Aslı KARA, Selma ŞAHİN, Tuğba GÜLSÜN, Naile ÖZTÜRK, İmran VURAL

Effect of precipitation inhibitors on supersaturation and solubility of furosemide

Furosemide is a widely used diuretic drug for the treatment of edema associated with heart, liver cirrhosis, renal diseases and hypertension. It is a Class IV drug with low aqueous solubility and low permeability according to Biopharmaceutics Classification System (BCS). Furosemide was chosen as a model drug to examine the effect of polymeric precipitation inhibitors (PPIs) on the supersaturation and solubility. Solubility and concentration change of furosemide as a function of time at pH 1.2 and 6.8 were determined to show the effects of PPIs on furosemide solubility. The 24 h equilibrium solubility of furosemide was 0.017 ± 0.004 and 3.62 ±0.201 mg/mL at pH 1.2 and pH 6.8 buffer solutions, respectively. PPI type and concentration (0.05%, 0.25%) did not increase furosemide solubility at pH 1.2. However, both hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidoneK17 (PVPK17) at two concentrations increased furosemide solubility at pH 1.2 and 6.8. In addition, viscosity of solutions was in the range of 2.2-3.7 centipoise, and it was not influenced by PPIs concentrations. Our results showed that designing supersaturated formulations using PPIs can be useful and promising to enhance solubility of furosemide.

PDF

___

[1] Khadka P, Ro J, Kim H, Kim I, Kim JT, Kim H, Cho JM, Yun G, Lee J. Pharmaceutical particle technologies: an approach to improve drug solubility, dissolution and bioavailability. Asian J Pharm Sci. 2014; 9(6): 304–316. [CrossRef]
[2] Prajapati BG, Patel MM. Conventional and alternative pharmaceutical methods to improve oral bioavailability of lipophilic drugs. Asian J Pharm. 2007; 1(1): 1–8.
[3] Miller JM, Beig A, Carr RA, Spence JK, Dahan A. A win–win solution in oral delivery of lipophilic drugs: supersaturation via amorphous solid dispersions increases apparent solubility without sacrifice of intestinal membrane permeability. Mol Pharm. 2012; 9(7): 2009–2016. [CrossRef]
[4] Warren DB, Benameur H, Porter CJH, Pouton CW. Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: a mechanistic basis for utility. J Drug Target. 2010; 18(10): 704–731. [CrossRef]
[5] Price DJ, Ditzinger F, Koehl NJ, Jankovic S, Tsakiridou G, Nair A, Holm R, Kuentz M, Dressman JB, Saal C. Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations - a pearrl review. J Pharm Pharmacol. 2019; 71(4): 483–509. [CrossRef]
[6] Xu S, Dai WG. Drug precipitation inhibitors in supersaturable formulations. Int J Pharm. 2013; 453(1): 36–43. [CrossRef]
[7] 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. [CrossRef]
[8] Wu CY, Benet LZ. Predicting drug disposition via application of bcs: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005; 22(1): 11–23. [CrossRef]
[9] Kashyap S, Singh A, Mishra A, Singh V. Enhanced sustained release of furosemide in long circulating chitosanconjugated plga nanoparticles. Res Pharm Sci. 2019; 14(2): 93–106. [CrossRef]
[10] Boles Ponto LL, Schoenwald RD. Furosemide (Frusemide) a pharmacokinetic/pharmacodynamic review (part I). Clin Pharmacokinet. 1990; 18(5): 381–408. [CrossRef]
[11] Klausner EA, Lavy E, Stepensky D, Cserepes E, Barta M, Friedman M, Hoffman A. Furosemide pharmacokinetics and pharmacodynamics following gastroretentive dosage form administration to healthy volunteers. J Clin Pharmacol. 2003; 43(7): 711–720. [CrossRef]
[12] Nielsen LH, Rades T, Müllertz A. Stabilisation of amorphous furosemide increases the oral drug bioavailability in rats. Int J Pharm. 2015; 490(1–2): 334–340. [CrossRef]
[13] Patel DD, Anderson BD. Effect of precipitation inhibitors on indomethacin supersaturation maintenance: mechanisms and modeling. Mol Pharm. 2014; 11(5): 1489–1499. [CrossRef]
[14] Tran P, Pyo YC, Kim DH, Lee SE, Kim JK, Park JS. Overview of the manufacturing methods of solid dispersion technology for improving the solubility of poorly water-soluble drugs and application to anticancer drugs. Pharmaceutics. 2019; 11(3): 1-26. [CrossRef]
[15] Kanikkannan N. Technologies to improve the solubility, dissolution and bioavailability of poorly soluble drugs. J Anal Pharm Res. 2018; 7(1): 44-50. [CrossRef]
[16] Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009; 98(8): 2549–2572. [CrossRef]
[17] Fong SY, Bauer-Brandl A, Brandl M. Oral bioavailability enhancement through supersaturation: an update and meta-analysis. Expert Opin Drug Deliv. 2017; 14(3): 403-426. [CrossRef]
[18] Shin SC, Kim J. Physicochemical characterization of solid dispersion of furosemide with tpgs. Int J Pharm. 2003; 251(1–2): 79–84. [CrossRef]
[19] Dalal L, Allaf AW, El-Zein H. Formulation and in vitro evaluation of self-nanoemulsifying liquisolid tablets of furosemide. Sci Rep. 2021; 11: 1315. [CrossRef]
[20] Granero G, Longhi MR, Mora MJ, Junginger HE, Midha KK, Shah VP, Stavchansky S, Dressman JB, Barends DM. Biowaiver monographs for immediate release solid oral dosage forms: furosemide. J Pharm Sci. 2010; 99(6): 2544– 2556. [CrossRef]
[21] Kaynak MS, Sahin S. Development and validation of a rp-hplc method for determination of solubility of furosemide. Turk J Pharm Sci. 2013; 10(1): 25–34.
[22] Schram CJ, Beaudoin SP, Taylor LS. Impact of polymer conformation on the crystal growth inhibition of a poorly water-soluble drug in aqueous solution. Langmuir. 2015; 31(1): 171–179. [CrossRef]
[23] Grahnén A, Hammarlund M, Lundqvist T. Implications of intraindividual variability in bioavailability studies of furosemide. Eur J Clin Pharmacol. 1984; 27(5): 595–602. [CrossRef]
[24] Iannuccelli V, Coppi G, Leo E, Fontana F, Bernabei MT. Pvp solid dispersions for the controlled release of furosemide from a floating multiple-unit system. Drug Dev Ind Pharm. 2000; 26(6): 595–603. [CrossRef]
[25] Markovic M, Zur M, Ragatsky I, Cvijić S, Dahan A. BCS Class IV Oral drugs and absorption windows: Regionaldependent intestinal permeability of furosemide. Pharmaceutics. 2020; 12(12): 1-16. [CrossRef]
[26] Zhu R. PhD Thesis. Investigation of enhancement of furosemide solubilization with cyclodextrins and a novel