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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access   Full Text Article                                                                                                                                                Research Article 

Development and In-Vitro Evaluation of Plantago ovata Based Rapid Disintegrating Tablets of Labetalol Hydrochloride                                            

Abhay Kumar Dubey*¹, Archana²

¹ Research Scholar, Department of Pharmaceutics, Saroj Institute of Technology and Management`, Lucknow (U.P.) 226002,       India

² Assistant Professor, Department of Pharmaceutics, Saroj Institute of Technology` and Management, Lucknow (U.P.) 226002,       India`

INTRODUCTION: 

The drug delivery through oral route is the most broadly accepted route of administration but’ tablet and capsule like conventional oral dosage forms bear difficulty in swallowing in case of pediatric and geriatric patients’, requirement of water for ingestion’, adverse drug interaction with GIT` (like gastric degradation, hepatic first pass drug metabolism’), drug’s slow onset of action and inconvenience to patients suffering from’ sudden coughing and recurring emesis and also motion sickness. In order to overcome these drawbacks of oral conventional dosage forms` there is a need of another option like rapid disintegrating tablet delivery system. A solid dosage forms means rapid disintegrating tablets are define as the tablets that in less than 60 seconds disintegrate rapidly in the oral or mouth cavity and then without water swallowed¹. Quick dissolution of tablets occurs due to rapid disintegration of tablets result in fast onset of action. These tablets are valuable to travelers who do not have access to water` because of no risk of obstruction of these kind of dosage form. The pre-gastric absorption of medications via rapid disintegrating tablets bypass hepatic first pass metabolism and gastric degradation’ resulting in minimizing the dose of drug and enhances the drug’s bioavailability. Thus, these rapid disintegrating tablets formulation improves drug molecule safety and efficacy by being a suitable and more convenient dosage form for the patients ^2,3,4,5. 

Labetalol HCL Pharmacologically act as a alpha-1 selective and beta non selective adrenergic antagonist in high blood pressure. This drug has particular indication during pregnancy induced hypertension`, which is associated with pre-eclampsia’ ⁶. It has good aqueous solubility, saliva and inherent ability’ to penetrate through oral mucosal tissues and within time duration of 2 to 4 hours the peak effects due to administration of single oral doses occur. But experience first pass metabolism which causes degradation of drug which is responsible for only 25% poor oral bioavailability having half-life of 4-6 hours^7,8. For overcoming this problem, we prepared rapid disintegrating tablets of labetalol hydrochloride using natural superdisintegrant Plantago ovata that have an own antihypertensive and other pharmacological actions with its disintegration property ^9,10,11.

MATERIALS AND METHODS

Labetalol HCL purchased from Triveni Interchem, Vapi, Gujarat. Plantago ovata purchased from Modern Agro Forestry, Lucknow. Microcrystalline cellulose purchased from International Speciality Product, USA. Maninitol purchased from Qindao Bright Moonsea Wood Group Co. Ltd. Magnesium stearate purchased from Central Drug House (P) Ltd, New Delhi. Talc purchased from Neelkanth Minichem, Jodhpur, Rajasthan. Aspartame purchased from Bharat Heavy Chemical, New Delhi. Mint Flavour purchased from Gogia Chemical Industries Pvt. Ltd, Greater Noida, Uttar Pradesh.

UV-visible spectrophotometer (UV- 2203 Systronics, Germany), Hot air oven (Oven-TC 544), Electronic balance (BSA224S-CW, Sartorius, Germany), Moisture analyser balance (MA35M-1 Sartorius, Germany), Melting point apparatus (Macro scientific works), Tap density tester (ETD 1020 Electrolab, India), Tablet punching machine (CMS-15, Cadmach machinery, Ahmedabad veego, India), Thickness tester (Vernier Caliper, Mitutoyo, India), Friability apparatus (VTP-2D Veego, India), Hardness tester (Harrison’s Machinery, New Delhi),  In- vitro disintegration apparatus (Electrolab), In-vitro dissolution apparatus (TDT-08L USP- Electrolab, India), FTIR (Agilent Cary 630 FTIR spectrophotometer) were used.

Preformulation study:

Preformulation means determination of properties combined of both physical- chemical properties and used to check purity of drug and compatibility of drug and excipients. Preformulation studies is performed using Physical appearance, Melting point, Solubility, UV spectroscopy` and FTIR.

Drug sample and excipients were noted for its organoleptic properties complied fully with pharmacopoeial specifications. Melting point of drug was recorded using melting point apparatus (Macro scientific works) by Capillary process. Solubility studies were performed in Ethanol, Methanol, Water, and 0.1 N HCL and in different basic pH buffers of 6.8, 7.2, 7.4, and 7.8. Ultraviolet- visible spectroscopy analysis performed using UV-visible spectrophotometer (UV-2203 Systronics, Germany) between 200 to 400nm for Identification and authentication of drug. FTIR study performed using the Fourier-transform infrared spectroscopy spectrophotometer (Agilent Cary 630 FTIR spectrophotometer). IR spectrum of drug and excipient recorded using potassium bromide (KBr) disk method. 

Preparation of ‘rapid disintegrating tablets’ by the method of Direct Compression:

A well-known method means direct Compression process is the simple and easiest technique for tablets manufacturing. By direct compression labetalol HCl based rapid disintegrating tablets were prepared with the help of analytical weighing balance, weighed the required amount of drug and other formulation additives. The drug was added in the above mixture of additives. Then passed through sieve for uniform size and then mixed them properly and finally compressed into the tablets^12,13,14. Formula for rapid disintegrating tablets was shown in (Table 1).

Table 1: Different Batches of Oral Disintegrating Labetalol HCl Tablets

Isolation of Plantago ovata mucilage: From Plantago ovata seeds mucilage was isolated by soaked these seeds of Plantago ovata for duration of 48 hours in solvent means distilled water. Then this distilled water containing seeds for a small number of minutes duration boiled and then into a distilled water complete mucilage released.  The released stuff which was collected from water from muslin cloth squeezed for purpose of filtration and separating out the marc. To filtrate for mucilage precipitation an acetone equal volume was added. Then the precipitated, separated mucilage’ was collected and oven dried below 60°C after that in desiccator stored for further use^15,16. 

Evaluation of rapid disintegrating tablets:

Formulation powder means powder blend of drug and suitable formulation excipients or additives. For this formulation powder before step of compression pre-compression evaluation tests or parameters like densities- bulk and tapped density, compressibility index, Hausner’s ratio and angle of repose`. Pre-compressional parameters (Micromeritic properties) were studied to determine the granules flow.

Angle of repose:

Cylinder method was used for angle of repose determination. In this cylinder method poured a powder mixture through a funnel and for obtaining maximum height (h) of cone funnel can be raised vertically. By knowing the heap radius (r) value the angle of repose (q) was determined by:

                        Ɵ = tan-¹(r/ h)

Where, q = angle of repose, 

h = heap height 

 r = of the heap circle radius

Bulk density:

For a parameter bulk density determination through a glass funnel powdered mixture pouring gently into a graduated cylinder (50 ml). Recorded the samples occupied volumes. 

Bulk density = weight of sample (gram) / sample occupied volume

Tapped density: 

By using funnel correctly weighed amount of powder mixture was added carefully to a graduated cylinder. Firstly note down the powder blend initial volume in the graduated cylinder and then powder mixture tapped for 500, 750 or 1250 tapping until powder mixture volume decrease is stop and noted the final volume of powder mixture after tapping means tapped volume. 

Tapped density = sample weight (gram)/ volume after tapping                                                                          

Carr’s index: 

Carr`s Index or ‘Compressibility index’ is the vital measures that is obtained from densities determination means determination of bulk and tapped density. 

I = Tapped density –Bulk Density/ Tapped density

Hausner’s ratio: 

It is defined as a parameter for inter particulate interactions measurement. 

Hausner's Ratio= Tapped Density/ Bulk density

Post-compression parameters:

Weight variation:

From each formulated tablet formulation randomly 20 tablets were selected. After that each tablet individually weighed then average weight from these individual weights and percentage weight variation was calculated.

Hardness: 

Monsanto hardness tester (Harrison’s Machinery, New Delhi). Used for hardness or crushing strength determination by pressure measurement for break the tablet placed diametrically. Between tester two jaws along its diametrical axis tablet was held. At this particular point the reading should be zero’ kg/cm². After that by rotating the knob a constant force was placed until the tablet gets broken down. At this point the value was noted.

Thickness: 

By digital venire calipers (Vernier caliper, Mitutoyo, India) thickness and diameter of each batch selected six tablets were determined. 

Friability:

The Friabilator (VTP-2D Veego, India) used to determine the tablets friability. Initially weighed the ten tablets then these initially weighed tablets in the friabilator transferred. At 25 rpm for the duration of four minutes the friabilator was operated. The tablets were weighed again’ (Wfinal). The formula used to determine percentage friability is as follows: 

Percentage friability = (initial weight–final weight x 100) / initial weight’ 

Wetting time and water absorption ratio:

Tissue paper piece folded two times in a small petri-dish containing 6 ml of water was placed. On the tissue paper surface a tablet was placed carefully. Then noted the time of wetting means time taken by water to attain tablet upper surface.

To calculated Water absorption ratio:

R = 100 x [weight of tablet after absorption – weight of tablet before absorption] / tablet weight before absorption

Percent drug content: 

Selected 10 tablets then powdered them. In 10ml phosphate buffer one tablet equivalent powder was weighed and dissolve after that up to 100ml volume make up. Filter above solution. From the filtrate taken 1ml filtrate in volumetric flask of 50ml and with 6.8 phosphate buffer to the mark diluted and analyzed at 303 nm spectrophotometrically.

In-vitro Disintegration time:

In disintegration test apparatus (Electrolab) in each of the six tubes a tablet is placed then placed the disks. 37±2°C temperature maintained by water and noted the whole tablet complete disintegration time. 

In-vitro drug dissolution studies: 

In in-vitro dissolution apparatus (TDT-08L Electrolab, India) at 50 rpm in dissolution media phosphate buffer pH-6.8 (900ml) the release profile of drug was studied. 37±0.5°C temperature was maintained. At every five minutes duration dissolution media of 5 ml were withdrawn and then filtered. At 303nm by the UV-Visible spectrophotometer drug released amount was determined and from standard calibration curve drug concentration was found. ^17,18,19.

RESULTS AND DISCUSSION

Preformulation study parameters results indicated that the drug candidate was of acceptable values.

Melting point of drug was detected at180-182˚C. It is found within standard melting point range.

The solubility of labetalol hcl was determined in Ethanol, Methanol like organic solvents, in water,   

0.1N HCl and in different basic pH buffers of 6.8, 7.2, 7.4, 7.8. It was found to be soluble in Ethanol, Methanol, Water, 0.1 N HCL and in different basic pH buffers of 6.8, 7.2, 7.4, and 7.8.

Ultraviolet-visible estimation of labetalol HCl was done by Ultraviolet-visible spectrophotometric method. In phosphate buffer 6.8 pH calibration curve was prepared at various concentrations (Table 2) and regressed for straight line. Good linearity indicated by 0.998 R2 value in phosphate buffer 6.8 pH (fig.1). Optical characteristics for calibration curve’ of labetalol HCl in phosphate buffer pH’ 6.8 are shown in (Table 3). Beer Lambert’s law was obey by calibration curve. The solvent medium was selected on the basis of solubility and it was found that labetalol HCl is soluble in phosphate buffer 6.8 pH. Prepared standard stock solution and scanned by UV spectrophotometer according to procedure mentioned in methodology section. Against phosphate buffer 6.8 pH as blank 303 nm λmax of a drug labetalol HCl was found, which complied with the prescribed value of λmax for labetalol HCl indicated to be reliable.

Labetalol HCl (fig. 2), a natural superdisintegrant Plantago ovata (fig. 3) and physical mixture of drug and polymer FTIR spectrum are taken (fig. 4). Between drug and excipients no significant interaction means compatibility was found.

Rapid disintegrating tablets of labetalol HCl were prepared successfully as per procedure given. Six batches were prepared successfully. 

Pre-compression evaluation tests or parameters like densities- bulk and tapped density, compressibility index, Hausner’s ratio and angle of repose. Pre-compressional parameters were studied to determine the granules flow. The optimized formulation (F6) angle of repose was found to be 24.28^o. All formulations angle of repose were found to be 24.28 ^o to 30.02 ^o indicating acceptable flow property. The optimized formulation (F6) bulk density was found to be 0.509 gm/cm³. Bulk densities of all prepared formulations were found in the range’ of 0.503 to 0.516 gm/cm³indicating acceptable flow property. The optimized formulation (F6) tapped density was found 0.610 gm/cm³. All formulations tapped density were found to be 0.610 to0.636 gm/cm³ indicating acceptable flow property. The optimized formulation (F6) Carr’s index was found 11.20%. All formulations carr’s index were found to be 11.20% to17.38%. The acceptable compressibility and flow property shows by all formulations. The optimized formulation (F6) Hausner’s ratio was found to be 1.125±0.002. All formulations Hausner’s ratio were found to be 1.125±0.002 to 1.220±0.002.

Post-compression parameters of the final formulated preparation were studied   successfully.

The optimized formulation (F6) weight variation was found to be 200.24mg. The weight variation was found in the range of 199 to 201 mg for all formulations. The optimized formulation (F6) hardness was found to be 3.91 kg/cm². The hardness was found in the range of 3.91 kg/cm2 to 4.67kg/cm² for all formulations. A good mechanical strength indicated by hardness test for all the formulations. The optimized formulation (F6) thickness was found to be 3.94mm. The thickness was found in the range of 3.81 mm to 3.94 mm for all formulations. The optimized formulation (F6) friability was found to be 0.70%. The friability was found in the range of 0.24 to 0.70% for all formulations. The optimized formulation (F6) wetting time’ and water absorption ratio’ were found to be 26.23 seconds and 90.01%. The wetting time and water absorption ratio was found between 26.23 to 40.96 seconds and 84.16 to 91.06% for all formulations. The optimized formulation (F6) % drug content was found to be 99.52%. The percentage drug content was found in the range of 98.42 to 99.52% for all formulations (Table 14). Formulations prepared by direct compression method showed disintegration time in range of 20sec to 40sec. The optimized formulation (F6) disintegration time was found 20 seconds. The optimized formulation (F6) in-vitro drug release were found to be 99.80% within 25 minutes (fig. 5). In-vitro drug study carried in phosphate buffer 6.8 pH for 25 min using in-vitro dissolution apparatus (TDT-08L Electrolab, India). In-vitro dissolution data of formulation showed that, formulation F1, F2 and F3 released 78.881%, 80.598% and 88.983% drug respectively within20-25 min and formulation F4, F5 and F6 released 93.234%, 98.283% and 99.80% respectively within 20-25 min (Table 16).

The present investigation successfully formulated the labetalol hydrochloride based rapid disintegrating tablets formulation concept offers drug quick release. In systemic circulation these tablets direct absorption takes place which avoids the labetalol hydrochloride drug first pass metabolism which ultimately results in the improvement in the bioavailability. In present work by direct compression process labetalol  hydrochloride based rapid disintegrating tablets were successfully formulated using Plantago ovata a natural superdisintegrant and other excipients such as microcrystalline cellulose belongs to a category of binder, mannitol belongs to a category of diluent, magnesium stearate belongs to a category of lubricant, talc belongs to a category of antiadherent and glidant, aspartame belongs to a category of sweetening agent and mint belongs to a category of flavouring agent. All the pre-compressional parameters like angle of repose’, densities means bulk and tapped densities, Hausner’s ratio and Carr’s index’ were studied. The compressed tablets were subjected to weight uniformity or weight variation test, hardness, thickness, percentage friability test, time of wetting, ratio of absorption of water, content uniformity or determination of drug content, in-vitro time for disintegration’ and in-vitro dissolution studies. 

FTIR determined the compatibility between drug and excipients means between drug and excipient there was no physico-chemical interaction. By direct compression method labetalol hydrochloride drug based rapid disintegrating tablets using different concentrations of Plantago ovata natural superdisintegrant were successfully prepared and without chipping, capping and sticking these tablets found to be superior. Within the formulated tablet drug uniform distribution indicating by uniform drug content in all formulated tablets.

Out of all formulated six tablets the tablet formulation number six means F6 gives maximum release of drug 99.80% which contains 18mg Plantago ovata. The optimized formulation F6 was found to be good with all parameters. From the results of disintegration time, dissolution profile concluded that the formulation F6 was found best amongst all formulated formulations. Formulation F6 containing 18mg Plantago ovata can be effectively used in rapid disintegrating tablets clinical formulation, especially in cases of hypertension. By studying above results Plantago ovata was most suitable superdisintegrant for formulation of rapid disintegrating tablets of Labetalol hydrochloride.

Table 2: In Phosphate Buffer 6.8 Ph Absorbance of Labetalol HCl at Various Concentrations

Table 3: Statistical Parameters of Labetalol HCl in Phosphate Buffer 6.8 pH 

Table 4: In-Vitro Time for Disintegration of F1-F6.

Table 5:  % Drug Content of F1-F6 Formulations

Table 6: Comparative Percent Cumulative Drug Release of F1-F6 Formulations of Labetalol HCl in Phosphate Buffer 6.8 pH

Figure 1: Standard calibration curve for Labetalol in phosphate buffer 6.8 pH

Figure 2: Labetalol HCl FT-IR Spectrum peaks

Figure 3: Plantago ovata FT-IR Spectrum peaks

Figure 4: Formulation F6 FT-IR Spectrum peaks

Figure 5: All formulation F1-F6 in-vitro dissolution profile in the phosphate buffer’ pH 6.8

In-vitro drug dissolution’ data of formulations reflected that, formulation F1, F2 and F3 released 78.881%, 80.598% and 88.983% drug respectively within 20-25 min and formulation F4, F5 and F6 released’ 93.234%, 98.283% and 99.80% respectively within 20-25 min.

CONCLUSION: 

The formulation F6 was found to be best ODT which offers minimum disintegration time (20 Seconds) and maximum % drug release (99.80%). These prepared tablets containing Labetalol HCl, can be useful in the treatment of high blood pressure with enhanced bioavailability. 

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