Abstract
The present study was designed to determine the applicability of a newly derived dimensionless number precipitation parameter, “supersaturation holding capacity (SHC)” in development of amorphous solid dispersion (ASD) of a rapidly crystallizing drug, nisoldipine. Also, ASD preparation from lab scale formulation technique to scalable spray drying technique followed by oral bioavailability study was demonstrated. Solution state screening of polymers was performed by determining nucleation induction time (tin) and SHC. With screened polymers, lab scale ASDs of nisoldipine were prepared using rotary evaporation (solvent evaporation) method, and the optimized stable ASDs were scaled up by spray drying. The ASDs were characterized by DSC, PXRD, and FTIR for amorphous nature and evaluated for apparent solubility, dissolution, and solid-state stability improvement. The spray dried ASDs were additionally evaluated for micrometric properties and oral bioavailability study.PVP grades demonstrated superior crystal growth inhibition properties (with 2–4-fold enhancements in SHC). ASDs prepared by both lab scale and scale-up technique using PVP stabilized the amorphous nisoldipine via antiplasticization effect that maintained the stability under accelerated stability conditions (40 °C/75% RH) for 6 months. Additionally, FTIR study confirmed the role of intermolecular interactions in amorphous state stabilization of PVP-based solid dispersions. PVP-based spray dried ASDs improved the apparent solubility 4-fold for PVP K17 and more than 3-fold for remaining spray dried ASDs. The enhanced solubility was translated to improved dissolution of the drug when compared with crystalline and amorphous form complementing the outcome of the solution state study. The spray dried ASD showed 2.3 and > 3-fold the improvement in Cmax and AUC (0–24 h) respectively when compared with crystalline nisoldipine during oral bioavailability study which highlights the significance of SHC parameter of polymers. The spray dried ASD has shown improved micromeritics properties then crystalline nisoldipine in terms of flow behavior.This unique study provides a rational strategy for selection of appropriate polymer in development of ASDs that can tackle both precipitation during dissolution and amorphous state stabilization in solid state and also considers the SHC in scale-up study.
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Kini A, Patel SB. Phase behavior, intermolecular interaction, and solid state characterization of amorphous solid dispersion of Febuxostat. Pharm Dev Technol. 2017;22(1):45–57.
Chauhan H, Kuldipkumar A, Barder T, Medek A, Gu CH, Atef E. Correlation of inhibitory effects of polymers on indomethacin precipitation in solution and amorphous solid crystallization based on molecular interaction. Pharm Res. 2014;31(2):500–15.
Kaushal AM, Gupta P, Bansal AK. Amorphous drug delivery systems: molecular aspects, design, and performance. Crit Rev Ther Drug Carrier Syst. 2004;21(3):133–93.
Price D, Ditzinger F, Koehl N, Jankovic S, Tsakiridou G, Nair A, et al. 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.
Chavan RB, Rathi S, Jyothi VGS, Shastri NR. Cellulose based polymers in development of amorphous solid dispersions. Asian J Pharm Sci. 2019;14(3):248–64.
Mahmah O, Tabbakh R, Kelly A, Paradkar A. A comparative study of the effect of spray drying and hot-melt extrusion on the properties of amorphous solid dispersions containing felodipine. J Pharm Pharmacol. 2014;66(2):275–84.
Chauhan H, Hui Gu C, Atef E. Correlating the behavior of polymers in solution as precipitation inhibitor to its amorphous stabilization ability in solid dispersions. J Pharm Sci. 2013;102(6):1924–35.
Brough C, Williams R. Amorphous solid dispersions and nano-crystal technologies for poorly water-soluble drug delivery. Int J Pharm. 2013;453(1):157–66.
Qian F, Huang J, Hussain MA. Drug–polymer solubility and miscibility: stability consideration and practical challenges in amorphous solid dispersion development. J Pharm Sci. 2010;99(7):2941–7.
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):132.
Price DJ, Ditzinger F, Koehl NJ, Jankovic S, Tsakiridou G, Nair A, et al. 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.
Miao L, Liang Y, Pan W, Gou J, Yin T, Zhang Y, et al. Effect of supersaturation on the oral bioavailability of paclitaxel/polymer amorphous solid dispersion. Drug Deliv Transl Res. 2019;9(1):344–56.
Alonzo DE, Zhang GG, Zhou D, Gao Y, Taylor LS. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm Res. 2010;27(4):608–18.
Ilevbare GA, Liu H, Edgar KJ, Taylor LS. Maintaining supersaturation in aqueous drug solutions: impact of different polymers on induction times. Cryst Growth Des. 2012;13(2):740–51.
Chavan RB, Thipparaboina R, Kumar D, Shastri NR. Evaluation of the inhibitory potential of HPMC, PVP and HPC polymers on nucleation and crystal growth. RSC Adv. 2016;6(81):77569–76.
Alonzo DE, Raina S, Zhou D, Gao Y, Zhang GG, Taylor LS. Characterizing the impact of hydroxypropylmethyl cellulose on the growth and nucleation kinetics of felodipine from supersaturated solutions. Cryst Growth Des. 2012;12(3):1538–47.
Ilevbare GA, Liu H, Edgar KJ, Taylor LS. Understanding polymer properties important for crystal growth inhibition impact of chemically diverse polymers on solution crystal growth of ritonavir. Cryst Growth Des. 2012;12(6):3133–43.
Ilevbare GA, Liu H, Edgar KJ, Taylor LS. Inhibition of solution crystal growth of ritonavir by cellulose polymers–factors influencing polymer effectiveness. CrystEngComm. 2012;14(20):6503–14.
Chavan RB, Lodagekar A, Shastri NR. Determination of precipitation inhibitory potential of polymers from amorphous solid dispersions. Drug Dev Ind Pharm. 2018;44(12):1933–41.
Rathi S, Chavan RB, Shastri NR. Classification of the crystallization tendency of active pharmaceutical ingredients (APIs) and nutraceuticals based on their nucleation and crystal growth behaviour in solution state. Drug Deliv Transl Res. 2020;10(1):70–82 1–13.
Chopra S, Venkatesan N, Betageri GV. Formulation of lipid bearing pellets as a delivery system for poorly soluble drugs. Int J Pharm. 2013;446(1):136–44.
Fu Q, Fang M, Hou Y, Yang W, Shao J, Guo M, et al. A physically stabilized amorphous solid dispersion of nisoldipine obtained by hot melt extrusion. Powder Technol. 2016;301:342–8.
Zong L, **ao Y, Chen L. Studies on improvement of dissolution and modification of dissolution rate of nisoldipine with binary solid dispersion [J]. Chin Pharm J. 2005;3:013.
Gupta P, Chawla G, Bansal AK. Physical stability and solubility advantage from amorphous celecoxib: the role of thermodynamic quantities and molecular mobility. Mol Pharm. 2004;1(6):406–13.
Lee H, Blaufox M. Blood volume in the rat. J Nucl Med. 1985;26(1):72–6.
Stypinski D, Wiebe L, Tam Y, Mercer J, McEwan A. Effects of methoxyflurane anesthesia on the pharmacokinetics of 125I-IAZA in Sprague–Dawley rats. Nucl Med Biol. 1999;26(8):959–65.
Guzman HR, Tawa M, Zhang Z, Ratanabanangkoon P, Shaw P, Gardner CR, et al. Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. J Pharm Sci. 2007;96(10):2686–702.
Tantishaiyakul V, Kaewnopparat N, Ingkatawornwong S. Properties of solid dispersions of piroxicam in polyvinylpyrrolidone. Int J Pharm. 1999;181(2):143–51.
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.
Gupta P, Bansal AK. Spray drying for generation of a ternary amorphous system of celecoxib, PVP, and meglumine. Pharm Dev Technol. 2005;10(2):273–81.
Davis M. Recent strategies in spray drying for the enhanced bioavailability of poorly water-soluble drugs. J Control Release. 2017;269:110–27.
Ziaee A, Albadarin AB, Padrela L, Faucher A, O'reilly E, Walker G. Spray drying ternary amorphous solid dispersions of ibuprofen–an investigation into critical formulation and processing parameters. Eur J Pharm Biopharm. 2017;120:43–51.
Chamsai B, Limmatvapirat S, Sungthongjeen S, Sriamornsak P. Enhancement of solubility and oral bioavailability of manidipine by formation of ternary solid dispersion with d-α-tocopherol polyethylene glycol 1000 succinate and copovidone. Drug Dev Ind Pharm. 2017;43(12):2064–75.
Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009;98(8):2549–72.
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The authors acknowledge the financial support from the Department of Pharmaceuticals (DoP), Ministry of Chemicals, and Fertilizers, Govt. of India.
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Chavan, R.B., Lodagekar, A., Yadav, B. et al. Amorphous solid dispersion of nisoldipine by solvent evaporation technique: preparation, characterization, in vitro, in vivo evaluation, and scale up feasibility study. Drug Deliv. and Transl. Res. 10, 903–918 (2020). https://doi.org/10.1007/s13346-020-00775-8
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DOI: https://doi.org/10.1007/s13346-020-00775-8