To improve the pharmaceutical properties of amorphous ciprofloxacin (CIP) succinate salts via formulation as polymer/amorphous salt solid dispersions (ASSDs).
ASSDs consisting of an amorphous CIP/succinic acid 1:1 or 2:1 salt dispersed in PVP or Soluplus were produced by spray drying and ball milling. The solid state characteristics, miscibility, stability, solubility and passive transmembrane permeability of the ASSDs were then examined.
The ASSDs had higher glass transition and crystallization temperatures than the corresponding amorphous succinate salts, and were also more stable during long-term stability studies. The results of inverse gas chromatography and thermal analysis indicated that the salts and polymers form a miscible mixture. The solubility of the pure drug in water and biorelevant media was significantly increased by all of the formulations. The permeability of the ASSDs did not differ significantly from that of the amorphous CIP succinate salts, however all samples were less permeable than the pure crystalline drug.
The formulation of amorphous CIP succinate salts as ASSDs with polymer improved their long-term stability, but did not significantly affect their solubility or permeability.
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Amorphous solid dispersion
Amorphous salt solid dispersion
- CS 1:1:
Ciprofloxacin hemisuccinate (ciprofloxacin/succinic acid 1:1)
- CS 2:1:
Ciprofloxacin succinate (ciprofloxacin/succinic acid 2:1)
Parallel artificial membrane permeability assay
Kawabata Y, Wada K, Nakatani M, Yamada S, Onoue S. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. Int J Pharm. 2011;420(1):1–10.
Mesallati H, Mugheirbi NA, Tajber L. Two faces of ciprofloxacin: investigation of proton transfer in solid state transformations. Cryst Growth Des. 2016;16(11):6574–85.
Paluch KJ, McCabe T, Müller-Bunz H, Corrigan OI, Healy AM, Tajber L. Formation and physicochemical properties of crystalline and amorphous salts with different stoichiometries formed between ciprofloxacin and succinic acid. Mol Pharm. 2013;10(10):3640–54.
Zhang C-L, Zhao F, Wang Y. Thermodynamics of the solubility of ciprofloxacin in methanol, ethanol, 1-propanol, acetone, and chloroform from 293.15 to 333.15K. J Mol Liq. 2010;156(2–3):191–3.
Zaki NM, Artursson P, Bergström CAS. A modified physiological BCS for prediction of intestinal absorption in drug discovery. Mol Pharm. 2010;7(5):1478–87.
Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001;48(1):27–42.
Brough C, Williams RO. Amorphous solid dispersions and nano-crystal technologies for poorly water-soluble drug delivery. Int J Pharm. 2013;453(1):157–66.
Crowley KJ, Zografi G. Water vapor absorption into amorphous hydrophobic drug/poly(vinylpyrrolidone) dispersions. J Pharm Sci. 2002;91(10):2150–65.
Yang J, Grey K, Doney J. An improved kinetics approach to describe the physical stability of amorphous solid dispersions. Int J Pharm. 2010;384(1–2):24–31.
Cheong H-A, Choi H-K. Enhanced percutaneous absorption of piroxicam via salt formation with ethanolamines. Pharm Res. 2002;19(9):1375–80.
Zhang G, Zhang L, Yang D, Zhang N, He L, Du G, et al. Salt screening and characterization of ciprofloxacin. Acta Crystallogr Sect B Struct Sci Cryst Eng Mater. 2016;72(1):20–8.
Mesallati H, Umerska A, Paluch K, Tajber L. Amorphous polymeric drug salts as ionic solid dispersion forms of ciprofloxacin. Mol Pharm. 2017;14(7):2209–23.
Djuris J, Nikolakakis I, Ibric S, Djuric Z, Kachrimanis K. Preparation of carbamazepine–Soluplus® solid dispersions by hot-melt extrusion, and prediction of drug–polymer miscibility by thermodynamic model fitting. Eur J Pharm Biopharm. 2013;84(1):228–37.
Knapik J, Wojnarowska Z, Grzybowska K, Tajber L, Mesallati H, Paluch KJ, et al. Molecular dynamics and physical stability of amorphous nimesulide drug and its binary drug–polymer systems. Mol Pharm. 2016;13(6):1937–46.
Patel JR, Carlton RA, Yuniatine F, Needham TE, Wu L, Vogt FG. Preparation and structural characterization of amorphous spray-dried dispersions of tenoxicam with enhanced dissolution. J Pharm Sci. 2012;101(2):641–63.
Kitak T, Dumičić A, Planinšek O, Šibanc R, Srčič S. Determination of solubility parameters of ibuprofen and ibuprofen lysinate. Molecules. 2015;20(12):21549–68.
Merck Millipore. Lipid-PAMPA with the MultiScreen® filter plates. Billerica, MA; 2004.
Wohnsland F, Faller B. High-throughput permeability pH profile and high-throughput alkane/water log P with artificial membranes. J Med Chem. 2001;44(6):923–30.
Baghel S, Cathcart H, O’Reilly NJ. Polymeric amorphous solid dispersions: A review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization of Biopharmaceutical Classification System class II drugs. J Pharm Sci. 2016;105(9):2527–44.
Caron V, Hu Y, Tajber L, Erxleben A, Corrigan OI, McArdle P, et al. Amorphous solid dispersions of sulfonamide/Soluplus® and sulfonamide/PVP prepared by ball milling. AAPS PharmSciTechnol. 2013;14(1):464–74.
Dorofeev VL. The betainelike structure and infrared spectra of drugs of the fluoroquinolone group. Pharm Chem J. 2004;38(12):698–702.
Parojčić J, Stojković A, Tajber L, Grbić S, Paluch KJ, Djurić Z, et al. Biopharmaceutical characterization of ciprofloxacin HCl-ferrous sulfate interaction. J Pharm Sci. 2011;100(12):5174–84.
Chen Y, Wang S, Wang S, Liu C, Su C, Hageman M, et al. Initial drug dissolution from amorphous solid dispersions controlled by polymer dissolution and drug-polymer interaction. Pharm Res. 2016;33(10):2445–58.
Shalaev EY, Gatlin LA. The impact of buffer on solid-state properties and stability of freeze-dried dosage forms. In: Jameel F, Hershenson S, editors. Formulation and process development strategies for manufacturing biopharmaceuticals. 1st ed. New Jersey: Wiley; 2010. p. 508.
Brostow W, Chiu R, Kalogeras IM, Vassilikou-Dova A. Prediction of glass transition temperatures: binary blends and copolymers. Mater Lett. 2008;62(17–18):3152–5.
Knopp MM, Tajber L, Tian Y, Olesen NE, Jones DS, Kozyra A, et al. Comparative study of different methods for the prediction of drug-polymer solubility. Mol Pharm. 2015;12(9):3408–19.
Greenhalgh DJ, Williams AC, Timmins P, York P. Solubility parameters as predictors of miscibility in solid dispersions. J Pharm Sci. 1999;88(11):1182–90.
Trasi NS, Boerrigter SXM, Byrn SR. Investigation of the milling-induced thermal behavior of crystalline and amorphous griseofulvin. Pharm Res. 2010;27(7):1377–89.
Karmwar P, Graeser K, Gordon KC, Strachan CJ, Rades T. Investigation of properties and recrystallisation behaviour of amorphous indomethacin samples prepared by different methods. Int J Pharm. 2011;417(1–2):94–100.
Ke P, Hasegawa S, Al-Obaidi H, Buckton G. Investigation of preparation methods on surface/bulk structural relaxation and glass fragility of amorphous solid dispersions. Int J Pharm. 2012;422(1–2):170–8.
Caron V, Tajber L, Corrigan OI, Healy AM. A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/polyvinylpyrrolidone. Mol Pharm Am Chem Soc. 2011;8(2):532–42.
Mafra L, Santos SM, Siegel R, Alves I, Paz FAA, Dudenko D, et al. Packing interactions in hydrated and anhydrous forms of the antibiotic ciprofloxacin: a solid-state NMR, X-ray diffraction, and computer simulation study. J Am Chem Soc. 2012;134(1):71–4.
Li X, Zhi F, Hu Y. Investigation of excipient and processing on solid phase transformation and dissolution of ciprofloxacin. Int J Pharm. 2007;328(2):177–82.
Sugano K. Permeability of a drug. In: Biopharmaceutics modeling and simulations: theory, practice, methods, and applications. 1st ed. New Jersey: Wiley; 2012. p. 170.
Beig A, Miller JM, Lindley D, Carr RA, Zocharski P, Agbaria R, et al. Head-to-head comparison of different solubility-enabling formulations of etoposide and their consequent solubility-permeability interplay. J Pharm Sci. 2015;104(9):2941–7.
Rodríguez-Ibáñez M, Sánchez-Castaño G, Montalar-Montero M, Garrigues TM, Bermejo M, Merino V. Mathematical modelling of in situ and in vitro efflux of ciprofloxacin and grepafloxacin. Int J Pharm. 2006;307(1):33–41.
Tam KY, Avdeef A, Tsinman O, Sun N. The permeation of amphoteric drugs through artificial membranes--an in combo absorption model based on paracellular and transmembrane permeability. J Med Chem. 2010;53(1):392–401.
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Mesallati, H., Tajber, L. Polymer/Amorphous Salt Solid Dispersions of Ciprofloxacin. Pharm Res 34, 2425–2439 (2017). https://doi.org/10.1007/s11095-017-2250-z
- amorphous salt solid dispersion