INTRODUCTION:

Fast dissolving tablets (FDTs) when put on tongue get disintegrate immediately and thus it releases the drug which dissolve or disperse in the saliva. Some drug are absorbed from the mouth,pharynx and esophagus as the saliva passes down into the stomach. In such cases,bioavailability of drug is considerably larger than observed from conventional dosage form.¹

Fast dissolving tablets (FDTs) are also called as orodispersible tablets, quick disintegrating tablets, mouth dissolving tablet, rapid dissolving tablets, porous tablets and rapimelts.

However of all the above terms, United state of pharmacopoeia (USP) approved these dosage forms as ODTs (orally disintegrating tablets). United State of Food and Drug Administration (USFDA) defined FDT as “A solid dosage form containing medicinal substance of active ingreedient which disintegrates quickly within matter of second when placed upon the tongue,” The disintegrating time for FDTs generally ranges from several seconds to about a minute.²

CHALLENGES IN FORMULATING FDT^3-5:

Palatability:

Most of the drugs are unpalatable through orally disintegrating drug delivery systems generally contain the medicament in taste-masked form. Fast dissolving tablet disintegrate or dissolve in patient’s oral cavity, thus releasing drug which comes in contact with taste buds, so taste-masking become a vital to patient compliance.

Mechanical Strength:

In order to allow Fast Dissolving Tablets to disintegrate in the oral cavity they are made of either very porous and soft moulded matrices or compressed into tablet with very low compression force which makes the tablet friable and/or brittle difficult to handle and obtain requiring specialized pill of blister packing that may at to the cost. Only some technologies can manufacture tablet that are satisfactorily hard and long-lasting to allow them to be packaged in multi dose bottles. Such as wowatab and durasolv by CIMA labs.

Hygroscopicity:

Some fast dissolving dosage forms are hygroscopic and cannot maintain physical reliability under normal circumstances of temperature and humidity. Therefore, they need protection from humidity which calls for particular product packaging.

Amount of drug:

The function of technologies used for FDTs limited by the amount of drug that can be incorporated into each unit dose. For lyophilized dosage forms, the dose of drug must be lesser than 400 mg for insoluble drugs and not as much of than 60 mg for soluble drugs. This parameter is mostly challenging when formulated as fast dissolving oral films.

Aqueous solubility:

Those drugs which are water soluble in nature contains various manufacturing challenges for the cause that they form eutectic mixtures, which outcomes in freezing-point depression and the development of a glassy solid state that may falls down upon exposure to air because of loss of behind structure during the sublimation process. This fall down occasionally can not permitted by using different matrix-forming ingredients such as mannitol that can stimulate crystallinity and thus, impart rigidity to the composition like amorphous.

Size of tablet:

According to survey it has been reported that the size of tablet which is easiest to swallow that is 7-8 mm while those tablets having size was one larger than 8 mm are easiest to hold. Thus, the tablet size that have both properties like easy to take and easy to handle is difficult to attain.

In recent years, significant awareness has been focused on the development of novel drug delivery systems (NDDS). The reason for this pattern transfer may be due to relatively low development cost and time required for introducing a NDDS is low as compared to a new chemical entity. In the form of NDDS, a presented drug molecule can get a ‘new life’, thereby rising its market value, competitiveness and patent life.

From the different NDDS formulations are available in market, Fast Dissolving tablets hold the foremost contribution for the reason that of their ease of administration and improved patient compliance. Complexity in swallowing a tablet or capsule is a general problem of all age groups, especially elderly and pediatrics, because of physiological changes related with these groups of patients. Some other ways in which patients that experience problems in using conventional oral dosage forms such as the mentally ill, uncooperative, nauseated patients and those which having conditions of motion sickness, sudden episodes of allergic attack or coughing.

To achieve these medical requirements, pharmaceutical technologists have developed a novel oral dosage form known as Fast Dissolving Tablets (FDTs) which disintegrate quickly in saliva, generally in a matter of seconds, without the need to take water. Drug dissolution, absorption, onset of clinical effect as well as drug bioavailability may be significantly greater than observed from conventional dosage forms.

In the present study an challenge was to formulate Fast Dissolving tablets of Levosalbutamol which is mainly protecting against all bronchoconstrictor problems used in treatment of anti-asthmatic.

Levosalbutamol Sulphate is activating of beta 2 adrenergic receptor on airway smooth muscle leads to activation of adenylate cyclase and there is an increase in the intracellular concentration of 3’ 5’ cyclic adenosine monophosphate (cyclic AMP) is occured. The increase in cyclic AMP associated with the activation of protein kinase A which is generally convert or inhibit phosphorylation of myosin and lower intracellular ionic calcium concentration resulting in muscle relaxation.

Levosalbutamol sulphate relaxes smooth muscle of all airway, from the trachea to the terminal bronchioles. Increased cyclic AMP concentration are also associated with the inhibition of the release of mediators from mast cell in the airways. Levosalbutamol sulphate act as a functional agonist that relaxes the airway irrespective of the spasmogen involved thearby protecting against all bronchoconstrictor challenges.

MATERIALS AND METHODS:

MATERIALS:

Levosalbutamol Sulphate was purchased from Swapnroop drug and Pharmaceuticals, Aurangabad, India. Microcrystalline cellulose (Avicel pH 102) and Aspartame was supplied by Gen Pharma, Mumbai, India. Kyron T 314 was supplied by Coral pharma Ahmedabad Other excipients used to preparethe fast dissolving tablets such as Crosscarmellose sodium Crosspovidone xl 10 was supplied by Glenmark Generics LTD and Magnesium stearate Talc was supplied by Molychem Mumbai. All drug and chemicals were used were of analytical grade.

Method of Preparation:

In this work, direct compression method with the aid of superdisintegrants was attempted for the formulation development of fast dissolving tablets of Levosalbutamol Sulphate. Dose of 5 mg is selected for the present study. Development of the formulation in the present study was mainly based on thetype and concentration of polymers and the properties of the drug. Various polymersin different concentrations were used so as toget tablets with good physical properties. The formulation design of fast dissolving tablets of Levosalbutamol sulphate is shown in Table no. 1.

Determination of Solubility:

Solubility of Levosalbutamol Sulphate was performed in solvents water, Phosphate buffer PH 6.8., methanol and ethanol.⁶

Determination of Melting point:

Melting point of pure Levosalbutamol sulphate was determined by open capillary method. The capillary tube was closed at one end by fusion and was filled with Levosalbutamol Sulphate by repeated tapings. The capillary tube was placedin a digital melting point apparatus. The instrument was set to automatically increasethe temperature of the heating bath at a rate of 100ºC min rise of temperature perminute. The rise in temperature was viewed through magnifying lens. Thetemperature at which the drug started melting was recorded. This was performedthrice and the average value was calculated.⁷

Drug Excipients Compatibility Study:

Drug Excipients Compatibility Study was carried out by Fourier Transform infrared spectroscopy (FT-IR spectrophotometer, Agilent Technologies, carry 630 FTIR.). The sample was analyzed in the region of 4000 and 400cm^-1. The mixture of drug and polymer in 1:1 ratio were mixed well and analyzed for FTIR spectroscopy.8

Evaluation of Levosalbutamol sulphate tablets:

Pre-compression parameters^9-11

Bulk Density, Tap Density, Carr’s Index and Hausner’s Ratio:

Bulk Density and Tap Density were subjected to Bulk and Tap density determination. Tapping cylinder method was used for determining bulk and tap density of granules were taken in 10 ml measuring cylinder. Initial volume (Bulk volume) and the volume after 100 tapings (Tap volume) were measured. From the results of Bulk and Tap densities, the Hausner’s ratio and Carr’s Index were calculated. Each micrometric property was performed in triplicate manner and reported.

Determination of angle of repose:

The flowability was assessed by determination of the angle of repose (θ) using fixed funnel method. Angle of repose is defined as the maximum angle possible between the surface of a pile of the powder and horizontal plane. Angle of repose has been used as indirect methods of qualifying powder flowability, because of their relation with interparticular friction.

Post compression Study:

Uniformity of thickness:

Thickness and diameter of both core tablets and coated tablets were measured using a calibrated vernier calipers. Three tablets of formulation were picked randomly and dimensions determined. It is expressed in mm and standard deviation was also calculated.¹²

Weight variation test:

To study weight variation 10 tablets of each pulse dose formulation were weighed separately and the test was performed according to the official method.¹²

Hardness test:

Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. Hardness of core tablets was determined using a validated dial type hardness tester. It is expressed in kg/cm². Three tablets were randomly picked from each batch and analyzed for hardness.The mean and standard deviation were also calculated.

Table No. 1 Formulation design of Levosalbutamol sulphate fast dissolvingTablets

Ingridents	F1	F2	F3	F4	F5	F6	F7	F8	F9
Levosalbutamol	5	5	5	5	5	5	5	5	5
Crosscarmellose	5	10	15	-	-	-	-	-	-
Polyplasdone XL-10	-	-	-	5	10	15	-	-	-
Kyron T-314	-	-	-	-	-		5	10	15
Microcrystalline cellulose	132	127	122	132	127	122	132	127	122
Magnesium stearate	3	3	3	3	3	3	3	3	3
Aspartame	3	3	3	3	3	3	3	3	3
Talc	2	2	2	2	2	2	2	2	2
Total Weight	150	150	150	150	150	150	150	150	150

Friability test:

For each pulse dose tablet formulation, the friability of 10 tablets was determined using the Roche friabilator (Camp –bell Electronics, Mumbai, India).

F= [Initial weight – Final weight/Initial weight] ×100

In vitro dispersion Time:

In vitro dispersion time was measured by dropping a tablet into a petridishcontaining 10 ml of Phosphate buffer PH 6.8. Threetablets from each formulation were randomly selected and tested. In vitro dispersiontime was found and expressed in second.¹³

Wetting time:

The method was applied to measure tablet wetting time. A piece of tissue paperfolded twice was placed in a small petri dish (i.d.= 6.5 cm) containing 10 ml of water, atablet was placed on the paper, and the time for complete wetting was measured.

Water absorption ratio¹⁴:

A piece of tissue paper folded twice was placed in a small petri dish containing6ml of water. A tablet was put on the paper and time required for complete wetting wasmeasured. The wetted tablet was then weighed. Water absorption ratio, R was determinedusing following equation.

R = 100 (Wa – Wb)/ Wb

Where,

Wb – weight of tablet before absorption

Wa – weight of tablet after absorption

Drug content determination:

Three uncoated tablets were selected randomly and average weight wascalculated. Tablets were crushed in a mortar and accurately weighed amount of tabletpowder was taken from the crushed blend. Then the samples were transferred tothree 100 ml volumetric flasks and were diluted up to the mark with Phosphate buffer PH 6.8 solution. The mixtures were filtered, appropriately diluted, andabsorbences were measured at λmax 276 nm against blank reference. The drugcontent in each tablet was calculated using the standard calibration curve of Levosalbutamol sulphate in Phosphate buffer PH 6.8 solution.¹⁵

In vitro drug release:

In vitro drug release of the samples was carried out using rotating paddle type apparatus. The dissolution medium, 900 ml of Phosphate buffer PH 6.8 solution, was placed into the dissolution flask maintaining thetemperature of 37±0.5ºC and rpm of 50. One tablet was placed in each flask ofdissolution apparatus. The apparatus was allowed to run for 5 min. Samples measuring 5 ml were withdrawn after every 2, 4, 6, 8, 10, 12, 14 and 16 min.Samples were filtered. The fresh dissolution medium wasreplaced every time to maintain sink condition. The collected samples were analyzed at 276 nm using dissolution medium as blank. The cumulative percentage drugrelease was calculated.¹⁶

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. The purpose of stability testing is to provide evidence on how the quality of a drugsubstance or drug product varies with time under the influence of a variety ofenvironmental factors such as temperature, humidity an light and enables recommended storage conditions, re-test periods and shelf lives to be established.ICH specifies the length of study and storage conditions:

Long term testing 25°C ± 2°C / 60 % RH ± 5 % for 12 months

Accelerated testing 40°C ±2 °C / 75 % RH ± 5 % for 6 months

In the present study, stability studies were carried out at 40°C / 75 % RH for a specific time period up to one month for the selected formulations.¹⁷

RESULTS AND DISCUSSION:

Determination of solubility:

Levosalbutamol sulphate was found to be freely soluble in water, very slightly soluble in ethanol (95%) and dichloromethane.

Determination of melting point:

The melting point of Levosalbutamol sulphate was found to be 228⁰C.

Evaluation of Levosalbutamol sulphate tablets:

Pre-compression parameters:

Table No. 2 Pre compression parameters of LS tablets

Formulation Code	Angle of Repose(Ɵ)	Bulk Density(g/cc)	Tapped Density(g/cc)	Carr’s Index	Haunser Ratio
F1	28.39±2.11	0.52±0.02	0.62±0.01	16.12±2.00	1.19±0.43
F2	24.22±2.45	0.54±0.02	0.60±0.02	13.12±2.13	1.11±0.78
F3	25.97±2.11	0.50±0.03	0.66±0.01	24.24±1.89	1.32±0.63
F4	27.18±2.45	0.50±0.01	0.59±0.02	15.25±1.98	1.18±0.45
F5	27.75±2.10	0.52±0.02	0.62±0.03	16.12±1.99	1.19±0.56
F6	28.39±1.46	0.50±0.03	0.60±0.01	16.66±1.70	1.20±0.87
F7	27.69±1.45	0.52±0.02	0.62±0.02	16.12±1.85	1.19±0.56
F8	26.56±1.20	0.52±0.02	0.60±0.03	16.12±1.63	1.15±0.56
F9	27.69±1.13	0.51±0.01	0.61±0.02	16.39±1.96	1.19±0.23

Pre-compression parameters play an important role in improving the flow properties of pharmaceuticals especially in tablet formulation. These include Angle of Repose, Bulk density, Tapped density, Carr’s index and Hausner’s ratio. Angle of repose of all the formulation was found to be ranging from 24.22-28.39, Bulk density was found to be 0.50-0.54 g/cc, Tapped density was in between 0.59-0.66g/cc, Carr’s index was found to be within 13.12-24.24, and Hausner ratio was found to be within 1.11-1.32 indicating compressibility of the tablet blend is good as reported in Table no. 2.

Post compression Study:

Table No. 3 Results of thickness, hardness, friability and weight variation of LS tablets

Formulation Code	Thickness (mm)	Hardness (kg/cm2)	Friability (%)	Weight Variation (mg)
F1	3.12±1.20	3.14±2.78	0.54±1.11	148±1.96
F2	2.98±1.56	3.69±2.11	0.66±1.13	151±1.56
F3	3.18±1.78	3.12±2.30	0.52±1.56	153±2.15
F4	2.85±1.56	3.20±1.36	0.53±1.90	149±2013
F5	2.96±1.74	3.47±2.00	0.67±2.10	148±2.00
F6	3.60±1.63	3.51±1.90	0.53±2.00	150±1.63
F7	3.11±2.11	3.12±1.58	0.63±1.23	150±1.97
F8	2.92±2.15	3.69±1.56	0.70±1.56	147±1.45
F9	3.00±1.90	3.00±1.15	0.66±1.98	150±1.52

The thickness of the tablet indicates that die fill was uniform. The thickness depends upon the size of the punch (8mm) and weight of the Tablet (150 mg). The thickness of the batch from F1-F9 was found to be 2.92-3.18 mm and Hardness was found to be 3.00-3.69 kg/cm² as reported in Table 8.5 and thus tablets were having good mechanical strength.

Friability is needed for tablets to with stand force of compression applied during the manufacture of tablets. The friability of all the formulated tablets of LS was found to be between 0.52-0.70 % is reported in Table 8.5 and all the formulated tablets of LS were shown the % friability within the official limits (i.e. not more than 1%).

Prepared tablets were evaluated for weight variation and percentage deviation from the average weight are reported in table 8.5 and was found to be within (±7.5) the prescribed official limits.

Table No. 4 Results of In vitro dispersion time, Wetting time and Water absorption ratio of LS tablets

Formulation code	In vitro dispersion Time(sec)	Wetting time (sec)	Water Absorption Ratio
F1	37±1.56	39±1.13	32.95±1.89
F2	34±2.10	36±1.16	34.29±1.78
F3	29±1.78	32±1.45	32.15±1.23
F4	36±1.36	38±1.87	35.16±1.56
F5	32±1.84	33±1.68	34.92±1.53
F6	28±1.60	30±2.11	32.14±1.69
F7	30±2.17	36±1.63	37.15±2.13
F8	27±2.11	33±1.65	38.11±1.97
F9	25±1.98	27±1.19	39.17±1.56

All the formulated tablets (F1-F9) have shown in vitro dispersion time of less than 60 seconds. Among all the formulation, tablets prepared with Kyron T 314 were shown disintegration time 25 sec. The obtained results were showed in Table No. 4.

The wetting time of the formulation (F1-F9) were found to be within 27-39 seconds. This complies with the official specifications. The results were showed in Table 4. The water absorption ration all the formulated batches were found to be 32-39 %. This was satisfactory in giving effective and better formulation of rapid dissolving tablets. The results were shown in Table 4.

Drug content determination:

The drug content of all nine formulations of Levosalbutamol sulphate tablets were

found to be within the range 94.88-97.92 which were within the limits of BP

specification. The drug content of all the formulation of Levosalbutamol sulphate

tablets is shown in fig. no. 5.

Fig. No. 3 Data for % drug content of LS tablets

In vitro drug release:

From the formulation batches F1-F9 in which Kyron T 314 showed more than 90% drug release. Among these nine formulations F9 showed highest drug release 97.71%. The data for in-vitro drug release of Levosalbutamol shown in fig. 4.

Fig. No. 4 In vitro drug release profile

Stability Study:

The formulation was subjected to short term stability study by storing the formulation at 40°C/75% RH up to three month. The formulation F9 was selected.

After one month the tablets were again analyzed for the hardness, friability, drug content uniformity and dispersion time. (Table-5).

CONCLUSION:

The identification characterstics of drug like solubility, melting point, λmax were performed to find out the purity of drug. All the parameters observed were satisfactory and were within the prescribed official limits. In this system direct compression method was used, microcrystalline cellulose (MCC) is used as a diluent, crosscarmellose sodium, crospovidone xl 10 (CP) and Kyron T 314 were used as superdisintegrants to prepared formula. The results obtained by FTIR studies revealed that there was no chemical interaction between the pure drug and excipients. The pre-compression parameters like bulk density, tapped density, Carr’s ‘index and angle of repose were determined. The final formulation showed acceptable flow properties. The post-compression parameters like the thickness, hardness, friability and in vitro dispersion time, wetting time, water absorption ratio and in vitro drug release were carried out and the values were found to be within IP, BP limits. Based on the results, formulation containing Kyron T -314 (F-9) was identified as ideal and better formulation among all formulations developed for LS tablets. In vitro release of optimized formulation of LS fast dissolving tablets of F-9 was found to be 97.71% drug release within 16 min with in vitro dispersion time being 25 sec. The stability study shows that no significant changes in drug content after one month accelerated stability study.

REFERENCES:

1. Bhandari S, Mittapalli RK.. Orodisprsible tablet: An overview. Asian Journal of Pharmaceutics. 2008: 2-11.

2. Velmuragan S, Vinushitha S. Oral Disintegreating Tablets: An Overview. International Journal of Chemical and Pharmaceutical Science. 1(2);2010:1-6.

3. Jagani H, Patel R. Fast Dissolving Tablets. Journal of Advances in Pharmacy and Health Research. 2011; 2(1): 57-70.

4. Saroha K, Mathur P. Mouth Dissolving Tablets: An Overview on Future Compaction Oral Formulation Technologies. Pelagia Research Library. 1(1);2010: 179-187.

5. Siddiqui A, Garg G. Fast Dissolving Tablets: Preparation, Characterization and Evaluation: An Overview. International Journal of Pharmaceutical Sciences Review and research. 4(2); 2010: 87-96.

6. Shelake S, Patil S, Patil S, Sangave S. Formulation and evaluation of fenofibrate-loaded nanoparticles by precipitation method. Indian J Pharm Sci. 80(3); 2018: 420-427.

7. Bandgar S. A , Shelake S. S., Patil S. S. Solubility enhancement of poorly soluble drug by Various techniques. World Journal of Pharmacy and Pharmaceutical sciences. 6(9); 2017: 1405-1416.

8. Shelake S, Mhetre R, Patil S, Patil S, Khade V. Formulation and evaluation of Microspheres for nasal delivery of antihypertensive drug. Indian J Pharm Sci. 80(3);2018:420-427.

9. Prajapati BJ, Patel B. Formulation, Evaluation and Optimization of Oraly Disintigrating Tablet Piroxicam. International Journal of Pharma Tech Reseach. 2(3); 2010:1893-1899.

10. Bangale GS, Yadhav GJ. New Generation of Orodispersible Tablets: Resent Advances and Future Prospect. International Journal Of Pharmacy And Pharmaceutical Science Research. 1(2);2011:52-62.

11. Agrawal VA, Rajurkar RM. Fast disintegrating Tablet as a New Drug Delivery: A Review. Pharmacophore. 2(1); 2011:1-8.

12. Raut Indrayani D., Bandgar Sandip A., Shah R. R., Chougule D.D. Formulation and Evaluation of Gastric Floating Tablet of Domperidone. Asian J. Res. Pharm. Sci. 4(1); 2014: 22-25.

13. Bandgar S. A. , Yadav A. V., Patil S. S. Formulation and Evaluation of Cefetamet Pivoxil Hydrochloride Dispersible Tablet by Using Taste Masking (Particle Coating) Approach. Journal of Pharmacy Research. 2(11); 2009:1789-1793.

14. Raut Indrayani D, Gharge Manisha, Dandwde Sonli, Mohite S.K., Magdum C.S. Formulation and Characterization of fast Dissolving tablets of Perindopril. Asian Journal of Pharmacy and Technology. 7(1); 2017: 51-55.

15. Shelake S., Khade V., Sangave P, Patil S. Development and Evaluation of Colon Specific Drug Delivery System via pH and Microbial Triggered Mechanism for Colon Cancer. American Journal of Pharmaceutical Research. 7(5); 2017: 218-228.

16. Bhati S, Sethi V. Formulation and evaluation of fast dissolving tablets of metoclopramide hydrochloride using natural sweetening agent of stevia leaf powder. Int. J. Res. Dev. Pharm. L. Sci. 3(1);2013:833-838.

17. Dekivadia M, Gudigennavar A, Patil C, Umarji B. Development and optimization of fast Dissolving tablet of levocetirizine HCL. International Journal of Drug Development and Research.4(2);2012:237-246.

Received on 30.08.2018 Modified on 02.10.2018

Research J. Pharm. and Tech 2019; 12(1): 142-148.

DOI: 10.5958/0974-360X.2019.00027.1

SR. No.	Formulation code	Hardness Kg/cm²	% Friability	Dispersion time (second)	% Drug content
1	F9	3.0	0.66	25	99.09