INTRODUCTION:

Oral cavity as a portal for delivering drugs to the systemic circulation. Notwithstanding the relatively poor permeability characteristics of the epithelium, a number are offered by this route of administration. Foremost among these are the avoidance of first-pass metabolism, ease of access to the delivery site, and the opportunity of sustained drug delivery predominantly via the buccal tissues. Oral mucosal drug delivery is an alternative method of systemic drug delivery that offers several advantages over both injectable and enteral methods. Because the oral mucosa is highly vascularised, drugs that are absorbed through the oral mucosa directly enter the systemic circulation, by passing the gastrointestinal tract and first-pass metabolism in the liver.

The demand of fast disintegrating tablets has been growing during the last decade, due to the high onset of action, patient compliance and characteristics of fast disintegrating sublingual tablets for the potential emergency treatment. In terms of permeability, the sublingual area of the oral cavity (i.e, the floor of the mouth) is more permeable than the buccal (cheek) area, which in turn is more permeable than the palatal (roof) of the mouth. Drug delivery through the oral mucous membrane is considered to be a promising alternative to the oral route. Fast disintegrating sublingual tablets may lead to significant improvements over current treatment options for specific patient group, for instance pediatric and geriatric patients. The sublingual route usually produces a faster onset of action than orally ingested tablets and the portion absorbed through the sublingual blood vessels bypasses the hepatic first-pass metabolic processes.

Various advantages offered by sublingual tablet like avoid first pass metabolism, fast onset of action, taken without use of water, absorption of drug through this route is 3-10 times higher than oral dosage form. Small volume of saliva provides fast disintegration in oral cavity.¹

Recently for novel drug delivery system, sublingual tablets are widely used due to Porous sublingual tablet prepare by Sublimation technique in which different polymers are used like combination of superdisintigrant and subliming agent provide better result.² The presence of highly porous surface of tablet is the key factor for rapid disintegration time. In this method subliming agent produced porosity in tablet ,So it provide less disintegration time as compared to direct compression tech. In sublimation tech. mixture of other excipients are also used along with Super disintegrant and sublimating agent evaporate at 60⁰C for 30 minutes, after that generation of porous surface on tablet as because of sublimating agent.³Metoprolol succinate itself class-I drug with high permeability and solubility so, which full fill criteria for sublingual drug delivery.⁴ Several advantages are offered by such technique over conventional technique like wet granulation including omitting step of eliminating water or organic solvents used as granulating agents, there is no risk of residual solvents, no need to drying step and less consumption of time and energy. Also in case of other technique Provide poor result in D.T. and % Cumulative release (%CPR) compared with sublimation tech. ⁵

Various fast dissolving tablets has been prepared by sublimation tech. by using various subliming agents like camphor, menthol, thymol etc. Which evaporate at 60^.c along with water soluble excipients like Mannitol, Sucralose. Therefore generation of porous surface on tablet this provides faster disintegration than Direct compression technique^{6, 7,
8}.

Metoprolol succinate is β1 selective blockers which is promising drug used useful in quick emergency diseases like cardiac heart failure (CHF), hypertension. It is available commercially in 23.75,25,50 mg strength as immediate release tablets. Its half life is about 3-7 hours. Its absolute and systemic oral bioavailability respectively 12% and 50% following oral administration as because of high first pass metabolism to metabolite o-desmethyle Metoprolol, α hydroxyl Metoprolol via cytochrome P-450 system .which is less potent than pure drug. ^{9, 10}

In the present study investigated concept for Sublingual tablet to provide prompt action in quick emergency disease like CHF, hypertension, angina. Sublingual tablet were generated using different polymers, Crosss povidone, Menthol, Mannitol, Sucralose, MCC. The data presented in this study show that sublingual tablet Produce quick action in feasible concept. This delivery system can be used for develop a new platform for provide quick action CHF, angina, hypertension.

MATERIALS AND METHODS:

MATERIALS

Cross povidone from Yarrow Chem. Pvt., Mumbai; Menthol from Suvidhinathnath Lab., Baroda; Sucralose from Himedia ltd., Mumbai; Mannitol from SRL Chem. Pvt., Mumbai; Microcrystalline cellulose (MCC) from Molychem Pvt., Mumbai; Methanol from Merck India Chemicals., Mumbai; Formic acid from Merck India Chemicals., Mumbai were purchased.

METHODS

Formulation of Tablets

Tablets were formed by sublimation techniques and optimization by 3² full factorial design.

Accurately weighed ingredients were sifted through sieve no.44 and thoroughly mixed for 10 min and magnesium stearate and other ingredients were added to the blend and thoroughly mixed. The tablets were compressed using Rotary tablet punching machine. The compressed tablets were than subjected to sublimation at 80°c for 30 min in vacuum oven. Table 2 shown composition of tablets as per 3² full factorial design.

Full Factorial Design

A 3² randomized full factorial design was adopted to optimize the variables. In this design two factors were evaluated each at three levels, and experimental trials were performed at all 9 possible combinations. Less runs are required as compare to other statistical design. In this design Menthol and Cross Povidone taken as independent variables and % friability and D.T. taken as dependant variables.

Below table 1 depicted about variables and transformed value of 3² full factorial design.

Table 1: Variables and their levels of 3² full factorial design

Independent Variable

Real value

Lower (-1)

Medium (0)

High (1)

Menthol [X₁]

Crosspovidone[ X₂]

2.5 %

2 %

4.5 %

3.5 %

6.5 %

5 %

Regression analysis

The responses were measured for each trial and then quadratic model was fitted by carrying out multiple regression analysis.

Y = b0 + b1X1 + b2X2 + b12X1X2 + b11X12 + b22X22…

Where, Y is the dependant variable, while b0 is the intercept and b1, b2, b11, b22, b12 are regression coefficients

Table 2: Composition of tablets by 3² full factorial design

Ingredients	Batches ( in mg)
Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
Metoprolol succinate	23.75	23.75	23.75	23.75	23.75	23.75	23.75	23.75	23.7
Menthol	3	3	3	5.4	5.4	5.4	7.8	7.8	7.8
Crosspovidone	2.4	4.2	6	2.4	4.2	6	2.4	4.2	6
Sucralose	2	2	2	2	2	2	2	2	2
MCC	36	36	36	36	36	36	36	36	36
Mg.stearate	1	1	1	1	1	1	1	1	1
Talc	1	1	1	1	1	1	1	1	1
Mannitol (up to 120 mg)	50.85	49.05	47.25	48.45	46.65	44.85	46.05	44.25	42.5
Total ( mg)					120

Contour plots

Contour plots are diagrammatic representation of the values of the response. They are helpful in the explaining relationship between independent and dependant variables. The two dimension contour plots were prepared using statistica software.

Response surface plots

Response surface plots are more helpful in understanding both the main and the interaction effect of variables. The effect of different levels of independent variables on the response parameters can also be predicted from the respective response surface plots.[for check point batch analysis Overlay plot was prepared by using Design expert software version .7.0 , Because of it gives more accurate and precise check point batch analysis than statistica software version 8.0]

EVALUATION PARAMETERS OF TABLETS

Drug excipients compatibility study

The interference study was carried out using FTIR and DSC analysis. The infrared absorption spectra of pure drug, pure polymer and physical mixture of polymerand drug were performed for polymer drug interaction studies between 4000 cm^-1to 400 cm^-1.^11,
12 The DSC analyses of pure drug and physical mixture of polymer and drug were carried polymer drug interaction studies out between 35-200⁰C.¹³

Evaluation of tablets

Tablets from all the formulation were subjected to following quality control tests. It is necessary for to find out optimized batch and methods of preparation of tablet in between direct compression and sublimation method.

General appearance

The general appearance of a tablet, its visual identity and over all “elegance” is essential for consumer acceptance, including tablet’s size, shape, surface texture, consistency and legibility of any identifying marking.

Size and shape

The size and shape of the tablet can be dimensionally described, monitored and controlled. Size was determined by vernier callipers.

Tablet thickness

Tablet thickness is an important characteristic in reproducing appearance and also in counting by using filling equipment. Some filling equipment utilizes the uniform thickness of the tablets as a counting mechanism. Ten tablets were taken and their thickness was recorded using vernier callipers.

Tablet hardness

Hardness of tablet is defined as the force applied across the diameter of the tablet in order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under condition of storage transformation and handling before usage depends on its hardness. Hardness of the tablet of each formulation was determined using Monsanto hardness tester.

Friability

Friability is measured of mechanical strength of tablets. Roche friabilator was used to determine the friability.

Disintegration test

The test was carried out on 6 tablets using the apparatus specified in I.P.-1996 distilled water at 37°C ± 2°C was used as a disintegration media and the time in second taken for complete disintegration of the tablet with no palable mass remaining in the apparatus was measured in seconds¹⁴.

Uniformity of weight

I.P. / E.P. procedure for uniformity of weight was followed, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight. The weight variation test would be a satisfactory method of determining the drug content uniformity¹⁵.

Wetting time

A piece of tissue paper (12 cm × 10.75 cm) folded twice was placed in a small petridish (ID = 6.5 cm) containing 6 ml of phosphate buffer pH 6.8. A tablet was put on the paper and placed amaranth or any other dye on tablet and the time for complete wetting was measured until full wetting of tablet andcolour dispersed on paper. Three trials for each batch and the standard deviation were also determined. The wetted tablet was then weighed.The same procedure was followed for determining the water absorption ratio¹⁶. The wetted tablet was weighed and the water absorption ratio, R, was dtermined according to the following eqn.

R = 100 (Wa –W_b₎ / W_b

W_a₌weight of tablet after wetting

W_b₌weight of tablet before wetting

Drug content

10 tablets were weighed and powdered; powder equivalent to 10 mg of Metoprolol succinate was weighed and dissolved in simulated saliva pH 6.8 and filtered the solution through the Whatman filter paper. The filtrate was collected and diluted to a sufficient amount with simulated saliva pH 6.8 till the concentration of the drug lies within the standard plot range. The diluted solution was analyze for Metoprolol succinate content by using UV-spectrophotometer (UV-1700 Shimadzu) using simulated saliva pH 6.8 solution as a blank.

Dissolution studies

The in vitro dissolution study was carried out in the USP dissolution test apparatus (Electro lab dissolution tester USP) type 2 (paddle). 300 ml of the dissolution medium (simulated saliva pH 6.8) was taken in covered vessel and the temperature was maintained 37°C ± 0.5°C. The speed of the paddle was set at 100 rpm. Sampling was done at 5, 10, 15, 20, 20 and 30 min interval. For each sample 5 ml of the dissolution medium was withdrawn and the same amount of dissolution medium pre-warmed at 37°C was replaced to the dissolution medium. The sample withdrawn was filtered with whatmann filter paper and diluted with simulated saliva pH 6.8 prior to analyze in the UV spectrophotometer (UV-1700 Shimadzu). The absorbance was measured at 211 nm and the cumulative % release was calculated¹⁷.

In-vivo bioavailability study of sublingual tablet in rabbit

Calculation for drug doses for laboratory animals

Calculation was carried out for appropriate drug doses given per animal’s weight, the prescribed dosage of the drug to be used, and recommended dose of drug given. Food and Drug Administration has suggested that the extrapolation of animal dose to human dose is correctly performed only through normalization to BSA, which often is represented in mg/m². The human dose equivalent can be more appropriately calculated by using the formula^[^18,19]

Animal dose =	Human dose ×	Animal weight
		Human weight

Animals were divided in two groups each group having 4 animals.(Table 3)

Table 3: In vivo bioavailability study groups

Groups	I	II
Treatment	Test	Standard
Dose(mg/kg)	1.18	1.18
No of animals	4	4
Route	Sublingual tablet	Oral solution

Sublingual tablet administration in rabbit

For sublingual tablet administration, the rabbit’s mouth was opened, and a forceps was inserted between the jaws. The tongue was elevated by using flat forceps, and the tablet was placed underneath by using another pair of forceps. The mouth was gently but firmly held shut for 5 minutes to prevent chewing or swallowing the tablet. Water 0.3 to 0.5 ml was administered immediately after dosing to facilitate tablet disintegration. Additional 0.7 to 0.5 ml water was administered at the end of the 5-minute immobilization time to remove any remaining drug from under the tongue. Marginal ear vein of the rabbit was used for collection of blood collection was fairly simple at this site. The area was shaved and cleaned with alcohol. The vein was occluded, the needle carefully inserted, and blood slowly withdrawn. A butterfly set used to avoid damage to the vessel if the animal moves. Gauze held with pressure over the vein puncture site for a few minutes to prevent hematomas from forming.^[20]

Blood sample collection and processing

Male Newzeal and Rabbits (2.0-3.0 kg) had free access normal standard chow diet and tap water. Animals were fasted for 12 hr prior to the experiments and were given water freely. The protocol the experiments was approved by the institutional animal ethical committee as per guidance of the committee for the purpose of control and supervision of experiments on animals.(SU/DPS/IAEC/1315) In the present study, rabbits (n = 3 per each treatment) were given orally as well as sublingually tablet 1.18 mg/kg of lisinopril. Blood samples were withdrawn from the marginal ear vein according to a predetermined time schedule at 0, 0.5, 1.0, 2.0, 4.0 and 8.0 collected in EDTA containing tubes. Blood samples were centrifuged at 12000 rpm for 10 min. And the plasma was removed and processed for extraction.

Extraction procedure for sample preparation

As a sample take 0.15-0.20 ml of the spiked plasma in the eppendroff tube was taken. 800 µl of Acetonitrile in the same eppendroff tube was added and vortexed the samples thoroughly for 2min. [Protin precipitation tech.] The samples were put in to centrifuge at 10000 rpm for 15 min. at 4°C. The supernant was transferred in to another per labeled eppendr off tube. 20 µl of the sample was injected into HPLC system.

Pharmacokinetics and statistical analysis

Pharmacokinetics and statistical analysis for plasma concentration Vs Time profile of Metoprolol succinate was performed on the data obtained from (Rabbit). Pharmacokinetic parameters T_max, C_max were calculated using plasma concentration Vs time profile (Actual time of sample collection) data of Metoprolol succinate in individual animal using statistical software. The area under the plasma concentration verses time curve from zero time to the last experiment point, (AUC_0-24h) was calculated by trapezoidal method. Here the plasma concentration versus time plot is divided into geometric figures whose area can be determined individually using appropriate geometric formula for each figure. The area under the curve of plasma concentration time graph is obtained by adding the area of each segment represented by the geometric figure. This plot yields one triangle and remaining trapezoids²¹. The following relationship is used to calculate area of each geometric figure.

AUC = ½(t₂ – t₁) × (c₁+c₂) +…………n

Area of triangle = (0.5) (height) (base)

Area of trapezoid = (0.5) (height) (sum of two parallel sides)

AUC = Area of triangle + Area of trapezoid

Stability testing

The accelerated stability study was carried out at 40°C and 75% RH. The sublingual tablets were packed in suitable packaging and stored in stability chamber for maintaining 75% RH and temperature maintained at 40C²².

The tablets were withdrawn after a period of 30 days and analyzed for physical characterization (Visual defects, Hardness, Friability, disintegrations, and dissolution etc.) and drug content.

RESULTS AND DISCUSSION

Developed sublingual tablet of Metoprolol succinate loaded With Cross povidone, Menthol, Sucralose, and MCC.Mannitol provides quick action in CHF, angina, hypertension and improved bioavailability of sublingual tablet prepared by sublimation method. By applying 3² full factorial design used for optimization of Menthol and Cross povidone as independent variables, by checking the effect on decedent variables like disintegration time and % Friability. Then Characterization of sublingual tablets done in preliminary study like angle of repose, Tapped density, Bulk density, Hausner’s ratio, Compressibility index, and done in post compression study like hardness, thickness, disintegration time, wetting time, water absorption time, in vitro dissolution time, % Friability.

All above parameters provide acceptable result in range as per IP/USP/specific guidelines. Drug excipients compatibility study done by FT-IR, DSC.

Drug Excipients Compatibility Study

FTIR analysis

Results of IR spectrum ,MS has indicating presence of absorption peak due to presence of NH₂, OH, Aliphatic OH respectively at 3139.5,2923.6 ,2874.84,2828.25 cm^-1suggesting that these functionalities are also present in the powder mixture. The aromatic ring and aromatic ether absorption are noticed from 1515.49 cm^-1 and 1240.96 cm^-1.The characteristics carboxylic acid salt of the drug and isopropayle ether and secondary alcohol exhibited absorption peak at 1186.91cm^-1. These are the characteristics of the MS ^23,24. FTIR analysis of pure drug Figure 1 (a) and overlay of drug and polymers shown in Figure 1 (b).

The entire above characteristic peak appears in the spectra of tablet formulation at the same wave number, indicating no modification or interaction between the drug and excipients.

From this it can be concluded that the drug has maintained its identity without losing its characteristics properties. It will not show any adverse effect in action of the formulation and helps to study the desired parameters in the present study.

DSC analysis

Samples were analyzed by DSC. The samples (3mg) were placed into a pieced aluminum sample container. The studies were performed under static air atmosphere in the temperature range of 35°C - 350°C at a heating rate of 5°C/minute. The peak temperatures were determined after calibration with a standard. The DSC thermo gram of Metoprolol succinate, pure excipients and tablet powder shown in figure 2(a) and 2(b). DSC thermograph of Metoprolol succinate exhibits endothermic Peak at 139.2°C corresponding to its melting point. Mixture of excipients and Metoprolol succinate shows endothermic peak at 138.85 °C which indicates almost no interaction. and D-Mannitol gives a endothermic peak at 164.2 °C.

Figure 1(a): FTIR analysis of pure drug

Figure 1(b): Overlay of Drug and Pure mixture and excipients

Figure 2 (a): DSC thermo grams of pure drug

Figure 2(b): DSC thermo grams of pure drug and excipients

Table 4: Pre compression parameters of 3² full factorial design

Batches	Angle of repose*	Bulk density* (gm/ml)	Tape density* (gm/ml)	Hausner’s ratio*	Carr's index* (%)
F-1	33.38 ±0.46	0.479 ±0.018	0.631 ±0.006	1.316 ±0.002	20.21 ±0.23
F-2	32.51 ±0.44	0.466 ±0.017	0.626 ±0.010	1.303 ±0.004	19.73 ±0.31
F-3	31.74 ±0.22	0.415 ±0.009	0.625 ±0.006	1.323 ±0.003	18.54 ±0.27
F-4	32.53 ±0.46	0.435 ±0.008	0.597 ±0.008	1.321 ±0.009	20.38 ±0.22
F-5	33.50 ±0.47	0.427 ±0.007	0.595 ±0.009	1.336 ±0.004	21.02 ±0.11
F-6 F-7 F-8 F-9	31.50 ±0.39 33.48 ±0.38 32.59 ±0.47 31.52 ±0.42	0.424 ±0.011 0.426 ±0.009 0.395 ±0.009 0.392 ±0.010	0.622 ±0.005 0.635 ±0.006 0.634 ±0.005 0.640 ±0.005	1.313 ±0.002 1.331 ±0.002 1.316 ±0.004 1.273 ±0.004	19.92 ±0.08 20.97 ±0.09 19.10 ±0.06 18.95 ±0.12

*± SD of 3 determinate

Table 5 :Post compressional parameters of 3² full factorial design

Formulation	Hardness (kg/cm²)	Thickness (mm)	Uniformity of weight (mg)	Drug content (%)	Wetting time (sec.)
F-1	3.43±0.081	3.29±0.025	117.6±0.67	97.61±0.78	44.33±1.52
F-2	3.23±0.082	3.28±0.028	117.7±0.69	97.87±1.14	35±1.0
F-3	3.32±0.089	3.28±0.021	117.4±0.70	101.02±1.52	24±2.0
F-4	3.23±0.051	3.29±0.023	117.09±0.73	96.96±0.94	36.66±1.52
F-5	3.45±0.054	3.28±0.026	117.1±0.78	97.91±1.10	27±1.02
F-6	3.26±0.051	3.29±0.021	117.3±0.70	100.55±1.65	21.33±2.08
F-7	3.43±0.081	3.28±0.022	117.01±0.69	99.20±1.52	30.66±2.08
F-8	3.26±0.054	3.29±0.020	117.3±0.70	97.71±1.34	25.33±2.08
F-9	3.25±0.056	3.28±0.026	116.6±0.53	101.06±1.98	18±1.0

*± SD of 3 determinate

Post compressional Parameters

All post compressional parameters like Hardness, Drug content, Thickness, Uniformity of weight, wetting time and water absorption ratio was shown in table 5.

As per above table hardness and thickness of all 9 batches were found in range. Drug content were found between 96% to 101 %. Wetting time was found between 18 to 44 sec. wetting time was decreased with increase in the concentration of super disintigrants.

Table 6: Post compressional parameters of 3² full factorial design

Formulation	Friability (%)	D.T.in sec.
F-1	0.325±0.0013	30.16±1.16
F-2	0.336±0.0005	26±0.63
F-3	0.393±0.0017	15.33±1.032
F-4	0.466±0.0017	28±0.894
F-5	0.494±0.0014	17±0.632
F-6	0.458±0.0010	12 ±0.632
F-7	0.691±0.0016	21.5±0.836
F-8	0.604±0.0010	14.16±0.752
F-9	0.543±0.0026	9.01±0.836

*± SD of 3 determinate

As per the above table 6 Friability was lies within limit for all formulations.

In Figure 4 and table 6 indicated that F-9 Batch high % Crosss povidone and Menthol produced less disintegration time (9 sec.) and optimum %friability (0.691%).

Invitro dissolution profile of 3²full factorial design:

F-9 batch which has high value of Cross povidone and Menthol generated more than 85% drug release within 2-4 minutes and more than 95% drug release in within 6-8 minutes.(Figure 5). In-vitro drug content in all the formulations was found to be in the range according to USP (90% TO 110%)] in 3² full factorial design hardness of tablet 3.2-3.5 kg/cm². As increase the concentration of Menthol and CP, % CPR is also increase.

Regression analysis of 3²full factorial design

The amount of subliming agent (menthol, X1) and the as a superdisintegrants (Crosss povidone, X2) were chosen as independent variables in a 3² full factorial design. A statistical model incorporating interactive and polynomial terms was used to evaluate the responses, where Y is the dependent variable, b₀ is the arithmetic mean response of the 9 runs, and bi is the estimated coefficient for the factor Xi.²⁵

Effect of independent variable on Disintegration time:

Y₂= 18.76 – 4.59 X₁– 7.16X₂ +0.55 X₁X₂+ 0.075 X₁² + 0.35 X₂²

The results of multiple linear regression analysis (reduced model) reveal that, on increasing the concentration of either Menthol or Crosss povidone, a decrease in disintegration time is observed; both the coefficients b1 and b2 bear a negative sign. When higher percentage of menthol is used, higher porosity is expected in the tablets. The water uptake and subsequent disintegration are thus facilitated. It is obvious that in the presence of higher percentage of superdisintegrant CP, higher degree of wicking is facilitated, which concluded through eqn. no. and figure 7 (a) and 7 (b). (Contour plot and RSP)

Overlay plots of two responses could be used to determine desired concentration of Menthol and Crosss povidone In above figure 8 yellow region of overlay plot showed desired range of responses.

By choosing any concentration of Menthol andCrosss povidine in this region, desired responses could be achieved.

Checkpoint batch analysis

From the overlay plot, check point was selected in order to obtain desired value of factors²⁶.

On the basis of desired criteria of % Friability and Disintegration time following batch was formulated to assess the reliability of the evolved equations. Below table 7 shows composition of check point batches.

Table 7: Formula of checkpoint batch

Ingredients	Level	Quantity [mg]
Menthol	4.76	5.71
Crossspovidone	4.91	5.89

The experimental values and predicted values of each response are shown in Table 7.

The percentage relative error of each response was calculated using the following equation:

% Relative error = [(Predicted value – Experimental value) / Predicted value] × 10

Table 8: Responses of checkpoint batch

Response

Experimental

Predicted value

% Relative

error

(% Friability )

0.446

0.470

5.04

Y2 (Disintegration

time)

12.36

11.82

4.54

Table 8 shows that the % relative error for the checkpoint batch was in the range of 5.04 – 4.54.Which is less than 8%, so statically acceptable. It was concluded that the experimental values and predicted values showed good agreement between each other.

Table 10: Calculation of model testing:

% Friability
Regression	D.F	SS	MS	F	R²
FM	5	0.114	0.022	38.005	0.98	F_cal=0.5
RM	2	0.113	0.056	121.15	0.97	F_tab=9.276
Error						D.F=(3,3)
FM	3	0.0018	0.0006			F_cal.<F_tab
RM	6	0.002	0.0004
Disintegration time
Regression	D.F	SS	MS	F	R²
FM	5	431.22	86.22	14.55	0.960	F_cal=0.082
RM	2	429.66	214.83	67.05	0.950	F_tab=9.276
Error						D.F=(3,3)
FM	3	17.76	5.92			F_cal.<F_tab
RM	6	19.22	3.20

In order to determine the change in In-vitro release profile on storage, stability study of formulation F9 was carried out at 40°C in a stability chamber having 75 % RH²⁸. Samples evaluated after one month showed no change in In-vitro drug release pattern as shown in figure 12. The pattern of drug release indicating good similarity of dissolution profiles before and after stability studies which would conclude by calculation of similarity factor f2 of In-vitro dissolution profile.

FT-IR analysis of Final formulation for stability study:

FT-IR peak analysis indicated that there was no change in any characteristics peak in final formulation after 1 month stability study, which indicated that there was no interaction during stability study indicated in figure 13.

Based on stability study it’s indicating no any changes should be occur in optimized formulations.

CONCLUSION:

Present study demonstrates that D.T. (9 sec.) and % friability (0.691%) is suitable for sublingual tablet prepared by sublimation method having 6.5% menthol and 5% cross povidone. These formulation hold great potential for treating emergency disease like Hypertension, CHF, and angina. On the basis of all studies we can concluded that batch having Menthol and crosspovidone provide successful result. Therefore Porous sublingual tablet prepared by sublimation method may be considered as promising drug delivery for treating emergency disease like Hypertension, CHF, and angina.

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Received on 29.11.2014 Modified on 24.12.2014

Res. J. Pharm. Dosage Form. & Tech. 7(1): Jan.-Mar. 2015; Page 30-43

DOI: 10.5958/0975-4377.2015.00006.3

Response(D.T)	b₀	b₁	b₂	b₁₁	b₂₂	b₁₂
FM	18.76	-4.59	-7.16	0.075	0.035	0.55
RM	18.76	-4.59	-7.16	--	--	--
Response (%Friability)	b₀	b₁	b₂	b₁₁	b₂₂		b₁₂
FM	0.48	0.13	-0.145	0.017	-0.015		-0.05
RM	0.48	--	-0.145	--	--		-0.05

Time in hrs.	Conc. (µg/ml) (sublingual)	Conc.( µg/ml) (oral)
0	0	0
0.33	16.22 ±0.165	6.21 ±0.265
0.66	33.23 ±0.051	21.23 ±0.361
1	53.89 ±0.653	37.18 ±0.351
1.5	47.05 ±0.280	42.12 ±0.308
2	38.54 ±0.14	30.05 ±0.404
4	23.98 ±0.296	18.85 ±0.218
6	18.23 ±0.200	12.83 ±0.378
8	11.52 ±0.222	7.51±0.350