Formulation and evaluation of Liquisolid compact of Nitrofurantoin

 Corresponding author: Anam Rafik Momin Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Formulation and evaluation of Liquisolid compact of Nitrofurantoin Anam Rafik Momin *, Shraddha Mitthu Chavan, Sachin Vitthal Datkhile and Rahul Prakash Lokhande. Department of Pharmaceutics Belhe, Pune, Maharashtra, India. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(03), 266-276 Publication history: Received on 17 April 2025; revised on 29 May 2025; accepted on 01 June 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.22.3.0542 Abstract This study focuses on improving the solubility and dissolution rate of Nitrofurantoin, a water-insoluble antimicrobial agent, using the liquisolid compact technique. Liquisolid technology offers a promising approach to enhance the bioavailability of poorly soluble, lipophilic drugs by converting them into dry, free-flowing, and compressible powder blends. In this research, Nitrofurantoin was dissolved in various non-volatile solvents such as Tween 20 and PEG 400 to create liquid drug formulations. These formulations were then adsorbed onto carrier materials like microcrystalline cellulose and coated with Talc to produce liquisolid powders. The resulting tablets were evaluated for both precompression (flow properties) and post-compression characteristics, including hardness, friability, disintegration time, and in vitro drug release. Results demonstrated a significant improvement in the dissolution rate of Nitrofurantoin from the liquisolid tablets compared to those prepared by direct compression. This enhancement is likely due to the increased surface area, improved wetting, and better solubilization of the drug in the chosen non-volatile solvents. Overall, the study confirms that the liquisolid compact technique is an effective and practical strategy to enhance the dissolution profile of Nitrofurantoin, which may lead to improved therapeutic outcomes. Keywords: Liquisolid compact; Dissolution rate; Solubility enhancement; Poorly water soluble drugs; Bioavailability 1. Introduction Liquisolid systems are innovative drug delivery formulations where liquid medications are converted into dry, freeflowing, and compressible powders. This approach involves blending liquid lipophilic drugs, drug suspensions, or solutions of poorly water-soluble solid drugs with suitable non-volatile solvents. These are then combined with carrier and coating materials to produce a dry, non-sticky powder blend that can be easily compressed into tablets. Carrier materials, such as various grades of microcrystalline or amorphous cellulose, serve as the base that absorbs the liquid medication. Coating materials, typically fine silica powders, help improve the flow and compression properties of the final formulation. However, there is a limit to how much liquid can be incorporated beyond a certain point, the blend may lose its desirable flow and compaction characteristics. 1.1. Mechanism of the Liquisolid Technique The liquisolid technique operates through a combination of absorption and adsorption. When the liquid drug formulation is added to a porous carrier like cellulose, it first gets absorbed into the material’s internal structure. The liquid is drawn into the carrier’s network of tiny pores and matted fibers. Once the absorption capacity is reached, the excess liquid then adheres to the surface of the particles a process known as adsorption. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(03), 266-276 267 The addition of a coating material, such as colloidal silica, is crucial at this stage. Thanks to its high surface area and excellent adsorptive properties, it wraps around the particles, helping to maintain the flowability and compressibility of the final blend. This dual mechanism ensures that the liquisolid system remains practical for tablet formulation while enhancing drug solubility and bioavailability. Figure 1 Mechanism of Liquisolid technique 2. Material and Method 2.1. Selection of excipients Tween 20 was used as liquid vehicle to prepare the liquid medication of the different concentrations. Microcrystalline cellulose was chosen as carrier material because of high surface area of Microcrystalline cellulose (1.18 m2/g) in comparison with other carriers. Talc was used as coating material. This has high adsorptive properties and large specific area, imparts good flow properties to the liquisolid systems Sodium starch glycolate was used as super disintegrate. Magnesium oxide used as flow activator and Magnesium stearate is used as a lubricant. 2.2. Pre-formulation studies of drug The following parameters were analyzed to determine the flow properties of the granules: Figure 2 Nitrofurantoin Powder • Bulk Density: It is the mass of the granules divided by the bulk volume. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(03), 266-276 268 • Tapped Density: It is measured after the powder in the graduated cylinder has been mechanically tapped until no further change in volume occurs. • Angle of Repose: Calculated by the formula: θ = tan⁻¹(h/r) where h is the height of the cone and r is the radius of the base. Figure 3 Angle of Repose Carr’s Index: Computed by the formula: Carr’s Index (%) = [(Tapped Density - Bulk Density) / Tapped Density] × 100 • Hausner’s Ratio: Calculated by the formula: Hausner’s Ratio = Tapped Density / Bulk Density Hausner's ratio lower than 1.25 indicates good flow properties. 2.3. Calibration Curve for Nitrofurantoin Using UV Spectroscopy 2.3.1. Preparation of Nitrofurantoin Standard Solution in 0.1N HCl. Accurately weighed 50 mg of Nitrofurantoin was dissolved in 50 ml of methanol. 10 ml aliquot was withdrawn from the above solution. It was added into a 100-ml volumetric flask, and volume was adjusted with 0.1N HCl up to the mark to get a final stock solution of 100 μg/ml. 2.3.2. Scanning of Nitrofurantoin in 0.1N HCl. The standard solution of the drug was scanned from 200 nm to 400 nm using a Shimadzu UV-1800 spectrophotometer. The wavelength of maximum absorption (λmax) was noted. 2.3.3. Procedure Aliquots of 0.2, 0.4, 0.6, 0.8, and 1 ml were taken from the stock standard solution and transferred to 10 ml volumetric flasks; the volume was then made up to 10 ml with 0.1 N HCl; thus, concentrations ranging from 2, 4, 6, 8, to 10 μg/ml were obtained. These solutions were measured for absorbance values at the λmax of 240 nm in the double beam UVspectrophotometer with blank of 0.1N HCl. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(03), 266-276 269 2.4. Formulation 2.4.1. Preparation of liquisolid powder systems Several liquisolid compacts were prepared as follows. The desired quantities of the previously weighed of the solid drug and the liquid vehicle (Tween 20) were mixed. The solution was then sonicated for 15 min until a homogeneous drug solution was obtained. Subsequently, the calculated weight (W) of the liquid medications (equal to 10 mg drug) were combined with the calculated amounts of the carrier material (Microcrystalline cellulose) (Q) and mixed thoroughly. The resulting wet mass was mixed with the calculated quantity of the coating material (Talc) (q), using a conventional mixing method to give simple admixture. Multiple factors were varied such as the concentrations of the drug in liquid vehicle PEG i.e. 10 %, 15 %, 20 % w/w and carrier: coat ratios (different R values) of which there were a range from 10 to 30 was utilized. Different liquid load factors (Lf) also from 0.230 to 0.292 were utilized. Then 10% magnesium oxide and 5% magnesium stearate were added. Lastly, 5 % w/w of sodium starch glycolate as a disintegrant was added to the above mixture. 2.4.2. Tablet preparation The final mixture was compressed on a multi mill rotary tablet machine using a flat faced punch and die, size of 12 mm. 2.4.3. Preparation of plain tablet of pure drug Plain tablets of pure Nitrofurantoin containing 10 mg of the dose were made on a tablet machine. Table 1 Composition of different Nitrofurantoin liquisolid compacts mathematical model Drug Concentratio n in Tween 20 Formulation No. R Value Liquid Load Factor (Lf) MCC (Q) (mg) Talc (q) (mg) SSG (mg) MgO (mg) Mg Stearate (mg) Tween 20 (mg) Total Wt. (mg) 10% F1 10 0.292 315.31 31.53 21.94 34.55 4.60 82.86 500 F2 20 0.246 338.65 16.93 21.94 34.56 4.61 74.98 500 F3 30 0.230 347.41 11.58 21.94 34.56 4.60 71.91 500 15% F4 10 0.292 314.83 31.47 22.59 34.56 4.61 78.14 500 F5 20 0.246 338.66 16.92 23.31 34.61 4.61 70.81 500 F6 30 0.230 346.97 11.56 22.51 34.56 4.60 67.83 500 20% F7 10 0.292 303.50 30.34 22.00 34.63 4.61 88.62 500 F8 20 0.246 326.28 16.31 21.94 34.56 4.61 80.26 500 F9 30 0.230 335.22 11.16 21.94 34.56 4.60 77.10 500 2.5. Post-Compression Evaluation The compressed tablets were tested for: • Weight Variation: The procedure started with twenty tablets randomly selected from the design batch. The individual weights of the twenty tablets were determined using a digital balance, and the average weight was calculated. The individual weights were compared to the average weight based on individual tablet deviation of not greater than ±5% standard deviation. • Thickness: The thickness of ten tablets was measured using a Vernier caliper to evaluate if the thickness was uniform. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(03), 266-276 270 Figure 4 Thickness • Hardness: The hardness of ten tablets was measured using a Monsanto hardness tester to evaluate mechanical strength or hardness. • Friability: Ten tablets were placed in a Roche friabilator at 100 rpm for 15 minutes in order to exercise abrasion. Tablet weight loss was recorded after dusting and should not be more than 1% as reported in pharmacopoeia. Figure 5 Friability Uniformity of Drug Content: Ten tablets were crushed and dissolved in water. After filtration, a portion of the sample was taken and the concentration was determined with a UV spectrophotometer at 233 nm, after dilution. 2.6. In vitro drug release The USP paddle apparatus was utilized for all in vitro dissolution studies. 900ml 0.1N HCl was utilized as a dissolution media using 50 rpm and 37 ± 0.5oC. Aliquots were withdrawn at appropriate times (5, 10, 15, 20, 25, 30, 45, and 60 minutes), filtered through what man filter paper, and diluted to 10 ml with 0.1N HCl. Sink conditions were maintained throughout the study. The samples were analyzed by UV/visible spectrophotometer at λ max of 240nm. 2.7. Stability studies The stability studies for tablets were performed by storing sample tablets from optimized batches for 1 month. The tablets were filled and packaged in aluminum, inside polyethylene coated aluminum and were stored in a stability control oven (Bio techno lab), 40˚C, 75% relative humidity, for 1 month. At the end of 1 month the samples were analyzed for various parameters including: physical appearance, % drug content. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(03), 266-276 271 3. Results and Discussion 3.1. Pre-formulation studies of drug 3.1.1. Characterizations of drug Table 2 Result of Organoleptic property Drug Appearance Observation Nitrofurantoin yellow amorphous powder yellow amorphous powder 3.1.2. Determination of Melting Point: Table 3 Result of Melting point Drug Melting Point Observation Nitrofurantoin 268-272oC 270oC 3.1.3. Angle of Repose Table 4 Result of angle of Repose Material Specification Observation Result Nitrofurantoin N.A. 27.82° Good Flow Property 3.1.4. Determination of Density Table 5 Result of Bulk density and Tapped density Material Bulk Density Tapped Density Result Nitrofurantoin 0.402 0.518 Fault Fracture Density (FFD) 3.1.5. Powder compressibility Table 6 Result of powder compressibility Material Compressibility Index Hausner’s Ratio Nitrofurantoin 18.52 1.22 3.1.6. pH of the solution Table 7 pH of Nitrofurantoin powder Test Specification Observation Result Nitrofurantoin N/A 6.3 Within range World Journal of Biology Pharmacy and Health Sciences, 2025, 22(03), 266-276 272 3.1.7. Solubility studies Table 8 Solubility of Nitrofurantoin in various solvents Sr. No. Solvent Solubility (%w/w) 1 Tween 20 13.42 2 PEG 400 10.62 3 Propylene glycol 8.74 4 Glycerin 4.75 5 Distilled water 0.0000041 6 Phosphate Buffer pH 6.8 0.0019 3.1.8. UV spectroscopy (determination of  max) The standard solution of Nitrofurantoin (10 g/ml) shows maximum absorbance at 240nm wavelength in 0.1N HCl. Figure 6 Calibration graph Table 9 Absorption data of Nitrofurantoin in 0.1N HCl Sr. No. Concentration (g/ml) Absorbance 1 2 0.142 2 4 0.260 3 6 0.378 4 8 0.489 5 10 0.610 3.2. Pre-formulation studies of formulation Formulae F1, F2, F3, F4, F5, F6, F7, F8 and F9 were proven to be acceptably flowing according to angle of repose, Carr’s index and Hausner’s ratio. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(03), 266-276 273 Table 10 Flowability parameters of nitrofurantoin liquisolid powder system Formulation Tap density Bulk density Angle of repose Cars index Hausner’s ratio F1 0.507± 0.011 0.424±0.013 27.92±1.26 16.38±2.41 1.20±0.02 F2 0.49±0.014 0.417±0.017 28.81±1.31 14.89±1.74 1.17±0.03 F3 0.513±0.010 0.445±0.012 29.90±0.95 13.25±1.23 1.15±0.02 F4 0.468±0.008 0.395±0.009 30.47±1.28 15.60±1.65 1.18±0.02 F5 0.481±0.006 0.419±0.008 30.05±1.10 12.91±0.98 1.15±0.01 F6 0.446±0.010 0.385±0.007 31.34±1.52 13.68±1.33 1.16±0.02 F7 0.527±0.013 0.439±0.012 32.71±1.68 16.71±1.79 1.20±0.03 F8 0.538±0.011 0.455±0.015 33.10±1.22 15.41±1.22 1.18±0.02 F9 0.511±0.009 0.421±0.011 26.88±1.06 17.61±1.28 1.21±0.01 3.3. Evaluation of liquisolid compacts Table 11 Evaluation of liquisolid compacts Formulation No. Thickness (mm) Diameter (mm)0 Hardness (kg/cm2 ) Weight Variation (g) Control 5.5 ± 0.0 9.5 ± 0.0 5.92 ± 0.58 0.505 ± 0.0051 F1 5.5 ± 0.0 9.5 ± 0.0 5.10 ± 0.60 0.552 ± 0.0020 F2 5.5 ± 0.0 9.5 ± 0.0 4.90 ± 0.66 0.610 ± 0.0018 F3 5.5 ± 0.0 9.5 ± 0.0 5.12 ± 0.70 0.627 ± 0.0025 F4 5.5 ± 0.0 9.5 ± 0.0 4.75 ± 0.26 0.365 ± 0.0023 F5 5.5 ± 0.0 9.5 ± 0.0 5.02 ± 0.50 0.405 ± 0.0018 F6 5.5 ± 0.0 9.5 ± 0.0 4.62 ± 0.55 0.422 ± 0.0020 F7 5.5 ± 0.0 9.5 ± 0.0 4.95 ± 0.30 0.285 ± 0.0022 F8 5.5 ± 0.0 9.5 ± 0.0 4.98 ± 0.80 0.312 ± 0.0021 F9 5.5 ± 0.0 9.5 ± 0.0 5.08 ± 0.60 0.328 ± 0.0024 Table 12 Evaluation of liquisolid compacts Formulation No. Friability (%) Disintegration Time (Sec)* % Drug Content* % Drug Release in 1 hr Control 0.89 107.33 ± 1.38 101.22 ± 1.67 62.47 F1 0.30 55.80 ± 0.16 95.66 ±1.22 89.33607 F2 0.44 50.07 ± 1.35 97.34 ± 2.05 97.22951 F3 0.33 56.00 ± 0.07 95.24 ±2.8 91.84426 F4 0.24 58.00 ± 1.00 91.95± 1.98 80.04098 F5 0.48 62.33± 0.07 90.84± 1.67 73.18033 World Journal of Biology Pharmacy and Health Sciences, 2025, 22(03), 266-276 274 F6 0.54 58.00 ± 2.00 93.66 ± 2.41 82.15082 F7 0.55 55.77 ± 1.76 93.80 ± 1.93 87.66885 F8 0.50 51.43 ± 1.43 91.20 ± 1.54 77.13607 F9 0.53 55.67 ± 0.71 94.00 ± 2.25 84.26066 3.4. In vitro drug release Table 13 In vitro drug release of all formulations Time F1 F2 F3 F4 F5 F6 F7 F8 F9 Control 0 0 0 0 0 0 0 0 0 0 0 5 25.35 31.6 14.64 18.24 13.53 12.57 13.26 10.2 12.9 10.1 10 37.02 40.8 25.53 28.83 19.8 19.89 21.66 14.13 19.11 14.5 15 43.2 51.53 37.65 41.13 25.56 32.16 27.51 20.43 21.66 18.97 20 56.13 60.13 47.73 46.53 32.04 42.51 37.83 25.14 27.57 22.5 25 62.49 69.33 57.21 52.56 42.48 56.01 46.89 35.43 39.33 30.01 30 69.25 78.69 64.35 58.53 51.69 61.53 57.6 44.91 49.14 39.48 45 82.26 88.86 78.01 64.83 61.8 70.83 63.05 55.5 58.47 49.01 60 92.67 97.5 88.53 76.15 73.51 79.92 70.8 71.21 68.1 62.47 3.5. Stability studies Table 14 Stability studies of formulation (F2) Evaluation parameter Temperature(25±20C& 60±5%RH) Temperature 40±2ºC & 75±5% RH Before Stability Storage After 10th Days After 20th Days After 30th Days Hardness (Kg/cm2) 4.83±0.11 4.83±0.11 8.82±0.09 4.82±0.12 Friability (%) 0.44±0.00 0.44±0.01 0.44±0.02 0.45±0.021 Weight Variation 598±0.01 598±0.01 598±0.01 598±0.01 Drug content (%) 97.34±2.05 97.34±2.02 96.62±0.06 96.75±0.12 Drug release (%) 97.22 97.12 97.02 96.89 4. Conclusion The aim of the present study was to enhance the solubility and dissolution rate of Nitrofurantoin, a poorly water-soluble antibacterial agent, in the form of liquisolid compact tablets. Pre-formulation studies were conducted to confirm the identification and purity of the drug, and solubility studies concluded that Tween 20 increased the solubility of Nitrofurantoin vs. non -volatile solvents used in the study. By using Spirea’s mathematical model, we developed several formulations by manipulating the drug concentration and ratio of carrier to coating materials to increase flowability and compressibility. Of the formulations tested, F2 (10% drug in Tween 20, R = 20) was the most successful tablet with respect to hardness, immediate disintegration, uniformity of drug content, and dissolution. F2 yielded a total of 97.5% drug release over 60 minutes, which is a significant increase from the controlled amounts released. In summary, the enhanced dissolution