Polymers in Medicine
2019, vol. 49, nr 1, January-June, p. 35–43
Publication type: original article
Influence of levodropropizine and hydroxypropyl-β-cyclodextrin association on the physicochemical characteristics of levodropropizine loaded in hydroxypropyl-β-cyclodextrin microcontainers: Formulation and in vitro characterization
1 Drug Delivery Research Group, Department of Pharmacy, COMSATS University Islamabad, Lahore, Pakistan
2 Faculty of Pharmacy, University of Central Punjab, Lahore, Pakistan
3 Punjab University College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, Pakistan
4 Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan
5 Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan
6 Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Pakistan
7 Sahara College of Pharmacy, Narowal, Pakistan
Background. Poorly water-soluble drugs do not dissolve well in aqueous-based gastrointestinal fluid; therefore, they are not well absorbed. Thus, employing a suitable solubility enhancing technique is necessary for such a drug. Drug/HP‑β‑CD complexation is a promising way to improve solubility and dissolution of a poorly water-soluble drug. Levodropropizine was used as a model drug in this study.
Objectives. The purpose of this research was to enhance the aqueous solubility and dissolution rate of levodropropizine by employing the inclusion complexation technique.
Material and Methods. A microparticle formulation was prepared from levodropropizine and hydroxypropyl-β-cyclodextrin (HP‑β‑CD) in a 1:1 molar ratio through the spray-drying technique. The host-guest relationship between levodropropizine and HP‑β‑CD was also investigated using the molecular docking computational methodology. The aqueous solubility and dissolution rate of levodropropizine in formulations were assessed and compared with those of the drug alone. X-ray diffraction (XRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR) were applied for the solid-state characterization of the prepared samples.
Results. According to the research outcomes, the levodropropizine/HP‑β‑CD formulation had enhanced the aqueous solubility (351.12 ±13.26 vs 92.76 ±5.00 mg/mL) and dissolution rate (97.83 ±3.36 vs 3.12 ±1.76% in 10 min) of levodropropizine, compared to the plain drug powder. The levodropropizine/ HP‑β‑CD formulation had converted the crystalline drug into its amorphous counterpart. Furthermore, no covalent interaction was found to exist between levodropropizine and HP‑β‑CD. The spray-dried particles were discrete. Each particle had a shriveled appearance.
Conclusion. The levodropropizine/HP‑β‑CD formulation is, therefore, recommended for the more effective administration of levodropropizine through the oral route.
dissolution rate, spray-drying, cyclodextrins, amorphous form, phase solubility
- Pappas DE, Hendley JO, Hayden FG, Winther B. Symptom profile of common colds in school-aged children. Pediatric Infect Dis J. 2008;27(1):8–11.
- Nasra J, Belvisi MG. Modulation of sensory nerve function and the cough reflex: Understanding disease pathogenesis. Pharmacol Ther. 2009;124(3):354–375.
- Dicpinigaitis PV, Morice AH, Birring SS, et al. Antitussive drugs-past, present, and future. Pharmacol Rev. 2014;66(2):468–512.
- Irwin RS, Curley FJ, Bennett FM. Appropriate use of antitussives and protussives. Drugs. 1993;46(1):80–91.
- Bolser DC. Current and future centrally acting antitussives. Respir Physiol Neurobiol. 2006;152(3):349–355.
- Weshahy SAE-F, Yaaqob MS, Morcos MN, Hassan DW, Youssef NF. Simultaneous determination of levodropropizine, methylparaben, and propylparaben in oral co-formulated syrup by rp-hplc method. J Chil Chem Soc. 2015;60(4):2729–2733.
- Daffonchio L, Clavenna G, Fedele G, Omini C. Levodropropizine. Drugs Today. 1995;31(31):299–305.
- Khoo S-M, Porter CJ, Charman WN. The formulation of halofantrine as either non-solubilizing PEG 6000 or solubilizing lipid based solid dispersions: Physical stability and absolute bioavailability assessment. Int J Pharm. 2000;205(1):65–78.
- Banderali G, Riva E, Fiocchi A, Cordaro C, Giovannini M. Efficacy and tolerability of levodropropizine and dropropizine in children with non-productive cough. J Int Med Res. 1995;23(3):175–183.
- General Notices. Subsection 5.30. Description and Solubility. United States Pharmacopeia 38. https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/usp-nf-notices/usp38_nf33_gn.pdf Accessed July 19, 2019.
- Maheshwari R, Chaturvedi S, Jain N. Novel spectrophotometric estimation of some poorly water soluble drugs using hydrotropic solubilizing agents. Indian J Pharm Sci. 2006;68(2):195–198. http://www.ijpsonline.com/articles/novel-spectrophotometric-estimation-of-some-poorly-water-soluble-drugs-using-hydrotropic-solubilizing-agents.pdf Accessed July 19, 2019.
- Kurozumi M, Nambu N, Nagai T. Inclusion compounds of non-steroidal antiinflammatory and other slightly water soluble drugs with α-and β-cyclodextrins in powdered form. Chem Pharm Bull. 1975;23(12):3062–3068.
- Maggi L, Canobbio A, Bruni G, Musitelli G, Conte U. Improvement of the dissolution behavior of gliclazide, a slightly soluble drug, using solid dispersions. J Drug Deliv Sci Technol. 2015;26:17–23.
- Samejima M, Noda K, Kobayashi M, Osawa T. Process for micronizing slightly-soluble drug. Google Patents; 1993. https://patents.google.com/patent/US5202129A/en Accessed July 19, 2019.
- Schott H, Kwan LC, Feldman S. The role of surfactants in the release of very slightly soluble drugs from tablets. J Pharm Sci. 1982;71(9):1038–1045.
- Goodman LS. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. Vol. 1549. New York, NY: McGraw-Hill 1996.
- Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–420.
- Dressman J, Butler J, Hempenstall J, Reppas C. The BCS: Where do we go from here? Pharm Technol. 2001;25(7):68–77.
- Badens E, Majerik V, Horváth G, et al. Comparison of solid dispersions produced by supercritical antisolvent and spray-freezing technologies. Int J Pharm. 2009;377(1):25–34.
- Perrut M, Jung J, Leboeuf F. Enhancement of dissolution rate of poorly-soluble active ingredients by supercritical fluid processes: Part I: Micronization of neat particles. Int J Pharm. 2005;288(1):3–10.
- Loftsson T, Jarho P, Masson M, Järvinen T. Cyclodextrins in drug delivery. Expert Opin Drug Deliv. 2005;2(2):335–351.
- Antoniadou-Vyza E, Buckton G, Michaleas SG, Loukas YL, Efentakis M. The formation of an inclusion complex of methocarbamol with hydroxypropyl-β-cyclodextrin: The effect on chemical stability, solubility and dissolution rate. Int J Pharm. 1997;158(2):233–239.
- Rekharsky MV, Inoue Y. Complexation thermodynamics of cyclodextrins. Chem Rev. 1998;98(5):1875–1918.
- Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins. 1. Drug solubilization and stabilization. J Pharm Sci. 1996;85(10):1017–1025.
- Thompson DO. Cyclodextrins–enabling excipients: Their present and future use in pharmaceuticals. Crit Rev Ther Drug Carrier Syst. 1997;14(1):104. http://www.dl.begellhouse.com/journals/3667c4ae6e8fd136,35a5d8f83a12d567,7e52d3af7787104d.html Accessed July 19, 2019.
- Miro A, Quaglia F, Giannini L, Cappello B, Immacolata La Rotonda M. Drug/cyclodextrin solid systems in the design of hydrophilic matrices: A strategy to modulate drug delivery rate. Curr Drug Deliv. 2006;3(4):373–378.
- Irie T, Uekama K. Pharmaceutical applications of cyclodextrins. III. Toxicological issues and safety evaluation. J Pharm Sci. 1997;86(2):147–162.
- Gould S, Scott RC. 2-Hydroxypropyl-β-cyclodextrin (HP‑β‑CD): A toxicology review. Food Chem Toxicol. 2005;43(10):1451–1459.
- Higuchi T, Connors A. Phase-solubility techniques. Adv Anal Chem Instrum. 1965;4(2):117–212.
- Yousaf AM, Kim DW, Cho KH, Kim JO, Yong CS, Choi H-G. Effect of the preparation method on crystallinity, particle size, aqueous solubility and dissolution of different samples of the poorly water-soluble fenofibrate with HP‑β‑CD. J Incl Phenom Macrocycl Chem. 2015;81(3–4):347–356.
- Shah VP, Noory A, Noory C, et al. In vitro dissolution of sparingly water-soluble drug dosage forms. Int J Pharm. 1995;125(1):99–106.
- Blanchard J, Proniuk S. Some important considerations in the use of cyclodextrins. Pharm Res. 1999;16(12):1796–1798.
- Albers E, Muller B. Cyclodextrin derivatives in pharmaceutics. Crit Rev Ther Drug Carrier Syst. 1995;12(4):311–337. http://www.dl.begellhouse.com/journals/3667c4ae6e8fd136,7663ffaa47121cf9,54f149ac174ecb02.html Accessed July 19, 2019.
- Frömming K-H, Szejtli J. Cyclodextrins in pharmacy. Dodrecht, the Netherlands: Springer; 1994. https://www.springer.com/gp/book/9780792321392 Accessed July 19, 2019.
- Loftsson T, Duchêne D. Cyclodextrins and their pharmaceutical applications. Int J Pharm. 2007;329(1–2):1–11.
- Joe JH, Lee WM, Park Y-J, et al. Effect of the solid-dispersion method on the solubility and crystalline property of tacrolimus. Int J Pharm. 2010;395(1):161–166.
- Zhao M-R, Wang L-S, Liu H-W, Wang Y-J, Yang H. Preparation, physicochemical characterization and in vitro dissolution studies of azithromycin-cyclodextrin inclusion complexes. J Incl Phenom Macrocycl Chem. 2016;85(1):137–149.
- Nalluri BN, Chowdary KPR, Murthy KVR, Satyanarayana V, Hayman AR, Becket G. Inclusion complexation and dissolution properties of nimesulideand meloxicam–hydroxypropyl-β-cyclodextrin binary systems. J Incl Phenom Macrocycl Chem. 2005;53(1):103–110.
- Mihajlovic T, Kachrimanis K, Graovac A, Djuric Z, Ibric S. Improvement of aripiprazole solubility by complexation with (2-hydroxy) propyl-β-cyclodextrin using spray drying technique. AAPS PharmSciTech. 2012;13(2):623–631.
- Upadhye SB, Kulkarni SJ, Majumdar S, et al. Preparation and characterization of inclusion complexes of a hemisuccinate ester prodrug of Δ9-tetrahydrocannabinol with modified beta-cyclodextrins. AAPS Pharm Sci Tech. 2010;11(2):509–517.
- Yonemochi E, Kitahara S, Maeda S, Yamamura S, Oguchi T, Yamamoto K. Physicochemical properties of amorphous clarithromycin obtained by grinding and spray drying. Eur J Pharm Sci. 1999;7(4):331–338.
- Mura P, Cirri M, Faucci M, Ginès-Dorado J, Bettinetti G. Investigation of the effects of grinding and co-grinding on physicochemical properties of glisentide. J Pharm Biomed Anal. 2002;30(2):227–237.