FORMULATION AND EVALUATION OF SUBLINGUAL TABLETS BY USING FENUGREEK SEED POWDER AS A SUPER DISINTEGRANT

Abstract

The aim of the study is to formulate and evaluate hydralazine fast dissolving sublingual tablets sing fenugreek seed powder as super disintegrants by direct compression method. Design of experiment was used to optimize the formulation. The tablets that were manufactured exhibited mechanical strength and good flow characteristics. A design expert presented the optimized formulation FIO for sublingual tablets containing 65 mg of fenugreek seed powder and 25 mg of sodium starch glycolate. It was discovered that the formulation FIO complied with the IP standards in terms of weight variation with crown diameter of 8 mm. The hardness and percentage friability were 4.34±0.38 kg/cm2 and 0.77% respectively. The wetting time for formulation FIO was 28±1.0 seconds. The percentage drug content of formulation FIO was found to 95.51±0.57%w/w. The in-vitro disintegration time for the formulation FIO was 57±0.58 seconds. The amount of drug released from formulation FIO at end of 14 min was 94.12±0.13%. Peppas model was the best fit model for formulation F 10, with n 0.37 and indicating a fickian diffusion drug release mechanism. The results of hydralazine sublingual tablets showed it as a potential candidate for usage as a substitute for parenteral treatment in the fast control of hypertension.

Specification

Description:FIELD OF INVENTION:
[0001] The present invention is related to formulation and evaluation of sublingual tablets by using fenugreek seed powder as a super disintegrant.

BACKGROUND:
[0002] The main objective of this study is to formulate and evaluate hydralazine fast dissolving sublingual tablets sing fenugreek seed powder as super disintegrants by direct compression method. Design of experiment was used to optimize the formulation. The tablets that were manufactured exhibited mechanical strength and good flow characteristics. A design expert presented the optimized formulation Fl0 for sublingual tablets containing 65 mg of fenugreek seed powder and 25 mg of sodium starch glycolate. It was discovered that the formulation F10 complied with the IP standards in terms of weight variation with crown diameter of 8 mm. The hardness and percentage friability were 4.34 0.38 kg/cm2 and 0.77% respectively. The wetting time for formulation FI0 was 28 1.0 seconds.

[0003] The percentage drug content of formulation FI0 was found to 95.51 0.57%w/w. The in-vitro disintegration time for the formulation FI0 was 57 0.58 seconds. The amount of drug released from formulation Fl0 at end of 14 min was 94.12 0.13%. Peppas model was the best fit model for formulation Fl 0, with n = 0.37 and indicating a fickian diffusion drug release mechanism. The results of hydralazine sublingual tablets showed it as a potential candidate for usage as a substitute for parenteral treatment in the fast control of hypertension.

[0004] Medications have been applied topically to the mucous membrane. However, there has been interest recently in the use of the oral cavity as a delivery method for medicines to reach the systemic circulation. The goal of sublingual drug delivery is to produce a rapid onset of pharmacological impact. All age groups are susceptible to dysphasia; however, it is most common in the elderly, young patients, mentally retarded patients, uncooperative patients, sick patients, and patients on limited liquid intake or diets. When drugs are administered under the tongue, they reach the bloodstream through the tongue's ventral surface and the bottom of the mouth. The term "sublingual administration" describes that a tablet that is absorbed through sublingual blood vessels avoids the hepatic first pass metabolic processes and usually begins to effect quicker than an oral dose.

SUMMARY:
[0005] The rate and amount of medication absorption from the sublingual tablets was much higher than that of the normal oral route, indicating a higher bioavailability. The optimized formulation FIO sublingual tablets had showed a equally good wetting time and disintegration time on compared to previous studies done using FSG as super disintegrants and SSG and a binder [28]. Formulation FIO had showed a quicker onset of action, and higher bioavailability making it ideal for lowering of blood pressure.

DETAILED DECSRIPTION OF FIGURES & TABLES:
[0006] Table 1: Pre-compression Parameters

[0007] Table 2: Formulation table for sublingual tablets

[0008] Table 3: DoE generated 32 factorial designs for Hydralazine sublingual tablet formulation.

[0009] Table 4: The Optimised formula proposed for Hydralazine sublingual tablets from DoE.

[0010] Table 5: Regression analysis of Formulation FlO

[0011] Table 6: Stability study for optimized formulation.

[0012] Fig. 1: Standard Graph of HYD in pH 6.8 Phosphate Buffer

[0013] Figure 2: FT IR Spectrum of pure a) Hydralazine b) physical mixture

[0014] Figure 3: Thermogram of pure a) Hydralazine b) physical mixture

[0015] Figure 6: the vitro Drug release Kinetics of formulation

DETAILED DESCRIPTION AND PROCEDURES:
[0016] Alpha med Formulations Pvt. Ltd. (Hyderabad) provided a gift sample of hydralazine (HYO). The local market was the source of fenugreek seed powder (FSP). We bought mannitol and microcrystalline cellulose (MCC) from Fisher Scientifics in Mumbai. Talc and sodium starch glycolate (SSG) were acquired from Loba Chemie Pvt. Ltd. in Mumbai. Thermo Fisher Scientific India Pvt Ltd was the supplier of saccharin and citric acid. The chemicals and other materials that were used were all analytical grade.

[0017] Pre-compression evaluation: Studies of compatibility following tests were performed on samples of the tested excipient, plain HHC, and their physical combination (1:1). Spectroscopy in the infrared (IR) Without first being compressed or mixed with potassium bromide, samples (2-4 mg) were placed directly into an infrared spectrophotometer (Shimadzu IR-435, Kyoto, Japan) and scanned between 4,000 and 500 cm-1 at room temperature. Infrared spectra were captured and examined. Weighted samples (2-4 mg) were placed into a differential DSC pan (STA 449 FJ Jupiter, Nietzsche, Germany). The pan was calibrated using a 99.9% pure indium standard, and nitrogen gas was continuously purged in accordance with the procedure over a temperature range of25 C to 350 C at a heating rate of 10 C/min.

[0018] The angle of repose, bulk density, tapped density, carrs index and Hausner's ratio were determined for the according to the standard procedures described. The angle of repose is the maximum angle that can occur between the powder surface of the heap and the horizontal plane. bulk density was determined by 50 ml graduated measuring cylinder linked to the bulk density was filled with a mass of powder equipment in order to calculate bulk density. By employing a measuring cylinder with a weighed quantity of powder within, the tapping method was used to determine the taped density. The cylinder was dropped three times at l inch and 2 second intervals in hight, and the tapped density was calculated. In order to maintain uniform weight, car's index is an important characteristic. It is calculated by using following formula by using Hausner's ratio, one can define a comparable index to show the flow qualities. The formula below can be applied in order to calculate ratios.

[0019] The angle of repose, bulk density, tapped density, Carr's index, and Hausner's ratio were determined according to standard procedures described in references. The angle of repose is defined as the maximum angle between the surface of a pile of powder and the horizontal plane. It ensures that the powder is free-flowing and dry. Angle of repose was determined by fixed funnel method. Represents the mass of a material per unit volume, including both the material itself and the void spaces between particles. Bulk density was determined using a 50 mL graduated measuring cylinder. The cylinder was filled with a known mass of powder, and the bulk density was calculated based on the volume it occupied.

[0020] Tapped density was measured using the tapping method. A measured quantity of powder was placed in a graduated cylinder, which was then dropped from a height of 1 inch at 2-second intervals. This process was repeated three times. The tapped density was then calculated based on the volume reduction after tapping. Carr's index is an important characteristic used to assess the compressibility of powders. It is calculated using the following formula 1. Hausner's ratio is another index that reflects the flow properties of powders. It can be calculated using the following formula 2

% compressibility index = (n(n-1) x^2 tapped density-bulk density)/(Tapped density ) X 100…………1

Hausner's ratio (H)= (tapped density)/(bulk density)…………………2


[0021] Optimization of the super-disintegrating agent by using 32 full factorial design: The super disintegrating agents were optimized using a 32 complete factorial design. Wetting time (Yl), in vitro disintegration (Y2) and in vitro dissolution studies (Y3) were considered dependent variables, whereas the amounts of FGS (Xl) and SSG (X2) were selected as an independent variable in 32 full factorial designs based on preliminary results. Using deign expert soft wear multiple linear regression analysis, ANOVA and contour plots were obtained and the influence of a factor on formulation was studied. The 32 full factorial design batches with 25 mg HHC were used in the experimental runs.

[0022] Formulation of sublingual tablet by direct compression method: the ingredients were passed through #80 mesh to maintain uniform size particles. Subsequently, accurately weight amount of the drug and fenugreek seed powder were mixed using a mortar and pestle until a homogeneous blend was achieved. Subsequently, a ten station Rimek tablet punching machine was used to compress the tablets using a 6 mm size punch.

[0023] Post compression Evaluation:20 Tablets were weighed separately in accordance with IP in order to get the average weight. 6 tablets were ingested, and the thickness was measured using a Vernier calliper as tablet thickness is a crucial parameter. Hardness of the 3 tablets from each formulation was measured by using hardness tester Pfizer [19]. A total of 6 ta lets were selected from each formulation was determined by Roche fabricator. The weight of the tablets was expressed in percentage using the following formula 3.
%Friability = Initial weight-final weight/final weight x 100………………….3
Wetting time was determined for IO tablets using method as described by Devendra Recontend uniformity was determined for 10 tablets was measured at 2'12 nm using a double beam UV-visible spectrophotometer

[0024] In vitro disintegration: Using a conventional tablet disintegration tester (Electro lab ED-2L; Electro lab India Pvt Ltd., Mumbai, Maharashtra, India), the disintegration of tablets was measured in phosphate buffer (pH 6.8) maintained at 0C 0.5 0C in order to comply with official regulations.

[0025] In vitro dissolution studies: With 500 ml of phosphate buffer (pH 6.8) and 50 revolutions per minute, the USP XXIV dissolution testing apparatus II (paddle method) was employed to evaluate how quickly the tablet formulations released the drugs. After filtering through a 0.45 membrane filter, the drug's absorbance in each sample was measured spectrophotometrically at Amax 272 nm for every 5, 7.5, 10, 15, and 20 min. The % cumulative drug release was calculated using an equation that was developed from an earlier standard calibration curve. The sublingual tablet formulation is used to determine the drug release mechanism and is used to evaluate the drug release profile for release kinetics, including zero order, first order, Higuchi and Kores Meyer Peppas. Appropriate statistical analysis is used to perfom1 all release kinetics.

[0026] Stability study of the optimized formulation: In compliance with ICH guidelines, short-term stability studies were carried out for one month by placing the tablets in at 40 0C ± 2 0C/75 ±5% RH.

[0027] Pre compression study and data: The powder was evaluated for pre-compression parameters like Angle of repose, Carr's index, Hausner ratio, Bulk density and Tapped density and these parameters showed that powder has a good flow property and the values were determined to be under the standard limit for all formulations and the result was shown in table.

[0028] FT IR Spectrum of pure Hydralazine: The IR spectrum of hydralazine in figure 2(a), showed a characteristic bond of N-H at 3215cm-1, adjacent H atoms on an aromatic ring at 880 cm-1, aromatic C-H at 3025 cm-I, and C=C at 1554 cm-I. From figure 2(b), spectrum of physical mixture showed N-H at 3248cm-1, C-H at 3004cm-1, C=C at I561cm-1, On an aromatic ring, adjacent H atoms are 885 cm-I. Thus, the drug excipient compatibility analysis showed that no significant change has been observed in the functional group peaks of HYD with all excipients. Hence excipient used were compatible with HYD.

[0029] The oxidation or recrystallization shown in the Fig.3(a) may be the cause of the endothermic peak seen at 280.98 C in the HYD spectrum. In Fig.3(b), the physical mixture's DSC curve at 277.46 C forms endothermic peaks, indicating HYD melting. There appears to be no interaction between the physical combination and the drug's natural state as indicated by the endothermic peaks of the HYD DSC curve.

[0030] Response 1 (Wetting Time): The formulae showed that the range was between 30 and 70 seconds. The best mathematical model to share the response y and factors (FSP and SSG) produced the following equation: WT= +58.67-l5.00*A- 6.17*B+l.75*AB-2.00*A2-2.50*82. A probability value less than 0.005 indicated that the created quadratic model was very significant, based on the analysis of variance (ANOVA) results. R2 was found to have a value of 0.9421. A straight line may be seen when the observed WT and anticipated WT are plotted Fig.4(a). Thus, it may be said that the equation has an elevated level of predictive power. Based on the 3D plot Fig.4(c) and factor regression coefficient values, it was determined that WT decreased as FGS concentration was increased. Compared to SSG, FGS has a faster WT because of its increased hydration capacity.

[0031] Response 2 (Disintegration Time): In the range Disintegration time values of all the formulation were found. DT= +51.56-24.83*A- 8.83*B+2.25* AB+3.17*A2-1.83*82was the equation extracted from the best suited mathematical model for R2 and the independent variables. A probability value less than 0.005 showed that the created quadratic model was very significant, according to the analysis of variance (ANOVA) results. R2 was found to have a value of 0.9941. A straight line may be observed when comparing the predicted and observed DT plots Fig.4(d). Thus, it may be said that the equation has a high degree of predictive power. Based on the 30 plots, it was found that increasing FGS decreased the disintegration time. Fig.4(f) and the regression coefficient values of the components. The outcomes also showed that OT was more significantly impacted by FGS. Compared of the SSG, FGS has a higher swelling. Capacity, which causes it to break down more quickly.

[0032] Response 3 (/11 vitro drug release): The individual in vitro dissolution response variables (R3) resulted in different combinations of factors HPMC and SSG based on 32 factorial designs. Extracted from the best response R2 fit to the independent variables, the equation was ID= +95.88-1.35*A-0.2867*B+0.0425*AB+0.6317*A2+1.49*B2. A probability value less than 0.005 indicated that the created quadratic model was very significant, based on the analysis of variance (ANOVA) results. R2 was found to have a value of 0.9530.

[0033] A straight line can be seen in the plot of observed ID vs expected ID Fig.4(g). Thus, it may be said that the equation has a high degree of predictive power. Based on the 3D plot Fig.4(i) and the factor regression coefficient values, it was found that ID decreased at the same time that the number of FGS and SSG increased. Additionally, the results showed that FGS was assigned a greater impact on ID.

[0034] Pre-compression studies: Formulation FlO showed 0.476 g/cm3 bulk density, and 0.555 g/cm3 tapped density. The estimated Carr's compressibility index was based on the two density measurements given. All powder mixes had good flow qualities, according to data on flowability and its compressibility, with an index of 14.9%. The angle of repose further demonstrated each powder blend's superior flow characteristics. The range of the angle of repose was 23.I 2 demonstrating good flow property.

[0035] Post compression studies: The Weight Variation of the material flowed freely; homogeneous die fill produced tablets with acceptable variance that complied with IP specifications. For Fl 0, the weight was 380 0.49 mg. For tablets containing 250 mg of J.P., the maximum permitted percentage weight fluctuation is 5%; formulation F10 has not gone above this limit. As a result, it was determined that formulation Fl 0 complied with the IP rules. The thickness of 10 was within the allowed deviation limit, or 5% of the standard value. In addition. the formulation Fl O's crown diameter measured 8 nm1. The Hardness formulation Fl 0 had hardness of 4.34 038 kg/cm2 seemed acceptable. Hence, excessive hardness should be avoided for these formulations.

[0036] The percentage friability of the formulation Fl0 was found to be 0.77%, falling within the allowed limit of l%. Therefore, Fl O's maximum friability was found to be 0.77%. Wetting Time For formulation Fl 0, the wetting time was 28 1.0 s. The drug content percentage of formulation FI0 was found to be 95.51 0.573/ow/w, falling within the allowed specified range. Disintegration is the period of time during which a solid dosage form dissolves and begins to absorb a medication when taken orally, and this was the primary focus of this study. Hardness is a major factor that impacts the disintegration process and has an effect on the disintegration time because it affects the matrix's porosity, which in tum impacts the water's capacity to pass through the matrix. For formulation FI 0, the in-vitro disintegration time was 57 0.58 seconds.

[0037] vitro drug release studies: 94.12 0.13% of the drug had been released after l 4min from formulation FI0. The findings showed that when more excipients were added to the formulation Fl0, the drug release reduced mentioned in fig. 5.

[0038] Drug release kinetics: According to the release kinetic parameters, the drug release mechanism was fickian diffusion (case I diffusional), as indicated by the peppas model, which yielded n = 0.37, was the best fit model for the optimized formulation (Fl 0). This model also had the highest regression coefficient value R2 mentioned in fig. 6.

[0039] HYD sublingual Tablets were created using the direct compression technique. The Design Expert @11 software was used to assess the ready-made tablet computers. ANOVA analysis revealed that Responses R1, R2, and R3 displayed a highly significant Quadratic model, as indicated by a probability value of less than 0.05. The boundaries of the design space can be seen by the middle region of the contour plot, which was marked in yellow. The confirmatory trial's results matched the estimated values found in the design space. F10 was the optimized formulation with FSP of 65 mg and SSG of 25 mg that was derived from the design space, and further evaluations have been performed.

[0040] The flow and compressibility ability data showed that formulation FlO has good flow qualities. The angle of repose further demonstrated Formulation Fl 0 powder blend's superior flow characteristics. Higher concentration of the super disintegrants FSP, the tablet had an excellent wetting time of 27 seconds and disintegration time of 57 seconds. The ability to form mucilage on contact with water of FSG attributed to good wetting time and disintegration time. The results showed that when the amount of FSG increased, the drug release from formulation F10 decreased due to swelling natural of FSP on contact with the fluid. The Peppas model, which proved that fickian diffusion, was the mechanism of drug release. Based on the other journals are developed Amlodipine besylate fast-dissolving tablets were created to increase patient adherence to hype11ension medication.

[0041]. The mucilage of Trigonella foenum graecum, sometimes known as fenugreek seed powder was utilised as a super disintegrant in the direct compression method of creating rapid sublingual tablets. Eight formulations containing different amounts of lactose, microcrystalline cellulose, fenugreek mucilage, and various excipients were made and assessed. Optimal formulation F6, with 5% fenugreek mucilage, showed 90% water absorption, 14 seconds for disintegration, and 22 seconds for wetting time, after 15 minutes, 63% of the medication was being released in vitro from the F6 formulation. Compared to previous studies using drug and FSG as a super disintegrant Fl 0 sublingual tablets has equally good wetting time and disintegration time. , Claims:Claims:
I/We Claim:
1.A method evaluating sublingual tablets using fenugreek seed powder as a super disintegrant, comprising:
a plain HHC;
a potassium bromide;
the plain HHC was mixed with potassium bromide samples;
whereby placed directly into an infrared spectrophotometer and scanned at room temperature;
the weighted samples were placed into a differential DSC pan;
the pan was calibrated using a 99.9% pure indium standard;
a nitrogen gas was continuously purged in accordance with the procedure over a temperature range of 25 0C to 3500C at a heating rate of 100C/min;
all the ingredients were passed through mesh to maintain uniform size particles;
an accurately weight amount of the drug and fenugreek seed powder were mixed using a mortar and pestle until a homogeneous blend was formed; and
a ten station rimek tablet punching machine was used to compress the tablets using a 6 mm size punch

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