Design and Evaluation of Fast Dissolving Tablets a Novel Natural Superdisintegrant is used in the Development of a BCS Class -II Drug

D. Chandra Sekhar Naik¹*, A. Bharathi²

¹Krishna University, Machilipatnam, Machilipatnam, Andhra Pradesh - 521003, India.

²KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada, Andhra Pradesh - 520004, India.

*Corresponding Author E-mail: chandu.desavath@gmail.com

ABSTRACT:

The main objective of the present investigation was to develop fast dissolving tablets for aceclofenac employing Ocimum gratissimum mucilage, a novel superdisintegrant by using 23factorial design. The mucilage was extracted from the seeds of Ocimum gratissimum and tested for flow properties. The senior development of fast dissolving tablets of Aceclofenac with novel natural mucilage as a superdisinitegrant in different ratios (0-5%) by using the direct compression method and Pre-compression and post-compression characteristics like water absorption (percent) and percent of drug dissolved at 5 min were evaluated for all of the formulated fast dissolving tablets. In all acceptable solvents and buffers, the mucilage powder was found to be a fine, free-flowing amorphous powder with good swelling properties. According to the FTIR and DSC investigations, there were no interactions between aceclofenac and the novel natural mucilage powder. In terms of drug content (98.0±0.14 to 99.9±0.05), hardness (3.8±0.03to 3.9±0.31), and friability (0.11±0.012 to 0.12±0.79), all of the formulation batches are of excellent quality. The batch with the improved formulation had a shorter disintegrant time (27±0.83). The improved formulation F2 has a shorter In–Vitro wetting time (19±0.69). The designed tablets' water absorption ratio was determined to be within the limit at (392.1±0.81). In 10 minutes, the cumulative drug dissolved in the optimised formulation F2 was determined to be (99.93%). As an outcome, it could be used in the formulation of fast dissolving tablets to provide an immediate release of the contained drug within 5 minutes.

KEYWORDS: Optimization, Fast dissolving, Super Disintegrante, DSC, FTIR.

INTRODUCTION:

The oral route of drug administration is widely accepted, providing for 50-60% of total dosage forms. Fast dissolving tablets (FDT) are solid dosage forms containing indicated substances that disintegrate quickly, usually within a few seconds, when placed on the tongue, necessitating the use of additional water to aid swallowing. Patients who have trouble swallowing will benefit greatly from fast-dissolving tablets. Because the increased life cycle of individuals, the elderly make up a significant portion of today's population.

Physiological and neurological conditions such as dysphasia, choking risk, and hand tremors are the most common reasons for patient non-compliance with traditional solid oral dosage forms¹.

The current study focuses on a systematic formulation approach for optimising Aceclofenac fast dissolving tablets using super disintegrants such as Ocimum gratissimum mucilage, croscarmellose sodium, and Crospovidone. A 23 factorial design was used to investigate the main and interaction effects of the three formulation variables, namely Ocimum gratissimum mucilage (A), Sodium starch Glycolate (B), and croscarmellose sodium (C), in each case, in order to find the formula with the shortest disintegration time and highest water absorption (%), as well as to allow arbitrary selection of tablets with immediate drug release within 5 minutes.²

MATERIALS AND METHODS:

Materials:

Aceclofenac pure drug obtained from yarrow chemicals Mumbai. Mannitol, Sodium starch glycolate, Croscarmellose sodium was obtained from Yarrow chem. products, Mumbai. Microcrystalline cellulose was bought from Qualigens fine chemicals, Mumbai. Talc and magnesium stearate was obtained from Molychem, Mumbai.

Isolation of Ocimum gratissimum mucilage (a novel disintegrate):

The seeds of Ocimum gratissimum were soaked in distilled water for 12 hours before being blended to separate the mucilage from the seeds. The volume was passed through eight folds of muslin cloth after 15 minutes of blending. The mucilage was precipitated from the filtrate by adding three parts acetone (75%) to the mucilage. After 6 hours of drying at 45°C, the powder was weighed to determine the yield³.

Characterization of Ocimum gratissimum mucilage(a novel disintegrate)^4-7:

The Ocimum gratissimum mucilage prepared was evaluated for the following:

Solubility: Ocimum gratissimum mucilage solubility was tested in various solvents like distilled water, aqueous buffers of pH 1,2,3,4,6 mentioned in IP and organic solvents such as alcohol, dichloromethane, chloroform, acetone and petroleum ether⁴.

pH: The pH of 1% w/v slurry was measured by pH meter⁴.

Melting point: Melting point was determined by using melting point apparatus⁴.

Viscosity: Viscosity of 1% dispersion in water was measured using Ostwald viscometer.

Swelling index: Mucilage powder (200 mg) was added to 10 ml of water and light liquid paraffin taken in two different graduated test tubes and mixed. The dispersion in the tubes was allowed to stand for 12 h. The volumes of the sediment in the tubes were recorded. The swelling index (%) of the material was calculated as follows^5.

Volume of sediment in water-volume of sediment in

light liquid paraffine

SI%= –––––––––––––––––––––––––––––––––––––––––––––– ×100

volume of sediment in light liquid paraffine

Test for gelling property:

Mucilage prepared were evaluated for their gelling property by heating a 7% w/v dispersion of each in water at 100°C for 30 min⁵.

Particle size:

Particle size analysis was done by sieving using standard sieves⁶.

Density:

Density (g/cc) was determined by liquid displacement method using benzene as liquid⁶.

Bulk density:

Both loose bulk density (LBD) and tapped bulk density (TBD) were determined by transferring the accurate weighed amount of sample in 50ml measuring cylinder, measured the volume of packing and tapped 50 times on a plane surface and tapped volume of packing recorded and LBD and TBD calculated by following formula⁷.

Mass of powder

LED = ––––––––––––––––––

Volume of packing

Mass of powder

TBD = ––––––––––––––––––––––––

Tapped volume of packing

Percentage compressibility index Percentage:

Compressibility of the powder mixed was determined by Carr’s Compressibility Index calculated by the following formula⁷.

TBD – LBD

% Carr’s Index = ––––––––––––– × LBD = loose bulk

TBD

TBD = Tapped bulk density

Angle of repose:

The frictional forces in loose powder or granules can be measured by the angle of repose. This is the maximum angle possible between the surface of a mass of powder or granules and the horizontal plane. The angle of repose is calculated⁷.

h h

tan θ = –––– θ = tan^-1––––

r r

θ = Angle of repose : h = Hight of pile : r = Radius of pile

Fourier transform infrared (FTIR) spectroscopy: FTIR spectra of mucilage were recorded on samples prepared in potassium bromide (KBr) disks using a, FTIR (Tokyo, Japan). The scanning range was 500 to 4000 cm^-1. Samples were mixed with (KBr) to form disks by means of a hydrostatic press at 6-8 tons pressure⁷.

Differential scanning calorimetry (DSC):

DSC therm Ocimum gratissimum rams of Aceclofenac and their mixtures (1:1) with Ocimum gratissimum were recorded on Perkin Elmer thermal analyzer samples (2-5 mg) were sealed into aluminum pans and scanned at a heating rate of 10°C min^-1over a temperature range 30–350°C.⁷

Preparation of Aceclofenac fast dissolving tablets:

The tablets were prepared by direct compression method employing 2³ factorial design in which 3 independent variables {superdisintegrants i.e., Ocimum gratissimum (A), sodium starch glycolate (B), Croscarmellose Sodium (C)} and 2 dependent variable (water absorption and percent of drug dissoved in 5 min) were selected. The composition of formulation given in table no 1 For Ocimum gratissimum (A), the lower level i.e., 0 % concentration and upper level i.e. 5% concentration. For sodium starch glycolate (B) and Croscarmellose Sodium (C), the lower level is zero concentration and higher level i.e., 5% concentration. For uniformity in particle size, each ingredient was passed through # 100 mesh sized screen before mixing. Ocimum gratissimum, sodium starch glycolate, Croscarmellose Sodium, mannitol and microcrystalline cellulose were accurately weighed and mixed using mortar and pestle, and the added to aceclofenac. Finally, talc and magnesium stearate were added to the powder mixture⁸.

Table 1: Formulae of aceclofenac fast dissolving tablets employing Ocimum gratissimum mucilage.

Ingredients (mg/tablet)	AF1	AF2	AF3	AF4	AF5	AF6	AF7	AF8
Aceclofenac	100	100	100	100	100	100	100	100
Ocimum gratissimum	----	25	---	25	---	25	---	25
Sodium starch Glycolate	----	---	25	25	---	---	25	25
Croscarmellose Sodium	----	---	---	---	25	25	25	25
Mannitol	130	105	105	80	105	80	80	55
MCC	250	250	250	250	250	250	250	250
Talc	10	10	10	10	10	10	10	10
Magnesium Stearate	10	10	10	10	10	10	10	10
Total	500	500	500	500	500	500	500	500

Evaluation of Aceclofenac fast dissolving tablets:^9-12

Hardness test:

Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablet was determined using Monsanto hardness tester and expressed in kg/cm^2,9.

Uniformity of weight:

Weight variation test was done with 20 tablets. It is the individual variation of the tablet weighed from the average weight of 20 tablets⁹.

Friability:

The friability of tablets was measured using a Roche fribilator. Tablets were rotated at 25 rpm for 4 min or up to 100 revolutions. The tablets were then reweighed after removal of fines and the percentage of weight loss was calculated⁹.

100 × W (initial) – w (final)

F = –––––––––––––––––––––––––

W (initial)

Drug content uniformity:

For content uniformity, ten tablets was weighed and powdered a quantity of powder equivalent to 10mg of Aceclofenac was extracted into pH 7.2 phosphate buffer and filtered. The Aceclofenac content was determined by measuring the absorbance spectrophotometrically at 276nm after appropriate dilution with pH 7.2 phosphate buffer. The drug content was calculated as an average of three determinations¹⁰.

Wetting time:

The wetting time of tablets was measured by placing five circular tissue papers in a petri dish of 0.10m in diameter. 10ml of water containing a water-soluble dye (amaranth) was added to the petri dish. A tablet was carefully placed on the tissue paper. The time required for water to reach the upper surface of the tablet was noted as wetting time¹¹.

Water absorption ratio:

A piece of tissue paper folded was kept in a small petri dish to which 6 ml of water was added. A tablet was kept on the tissue paper and allowed to completely wet. The wetted tablet was then weighed. Water absorption ration R was determined using the following equation¹¹.

(Wd – We)

R = ––––––––––––

Where,

Wd = Tablet weight after water absorption.

We = Tablet weight before water absorption.

In–vitro disintegration time:

Disintegration time for FDTs was determined using USP disintegration apparatus 0.1 N HCl buffer. The volume of medium was 900ml and the temperature was 37±0.2 °C. The time in second taken for complete disintegration of the tablet with no palatable mass remaining in the apparatus was measured¹².

In–vitro dissolution studies:

The in vitro dissolution rate study of Aceclofenac fast dissolving tablets were performed using 8 stage dissolution test apparatus (lab india ) fitted with paddles (50 rpm) at 37±0.5°C, using pH 7.2 phosphate buffer (900 ml) as a dissolution media. At the predetermined time intervals, 5ml samples were withdrawn, filtered through a 0.45μ membrane filter, diluted and assayed at 276nm using an Analytical technol Ocimum gratissimum Eli co SL 218 UV/Visible Double beam spectrophotometer. Cumulative percentage release was calculated using standard absorbance from the calibration curve. All the dissolution experiments were conducted in triplicate (n = 3)¹².

RESULTS AND DISCUSSION:

The seclusion of Ocimum gratissimum adhesive was viewed as fine, free-streaming great gulping powder. It was insoluble in fluid solvents and insoluble in natural solvents tried (methanol, petrol ether, dichloromethane, and chloroform). The pH of 0.1% fluid scattering was viewed as 7.62±0.001.Ocimum gratissimum adhesive displayed great expanding in water. The expanding file was viewed as 100%±0.003% demonstrating that it is reasonable for superdisintegrant. All micrometric properties showed great stream properties required assembling of tablets. The thickness of Ocimum gratissimum adhesive was viewed as 0.3012±0.0004g/cc. The point of rest and compressibility record showed great stream properties of Ocimum gratissimum adhesive.

The FTIR range of Ocimum gratissimum adhesive is displayed in fig. (1 and 2). The presence of pinnacle retention at 1434.10 cm-1 trademark pinnacle of ester, so from FTIR studies; it was presumed that Ocimum gratissimum adhesive (ester) was framed when the adhesive was permitted to respond with formic corrosive. As the Ocimum gratissimum adhesive was somewhat fine powder and it had gotten every one of the attributes of superdisintegrants it was reasoned that Ocimum gratissimum adhesive can be utilized as novel superdisintegrant in the detailing of quick dissolving tablets.

Fig. 1: Fourier transform infrared pure Aceclofenac

Fig. 2: Fourier transform infrared Aceclofenac and mucilage

Evaluation of tablets:

Hardness:

The hardness of tablets from all bunches was viewed as in the scope of 3.8±0.03kg/cm² to 3.9±0.31kg/cm². All tablets were found hard enough so they could undoubtedly endure the taking care of and capacity conditions without becoming broken.

Friability:

All the tablets exhibited acceptable friability as none of the tested batches showed percentage friability that exceeded 1%. The percent friability of all batches found in the range of 0.11±0.012% - 0.12±0.79% indicating good mechanical resistance of tablets. Thus, it was proved that tablets could withstand the pressure, mechanical shocks during handling, transportation, storage and manufacturing processes.

Drug content:

Drug content of all the formulation batches was found to be between 98.9±0.01 to 99.8±0.37. Hence, it can be concluded that all the formulations are having an accurate amount of drug distributed uniformly in powder mass and followed acceptable limits as per IP ¹⁴. i.e. 85 to 115 % of average content table 2.

Disintegration studies:

In vitro disintegration time was done by the USP disintegration apparatus. The disintegration rate has a correlation with water absorption capacity of disintegrate and The in vitro disintegration time was found between 239±0.10 to 27±0.83s. The outcomes were tabulated and data demonstrated in table 2. All the formulation showed disintegration time of less than 240s. It was found that the formulation F8 will show least disintegration time 27s as compare to other formulation. The order for a disintegration time in the fast dissolving tablet was found to be F8 <F6 <F5 <F2 <F7 <F4 <F3 <F1. The order of disintegration time may be due to the interaction and main effects of the super disintegrants used in the fast dissolving tablets.

Water absorption ratio and wetting time:

The water absorption ratio founded from 104.06±0.73 to 392.1±0.81s. This increased behavior due to the water taking the ability of super disintegrants. The wetting time found was tabulated and data demonstrated in table 2 and fig no. 8, 8a and 8b. It was found that the formulation F2 containing 5 % mucilage and 5 % croscarmellose sodium showed less wetting time i.e. 19±0.69s compared to other formulations.

Table 2: Physical properties: hardness, friability drug content of Acelofenac fast dissolving tablets prepared by direct compression method involving mannitol as a diluents

Formulation code	Hardness (kg/cm2)	% Friability	Disintegration time (sec) mean	Wetting time (Sec) mean	Water Absorption ratio (%)	Uniformity of content mean
AF1	3.9±0.003	0.11±0.012	239±0.10	171±0.84	104.06±0.73	99.8±0.37
AF2	3.9±0.05	0.11±0.72	37±0.83	19±0.69	392.1±0.81	99.9±0.02
AF3	3.9±0.07	0.12±0.35	43±0.35	11±0.68	116.16±0.93	98.9±0.01
AF4	3.8±0.09	0.12±0.79	41±0.84	9±0.23	254±0.75	99.9±0.05
AF5	3.8±0.03	0.12±0.78	32±0.84	29±0.15	175.3±0.78	99.4±0.16
AF6	3.9±0.31	0.11±0.38	30±0.72	10±0.37	279.4±0.37	98.9±0.37
AF7	3.8±0.032	0.12±0.71	40±0.46	21±0.39	199.13±0.52	99.1±0.08
AF8	3.9±0.015	0.12±0.39	27±0.83	10±0.47	353.8±0.14	98.0±0.14

Figure 3: Water absorption ratio of aceclofeanc fast dissolving tablets employing novel superdisintegrate

In vitro dissolution studies:

Figure 4: Dissolution profiles of Aceclofenac fast dissolving tablets employing natural superdisintegrate(F1-F8)

Figure 5: Log time Vs log percent undissolved of Aceclofenac fast dissolving tablets employing natural superdisintegrate(F1-F8).

Dissolution rate depends on the water absorption of the disintegrant, among all the formulations F2 has more water absorption and has greater dissolution rate and then this is the other conformance test for correct selection of desirable. In vitro dissolution studies of all the formulation were done and depicted in fig. 4 and 5. In all formulations F2 formulation was selected as the promising formulation containing 5 % ocimum gratisismum and 5 % with 99.84% release in 10 min.

The dissolution parameters of the formulation from (F1–F8) which were made by direct compression method were shown in the table: 1. In all these cases the PD5 (percent dissolved in5 min) was more in F4 which consists at 5% ocimum gratisimum, and 5% sodium starch glycolate. The same was in the case of water absorption and percent of drug dissolved in 5 min). The water absorption and percent of drug dissolved in 5 min revels that starch xanthate was effective at 5% along with 5% croscarmellose sodium when the formulation swere made by direct compression using these superdisintegrants. From the results, it was concluded that ocimum gratisimum (new super disintegrant) could be used as a super disintegrant in the formulation of fast dissolving tablets of Aceclofenac. To evaluate the individual and combined effects of the three factors involved, fast dissolving tablets were formulated employing selected combinations of the factors as per 23-factorial design. The fast dissolving tablets and release parameters (percent drug released in 5 min) of the fast dissolving formulated were analyzed as per ANOVA of 23-factorial design. indicated that the individual effects of ocimum gratisimum (A), sodium starch glycolate (B) and croscarmellose sodium (C), as well as the combined effects of AB, AC, BC and ABC factors, were significant (P<0.05) on water absorption and percent of drug dissolved 5 min of Aceclofenac fast dissolving tablets.

Independent variables and response variables can be co-related by using a polynomial regression algorithm. It is a second order model equation, for the 2n experimental design polynomial equation was written as Equation.

Y= β0 + β1A + β2B + β3C + β1β2 AB + β1 β3 AC + β2β3 BC + β1β2 β3 ABC

Where, Y is the measured response

β0 is the arithmetic mean response

β1, β2, β3, β1β2, β1 β3, β2β3, β1β2 β3 are the coefficients for the corresponding factors A, B, C, AB, AC, BC, and ABC are the percentages of ocimum gratisimum, sodium starch glycolate and croscarmellose sodium and interaction terms respectively. Following formula was used to calculate the coefficient and it was given as Equation. β = Σ XY/2n

Where β	:	Coefficient
X	:	Corresponding variable (A,B,C)
Y	:	Response value (Percent dissolved in 5 minutes or Dissolution efficiency in 5 minutes
n	:	Level

Contour plots and response surface plots were drawn by using Star Ease, Inc. (Minneapolis, MN) Design Expert 11 Version software.

(a) Response Surface Plot (b) Contour Plot

Fig No: 7 Effect of Ocimum gratisimum (A) and Sodium starch glycolate (B) on Dissolution in 5minutes of Aceclofenac Fast Dissolving Tablets:

Tablet No: 3 ANOVA of Drug dissolved in 5 min of Aceclofenac Fast Dissolving Tablets Formulated Employing Ocimum gratissimum

Source of variance	degree of freedom	sum square	mean sum square (sum square/d.f)	variation ratio (f) (mss/mss error)	f ratio	significant/ non significant
Replicates	2	-0.0125	-0.00625	-1.09375	2.77	P>0.05
Treatments	7	17835.8	2547.9757	445895.75	4.66	P<0.05
No superdisintegrant	1	107377.2	107377.2	18791010	4.66	P<0.05
Ocimum gratissimum	1	9083.929	9083.929	1589687.6	4.66	P<0.05
SSG	1	1333.55	1333.55	233371.25	4.66	P<0.05
Ocimum gratissimum x SSG (AB)	1	926.2838	926.2838	162099.67	4.66	P<0.05
CCS	1	3214.146	3214.146	562475.55	4.66	P<0.05
Ocimum gratissimum x CCS (AC)	1	1271.088	1271.088	222440.4	4.66	P<0.05
SSG x CCS(BC)	1	1151.489	1151.489	201510.58	4.66	P<0.05
Ocimum gratissimum x SSGx CCS(ABC)	1	855.3816	855.3816	149691.78	4.66	P<0.05
ERROR	14	0.08	0.0057143
Total	23	17835.9

The concentration level of independent variable i.e. superdisintegrants at which optimum response was obtained was studied from the independent variables and their interaction effects on the responses. From the polynomial equations it was clearly evident that superdisintegrants (Ocimum gratissimum, sodium starch glycolate, croscarmellose sodium) A, B, C and interactions between A, B and C showed positive effect on the percent dissolved in 5 minutes and water absorption of aceclofenac fast dissolving tablets, whereas interactions between the AB, AC and AC showed negative effect on the percent dissolved in 5 minutes and water absorption of acecofenac fast dissolving tablets. Contour plots, indicate that low levels of Ocimum gratissimum (A) and high levels of sodium starch glycolate (B) and croscarmellose sodium (C) favours the percent dissolved in 5 minutes and water absorption of aceclofenac fast dissolving tablets. To obtain more percent dissolved in 5 minutes and more water absorption high levels of superdisintegrants i.e Ocimum gratissimum (A), sodium starch glycolate (B), croscarmellose sodium (C) are needed in formulation of aceclofenac fast dissolving tablets.

The results of physical properties of aceclofenac fast dissolving tablets, in-vitro disintegration time and in-vitro dissolution studies, it was known that the formulation F8 employing 5% concentration of Ocimum gratissimum 5% concentration of sodium starch glycolate and 5% croscarmellose sodium exhibited more percent dissolved in 5 minutes and water absorption. Hence, F8 is considered as an ideal formulation of aceclofenac, whereas formulation F2 with novel superdisintegrant i.e. Ocimum gratissimum in the concentration range of 5% is also comparable to the formulation F8. Therefore, when compared to F8, F2 was found to be more economical with single novel superdisintegrant.

CONCLUSION:

Ocimum gratissimum is an eficient superdisintegrant for fast dissolving tablets. The disintegration and water absorption of the fast dissolving tablets of Aceclofenac was good and depended on the concentration of superdisintegrant employed i.e. Ocimum gratissimum (5%), and sodium starch glycolate (5%). The formulated fast dissolving tablets of aceclofenac employing ocimum gratisimum and croscarmellose sodium exhibited good dissolution drug dissolved in 5 min which can be used for the fast therapeutic action of aceclofenac .

Overall, Ocimum gratissimum was found to be a super-disintegrant when combined with sodium starch glycolate, the dissolution dissolved in 5 min of aceclofenac was enhanced and hence it could be used in the formulation of fast dissolving tablets to provide immediate release of the contained drug within 5 min.

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Received on 18.01.2022 Modified on 11.05.2022

Research J. Pharm. and Tech 2023; 16(4):1861-1868.

DOI: 10.52711/0974-360X.2023.00305