Formulation Development and Evaluation of Quetiapine fumarate Extended-Release tablet by using 2³ Factorial designs

Yogesh S. Purkar*, Rajendra K. Surawase

Department of Pharmaceutics, Loknete Dr. J. D. Pawar College of Pharmacy, Manur, Tal. - Kalwan,

Dist. - Nashik 423501, Maharashtra, India.

*Corresponding Author E-mail: yogeshpurkar5074@gmail.com

ABSTRACT:

Purpose: Extended-release tablets function somewhat like modified-release medications in that their active ingredient is released slowly over a predetermined length of time. Extended-release tablets deliver a drug to the body gradually, guaranteeing a longer therapeutic effect than immediate-release tablets, which offer quick absorption. With their "ER" or "XR" markings, these tablets are designed to keep medication levels constant for extended periods of time. People who might not react well to immediate-release drugs are advised to take them, which are usually taken once daily. Method: The use Wet granulation process can be utilizing for manufacturing extended-release tablet utilizing polymer such as HPMC K100, HPMC K15 and Ethyl cellulose. Result: FTIR analysis indicated no interaction between the medication and its excipients. The developed ER tablet using the wet granulation process. The developed extended-release tablet ranges in weight variation from 250-256mg. It was discovered that the friability 0.32 to 1.32%. The swelling index optimized batch was 85.01%. The drug optimised batch had a 98.94% in vitro release rate. Conclusion: A combination of HPMC K100, HPMC K15, and ethyl cellulose was effectively employed in the creation of Quetiapine fumarate extended-release matrix tablets. The examined extended-release matrix tablet produced optimal smooth blood levels of quetiapine fumarate for a full day and shown a strong in vitro and in vivo association. Because of its extended-release characteristics over an extended period of time, this quetiapine fumarate formulation appears to be a safer and better therapeutic choice for increased tolerance than traditional tablets.

KEYWORDS: Extended release, Half-life, Matrix System, Wet granulation, Polymer.

INTRODUCTION:

The most popular way of administering medication is orally, in part due to its convenience and in part to the fact that gastrointestinal physiology permits more design flexibility in dosage forms than most other methods¹.

Terms like depot products, modified release, ER, or long-lasting release are utilised to describe drug delivery strategies intended to achieve or prolong the therapeutic benefit by continuously releasing medicine for a prolonged length of time following administration with a single dose². Quetiapine is an atypical antipsychotic that is administered to treat schizophrenia and bipolar disorder. A psychiatrist diagnoses bipolar disorder, also known as bipolar affective disorder (previously known as manic-depressive sickness or manic depression), which is a mood condition. Individuals with bipolar disorder may experience manic or hypomanic periods that alternate with depressed ones³.

QF, also known as 2-[2-(4-dibenzo[b,f][1,4]thiazepin-11 yl-1-piperazinyl)ethoxy] ethanol fumarate 11, is an atypical antipsychotic drug used to treat bipolar disorder and schizophrenia. It is a member of the dibenzothiazepine chemical class⁴. Due to its limited solubility throughout its therapeutic pH range and high permeability, QF is classified as a category II BCS medication. At roughly six hours, quetiapine has a brief half-life.

The ER formulation was created a few years ago with the intention of reducing side effects and encouraging patient compliance through controlled drug release. Overall, quetiapine has a fair risk/benefit profile and is a solid first-line option for treating schizophrenia. Giving once-daily formulations is one way to increase medication adherence.

Quetiapine fumarate (QF), is multi-receptor antagonist, may interact with a wide variety of neurotransmitter receptors. It has been demonstrated that QF has high affinity for histamine, α-adrenergic, and 5-HT2 receptors in the human brain, but a small affinity for dopamine D1 and D2 receptors. Compared to traditional antipsychotics like haloperidol and chlorpromazine, QF shows outstanding efficiency in curing both the positive and negative signs of schizophrenia, as well as a low incidence of extrapyramidal symptoms (EPS)⁵. Furthermore, QF can improve patients' cognitive performance and has a neuroprotective impact. Due to the aforementioned qualities, QF is currently the preferred option for treating brain disorders in clinics¹.

The main objective of the current study is to increase the solubility and rate of dissolution of quetiapine fumarate by creating an extended-release matrix tablet employing a hydrophilic polymer HPMC K100, HPMC K15, and ethyl cellulose using a wet granulation approach. Formulation of ER

MATERIAL AND METHOD:

Material: The materials listed below are received and used as: Quetiapine fumarate was obtained from Balaji Drug, Nashik, and ethyl cellulose and HPMC K100 and HPMC K15 polymers was obtained Research-Lab Fine Chem Industries, Mumbai. Excipients include isopropyl alcohol, magnesium stearate, talc, microcrystalline cellulose, and PVP K30 (Research-Lab fine chem industries, Mumbai).

Preparation of standard curve of QF in Phosphate buffer (pH 6.8): From the working standard of different concentration (5, 10, 15, 20, 25µg/ml) were analysed using Uv-Visible spectrophotometer at λmax value. A graph was plotted against concentration (µg/ml) vs. absorbance

Design of experiment by using 2³factorial designs: 2³ factorial designs were utilised by Design of expert software: The formulation of an extended-release tablet containing quetiapine fumarate was developed using 2³ factorial designs, wherein factors and levels (high, low) of HPMC K100, HPMC K15, and ethyl cellulose were regarded as independent factors, while drug release and swelling index were considered as dependent variables.

Preparation of granules by using wet-granulation method:

The Wet Granulation Technique was used to create tablets containing quetiapine fumarate in varying strengths of polymers. Each ingredient was present in the necessary amounts, each measured separately. First, all the components were sieved. Drop by drop, isopropyl alcohol was added to the mixture to create a mass that was ready for granulation. An 8# screen was used to prepare and granulate the wet bulk, and granules were dried for an hour at 60°C. Granule fractions are preserved after the dried granules are run through a 10# filter^6,7.

Extended-release tablet compaction:

Granules were moved within a polybag. Diffusion granules were then made by combining talc and magnesium stearate. They were subsequently crushed into separate tablets using an 8 mm round punch perforated tablet press. Each tablet has a weight appropriate for 250mg and 50mg of quetiapine Fumarate in each formulation mentionedin.

Table 1: Formulation Table for Quetiapine Fumarate Tablet

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8
Quetiapine Fumarate	50	50	50	50	50	50	50	50
HPMC K100M	45	15	15	15	45	45	45	15
HPMC K15	15	45	15	45	15	45	45	15
Ethyl Cellulose	20	60	20	20	60	60	20	60
PVP K30	5.5	5.5	5.5	5.5	5.5	5.5	5.5	5.5
Magnesium stearate	5.24	5.24	5.24	5.24	5.24	5.24	5.24	5.24
Talc	10	10	10	10	10	10	10	10
MCC	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg	Up to 250mg
Iso-Propyl Alcohol	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.	Q.S.

Post compression evaluation:

Following compression, official and unofficial techniques were used to assess Quetiapine fumarate ER tablets for various criteria, including weight fluctuation, hardness, thickness, friability, and assay¹⁰. Wensar PEG-300 electronic precision balance was used to measure weight variation. A tablet normally needs to be broken with at least 4kg of force¹¹, and this was the tablet hardness limit used in this investigation. The hardness of the tablets was measured using the Monsanto hardness tester (13-1). The tablet's thickness was measured with an Aerospace SR 44 digital Vernier Calliper. (Veego UFT-1) was used to test the friability of compacts of each formulation. For four minutes, the friability tests were run at 100 revolutions per minute or 25 rotations per minute. The following formula was used to compute the initial and final weight of ten tablets in order to perform the friability test^8,9.

Initial wt – final wt

Friability = –––––––––––––––––––––––––––––––× 100

Initial weight

Fourier transform infrared spectroscopy (FTIR) studies of Quetiapine Fumarate:

"Fourier Transform Infrared Spectroscopy," or "FTIR" spectroscopy (Bruker-Alpha II), works on the basis that some infrared light enters the sample and is absorbed by the substance. In order to confirm the drugs and excipient interactions in the formulation, this method of investigation of Functions group on Drugs and their Excipients is helpful as well.

Drug content:

Five tablets were pulverized and measured. 100ml of pH 6.8 phosphate buffer were combined with 50mg of QF equivalent powder, and the mixture was then finely filtered. Then, using a UV-visible spectrophotometer, the substance was diluted with an appropriate solvent and examined for drug content at 255nm^10,11.

Swelling index:

Using a Petri dish approach, the swelling index of quetiapine tablets was calculated. Three tablets were chosen at random, and the weight of each tablet was noted separately. The tablets were put in Petri dishes, and they were immersed in 0.1 N HCl for two hours, then five hours in phosphate buffer (pH 6.8). The tablet contents were taken out after the allotted amount of time, the extra surface water was carefully wiped with tissue paper, and the tablets were weighed once again^12,13.

In- Vitro dissolution study:

A class II dissolution apparatus compliant with United States Pharmacopoeia (USP) was used for the in-vitro drug release investigation. In order to simulate digestive circumstances, 900 millilitres of 0.1 N HCl (pH 1.2) were employed first, and then phosphate buffer (pH 6.8). The temperature was kept at 37°C±0.5°C while the paddle rotated at 50 revolutions per minute. To imitate gastrointestinal conditions, the tablets were first submerged in 900ml of 0.1 N HCl for two hours. To replicate circumstances in the small intestine, 900 millilitres of phosphate buffer (pH 6.8) was added to the dissolving media and left for the remaining 22hours. To maintain sink conditions, 5ml samples were taken out on a regular basis, filtered using Whatman filter paper, and then an equivalent volume of fresh dissolving medium was added¹⁴.

RESULT:

Analytical method:

Calibration curve of QF using phosphate buffer (pH 6.8): The calibration curve of QF was taken in phosphate buffer (pH 6.8). The absorbance values for all the solution were table respectively and their standard curve in given in figure

Table 2: UV absorbance of of using Phosphate buffer (pH 6.8)

Sr. No.	Concentration (In ppm)	Absorbance
1	5	0.299±0.006
2	10	0.584±0.002
3	15	0.79±0.001
4	20	1.015±0.005
5	25	1.20±0.004

Figure 1: Calibration curve of QF using phosphate buffer solution (pH 6.8)

Compatibility Study:

Studies on drug-excipient compatibility:

Physical examination of the medication and its excipient ingredients was used to conduct the drug-excipient interaction investigation. The drug mixture and each excipient (1:1) ratio are placed in rubber-sealed vials and sealed hermetically. The vials are then stored for 30 days at 40°C and 75% relative humidity in the stability chamber, an environmental test chamber. The sample showed no alterations.

FTIR studies of Quetiapine Fumarate:

"Fourier Transform Infrared Spectroscopy," or "FTIR" spectroscopy, works on the basis that some infrared light enters the sample and is absorbed by the substance. A probable interaction between pure quetiapine fumarate and the excipients in the formulations was detected by the drug polymers compatibility investigations utilizing FTIR spectroscopy. The acquired infrared spectra of the pure QF and tablet formulations showed no signs of a drug-excipient interaction or of drug peaks shifting or masking due to the excipients' presence. The FTIR spectra of pure QF and formulations, shown in Figures 3 and 8, indicate that there was no interaction between QF and any of the excipients used in the current experiment.

Differential Scanning Calorimetry (DSC) of Quetiapine Fumarate:

The thermogram of Quetiapine fumarate shows a sharp endothermic peak with onset temperature 175.16C and peak temperature 179.58C, which corresponds to its melting point.

Pre-compression Granule Analysis:

The bulk density for all formulations was found to be between 0.31 and 0.41 (gm/ml), whereas the tapped density ranged from 0.36 to 0.44 (gm/ml). The angle of repose for the powder blend for all formulations was found to be between 20.15° and 34.59°. This indicates that the flowability of the powder is good and necessary for proper flow. All formulations' powder blends' Carr's index values fell between 11.11 and 17.94%, indicating good or reasonable flowability for the appropriate flow of the powder blend. This range is considered acceptable. It was discovered that the Hausner’s ratio ranged from 0.73 to 1.21. All these results indicated that the granule mixture possesses good flow of granules and compressibility properties.

Figure 2: (a) FTIR Spectra of Quetiapine fumarate; (B) Differential Scanning Calorimetry of Quetiapine fumarate; (c)FTIR Spectra of Quetiapine fumarate + All Excipients

Table 3: Pre-Compression Evaluation of Granules

Formulation code	Bulk density (gm/ml)	Tapped density	Hausner ratio	Carr’s index (%)	Angle of repose (θ)
F1	0.32±0.02	0.38±0.12	0.84	15.78±4.17	30.02±3.70
F2	0.33±0.04	0.40±0.9	0.73	17.05±5.56	28.19±3.62
F3	0.32±0.06	0.39±0.16	1.21	17.94±5.30	34.59±4.96
F4	0.32±0.02	0.36±0.02	1.12	11.11±4.78	32.66±3.48
F5	0.31±0.03	0.36±0.08	1.16	13.88±4.17	26.60±3.42
F6	0.41±0.03	0.44±0.06	1.07	15.51±1.08	20.15±4.72
F7	0.35±0.08	0.40±0.03	0.75	12.05±3.98	28.39±3.96
F8	0.40±0.12	0.37±0.06	1.15	13.51±4.92	28.29±4.07

Optimization of formulation using 2³factorial designs:

The eight batches were prepared using three independent variables i.e., HPMC K 100, HPMC K 15 and Ethyl cellulose at two levels and, the effect was studied on i.e., drug release and Swelling index. Full and reduced model assessment for the dependent variables Responses from Y1 and Y2 ranged from 98.94 to 86.75 and 85.1 to 66.1, respectively. Using software designed for experts, all the replies were fitted to different models. The best-fitting models were found to be quadratic. The values of R2, Predicted R2, SD, and % CV are displayed in the table along with the regression equation generated for each response show in Table 8.

Full model for Y1 (% drug release):

Finished Equation with Coded Factors:

Drug Release = +93.69-0.88*A-0.69*B+0.63*C-0.65*A*B-2.86*A*C-2.20*B*C

+0.41*A*B*C

Figure 8-9 illustrates that whereas A (HPMC K100) and C (Ethyl Cellulose), the independent variables, had a negative impact on drug release, B (HPMC K15) had a beneficial effect.

Full model for Y2 (Swelling index):

Swelling index = +75.84-2.46*A+1.15*B+1.38*C-1.55*A*B-2.62*A*C-2.74*B*C

+2.76*A*B*C

Figure 10-11 illustrates that whereas A (HPMV K100) and B (HPMC K15), the independent variables, had a positive impact on friability, C (Ethyl Cellulose) had a negative effect.

Post Compression Evaluation of Quetiapine Fumarate: For every formulation, a weight variation of between 250 and 256.50 mg and a diameter variation of between 8.00 mm were obtained. All formulas' tablet thicknesses were found to be within a good range, measuring between 4.23 and 4.26 mm. All of the formulations' tablet hardness was found to be between 4.23 and 4.26 kg/cm2, which is within an acceptable range and considered satisfactory. It was discovered that the friability ranged from 0.40 to 1.32% (Table 4).

Figure 3: (a)Contour plot for Y1 (% dissolution); (B) Effect of independent variables on drug release 3D surface plot; (c) Contour plot for Y2 (Swelling index); (d) Effect of independent variables on swelling index time 3D surface plot.

Table 3: Summary of results of regression analysis for responses Y1 and Y2

Models	R²	Adjusted R²	Predicted R²	SD	% CV
Response (Y1) Quadratic	0.9440	0.9021	0.7761	1.31	1.39
Response(Y2) Quadratic	0.9309	0.8792	0.7238	1.89	2.47

Table 4: Post-Compression evaluations of Quetiapine Fumarate

Formulation code	Weight Variation (mg)	Diameter (mm)	Thickness (mm)	Hardness (kg/cm²)	Friability (%)
F1	252±1.82	8.00	4.23±0.52	6.39±1.12	1.32±0.04
F2	253±2.32	8.00	4.24±0.66	6.23±1.06	0.40±0.06
F3	252.5±2.22	8.00	4.25±0.72	6.46±1.62	0.80±0.06
F4	253.5±2.16	8.00	4.23±0.84	6.43±1.43	0.32±0.02
F5	256.50±3.02	8.00	4.24±0.32	6.66±1.54	0.72±0.08
F6	251±0.82	8.00	4.23±0.26	6.29±1.46	0.48±0.04
F7	252.5±1.64	8.00	4.26±0.46	6.32±1.12	0.60±0.08
F8	250±0.84	8.00	4.24±0.72	6.1±0.98	0.56±0.06

Table 5: Characterization of swelling index

Time (Hrs.)	F1	F2	F3	F4	F5	F6	F7	F8
0	0	0	0	0	0	0	0	0
1	22	19	20	24.6	24	25.5	28	23
2	26.21	27.3	36.2	35.4	34.05	28.85	22.01	32.2
3	42.56	46.5	38.41	44.66	60.53	47.02	41.9	37.5
4	56.21	49.35	41.5	54.78	65.04	57.9	44.2	45.52
5	64.6	55.22	64.66	63.84	68.45	62.5	57.88	63.02
6	78.45	66.02	61.78	72.53	64.78	75.11	67.50	67.6
7	82.5	74.02	66.10	71.75	75.04	85.10	79.5	72.5

Figure 4: (a) Swelling index of F1 to F4; (b) Swelling index of F5 to F8

Table 6: In vitro % Drug Release of Quetiapine Fumarate

Time (Hrs.)	Dissolution Medium	F1	F2	F3	F4	F5	F6	F7	F8
0	0.1 N HCL	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
1		9.02	4.8	15.83	8.01	4.50	8.15	6.98	4.50
2		18.08	9.80	31.66	16.03	9.54	16.30	17.90	8.65
3	Phosphate Buffer 6.8 PH	31.16	30.05	41.19	21.81	30.67	17.99	35.61	36.62
6		45.23	48.61	58.74	38.70	57.35	48.15	56.30	57.39
8		53.01	58.36	66.25	47.37	74.89	62.36	61.43	63.66
12		66.04	66.02	78.92	66.98	85.37	68.67	69.65	69.46
24		91.88	97.25	86.75	89.20	96.39	98.94	93.65	95.47

Figure 5: (a)In Vitro Drug Release Batch F1 to F4; (b) In Vitro Drug Release Batch F5 to F8

Stability study:

According to standard ICH requirements, the final formulation in the stability study required to be maintained at a minimum temperature of 40°C and 75% relative humidity for a minimum of one month.

DISCUSSION:

In order to achieve zero order release, the primary goal of the controlled release drug delivery system is to develop an extended-release system that is both economical and effective and can administer medications at a constant rate. Extended-release QF tablets were formulated using a wet granulation method, incorporating various hydrophilic and hydrophobic polymers. The impact of these polymers on drug release was thoroughly evaluated. The extended-release tablets were developed with the aid of Design-Expert software, using polymers such as HPMC K15, HPMC K100, and ethyl cellulose in different concentrations, as detailed in Table 1. Magnesium stearate and PVP-K30 were consistently used in all formulations at fixed amounts of 5% and 2.62%, respectively. The utilization of both hydrophilic and hydrophobic polymers is a common practice to achieve a controlled release system. Previously, HPMC polymers with varying viscosities (i.e., K4M, K15M, and K100M) have been used as matrix formers in sustained release systems. Polyvinyl pyrrolidone (PVP), also known as povidone, is utilized as a solubilizer in both oral and parenteral formulations. It has been shown to enhance the dissolution of poorly soluble drugs in solid dosage forms. Microcrystalline cellulose is used as a binder, diluent, and lubricant in oral and capsule formulations. HPMC can increase the dissolution rate and disperse less soluble drug¹⁵.

FTIR study it was found to be no physical or chemical interaction between the drug and the polymers it will match standard reference.

It was discovered via the calibration curve analysis that the absorbance was linear. The calibration curve yielded the equation y = 0. 0446x + 0.108, and an R2 value of 0.9945 were discovered in 6.8 phosphate buffer and in HCL equation y = 0.0446x + 0.108, and an R2=0.9945.

ER tablet of QF were successfully prepared using factorial design. From the various evaluated parameter that the tablet shows excellent result like drug release was found to be in range of 86.75 to 98.94%, swelling index in range 66.10 to 85.10%, % drug content in range of 79.67 to 98.50. From the evaluation parameters evaluated it was concluded that the batch F6 was give optimise result compare to another batch.

The prepared tablets were stable for 1 month when a study was conducted in a stability chamber.

CONCLUSION:

The current study developed extended-release tablets containing Quetiapine fumarate. The substance was determined to be pure Quetiapine fumarate by means of FTIR and UV visible spectrophotometric analysis findings of drug identification tests. An FTIR analysis of the medication and excipient compatibility revealed no interaction. At 255 nm, Quetiapine fumarate had the maximum absorption. Three polymers were used in the formulation: ethyl cellulose, HPMC K100, and HPMC K15. The wet granulation procedure was used to create the polymers. The proportion of medication release in the ER tablets after 24 hours varied from 98.94%. The metrics employed to display the data in a standard range were micromeritic characteristics, bulk density, tapped density, Carr's index, Hausner's ratio, and angle of repose. A phosphate buffer with a pH of 6.8 and 0.1N HCl were used to dissolve the solvent. The F6 Batch had the maximum drug release in a 24-hour period (98.94%), while the F3 Batch had the lowest rate of drug release (86.75%). The findings showed that increasing the concentration of ethyl cellulose and HPMC K100 extends the time that the drug is released. The study findings indicate that the 2^3_factorial design, which makes use of ethyl cellulose, HPMC K15, and HPMC K100, is a successful method for creating ER tablets that contain Quetiapine fumarate.

ACKNOWLEDGEMENT:

We are grateful to the Teacher’s and Principal of Loknete Dr. J. D. Pawar College of Pharmacy, Manur, and Tal. Kalwan for their helpful guidance.

CONFLICT OF INTEREST:

The author’s state that has no conflicts of interest.

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Received on 12.08.2024 Revised on 11.09.2024

Accepted on 06.10.2024 Published on 18.11.2024

Available online from December 19, 2024

Res. J. Pharma. Dosage Forms and Tech.2024; 16(4):301-308.

DOI: 10.52711/0975-4377.2024.00047