INTRODUCTION:

Oral routes of drug administration have wide acceptance up to 50-60% of total dosage forms. Solid dosage forms are popular because of ease of administration, accurate dosage, self medication, pain avoidance and most importantly the patient compliance. The most popular solid dosage forms are being tablets and capsules; one important drawback of this dosage forms for some patients, is the difficulty to swallow. Drinking water plays an important role in the swallowing of oral dosage forms. Difficulty in swallowing tablet is a common problem of all age groups, especially elderly and paediarics, because of physiologic changes associated with these groups of patients.

Many patients feel difficulty in swallowing conventional tablets when water is not available, in the case of the motion sickness (kinetosis) and sudden episodes of coughing during the common cold, allergic condition and bronchitis. For these reason, tablets that can rapidly dissolve or disintegrate in the oral cavity have attracted a great deal of attention. Orodispersible tablets are not only indicated for people who have swallowing difficulties, but also are ideal for active people. Fast dissolving tablets are also called as mouth-dissolving tablets, melt-in mouth tablets, Orodispersible tablets, rapimelts, porous tablets, rapid dissolving tablets, quick dissolving tablets, etc.,^1-3. The united states of food and drug administration center for drug evaluation and research (FDA) defines, in the ‘orange book’, an ODT as “a solid dosage form containing medicinal substances, which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue”⁴. The significance of these dosage forms is highlighted by the adoption of the term, “Orodispersible tablet”, by the European pharmacopoeia which describes it as a tablet that can be placed in oral cavity where it disperses rapidly before swallowing⁵.

Labetalol hydrochloride is a selective α- and nonselective β-adrenergic blocking agent. It is used in management of hypertension, alone or in combination with other classes of antihypertensive agents.

Labetalol hydrochloride is rapidly and almost completely absorbed (i.e., 90–100%) from the GI tract following oral administration. It undergoes extensive first-pass metabolism in the liver and/or GI mucosa. Absolute bioavailability is about 25%. Therefore to improve bioavailability and patient compliance in this study attempt has been made to develop fast dissolving tablets of Labetalol HCl using camphor as subliming agent with different superdisintegrants to enhance the onset of action of drug.

MATERIALS AND METHODS:

Materials

Labetalol HCl was obtained from Celon Labs Ltd. Hyderabad, India as gift sample. All the other solvents, reagents and chemicals used were of either Pharmacopoeial or analytical grade.

Methods

Drug excipient compatibility study:

This study has been done to check whether there is any compatibility related problems are associated with drug and excipients used for the formulation of tablet.

Fourier Transform Infrared (FTIR) Spectral analysis

FTIR spectra of pure drug and physical mixture of drug and excipients were recorded on samples prepared in potassium bromide (KBr) disks using a FTIR Spectrophotometer, (FTIR-8300, Shimadzu, Japan). Samples were prepared in KBr disks by means of a hydrostatic press at 6-8 tons pressure. The scanning range was 400 to 4000 cm^-1.

Differential Scanning Calorimetry (DSC) analysis

DSC analysis was performed using Shimadzu DSC-60, Shimadzu Limited Japan. A 1:1 ratio of drug and excipient was weighed into aluminum crucible. And sample was analyzed by heating at a scanning rate of 20⁰C over a temperature range 40-430⁰C under nitrogen environment.

Preparation of labetalol fast dissolving tablets

Preparation of orodispersible tablets using sublimation method Sublimating agents resulted in rapid disintegration of tablets due to the phenomenon of sublimating which improves dissolution. Specified quantity of Labetalol and other excipient according to formula given in the table 1 were weighed and passed through 60 # screen prior to mixing. All the materials were transferred to mortar and triturated till the mixture was uniform. The resulting powder mixture was compressed into tablets using ten stations Cemach tablet compression machine. The tablets were dried at 60°C in oven till constant weight obtained.

Table1: Composition of Labetalol FDT’s using sublimation method

Ingredients (mg/tablets)	Formulations
Ingredients (mg/tablets)	S1	S2	S3	S4	S5	S6	S7
Labetalol	50	50	50	50	50	50	50
Camphor	5	10	-	-	-	-	-
Menthol	-	-	5	-	-	-	-
Ammonium bicarbonate	-	-	-	5	10	-	-
Thymol	-	-	-	-	-	5	10
Avicel pH 102	38	33	38	38	33	38	33
Aspartame	2	2	2	2	2	2	2
Sodium stearyl fumarate	1	1	1	1	1	1	1
Talc	2	2	2	2	2	2	2
Orange flavour	2	2	2	2	2	2	2
Total weight (mg)	100	100	100	100	100	100	100

1. Evaluation of fast dissolving tablets

i) Pre-compressional studies^6-15

Angle of Repose (Ө):

The frictional force in a loose powder or granules can be measured by angle of repose. The angle of repose of API powder was determined by the funnel method. The accurately weighed powder blend was taken in the funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touched the apex of the powder blend. The powder blend was allowed to flow through the funnel freely on to the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation.

Ө = tan^-1 (h/r)

Where, Ө is the angle of repose, h is the height of pile and r is the radius of the base of pile.

ii) Bulk Density and Tapped density:

Loose bulk density (LBD) and tapped bulk density (TBD) of tablet blends were determined using bulk density apparatus. Tablet blend was passed through #18 sieve to break the clumps and transferred to 100ml graduated cylinder. Initial volume was observed. The cylinder was tapped initially 200 times from a distance of 14±2 mm. The tapped volume was measured to the nearest graduated unit. This was repeated for other tablet blends. The LBD and TBD were calculated in g/ml using following formula:

LBD = weight of the powder / volume of the packing

TBD = weight of the powder / tapped volume of the packing

iii) Carr’s Index:

The Compressibility Index of the powder blend was determined by Carr’s compressibility index. It is a simple test to evaluate the BD and TD of a powder and the rate at which it is packed down. The formula for Carr’s Index is as below,

Carr’s Index (%) = [(TBD-LBD) x100]/TBD

Where,

LBD = Loose Bulk Density and

TBD = Tapped Bulk Density

iv) Hausner ratio:

The Hausner’s ratio is a number that is correlated to the flowability of a powder or granular material. The Hausner ratio of the powder was determined by the following equation:

Hausner ratio = TBD / LBD

a) POST-COMPRESSIONAL STUDIES^6-15

i) General appearance:

The fast dissolving tablets, morphological characterization which includes size, shape, colour, presence or absence of odour, taste surface texture was determined.

ii) Thickness and diameter:

Five tablets were picked from each formulation randomly and thickness and diameter was measured individually. It is expressed in mm and standard deviation was also calculated. The tablet thickness and diameter was measured using vernier caliper.

iii) Hardness:

Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Monsanto hardness tester. It is expressed in kg/cm². Five tablets were randomly picked and hardness of the same tablets from each formulation was determined. The mean and standard deviation values were also calculated.

iv) Friability test:

Friability test is performed to assess the effect of friction and shocks, which may often cause tablet to chip, cap or break. Roche Friabilator was used for the purpose. Pre-weighed sample of ten tablets were placed in the Friabilator, which was then operated at 25 rpm for 4 minutes or ran upto 100 revolutions. After 100 revolutions the tablets were dusted and reweighed. Compressed tablets should not lose more than 1% of their weight.

The % friability was then calculated by the following formula:

Percentage friability = (Initial weight - Final weight) × 100

Initial weight

v) Weight variation:

20 tablets were selected randomly from each formulation and weighed individually to check for weight variation. The US Pharmacopoeia allows a little variation in the weight of a tablet. The following percentage deviation in weight variation is allowed.

vi) Drug content uniformity:

Twenty tablets were weighed and powdered. Powder equivalent to 50 mg drug was transferred into a 100 ml volumetric flask. Volume was made with phosphate buffer pH 6.8. After few minutes the solution was filtered; rejecting first few ml of the filtrate. 10ml of filtrate was taken in a 50 ml volumetric flask and diluted up to the mark with phosphate buffer pH 6.8 and analyzed spectrophotometrically at 302 nm. The concentration of Labetalol (in µg/ml) was calculated by using the standard calibration curve of Labetalol.

vii) Wetting time and water absorption ratio:

A piece of tissue paper folded twice was placed in a small petridish (i.d = 6.5 cm) containing 6 ml of water. A tablet was placed on the paper and the time required for complete wetting was then measured.

The water absorption ratio, R, was determined using the following equation,

R = Wa - Wb × 100

Where,

Wb is the weight of the tablet before water absorption and

Wa is the weight of the tablet after water absorption.

viii) In vitro dispersion time:

One tablet was placed in a beaker containing 10 ml of phosphate buffer pH 6.8 at 37 ± 0.5ºC and the time required for complete dispersion was determined.

ix) In vitro disintegration time:

In vitro disintegration time was performed by apparatus specified in USP at 50 rpm. Phosphate buffer pH 6.8, 900 ml was used as disintegration medium, and the temperature of which was maintained at 37±2°C and the time in second taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured in seconds.

x) In vitro drug release studies:

In vitro drug release studies were carried out using dissolution apparatus USP type XXIII at 50 rpm. The dissolution medium consisted of 900 ml of Phosphate buffer pH 6.8 maintained at 37±1⁰C. The drug release at different time intervals was measured using a double beam UV Spectrophotometer at 302 nm.

xi) Data Analysis:

Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release rate kinetics of the dosage form, the obtained data were fitted into zero-order, first order, Higuchi, Korsmeyer-Peppas release model and Hixson-Crowell equation.

xii) Stability Studies:

Stability of a drug has been defined as the ability of a particular formulation, in a specific container, to remain within its physical, chemical, therapeutic and toxicological specifications.

In the present study, stability studies were carried out at 25⁰C ± 2⁰C/60% ±5% RH and 40⁰C± 2⁰/75% ± 5% RH for a period of 60 days for the selected formulations. The formulations were then evaluated for changes in the physicochemical properties, wetting time, in vitro disintegration time and in vitro drug release.

RESULTS AND DISCUSSION:

Oral drug delivery remains the preferred route for administration of various drugs. Solid dosage forms are popular because of ease of administration accurate dosage, self-medication, pain evasion and most importantly the patient compliance. Fast dissolving tablets are those when put on tongue disintegrate instantaneously releasing the drug which dissolves or disperses in the saliva. The faster the drug into solution, quicker the absorption and onset of clinical effect. The purpose of this research was to develop fast dissolving tablets of Labetalol hydrochloride using sublimation method along with other excipients. The prepared tablets were evaluated for physiochemical properties, wetting time, water absorption ratio, in vitro dispersion time, in vitro disintegration time, in vitro dissolution studies and stability studies.

Drug-excipient compatibility studies:

Fourier Transform Infrared (FTIR) Spectroscopy

Physical mixture of Labetalol and formulative ingredients were subjected for IR spectroscopic analysis to ascertain whether there was any interaction between drug and excipients used. The IR spectras showed similar characteristic peaks at their respective wavelengths with minor differences. The similarity in the peaks indicated the compatibility of drug with formulation excipients. IR spectra of the physical mixture of drug with formulative ingredients were depicted in figure 1 to 2.

Evaluation parameters:

A) Precompressional parameters:

Powder ready for compression containing drug and various excipients were subjected for various precompressional evaluation parameters such as bulk density, tapped density, compressibility index, Hausner’s ratio and angle of repose. Pre-compressional parameters (Micromeritic properties) were studied to determine the flow properties of granules, to achieve uniformity of tablet weight. The results of all the preformulation parameters are given table 2.

Angle of repose (θ)

The data obtained from angle of repose for the formulations of sublimation method were found to be in the range of 31.400 to 32.890

Bulk density

Loose bulk density (LBD) for the blend was performed. The loose bulk densities for the formulations of sublimation method varied from 0.39 gm/cc to 0.42 gm/cc.

Tapped density

Tapped bulk density (TBD) for the blend was performed. The tapped bulk densities for the formulations of sublimation method varied from 0.48 gm/cc to 0.50 gm/cc.

Carr’s consolidation index

The results of Carr’s consolidation index or compressibility index (%) for the sublimation formulation blend ranged from 14.75% to 19.45%.

Hausner ratio

Hausner ratio of sublimation formulations showed between 1.17 to 1.24

B) POST-COMPRESSIONAL PARAMETERS:

All the tablet formulations were evaluated for parameters such as shape, colour, thickness, hardness, friability, weight variation, drug content, in vitro disintegration time, in vitro dispersion time, wetting time, in vitro dissolution studies, model fitting of release profile and stability studies.

a) General appearance:

All the fast dissolving tablets from each batch were found to be flat, white in color, circular in shape and having good physical appearance. There was no change in the color and odour of the tablets from all the batches.

b) Thickness and diameter:

Thickness and diameter of all prepared fast dissolving tablets was measured by using calibrated vernier callipers. Tablet thickness should be controlled within ±0.1% variation of standard value to facilitate packaging and consumer acceptance. The mean thickness and diameter was almost uniform in all the formulations and values of tablets prepared by sublimation method were ranged from 2.57 mm to 2.62 mm, 4.01 to 4.03 mm respectively. The standard deviation values indicated that all the formulations were within the range.

c) Hardness:

Tablets require certain amount of strength, hardness to withstand mechanical shocks during manufacture, packaging and shipping. The hardness of all the tablets prepared by sublimation methods was maintained within the range of 2.52 kg/cm²to 2.83 kg/cm². In all the formulations the hardness test indicates good mechanical strength. In case of sublimation technique the hardness of tablet decreases with increase in amount of sublimable component. The obtained results revealed that the tablets were having good mechanical strength and compactness.

d) Friability:

Adequate tablet hardness and resistance to friability are necessary to prevent damage to the tablet during manufacture, packing and transport.

The friability was found in all sublimation formulations in the range 0.66 to 0.69%, well within the approved range (<1%) which indicates the tablets had god mechanical resistance.

e) Weight variation:

The weight variation was found in the range of 99 to 100 mg for sublimation formulations. The weight variation results revealed that average percentage deviation of 20 tablets of each formula was less than ± 7.5% i.e. in the Pharmacopoeial, limits which provide good uniformity in all formulations.

f) Mouth feel:

The prepared formulations were subjected for mouth feel. The volunteers felt good taste in all the formulations prepared by sublimation method. As the drug is slightly bitter the presence of Aspartame and orange flavour in all the formulations showed good, palatable taste.

g) pH:

pH of the solution of all the tablets prepared by sublimation method was found to be between 7.1 to 7.5, which suggest that the tablets can be conveniently administered orally and will not cause any discomfort.

h) Drug content:

To evaluate a tablet’s potential for efficacy the amount of drug in the tablet need to be monitored from tablet to tablet and batch to batch. The percentage drug content was found to be in the range of 98.29 to 99.78% for sublimation formulations. All the results were summarized in table 3.

i) Wetting Time:

Wetting time is an important parameter related to water absorption ratio, which needs to be assessed to give an insight to the disintegration properties of the tablets. Wetting is closely related to the inner structure of the tablets and the hydrophilicity of the excipients. Wetting time was used as a parameter to correlate with disintegration time in oral cavity. This is an important criterion for understanding the capacity of disintegrants to swell in presence of little amount of water. Since the dissolution process of a tablet depends upon the wetting followed by disintegration of the tablet, the measurement of wetting time may be used as another confirmative test for the evaluation of dispersible tablets.

Formulation batches S1 to S7 comprised of four different types of subliming agents, wetting time was found between 18.11 and 39.63 seconds. These batches showed wide variation in their wetting time because of change in not only type but also amount of subliming agents taken for study. In this formulation containing ammonium bicarbonate gave better wetting time than rest of three subliming agents.

Table 3: Post compression evaluation of Labetalol FDT’s using sublimation method

Formulation Code	Thickness (mm)*	Diameter (mm)*	Hardness (kg/cm²)*	Friability (%)**	Weight variation test (mg)***	Drug Content (%)***	pH	Mouth feel
S1	2.57±0.005	4.02±0.02	2.66±0.28	0.66±0.04	99.69±1.37	98.70±0.73	7.4	+
S2	2.60±0.028	4.01±0.02	2.74±0.28	0.68±0.02	100.26±0.931	98.55±0.09	7.5	+++
S3	2.59±0.015	4.03±0.02	2.83±0.28	0.68±0.08	99.22±1.230	99.30±0.56	7.4	++
S4	2.61±0.045	4.01±0.01	2.66±0.28	0.66±0.01	99.96±1.47	99.78±0.28	7.2	+
S5	2.61±0.037	4.01±0.03	2.83±0.28	0.66±0.04	100.21±1.322	98.65±0.51	7.5	+++
S6	2.62±0.028	4.01±0.04	2.52±0.00	0.69±0.02	99.97±0.493	98.58±0.44	7.2	+
S7	2.61±0.02	4.03± 0.04	2.83±0.28	0.67±0.03	101.15±1.10	98.29±0.75	7.1	+++

*All values are expressed as mean ± SE, n=5; **All values are expressed as mean ± SE, n=10; ***All values are expressed as mean ± SE, n=20; += Average; ++= good, +++= excellent

Figure 6: Comparison between in vitro disintegration time and in vitro dispersion time of various formulations of Labetalol FDT’s using sublimation method

Figure 7: Comparison of dissolution profile of various formulations of Labetalol FDT’s using sublimation method

Table 4: Model fittings of release profile of optimized formulated Labetalol FDT’S using different models

FORMULATION

CODE

MATHEMATICAL MODELS (KINETICS)

Zero Order

First Order

Higuchi Matrix

Peppas

Hixson Crowell

Best Fit Model

0.771

0.955

0.985

0.721

0.938

Higuchi matrix

Table 5: Results of stability study of formulation F3 and S5 stored at 25⁰C ± 2⁰C/60% ±5% RH

Formulation Code	Tested in days	Thickness (mm)	Hardness (Kg/cm²)	Friability (%)	Weight variation (mg)	% Drug content
S5	20	2.61±0.03	2.83±0.28	0.66	100.21±0.32	98.65
	40	2.60±0.02	2.83±0.21	0.64	100.20±0.12	98.64
	60	2.59±0.04	2.83±0.20	0.65	100.19±0.42	98.64

Table 6: Results of stability study of formulation F3 and S5 stored at 40⁰C± 2⁰C/75% ± 5% RH

Formulation Code	Tested in days	Thickness (mm)	Hardness (Kg/cm²)	Friability (%)	Weight variation (mg)	% Drug content
S5	20	2.60±0.03	2.83±0.28	0.66	100.21±0.32	98.65
	40	2.59±0.02	2.83±0.21	0.64	100.19±0.12	98.63
	60	2.58±0.04	2.83±0.20	0.65	100.20±0.42	98.63

o) Stability Studies:

Stability studies of formulation S5 was performed at 25⁰C ± 2⁰C/60% ±5% RH and 40⁰C ± 2⁰C /75% ± 5% RH for a period up to 60 days.

The samples were withdrawn for every 20 days interval and the tablets were analyzed for appearance, thickness, hardness, friability, weight variation, drug content uniformity, in vitro disintegration, wetting time and in vitro drug release up to 60 days.

The results obtained for physicochemical properties, wetting time, in vitro disintegration time and in vitro drug release of formulation S5 at 25⁰C±2⁰/ 60%±5% RH and 40⁰C ± 2⁰/75% ± 5% RH showed not much variation in any parameter. From these results it was concluded that formulations were stable and retained its original properties (table 5-6).

CONCLUSION:

In this research work ODTs of Labetalol HCl were successfully formulated by direct compression method using sublimation method.

From the study conducted and from the observations and the results obtained thereof, following conclusions were drawn:

· FTIR studies concluded that drug and excipients were compatible with each other.

· The flow properties of the formulation powder have good flow property which is an important aspect for the ODT formulations.

· The formulated tablets were satisfactory in terms of hardness, thickness, friability, weight variation, drug content, wetting time, water absorption ratio, in vitro disintegration time, in vitro dispersion time and in vitro drug release.

· The disintegration studies revealed that the tablets prepared with ammonium bicarbonate as subliming agent showed faster disintegration as compared to tablets prepared with rest of subliming agent.

· Dissolution studies confirmed that tablets prepared with ammonium bicarbonate as subliming agent show faster drug release as compared to tablets prepared with rest of subliming agent.

· Direct compression method is the best method for the formulation of ODTs. This method is also very economical and time saving. Similarly ammonium bicarbonate was found to be the best subliming agent among all with 10 percent concentration yielding the best results.

· Formulations containing ammonium bicarbonate as subliming agent showed least wetting time and in vitro disintegration time.

· Formulation S5 were found to be the best on the basis of wetting time, in vitro disintegration time and in vitro drug release.

· Short term stability studies carried out were confirmative of the drug stability in the tablets during the present study.

ACKNOWLEDGEMENTS:

The authors are thankful to the Management and Principal of Karavali College of Pharmacy, Mangalore for providing the all facilities to conduct the research work and the authors are also thankful to Celon Labs Ltd. Hyderabad, India for generous gift sample of Labetalol HCl.

REFERENCES

1. D. Bhowmik, B. Chiranjib, Krishnakanth, Pankaj, R. Margret Chandira, Fast Dissolving Tablet: An Overview. J Chem Pharm Res. 2009, 1(1), 163-177

2. H. Seager, Drug delivery products and zydis fast dissolving dosage form. J Pharm Phamacol. 1998, 50, 375-382.

3. J.P .Renon, S. Corveleyn, Freeze-dried rapidly disintegrating tablets, US Patent No 6, 010, 719, 2000.

4. S. Bharadwaj, V. Jain, S. Sharma, R. C. Jat, S. Jain, Orally Disintegrating Tablets: A Review.Drug Invention Today. 2010, 2(1), 81-88.

5. D. Brown. Orally Disintegrating Tablets-Taste over Speed. Drug Del Tech. 2003, 3, 58-61.

6. Subrahmanyam CVS. Textbook of physical pharmaceutics. Delhi: Vallabh Prakashan; 2005:28-32.

7. Subrahmanyam CVS, Thimmasetty J, Shivanand KM, Vijayendraswamy SM. Laboratory manual of industrial pharmacy. Delhi: Vallabh Prakashan; 2006: 32.

8. Ministry of Health and Family Welfare (India). Indian Pharmacopoeia. New Delhi: The Controller of Publications; 1996.

9. Banker SG, Anderson NR. Tablets. In: Lachman L, Lieberman HA, Kanig JL, editors. The theory and practice of industrial pharmacy. 3rd ed. Bombay: Varghese Publishing House; 1991.

10. United States of Pharmacopeia-National Formulary. USP 30 – NF 25. Rockville, MD: The United States Pharmacopeial Convention Inc; 2007. Vol 1.p.644, 242, 645, 731 and 634.

11. Jacob S, Shirwaikar A, Joseph A, Srinivasan K. Novel Co-Processed Excipients of Mannitol and Microcrystalline Cellulose for Preparing Fast Dissolving Tablets of Glipizide. Indian J Pharm Sci 2007; 69(5): 633-39.

12. Sweetman SC, editor. Martindale: The Complete Drug Reference. 33^rd ed. London: Pharmaceutical Press; 2002:1235-7.

13. Jha SK, Vijayalakshmi P, Karki P, Goli D. Formulation and evaluation of melt-in-mouth tablets of haloperidol. Asian J Pharm 2008; 2(4): 255-60.

14. United States Pharmacopoeia, “In vitro Dissolution”. Asian edition. United States Pharmacy Convention Inc; 2000:1941-3.

15. Shukla V, Manvi FV. Effect of different superdisintegrants on isoniazid dispersible tablet for oral tuberculosis. Der Pharma Chemica 2010; 2(4): 65-78.

Formulation Code	Angle of Repose	Bulk Density (gm/cc)	Tapped Density (gm/cc)	Carr’s Index %	Hausner Ratio
S1	31.66±0.53	0.41±0.007	0.49±0.008	17.35±2.051	1.21±0.030
S2	31.40±0.55	0.42±0.005	0.50±0.005	16.56±1.106	1.19±0.015
S3	32.75±0.37	0.39±0.007	0.48±0.009	19.06±0.316	1.23±0.004
S4	33.18±0.35	0.42±0.005	0.49±0.007	14.75±2.061	1.17±0.028
S5	31.83±0.27	0.39±0.004	0.48±0.012	18.41±2.255	1.22±0.033
S6	32.04±0.23	0.39±0.005	0.49±0.005	19.45±1.113	1.24±0.017
S7	32.89±0.36	0.41±0.005	0.50±0.006	18.58±1.610	1.22±0.024