ± 0.25	0.37 ± 0.02	101.3 ± 3.05	No floating	-
F2	405.4 ± 4.9	4.53 ± 0.208	3.76 ± 0.3	0.35 ± 0.03	101.4 ± 2.1	No floating	-
F3	404.9 ± 6.4	4.36 ± 0.15	3.66 ± 0.32	0.27 ± 0.03	95.6 ± 1.5	32	>12
F4	412.2 ± 5.6	4.56 ± 0.35	3.5 ± 0.17	0.45 ± 0.03	94.33 ± 2	127	6
F5	402.61 ± 6.1	4.46 ± 0.4	3.8 ± 0.20	0.45 ± 0.03	102.1 ± 2.1	136	8
F6	401.9 ± 6	4.46 ± 0.15	3.9 ± 0.1	0.25 ± 0.015	101.2 ± 2.3	147	9
F7	405.6 ± 8.7	3.96 ± 0.15	3.8 ± 0.30	0.35 ± 0.035	96.6 ± 2.4	30	>12
F8	404.6 ± 2	4.53 ± 0.2	4.03 ± 0.05	0.43 ± 0.04	95.1 ± 2	35	>12
F7a	402.1 ± 5.03	5.06 ± 0.5	3.7 ± 0.15	0.45 ± 0.03	96.3 ± 1.2	45	>12
F7b	401.1 ± 1.5	4.8 ± 0.45	3.7 ± 0.32	0.26 ± 0.02	95.6 ± 2.5	50	>12
F7c	403.6 ± 7.2	4.73 ± 0.65	3.6 ± 0.05	0.44 ± 0.04	97.6 ± 1.5	81	>12
F8a	402.5 ± 4.04	4.63 ± 0.51	3.8 ± 0.15	0.34 ± 0.03	101 ± 1.2	49	>12
F8b	401.8 ± 7.3	4.6 ± 0.3	3.7 ± 0.32	0.36 ± 0.023	100.6 ± 3.7	53	>12
F8c	402.7 ± 5.03	4.7 ± 0.3	3.9 ± 0.25	0.27 ± 0.04	104.3 ± 3.9	76	>12

Data represents mean ± SD (n=3)

Table 5. Percent swelling of formulations with HPMC K4M, HPMC K15M, and HPMC E4M.

Time(h)	F1	F2	F3	F4	F5	F6	F7	F8
1	-	-	18.9 ± 0.3	14.05 ± 0.6	14.8 ± 0.94	19.6 ± 0.42	19.98 ± 0.7	16.9 ± 0.5
2	-	-	27.4 ± 0.05	19.2 ± 0.38	20.7 ± 0.92	24.4 ± 0.95	25.06 ± 0.7	26.4 ± 0.65
3	-	-	57.3 ± 0.31	44.6 ± 0.66	47.6 ± 0.53	50.3 ± 0.41	52.3 ± 0.61	55.3 ± 0.41
4	-	-	75.1 ± 0.66	58.6 ± 0.82	61.3 ± 0.35	65.1 ± 0.76	67.1 ± 0.89	70.1 ± 0.56
6	-	-	83.8 ± 0.33	70.5 ± 0.33	74.3 ± 0.71	76.8 ± 0.93	79.8 ± 0.53	75.8 ± 0.43
8	-	-	80.5 ± 0.66	68.9 ± 0.98	73.6 ± 0.53	75.5 ± 0.46	77.5 ± 0.76	77.5 ± 0.76
10	-	-	79.2 ± 0.66	66.1 ± 1.02	68.9 ± 0.98	73.2 ± 0.89	75.2 ± 0.6	74.2 ± 0.36
12	-	-	76.9 ± 0.82	60.7 ± 0.33	64.2 ± 0.53	70.9 ± 0.82	72.9 ± 0.98	73.9 ± 0.89

Data represents mean ± SD (n=3)

In vitro drug release studies:

Table 6. In vitro drug release data of formulations containing directly compressible lactose.

Time (h)	F1	F2	F3	F4	F5	F6	F7	F8
0	0	0	0	0	0	0	0	0
0.5	102.1 ± 0.3	92.3 ± 0.47	36.51 ± 0.82	8.2 ± 0.19	14.5 ± 0.43	16.8 ± 0.23	4.98 ± 0.98	8.71 ± 0.7
1	-	94.7 ± 0.18	48.36 ± 0.62	27.4 ± 0.15	24.3 ± 0.65	25.3 ± 0.98	13.7 ± 0.89	14.66 ± 0.6
2	-	96.7 ± 0.51	60.49 ± 0.77	47.09 ± 0.58	43.6 ± 0.45	41.4 ± 1.06	26.3 ± 0.67	22.63 ± 0.5
4	-	97 ± 1.40	69.18 ± 1.38	64.98 ± 0.58	61.3 ± 0.23	66.1 ± 1.43	38.4 ± 0.56	34.11 ± 0.4
6	-	98.2 ± 0.26	77.99 ± 0.57	80.72 ± 0.45	80.2 ± 0.56	79.0 ± 0.76	53.5 ± 0.45	50.4 ± 0.3
8	-	99.7 ± 0.62	82.99 ± 0.25	90.06 ± 0.23	85.6 ± 0.33	95.3 ± 0.65	66.2 ± 0.86	72.32 ± 0.9
10	-	-	83.22 ± 0.39	88.74 ± 0.39	94.4 ± 0.43	100.2 ± 0.48	73.4 ± 0.79	83.3 ± 0.6
12	-	-	83.8 ± 0.06	91.77 ± 0.87	95.4 ± 0.23	-	82.8 ± 0.54	94.06 ± 0.3

Data represents mean ± SD (n=3)

The in vitro dissolution testing was performed and the results of the formulations were expressed in tables 6 and figure 2. According to US FDA for controlled release tablets the drug release at 2hours should be less than 33% and at 12 hours it should be more than 80%. As the F4 formulation contain a lower viscosity grade polymer compared with that of F5, F6, F7 other polymers the release rate was faster probably owing to less polymer entanglement and less gel strength and also to the larger effective molecular diffusion area at lower viscosity as compared with higher viscosity grades of HPMC. Moreover, the tablets formed by the higher viscosity grade HPMC would have more gel strength than the one formed by the lower viscosity grade because of which, the erosion would be less.

As the concentration of the polymer increased from F5 to F7 the drug release was decreased. It increased from 14.67 to 4.98 from F5 to F7 respectively. The differences in the release may be due to the amount of gel layer formed on the surface of the tablets. HPMC K4M at higher concentrations results in a greater amount of gel being formed. This gel increases diffusion length so that drug release was decreased. The formulations F1, F2 and F3 were formulated by varying the concentrations of sodium bicarbonate. When the concentration of sodium bicarbonate was less, the tablets could not float immediately and total effervescence was seen. This might be due to the gas generated was not sufficient to keep the formulation float immediately. When amount of sodium bicarbonate was increased above 80 mg the tablet float immediately and release was good.

And the best formulations F7 and F8 were further studied by preparing the formulations with other diluents like Pharmatose, Lactopress, and microcrystalline cellulose and the in vitro drug release studies were given in table 7 and 8 and the drug release was found to be changing with different diluents. F7 formulation was optimized basing on the invitro drug release. The regression coefficient (R²) values of release data of all formulations obtained by curve fitting method for zero order, first-order, and Higuchi and Korsmeyer-Peppas model are reported in table 9. Most of the formulations follow the zero order and Higuchi model. For the optimized formulation F7 and F8 the R² value of zero order 0.972 and 0.992 (nearer to 1) is dominant than the other models.

The mechanism of drug release is predicted by using according to Korsmeyer - Peppas. The n value of optimized formulation F7 was 0.079. This indicates that the drug release mechanism is of fickian diffusion. The R² value of F7 formulation for Zero-order is near to 1 which indicated the drug release mechanism is of zero-order resulting from constant surface area and controlled swelling/ erosion provided by the changing geometry of the system as shown in table 9.

Figure 2. Dissolution profiles of formulations containing directly compressible lactose.

Figure 3. In vitro dissolution profile of F7 formulations compared with different diluents like Pharmatose, Lactopress, and Microcrystalline cellulose.

Table7. In vitro dissolution data of F7 formulations compared with different diluents like Pharmatose, Lactopress, and microcrystallinecellulose.

Time (h)	F7	F7a	F7b	F7c
0	0	0	0	0
0.5	4.98 ± 0.29	11.1 ± 0.87	11.1 ± 0.92	6.96 ± 0.65
1	13.74 ± 0.76	22.5 ± 0.37	18.2 ± 0.56	11.4 ± 0.45
2	26.38 ± 0.54	29.8 ± 0.98	31.02 ± 0.72	18.2 ± 0.78
4	38.4 ± 0.79	59.7 ± 0.77	50.52 ± 0.34	29.4 ± 0.54
6	53.5 ± 0.12	61.7 ± 0.34	59.32 ± 0.67	35.17 ± 0.88
8	66.2 ± 1.98	77.3 ± 0.45	76.1 ± 0.82	58.35 ± 0.53
10	73.45 ± 0.4	82.3 ± 0.52	80.2 ± 0.63	70.01 ± 0.23
12	82.8 ± 0.34	83.5 ± 0.66	83.7 ± 0.56	82.01 ± 1.34

Data represents mean ± SD (n=3)

Table 8. In vitro dissolution data of F8 formulations compared with different diluents like Pharmatose, Lactopress, and microcrystallinecellulose.

Time(h)	F8	F8a	F8b	F8c
0	0	0	0	0
0.5	8.71 ± 0.36	29.15 ± 0.44	56.96 ± 0.3	30.53 ± 0.36
1	14.6 ± 0.6	41.30 ± 0.89	60.78 ± 0.22	37.22 ± 0.4
2	22.6 ± 0.72	51.89 ± 0.82	69.65 ± 0.21	47.54 ± 0.27
4	34.1 ± 0.92	69.84 ± 0.96	78.93 ± 0.17	64.32 ± 0.5
6	50.42 ± 0.71	83.55 ± 0.76	87.21 ± 0.09	74.44 ± 0.83
8	72.32 ± 3.18	98.04 ± 1.6	98.03 ±0.81	95.82 ± 0.19
10	83.35 ± 1.7	100.4 ± 0.8	100.3 ± 1.22	103.6 ± 1.04
12	94.06±3.7

Table 9: Release kinetics of optimized formulations

Formulation	Zero order	First order	Higuchi	Korsmeyer and Peppas	Peppas (m)
F7 R²value	0.972	0.867	0.997	0.972	0.079

FTIR RESULTS:

Table 10. FTIR spectra results comparison

Functional group stretching	Quetiapine fumarate	HPMC K100 LV	Optimized formulation (F7)	Optimized formulation (F8)	Inference
C-H	2852.52cm^-1	-	2850 cm^-1	2905.3 cm^-1	Slight change in wavelength
C=O	1760.01 cm^-1	-	1755 cm^-1	1759.4 cm^-1	Slight change in wavelength
C=O	-	2380.03 cm^-12310.27 cm^-1	2379.65 cm^-1, 2311.76	2382.15 cm^-1, 2310.43 cm^-1	Slight change in wavelength
C-O	-	1048.58 cm^-1	1034.58 cm^-1	1039.99 cm^-1	Slight change in wavelength
C=C	1695.5 cm^-1	-	1694.2 cm^-1	1693.8 cm^-1	Slight change in wavelength
C-N	1551.67cm^-1	-	1546cm^-1	1548.01 cm^-1	Slight change in wavelength
C-C	1214.4cm^-1	-	1207.2 cm^-1	1207.3 cm^-1	Slight change in wavelength
CH=CH	655.62 cm^-1	-	698 cm^-1	654.7 cm^-1	Slight change in wavelength

To get evidence of possible chemical interaction of drug with the excipients, FTIR analysis was usedand table 10 shows the IR spectra of quetiapine fumarate, HPMC K100 LV, and the F7 and F8 formulation. Pure drug has shown no alteration in the characteristic peaks of drug and optimized formulations. The peaks were suggesting there was no interaction between the drug and polymers.

CONCLUSION:

Gastroretentive floating tablets by gas generating technique were successfully prepared with sodium bicarbonate and hydrophilic polymers like HPMC K4M, HPMC K15M, HPMC E4, and HPMC K100LVand gas-generating agent sodium bicarbonate wereprovided the buoyancy and drug release.The release rate was faster with lower viscosity grades of HPMC, probably owing to less polymer entanglement and less gel strength and also to the larger effective molecular diffusion area at lower viscosity as compared with higher viscosity grades of HPMC.The regression coefficient (R²) values of release data of all formulations obtained by curve fitting method for zero-order, first-order, and Higuchi and Korsmeyer-Peppas model. For the optimized formulations F7 and F8, the R² value of Zero order is 0.972 and 0.992 respectively (nearer to 1) is dominant than the other models indicating that the drug release follows zero order. The n value of optimized formulation F7 and F8 are 0.079 and 0.08 respectively indicating that the drug release mechanism is of fickian diffusion. FTIR studies showed there was no interaction between drug and polymer.

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Received on 26.03.2020 Modified on 10.04.2020

Res. J. Pharma. Dosage Forms and Tech.2020; 12(2): 83-88.

DOI: 10.5958/0975-4377.2020.00015.4