Physical stability and dissolution of ketoprofen nanosuspension formulation: Polyvinylpyrrolidone and Tween 80 as stabilizers

Pharmacia 70(1): 209–215 DOI 10.3897/pharmacia.70.e96593 Research Article Physical stability and dissolution of ketoprofen nanosuspension formulation: Polyvinylpyrrolidone and Tween 80 as stabilizers Tengku Ismanelly Hanum1,2, Azizah Nasution1, Sumaiyah Sumaiyah1,2, Hakim Bangun1,2 1 Faculty of Pharmacy, Universitas Sumatera Utara, Medan, 20155, Indonesia 2 Nanomedicine Center of Innovation, Universitas Sumatera Utara, Medan, 20155, Indonesia Corresponding author: Azizah Nasution () Received 21 October 2022 ♦ Accepted 27 February 2023 ♦ Published 14 March 2023 Citation: Ismanelly Hanum T, Nasution A, Sumaiyah S, Bangun H (2023) Physical stability and dissolution of ketoprofen nanosuspension formulation: Polyvinylpyrrolidone and Tween 80 as stabilizers. Pharmacia 70(1): 209–215. https://doi.org/10.3897/pharmacia.70.e96593 Abstract This study was conducted to improve the dissolution of ketoprofen in nanosuspensions. Ketoprofen nanosuspensions were prepared by a solvent evaporation method using polyvinylpyrrolidone (PVP) and Tween 80 as stabilizers at varied ratios with ketoprofen. Ethanol was used as a solvent for ketoprofen. Physical stability and dissolution of the produced ketoprofen nanosuspensions and conventional suspension were analyzed and compared. The parameters evaluated for their stability for a three-month period were pH, appearance, odor, color, particle size, zeta potential, polydispersity index (PI), and dissolution compared with ketoprofen suspension. Ketoprofen and PVP ratios of 1:1 and 1:1.5 had nano-scale particle sizes of 78.47±0.61 and 156.9±1.55, respectively. These nanosuspensions had stable pH, appearance, odor, color, particle size, and PI at room temperature. The dissolution rates of ketoprofen nanosuspensions were higher compared to that of ketoprofen conventional suspension. PVP and Tween 80 improved ketoprofen nanosuspension dissolution and was stable at room temperature for three months. Keywords dissolution, nanosuspension, ketoprofen, polyvinylpyrrolidone, Tween 80 Introduction The pharmacological activity of a drug is determined by its bioavailability and dissolution at the absorption site. Thus, any problems associated with dissolution will decrease the required pharmacological effect. Ketoprofen is classified into non-steroidal anti-inflammatory drugs (NSAIDs) that have a mechanism of action of inhibiting cyclooxygenase (COX) and lipo-oxygenase (LOX) enzymes. Ketoprofen’s therapeutic dose is 150–300 mg/day. Few problems are associated with ketoprofen. It is included in class II of the Biopharmaceutical Classification System (BCS) in which it has low solubility in water with high membrane permeability, thus only slightly absorbed in the digestive tract (Shohin et al. 2012). In addition, other problems with ketoprofen are that it has a short half-life (about 1–3 hours), a low area under the plasma concentration-time curve, and a short duration of action, consequently requiring repeated administration to maintain its therapeutic effect. Its multiple dose administration produces high plasma level fluctuations which tend Copyright Ismanelly Hanum T et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 210 Ismanelly Hanum T et al.: Physical stability and dissolution of ketoprofen nanosuspension formulation to result in adverse effects, including irritation and gastric bleeding for patients. Therefore, efforts to improve ketoprofen dissolution and reduce its particle size should be sought. Various strategies have been suggested to improve the dissolution of drugs with low solubility, including salt formation, surfactant use, and micronization. Micronization alone is not sufficient to increase the bioavailability of insoluble drugs. Therefore, this problem is a challenge to motivate researchers to develop nano-size pharmaceutical preparations (< 1 µm) that could increase the dissolution rates of the drugs as well as their bioavailabilities (Shid et al. 2013; Yadollahi et al. 2015; Gadhari et al. 2022). Nanosuspension is a colloidal submicron dispersion of pure drug particles in a liquid phase stabilized by surfactants and polymers. Nanosuspensions can be manufactured by applying bottom-up and top-down technologies. One of the bottom-up technologies is the dissolution of water-insoluble drugs in volatile organic solvents. While top-down technology includes ball milling with high-pressure homogenization, in which particles are fragmented into submicron units (Thakkar et al. 2011). A previous study undertaken to improve the dissolution of ketoprofen was the utilization of high-pressure homogenization techniques with variations of hydrogenated phosphatidylcholine, poloxamer 188, and sodium lauryl sulphate. This study indicated that the nanosuspension produced had a particle size of 322.7 nm and was stable for more than one month (Amin et al. 2013). Another study also indicated that ketoprofen nanosuspension could be manufactured utilizing a solvent evaporation technique with few polymers as stabilizers (PVP, HPMC, poloxamer) and surfactant (Tween 80). These stabilizers could increase the dissolution rate of ketoprofen (Wais et al. 2017). Additionally, a study argued that to enhance the solubility of ketoprofen by using DenaDM100 consisting of a soft polymeric fast rotating conical rotor sitting within a conical polymeric sleeve produced nanoparticles with a size of below 200 nm (Khan et al. 2019). In the present study, the solvent evaporation method was chosen to prepare ketoprofen nanosuspension by a solvent evaporation technique since this technique is fast and easy to perform in a laboratory scale (Afifi et al. 2015; Ainurofiq et al. 2021). Methods Preparation of artificial gastric medium (pH 1.2) Two grams of sodium chloride were added with 7 ml of concentrated hydrochloric acid and then added with distilled water to make up the final solution of 1000 mL (USP. 2019). Preparation of ketoprofen standard stock solution and absorption curves As much as 15 milligrams of ketoprofen were dissolved in a sufficient amount of 0.1 N HCl in a 50-ml volumetric flask. The solution was diluted with the solvent to make up the final solution of 50 ml. The concentration of this stock solution was 150 ppm (µg/ml). The standard stock solution (2.6 mL) was pipetted, then transferred into a 25-ml volumetric flask. Hydrochloric acid (0.1 N) was then added into the flask to make up the final solution volume of 25 ml. The obtained ketoprofen concentration was 32 ppm (µg/mL) and was measured using a UV spectrophotometer at a wavelength of 200–400 nm to obtain its maximum absorption wavelength, 260 nm. This wavelength was set to measure the dissolution of all samples. Preparation of ketoprofen calibration curves The standard stock solutions of 0.7, 1.7, 2 (...truncated)