INTRODUCTION:

A fast-dissolving drug delivery system (FDDS) is a dosage form that rapidly disintegrates in saliva within seconds when placed on the tongue, eliminating the need for water or chewing.¹ Despite of tremendous development. In drug delivery systems, the oral route is favored for drug administration because of its numerous advantagesIn drug delivery systems, the oral route is favored for drug administration due to its numerous advantages, including low therapy costs, ease of administration, accurate dosing, suitability for self-medication, avoidance of pain, versatility, and, most importantly, high patient compliance. Fast dissolving tablets (FDTs) have been developed to cater to the needs of pediatric, geriatric, and bedridden patients, as well as active individuals who are busy or traveling and may not have access to water.

Tablets and capsules are widely accepted dosage forms; however, a significant drawback is dysphagia, or difficulty swallowing. This issue has led to the development of novel solid dosage forms, such as FDTs, which disintegrate and dissolve rapidly in saliva without the need for drinking water. Vilazodone Hydrochloride (VH) an antidepressant agent was approved by US Food and Drug Administration (US FDA) in 2011⁴. Through VH is absorbed after oral intake but has a bioavailability of only 72%. However, FDTs can increase bioavailability by allowing pre-gastric absorption of the drug from the mouth, pharynx, and esophagus as saliva carries it to the stomach. Therefore, an attempt was made to formulate and optimize FDTs using central composite design (CCD) to achieve a quicker onset of action. This was done by varying the concentrations of thymol (THY) as a sublimating agent and Lepidium sativum seed mucilage (LSSM) as a super disintegrant⁷.

MATERIAL AND METHODS:

Materials:

VH was procured as gift sample from Jubilant Life Science Ltd. (Noida, India). Thymol, Sucrose, Loba Qualigens fine labs (Mumbai, India). Mannitol, SD fine chem. (Mumbai, India) Talcum, Sodium starch glycolate, Magnesium stearate, Central Drug House (New Delhi, India). All chemicals were of good analytical grade and double distilled water was used during the complete project.

Extraction of mucilage from Lepidium sativum Linn seeds:

The Lepidium sativum Linn seeds (100 g) were allowed to soak for twelve hours in distilled water. After soaking for desired period of time, this was allowed to pass through the blender to separate mucilage from seeds. The prepared content was passed through muslin cloth. Precipitation of mucilage from the filtrate was done with continuous addition of one litre of acetone. The powder was passed through 80 # mesh sieve and dried at 55ºC for 6 hr^8,9.

Drug – Excipient interaction study:

Compatibility Study was carried by using FT-IR Spectroscopy (Perkin Elmer FT-IR spectrum BX, Germany). he samples were previously ground and thoroughly mixed with KBr in a 1:100 ratio (sample/ KBr). Transparent pellets were formed by compressing the samples with KBr at a pressure of 5 tons using a hydraulic press. The KBr discs were then prepared for scanning over a range of 4400-400 cm⁻¹^{10, 11, 12}.

Experimental Design (CCD):

A Central Composite Design (CCD) with α = 1 was employed following the standard protocol. In this study, the independent variables were the concentrations of THY (X1) and LSSM (X2), while the dependent variables included wetting time (WT), disintegration time (DT), and drug release at 5 minutes (Q5m). Tables 1 and 2 summarize all the experimental runs, detailing both the coded and actual levels of the independent variables. ^{13, 14}

Table 1: CCD and level of Independent variables

Formulation Code	Coded Values		Actual Values
	Factor X1	Factor X2	Factor X1 (mg)	Factor X2 (mg)
F1	1	-1	8	4
F2	0	0	6	6
F3	0	-1	6	4
F4	-1	-1	4	4
F5	-1	1	4	8
F6	-1	0	4	6
F7	0	0	6	6
F8	0	0	6	6
F9	0	0	6	6
F10	1	0	8	6
F11	0	1	6	8
F12	0	0	6	6
F13	1	1	8	8

Preparation of Tablet Blend:

VH FDT (10 mg) was prepared by sublimation technique as per the formula mentioned in Table 2.

Table 2: VH FDT formula

S. No.	Ingredients	Quantity (mg)
1	Vilazodone hydrochloride	10
2	Lepidium sativum seed mucilage	4-8
3	Thymol	4-8
4	Sucrose	10
5	Microcrystalline cellulose	20
6	Magnesium stearate	1
7	Talcum	1
8	Flavor (orange)	1
9	Mannitol	qs 80

All the dried ingredients including VH were passed through #sieve 44 and mixed properly in a lab scale double cone blender (Bhagwati, Gujarat, India). Tablet blend was compressed on 16 rotatory stations, 5 mm round flat punch using Rimek Minipress-1 (Karnavati, Cadila, India). Compressed tablet were allowed for sublimation of THY in Hot air oven (Asian test Equipment, Ghaziabad, India) at 60ºc till constant weight was found for complete removal of THY to make it highly porous^15,16.

Evaluation:

The formulated tablets, following sublimation, were evaluated for various physicochemical parameters, including general appearance, weight variation, hardness, friability, porosity, and morphology.^17-21

Wetting time:

A circular tissue paper with a diameter of 6.5cm was placed on a petri dish containing 6 ml of water. A tablet was then placed on the tissue paper, and the time was carefully noted when the water reached the upper surface of the tablet^22,23.

Scanning electron microscopy:

The surface characteristics of the formulation were analyzed using a scanning electron microscope (SEM) (JEOL JSM-6360, Japan). The samples were mounted on double-sided tape on aluminum stubs and then sputter-coated with gold using a fine coat ion sputter (JEOL)²⁴.

Disintegration time test:

Six tablets were randomly taken and placed in a tablet disintegration test apparatus (USP Disintegration Apparatus). Disintegration media was taken as distilled water maintained at 37±2ºC. Time for disintegration was noted²⁵.

In vitro drug release:

Release study was conducted in USP II dissolution apparatus with a speed of 50rpm taking 900 mL of phosphate buffer (pH-6.8). Aliquots were withdrawn at predefined intervals, proper sink conditions were maintained during the test. Samples were filtered before absorption determination using UV- visible spectrophotometer at 240 nm^26,27.

Data optimization:

The optimization study was conducted using a 3232 central composite design (CCD). Two independent variables were selected: the super-disintegrant (Lepidium sativum seed mucilage, LSSM, X1) and the sublimating agent (thymol, THY, X2). The effects of these independent variables were investigated on the dependent responses, including disintegration time (DT), wetting time (WT), and drug release at 5 minutes (Q5m). The experimental points followed the design outlined in Table 2. Polynomial equations were generated to express the functions of the independent variables (LSSM and THY) as shown in the equation 3.

Y = b₀ + b₁ X₁ + b₂ X₂ + b₃ X₁X₂ + b₄ X₁₂ + b5 X₂₂ +b6 X₁X₂₂ + b₇X_{1 2}X₂₁(3)

Where Y is the dependent variable, b₀ is the arithmetic mean response of the thirteen runs.

Effects of independent variable such as X1 and X2 govern the average result of changing one factor at a time, starting from its lower values till its higher values. More efficiently 3² CCD prefer to determine the influence of individual variable using minimum experimentation. In present work 3²CCD was chosen for the optimization of formulations, as the values of the response surfaces were not known from the previous findings. Depending on the trials of per formulation, concentration of LSSM were selected as 4,6 and 8 mg whereas THY concentration were 4,6 and 8 mg. Optimized product was validated taking total six formulations as check-points. ^28,29,30..

Stability Study:

Optimized formulation was preceded for stability protocol as per the guidelines mentioned in ICH (International conference on Harmonization) at 40ºC and 75% RH using stability chamber for 30 days ^31,32.

Antidepressant activity:

Male Wistar rats weighing 150-250 grams were selected for the study. These rats were acclimated to controlled humidity settings (50–55%), a temperature of 23 ± 2 °C, and 12-hour light/dark cycles in the experimental room. Pharmacological activity was conducted according to the prescribed guidelines of CPCSEA, Government of India, and approved by the institutional animal ethical committee. The study was divided into four groups (n=6). Drugs or vehicles were administered to the animals 60 minutes prior to the study. Group I served as the negative control and received saline (2 ml/kg orally). Group II was the positive control and received the standard drug Escitalopram (10 mg/kg orally). Group III received the standard drug Imipramine (10 mg/kg orally), while Group IV received the optimized formulation (400 μg/kg orally).³³

Forced Swim Test:

Rats of each gender were placed separately in a cylindrical container filled with water (diameter 10 cm, height 25 cm, water depth 19 cm) at a temperature of 25±1°C for the Forced Swim Test (FST). The experimental design called for giving the therapy sixty minutes before the trial began. Every animal was made to swim for six minutes, with the final four minutes of the test being used to measure and record the length of immobility³³.

RESULTS AND DISCUSSION:

Drug Excipients interaction study:

FT-IR graph was obtained for identification of various functional groups.IR spectrum of VH and VH with all excipient is shown in Fig.1 (a), (b) and Fig. 1(c) showing comparative FT-IR spectrum of drug and drug with Excipient. Test for intermolecular interaction between VH and excipients. Pure VH exhibits characteristic infrared spectra in the scanning range of 4400-400 cm⁻¹, indicating the presence of carboxyl (CONH₂) functional groups. The spectra show a general carboxyl amide (C=O) peak at 1690-1630 cm⁻¹. Additionally, the amide functional group, which combines the features of amides and ketones due to the presence of both N-H and C=O bonds, presents a very strong, somewhat broad band in the range of 3100-3500 cm⁻¹ for the N-H stretch. All specific characteristic features of VH are retained in the formulation, clearly indicating that there is no interaction between VH and the excipients.

Figure 1: Compatibility study data for drug and excipient (a) FT-IR spectrum of VH (b) FT-IR spectrum of VH with excipients (c) comparative FT-IR spectrum of drug and drug with excipients

Characterization of formulated FDT:

Characterization of formulated FDTs was done for different parameters such as weight variation, hardness, Friability, DT, WT and Q5m and results are as shown in table 6.

Scanning Electron Microscopy:

SEM analysis show that the tablet remain intact, crack free after compression all the particles are tightly packed as shown in Figure 2 (a) and (b) but after sublimation under vacuum oven tablet show pores as it contain THY as a sublimating agent that evaporates leaving the pores inside the tablet. As pores developed penetration capacity increases. This can be evident that by the figure as the particles of tablet become smaller and a bit porous after sublimation in Fig.2 (c) and (d).

Figure 2: SEM analysis of tablet before sublimation (a) and (b), after sublimation (c) and (d)

In vitro Drug release:

Q5m was found to be increase on increasing the concentration of super disintegrant ( LSSM) and sublimating agent (THY). Rapid the WT, and DT resulted in faster Q5m. The drug profile of various formations is ranging from 99.35-101.30% as shown in table 3. Fig.3 showing the drug release profile of various batches.

Figure 3: Drug release profile (Q5m)

Table 3: Dependent Variables results of various batches

S. No	Batch Code	DT	WT	Q5m
1	F1	21.8(±0.80)	18.9(±0.05)	99.47(±1.20)
2	F2	22.4(±1.03)	20.8(±0.49)	97.07(±0.98)
3	F3	26.9(±1.09)	22.7(±0.97)	95.35(±0.75)
4	F4	28.8(±0.90)	28.0(±1.06)	91.43(±0.98)
5	F5	26.3(±0.88)	22.8(±1.48)	97.18(±0.89)
6	F6	27.5(±0.94)	25.8(±0.98)	94.67(±0.71)
7	F7	22.5(±0.71)	20.7(±1.50)	97.03(±0.62)
8	F8	22.5(±0.77)	20.7(±1.17)	97.15(±0.06)
9	F9	22.4(±1.06)	20.7(±1.51)	97.21(±0.49)
10	F10	18.8(±0.86)	18.0(±0.95)	101.01(±0.85)
11	F11	18.5(±0.68)	18.7(±0.32)	99.47(±0.90)
12	F12	22.4(±1.18)	20.8(±0.56)	97.91(±0.80)
13	F13	14.3(±1.31)	17.1(±0.67)	103.62(±0.82)

Data analysis:

Statistical analysis of the data clearly indicates that the values for disintegration time (DT), wetting time (WT), and drug release at 5 minutes (Q5m) are strongly dependent on the selected independent variables. Equations 4-6 relate the responses of DT, WT, and Q5m, respectively. The ANOVA results for the various dependent variables are as follows:

DT = 22.48-4.35 A-3.95 B-1.27 AB+0.6700 A²-0.0300 B²+1.42 A²B-0.3750 AB²-0.2950 A²B² …….(4)

WT=20.74-3.90 A-2.00 B+0.9500 AB+1.16 A²-0.0400 B²+0.1500 A²B+0.3000 AB²-0.2600 A²B² …….(5)

Q5m = 97.00+3.50 A+2.00 B-0.5000 AB+0.5000 A²+0. 0B²0+0.50 A²B+0.0AB²+0.00A²B² ……(6)

Response Surface Analysis:

3-dimensional response surface plots and their corresponding contour plots to investigate their response properties are shown in Fig. 8 (a)and (b) for DT (c) and(d) for WT (e) and (f)For Q5m

Disintegration and wetting time:

It was observed that the response of dependent variable DT and WT had greatly influence by independent variable i.e. LSSM and THY. As DT is the most important factor to optimize FDT. There was an almost linear increase in the DT with increase in the levels of both independent factors. The results of multiple linear regression analysis showed that both coefficients X1 and X2 have negative signs. Therefore, increasing the concentrations of both LSSM and THY is expected to decrease disintegration time (DT) and wetting time (WT). However, the effect of THY is more pronounced compared to LSSM in both cases. THY, when incorporated into the formulation, makes the tablet porous and enhances the capillary and wicking action of LSSM. The formation of pores in the tablet layers increases water uptake capability, as revealed by the response surface and the mathematical model, thus facilitating a reduction in DT.

Drug release (Q5m):

Dependent factors independently exerted a significant positive influence on the Q5m. However the effect of X1 is more pronounced than X2, revealed by the response surface and the mathematical model. Percentage drug release varies in somewhat linear fashion with increase in the amount of LSSM as well as THY simultaneously. Overlay plot of optimized batch as shown in Fig. 4.

The statistical model was validated by comparing the predicted responses of all formulated batches with their corresponding experimentally observed values, as shown in Table 4. The close agreement between the predicted and observed values indicates that the models developed to predict the responses were not only statistically significant but also valid for predicting values very close to the experimentally observed ones, as depicted in Fig. 5.

Figure 4: Response surface and counter plot for (a) and (b) for (DT), (b) and (c) (WT) and (e) and (f) (Q5m) showing influence of concentration of independent variables and Overlay plot for optimized batch

Table 4: Validation of response surface methodology

Batch Code	Lssm *Lepidium sativum* Seed Mucilage	Thy	Respone	Predictedva va Value	Actual Value	Percentage Error
OPTIMIZED BATCH	6.73	6.51	DT	19.94	19.93(±0.11)	0.06
			WT	18.18	18.21(±0.63)	-0.16
			Q5m	95.92	95.83(±0.09)	0.11
1	7.25	6.55	DT	18.83	18.74(±0.37)	0.48
			WT	17.28	17.29(±0.51)	-0.09
			Q5m	98.31	98.45(±0.27)	-0.16
2	7.06	7.35	DT	17.41	17.369(±0.11)	0.25
			WT	16.50	16.555(±0.19)	-0.31
			Q5m	95.99	96.091(±0.72)	-0.12
3	7.22	6.19	DT	17.79	17.703(±0.51)	0.54
			WT	19.63	19.592(±0.31)	0.22
			Q5m	98.42	98.497(±0.22)	-0.09
4	7.42	6.29	DT	17.316	17.374(±0.19)	-0.33
			WT	19.031	18.889(±0.63)	0.75
			Q5m	99.463	99.569(±0.25)	-0.12
5	7.69	7.28	DT	6.221	16.27(±0.07)	-0.30
			WT	16.466	16.403(±0.16)	0.38
			Q5m	99.839	99.274(±0.31)	0.63
6	7.40	4.14	DT	19.967	19.866(±0.5)	0.51
			WT	17.909	18.221(±0.63)	-1.74
			Q5m	99.376	99.291(±0.57)	0.10

Figure 5: Predicted versus observed response for (a) DT (b) (WT) (c) (Q5m)

Stability study:

The formulation was evaluated for all the physical parameters like WT, DT and Q5m. The results are mentioned below Table IX., found no significant difference in the parameters.

Table 5: Stability Study

S. No	DAYS	DT(s)	WT(s)	Q5m (%)
1	00	19.94	18.18	95.92
2	30	21.14	20.05	95.54

Antidepressant activity:

The antidepressant properties of optimized formulation, escitalopram, and imipramine were investigated by the observation of alterations in the immobility duration in the Forced Swim Test (FST). When compared to the control group animals that were given only the vehicle and significantly reduced (p<0.01) the immobility duration in both TST and FST.

Table 6: Effect of optimized batch on immobility time in Forced swim test

Treatment	Dose (mg/kg)	FST duration of immobility (s)
Control		135.46 ±0.6
Escitalopram	4	57.65 ±5.13
Imipramine	4	60.51±3.20
Optimized formulation	400mcg/kg	44.76±3.11

CONCLUSION:

The optimized batch of Fast Dissolving Tablets (FDT) was successfully formulated using both sublimating and direct compressed tablet processes. The manifold advantages of FDT are expected to significantly enhance patient compliance, dosage convenience, rapid onset of action, fast disintegration, minimal side effects, and good stability. The formation of a porous tablet is a critical objective in FDT formulation to improve water uptake capacity, facilitating rapid disintegration. Tablets containing highly swellable Lepidium sativum seed mucilage (LSSM) disintegrant exhibited high porosity, albeit with the highest wetting time (WT) and disintegration time (DT). This suggests that a systematic formulation approach can lead to reaching an optimum point efficiently. The sublimation technique emerged as an effective alternative approach compared to using other expensive adjuvants in FDT formulation.

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Received on 21.01.2024 Modified on 08.05.2024

Research J. Pharm. and Tech 2024; 17(11):5584-5590.

DOI: 10.52711/0974-360X.2024.00852