Solubility and Dissolution enhancement of paracetamol using in situ micronization by solvent change method

Paper Details

Research Paper 10/08/2022
Views (713) Download (87)

Solubility and Dissolution enhancement of paracetamol using in situ micronization by solvent change method

Alalor Christian Arerusuoghene, Okafo Sinodukoo Eziuzo, Avbunudiogba John Afokoghene, Atimah Charles Onajite
Int. J. Biosci.21( 2), 10-20, August 2022.
Certificate: IJB 2022 [Generate Certificate]


Dissolution is the rate-limiting step for the absorption of drugs in class II of the Biopharmaceutics Classification System (BCS) resulting in poor bioavailability. This present study was aimed at determining the outcome of in situ micronization technique on the dissolution and solubility profiles of paracetamol. Six formulations of paracetamol microcrystals were produced by the solvent change method using HPMC and PVP K30 as stabilizing agents. The solubility, percentage drug content, and dissolution patterns of the produced microcrystals were all tested.  The study revealed that paracetamol solubility was increased up to 5-fold in the PVP K30 stabilized paracetamol microcrystal and a 4.5-fold increase for HPMC stabilized paracetamol microcrystal. The time course of dissolution was improved significantly from 0.6%/min for plain paracetamol to 1.1%/min and 1.2%/min for HPMC and PVP K30 stabilized paracetamol microcrystal respectively. Formulation P6, with 0.08 g of PVP K30 as stabilizing agents and anti-solvent to solvent ratio of 1:6 was the optimized formulation having a 5-fold solubility increase, 98.3% content of active and 95.32% drug release in 60 minutes. The solvent change approach of the in situ micronization technique could be used for the augmentation of solubility and dissolution of paracetamol.


Amal AE, Ayobami J, Ebtessam E. 2012. In-situ controlled crystallization as a tool to improve the dissolution of glibenclamide. International Journal of Pharmaceutics 428, 118-120.

Brodka PK, Peter L, Peter G, Heribert H. 2003. Influence of mechanical activation on the physical stability of salbutamol sulphate. European Journal of Pharmaceutics and Biopharmaceutics 56, 393-400.

Buddha RS, Raja RP. 2009. Spectrophotometric Method for the Determination of Paracetamol.  Journal of Nepal Chemical Society 24(1), 520-525.

Chiou D, Langrish TAG. 2008. A comparison of crystallisation approaches in spray drying. Journal of Food Engineering 88, 177.

Daravath B, Naveen C, Vemula SK, Tadikonda RR. 2017. Solubility and dissolution enhancement of flurbiprofen by solid dispersion using hydrophilic carriers. Brazilian Journal of Pharmaceutical Sciences 53(04).

Deelip D, Jatin P, Devendra Y, Amit P, Ashok P. 2010. Particle engineering techniques to enhance dissolution of poorly water-soluble drugs, International Journal of Current Pharmaceutical Research 2(1).

European Pharmacopoeia. 2002. suppl. 4.1. Council of Europe, European Directorate for the quality of medicines, Strasbourg, Tablet monograph, 0478.

Fang Z, Jaakko A, Fang T, Dorothy JS, Thomas R. 2009. Influence of particle size and preparation methods on the physical and chemical stability of amorphous simvastatin. European Journal of Pharmaceutics and Biopharmaceutics 71(1), 64-70

Filippos K, Yunhui WU. 2008. Understanding the effect of API properties on bioavailability through absorption modelling. Journal of the American Association of Pharmaceutical Scientists 10(4), 516-525.

Gibson M. 2001. Pharmaceutical pre-formulation and formulation – a practical guide from candidate drug selection to commercial dosage form. HIS Health Group, Englewood.

Irngartinger M, Camuglia V, Damm M, Goede J, Frijlink J. 2004. Pulmonary delivery of therapeutic peptides via dry powder inhalation: effects of micronisation and manufacturing. European Journal of Pharmaceutics and Biopharmaceutics 58, 7-14.

Jalay JT. 2011. A review on micronization techniques. Journal of Pharmaceutical Science and Technology 3(7), 651-681.

Kausalya J, Suresh K, Padmapriya S, Anusha R, Senthilnathan B. 2011. Solubility and dissolution enhancement of telmisartan using various techniques. International Journal of PharmTech Research 3, 1737–49.

Kawashima Y. 2001. Nanoparticulate systems for improved drug delivery. Advanced Drug Delivery Reviews 47, 1-2.

Kim ST, Kwon JH, Lee JJ, Kim CW. 2003. Microcrystallization of indomethacin using pH shift method. International Journal of Pharmaceutics 263 (1-2), 141-150.

Koennings S, Sapin A, Blunk T, Menei P, Goepferich A. 2007. Towards controlled release of BDNF – manufacturing strategies for protein-loaded lipid implants and biocompatibility evaluation in the brain, Journal of Controlled Release 119, 163-172.

Leena P, Jouni H. 2010. Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods. Journal of Pharmacy and Pharmacology 62, 1569-1579.

Masoud B, Sima R. 2007. Production of micro-and nano-composite particles by supercritical carbon dioxide. Journal of Supercritical Fluids 40, 263-283.

Mattia C, Coluzzi F. 2009. What anesthesiologists should know about paracetamol (acetaminophen). Minerva Anestesiologica 75(11), 644-53.

Mauludin R, Muller RH, Keck CM. 2009. Development of an oral route nanocrystal formulation. International Journal of Pharmaceutics 370, 202-209.

Miranda A, Millan M, Carballo I. 2007. Investigation of the influence of particle size on the excipient percolation thresholds of HPMC hydrophilic matrix tablets. Journal of Pharmaceutical Sciences 96, 2746-2756.

Mullarney MP, Leyva N. 2009. Modeling pharmaceutical powder-flow performance using particle-size distribution data. Pharmaceutical Technology 33(2), 126-134.

Nighute AB, Bhise SB. 2009. Preparation and Evaluation of Rifabutin Loaded Polymeric Microspheres. Research Journal of Pharmacy and Technology 2(2), 371-374.

Pasquali I, Bettini R, Giordano F. 2006. Solid-state chemistry and particle engineering with supercritical fluids in pharmaceutics. European Journal of Pharmaceutical Sciences 27, 299-310.

Rasenack N, Muller BW. 2002. Dissolution rate enhancement by in situ micronization of poorly water-soluble drugs. Pharmaceutical Research 19(12), 1894-1900.

Rasenack N, Muller BW. 2002. Ibuprofen crystals with optimized properties. International Journal of Pharmaceutics 245, 9-24.

Rasenack N, Muller BW. 2004. Micron-size drug particles: common and novel micronization techniques. Pharmaceutical Development and Technology 9(1), 1-13.

Rasenack N, Hartenhauer H, Muller BW. 2003. Microcrystals for dissolution rate enhancement of poorly water-soluble drugs. International Journal of Pharmaceutics   254, 137-145.

Rasenack N, Steckel H, Muller BW. 2004. Preparation of microcrystals by in situ micronization. Powder Technology 143-144, 291-296.

Roya T, Varshosaz J, Mostafavi SA, Ali N. 2009. Dissolution enhancement of glipizide using pH change approach in the presence of twelve stabilizers with physic-chemical properties.  Journal of Pharmaceutical Sciences 12(3), 250-265.

Sharma P, Denny WA, Garq S. 2009. Effect of wet milling process on the solid-state of indomethacin and simvastatin. International Journal of Pharmaceutics 380(1–2), 40-48.

Steckel H, Rasenack N, Muller BW. 2003. In-situ micronization of disodium cromoglycate for pulmonary delivery. European Journal of Pharmaceutics and Biopharmaceutics 55, 173-180.

Sunday AS, Simon C. 2006. Particle engineering techniques for inhaled biopharmaceuticals.  Advanced Drug Delivery Reviews 58, 1009-1029.

Sung TK, Jai-Hyun K, Lee JJ, Kim CW. 2003. Microcrystallization of indomethacin using pH shift method, International Journal of Pharmaceutical Research 263, 141-150.

Varshosaz J, Talari R, Mostafavi SA, Nokhodchi A. 2008. Dissolution enhancement of glipizide using in situ micronization by solvent change method. Powder Technology 187, 222-230.

Yohei K, Koichi W, Manabu N, Shizuo Y, Satomi O. 2011. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. International Journal of Pharmaceutics 420, 1-10.