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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

Copyright  © 2021 The  Author(s): This is an open-access article distributed under the terms of the CC BY-NC 4.0 which permits unrestricted use, distribution, and reproduction in any medium for non-commercial use provided the original author and source are credited

Open Access  Full Text Article                                                                                                                                       Research Article 

Formulations of sustained release matrix tablets of Furosemide using natural and synthetic polymers

Shivani Soni, Vivek Jain, Sunil Kumar Jain, Pushpendra Kumar Khangar*

Adina Institute of Pharmaceutical Science, NH86A, Lahdara, Sagar, MP 470001

INTRODUCTION 

Oral administration of drugs is generally preferred, especially over parenteral administration. Oral products are produced in a extra cost-effective way in contrast with parenteral products and report for about 60% of all prescription products universal¹. Sustained-release oral drug products are intended to gradually release the active ingredient above an extensive time following administration and present noteworthy benefits above conventional orally administered products, counting decrease side effects, enhance safety and patient compliance by reducing the incidence of dosing and reduced drug plasma-concentration variations^{2, 3}. Matrix formulations of hydrophilic and/or hydrophobic polymers have been employed to manage the release of drugs^{4, 5} and can be created using conventional processing equipment. Formulation based on a hydrophilic matrix was selected, as it is recognized to provide robust formulae that can be manufactured by standard tabletting technology. In accumulation, it is probable to manufacture such formulations without using organic solvents; environmental dangers connected with such solvents cause immense concern and they often yield trace remains in finished products. Sustain release dosage forms are easily manufactured using matrix system of different control release excipients including hydrophilic polymers such as HPMC, insoluble gum and waxes are used (for extending the release of drugs) as matrix-forming components in solid dosage forms. HPMC has been employed extensively as hydrophilic matrix former in oral controlled-release dosage forms for different drugs. Its reputation can be accredited to the polymer’s non-toxic nature, small persuade of processing variables on drug release, alleviate of compression, and its capability to accommodate elevated levels of drug loading, its aptitude to swell upon jellification once in contact with water^6-8. Waxes have an advantage over other materials because it is chemically inert against other materials. The waxy and hydrophobic substances are simply erodible and well control the release pattern of the drug through the mechanism of erosion and pore diffusion. A lot of researchers employed carnauba wax as deterrent material in dissimilar sustained released formulations^{9, 10}. Xanthan gum is an elevated molecular weight extracellular polysaccharide, created on commercial scale by the viscous fermentation of gram negative bacterium Xanthomonas campesteris. The molecule consists of a backbone equal to that of cellulose, with side chains connected to interchange glucose residues. It is a hydrophilic polymer, which until lately had been limited for employ in thickening, suspending and emulsifying water based systems¹¹. The hydrophilic polymers expand a viscous gelatinous surface barrier after hydration; this gelatinous barrier manages the drug release from matrix systems¹². Furosemide (4-chloro-2-furfurylamino- 5-sulphamoyl benzoic acid) is a drug with a diuretic action which proceeds at the renal level on the ascending limb of the loop of Henle. The half life of furosemide is upto 100 minutes, dose ranges 20-40 mg and bio­availability is 43-69%. Furosemide is used in management of hypertension and also as diuretics. Sustained-release tablets of furo­semide give steady plasma concentra­tion with fewer recurrent administrations and also reduce the side effects to a few extents. This could expand its secure administration and improve patient com­pliance¹³. Therefore, the aim of present study was to assess the strength of xanthan gum, beeswax and HPMC K4M on sustaining the release of furosemide from the matrix system. Furthermore, the influence of dissimilar polymers nature and concentration was evaluated on the release pattern of furosemide.

MATERIALS AND METHODS 

Materials

Furosemide was obtained as a gift sample from Wokhardth Pharma Pvt. Ltd Aurangabad. Suitable grade of HPMC K4M was obtained from Colorcon Asia Pvt Ltd Goa. Xanthan gum was obtained from Bangalore Fine Chem, Bangalore.  Lactose DC kindly provided from Merck (Germany). Bees wax was procured from Sigma-Aldrich (USA). Talc, MCC, PVP K-30 and magnesium stearate was purchased from Loba chem Pvt. Ltd., Mumbai (India).  All other solvents and reagents were purchased from Merck (Germany) and were of analytical grade.

Methods

Preformulation studies

Physical characteristics: By visual examination, the drug was recognized for physical characters like colour, texture, odour etc.

Solubility

Solubility of the drug was indomitable by taking some quantity of drug (about 1-2 mg) in the test tube separately and added the 5 ml of the solvent (water, ethanol, methanol, 0.1N HCL, 0.1N NaOH, chloroform and 7.4 pH buffer) Shake vigorously and kept for some time. Note the solubility of the drug in various solvents (at RT).

Melting point determination

Melting point of drug was indomitable by Open capillary method. 

Determination of λ _max of furosemide

Accurately weighed 10 mg of drug was dissolved in 10 ml of phosphate buffer pH 5.8 solutions in 10 ml of volumetric flask. The resulted solution 1000µg/ml and from this solution 1 ml pipette out and transfer into 10 ml volumetric flask and volume make up with phosphate buffer pH 5.8 solution. Prepare suitable dilution to make it to a concentration range of 2-10μg/ml. The spectrum of this solution was run in 400-800 nm range in U.V. spectrophotometer (ShimadzuUV-1600, Japan). A graph of concentration Vs absorbance was plotted.

FTIR spectroscopy 

Identification of furosemide was done by FTIR spectroscopy with respect to marker compound. Furosemide was obtained as white to brownish powder. It was identified from the result of IR spectrum as per specification. FTIR spectra recorded on KBr disk method using Brukers Alpha Spectrophotometer with IR solution software. Sample powder was thoroughly mixed by triturating with KBr in a glass mortar with pestle and compressed into disks in a hydraulic press. FTIR spectra of all the samples were recorded over a spectral region from 4700 to 400 cm-1 using 20 scans with 4 cm-1 resolution.

Method for preparation of sustained release furosemide matrix tablets 

Sustained release tablets of furosemide were prepared using natural gummy and waxy materials (Xanthan gum, bees wax) and synthetic polymers (HPMC K4M). This controlled release natural and synthetic materials were employed in different ratios with the drug i.e. 1:1, 1:2 and 1:3, while the amount of the furosemide was kept constant as 20mg. Lactose DC, talc and magnesium stearate were employed as filler, lubricant and anti-adherent respectively. The composition of different formulations of sustained release matrix tablets is presented in Table 1. All the ingredients were reduced and uniform their particle size by passing through # 100 sieves size then accurately weighed individually and mixed in a mortar with pestle using geometrical dilution method and then directly compressed into tablets using a single punch rotary tablet machine using 10 mm flat punches. 

Table 1: Composition of SR matrix tablet of furosemide

Evaluation of furosemide SR matrix tablets

Pre-compression parameters

Angle of repose

The angle of repose of blends was established by the funnel method. The exactly weighed 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 heap of the blend. The blend was allowed to flow from the funnel on the surface. The diameter and height of the heap formed from the blend were measured. The angle of repose was calculated using the following formula¹⁴.

Tan Ѳ= h/r

Where, “h” is the height of the heap and “r” is the radius of the heap of granules.

Bulk density (BD)

An exactly weighed powder blend from every formula was lightly shaken to break any agglomerates formed and it was introduced in to a measuring cylinder. The volume occupied by the powder was measured which gave bulk volume. The furosemide of powder blends was determined using the following formula¹⁵.

Bulk density = Total weight of powder/Total volume of powder

Tapped bulk density (TBD)

An exactly weighed powder blend from every formula was lightly shaken to break any agglomerates formed and it was introduced into a measuring cylinder. The measuring cylinder was tapped until no further change in volume was noted which gave the tapped volume. The TBD of powder blends was determined using the following formula¹⁶.

TBD = Total weight of powder/Total volume of tapped powder

Carr’s compressibility index

The Carr’s compressibility index was calculated from bulk density (BD) and tapped density of the blend. A quantity of 2gm of blend from each formulation, filled into a 10 ml of measuring cylinder. Initial bulk volume was measured, and cylinder was allowed to tap from the height of 2.5 cm. The tapped frequency was 25 ± 2/min to measure the tapped volume of the blend. The BD and tapped density were calculated by using the bulk volume and tapped volume. Carr’s compressibility index was calculated using the following formula^{17, 18}.

Carr’s compressibility index (%) = [(Tapped density-Bulk density) ×100]/Tapped density

Hausner’s Ratio

It is the measurement of frictional resistance of the drug. The ideal range should be 1.2-1.5, it was determined by the ratio of tapped density and bulk density.

HR = Tapped Density/ Bulk Density

Post-compression parameters

Shape of tablet

Directly compressed tablets were inspected under the magnified lens for the shape.

Thickness

20 tablets from the envoy sample were arbitrarily taken and individual tablet thickness was measured by using digital vernier caliper¹⁹.

Hardness

Tablet hardness was calculated by using Monsanto hardness tester. From each batch 6 tablets were calculated for the hardness and average of six values was noted along with standard deviations.

Friability test

From every batch, 10 tablets were exactly weighed and placed in the friability test apparatus (Roche friabilator). Apparatus was operated at 25 rpm for 4 minutes and tablets were observed while rotating. The tablets were then taken after 100 rotations, de dusted and reweighed. The friability was calculated as the percentage weight loss. % friability was calculated as follows

% Friability = (W1 – W2) x 100/W1

Where W1 = Initial weight of the 10 tablets, W2 = Final weight of the 10 tablets after testing.

Friability values below 0.5-1% are generally acceptable⁸.

Weight variation test

To study weight variation individual weights (WI) of 20 tablets from every formulation were noted using electronic balance. Their average weight (WA) was calculated. % weight variation was calculated. Average weights of the tablets along with standard deviation values were calculated.

Drug content 

The test is obligatory for tablets with 10 mg or less weight of active ingredient. 10 randomly selected tablets from every formulation (F1 to F9) were finely powdered and drug equivalent  to  10  mg of drug dissolved in 10 ml  phosphate buffer pH 5.8 sonicate it for 20 minutes,   till  the  entire   drug leached  out  from   complex,  then  the   solution was  filtered  through   whatman  filter  paper No. 41. From this solution take 1 ml and diluted up to 100 ml with phosphate buffer pH 5.8 and the drug content was determined spectrophotometrically at 272 nm.

Dissolution rate studies

In vitro drug release of the sample was done using USP-type II dissolution apparatus (Paddle type). The dissolution medium, 900 ml Phosphate buffer pH 5.8 was set into the dissolution flask maintaining the temperature of 37±0.5⁰c and rpm of 50. One furosemide tablet was set in every container of dissolution apparatus. The mechanical assembly was permitted to keep running for 12hours. Sample measuring 5ml were pulled back after time intervals up to 12 hours using 5ml pipette. The new disintegration medium (37⁰C) was supplanted each time with a similar amount of the sample and takes the absorbance at 272nm using spectroscopy.

RESULTS AND DISCUSSION

Solubility of furosemide was slightly soluble in water, chloroform, ether; soluble in acetone, methanol, dilute NaOH, DMF; less soluble in ethanol. The melting point of furosemide was 204-206ºC. λ _max of furosemide was establish to be 272 nm by using U.V. spectrophotometer (UV-1600 Shimadzu, Japan) in linearity range 2-10µg/ml. Identification of furosemide was done by FTIR spectroscopy with respect to marker compound. It was identified from the consequence of IR spectrum as per specification Fig.1. Tablet powder blend was subjected to different pre-compression parameters Table 2. The angle of repose values shows that the powder blend has good flow properties. The bulk density of all the formulations was established to be in the range of 0.47 ± 0.11to 0.54 ± 0.09 (gm/ml) showing that the powder has good flow properties. The tapped density of all the formulations was establish to be in the range of 0.56 ± 0.05 to 0.65 ± 0.06 demonstrating the powder has good flow properties. The compressibility index of all the formulations was establish to be ranging between 16.4 ± 0.13 to 21.5 ± 0.03 which demonstrate that the powder has good flow properties. All the formulations have shown the Hauser’s ratio ranging between 1.15 ± 0.13to 1.26 ± 0.13indicating the powder has good flow properties. The consequences of post-compression parameters such as the uniformity of weight, hardness, thickness, friability and disintegration time of the tablets are given in Table 3. All the tablets of dissimilar batches complied with the official requirements of uniformity of weight. The hardness of the tablets ranged from 9.1±0.11 to 9.5±010 kg/cm² and the friability values were less than 0.5% indicating that the matrix tablets were compact and hard. The thickness of the tablets ranged from 4.21 ± 0.35 to 6.64 ± 0.03mm. All the formulations satisfied the content of the drug as they contained 95.9 ± 103.1 ± 2.8 % of furosemide and good uniformity in drug content was observed. Thus all the physical attributes of the prepared tablets were found be practically within control. The tablets were evaluated for in vitro dissolution studies in phosphate buffer pH 5.8 for 12 hrs. The results of the optimized formulation F-9 showed maximum drug release i.e. 89.47 ± 0.24% at the end of 12 hrs. The results of release studies of formulations F9 was shown in Table 4.

CONCLUSION 

Dissolution studies consequences indicated that the furosemide release from formulated tablets was not usually comparable and steady for all formulations containing dissimilar control releasing materials. In general reduce in furosemide release rate with respect to decrease in ratio of HPMC in formulations. The initial burst of matrix tablets had been seized using high viscosity grades polymers. Furthermore, xanthan gum and HPMC polymers demonstrated constant and controlled release rate and no modification were observed up to 12 hrs. Direct compression uses the smallest amount of machinery and man power.

Figure 1 FT-IR spectrum of pure drug furosemide

Table 2: Result of pre-compression properties of furosemide matrix tablets

Table 3: Results of post compression properties of IB matrix tablets

Table 4: In-vitro drug release data for optimized formulation F-9

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