889
Views
65
CrossRef citations to date
0
Altmetric
Review

Oral bioavailability enhancement through supersaturation: an update and meta-analysis

, &
Pages 403-426 | Received 17 May 2016, Accepted 20 Jul 2016, Published online: 11 Aug 2016

References

  • Frank KJ, Rosenblatt KM, Westedt U, et al. Amorphous solid dispersion enhances permeation of poorly soluble ABT-102: true supersaturation vs. apparent solubility enhancement. Int J Pharm. 2012;437:288–293.
  • Guzmán HR, Tawa M, Zhang Z, 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;96:2686–2702.
  • Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009;98:2549–2572.
  • Kawakami K. Theory and practice of supersaturatable formulations for poorly soluble drugs. Ther Deliv. 2015;6:339–352.
  • Sun DD, Lee PI. Haste makes waste: the interplay between dissolution and precipitation of supersaturating formulations. AAPS J. 2015;17:1317–1326.
  • Xu S, Dai W-G. Drug precipitation inhibitors in supersaturable formulations. Int J Pharm. 2013;453:36–43.
  • Kawakami K. Modification of physicochemical characteristics of active pharmaceutical ingredients and application of supersaturatable dosage forms for improving bioavailability of poorly absorbed drugs. Adv Drug Deliv Rev. 2012;64:480–495.
  • Loftsson T, Brewster ME. Cyclodextrins as functional excipients: methods to enhance complexation efficiency. J Pharm Sci. 2012;101:3019–3032.
  • Lee TW-Y, Boersen NA, Hui H-W, et al. Oral delivery of poorly soluble compounds by supersaturated systems. Ther Deliv. 2011;2:685–690.
  • Greco K, Bogner R. Solution-mediated phase transformation: significance during dissolution and implications for bioavailability. J Pharm Sci. 2012;101:2996–3018.
  • Griffin B. Advances in lipid-based formulations: overcoming the challenge of low bioavailability for poorly water soluble drug compounds. Am Pharm Rev. 2012;15:41–47.
  • da Costa Mathews C, Sugano K. Supersaturable formulations. Drug Deliv Syst. 2010;25:371–374.
  • Warren DB, Benameur H, Porter CJH, et al. Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: a mechanistic basis for utility. J Drug Target. 2010;18:704–731.
  • He Y, Ho C. Amorphous solid dispersions: utilization and challenges in drug discovery and development. J Pharm Sci. 2015;104:3237–3258.
  • Newman A, Nagapudi K, Wenslow R. Amorphous solid dispersions: a robust platform to address bioavailability challenges. Ther Deliv. 2015;6:247–261.
  • Leone F, Cavalli R. Drug nanosuspensions: a ZIP tool between traditional and innovative pharmaceutical formulations. Exp Opin Drug Deliv. 2015;12:1607–1625.
  • Dokania S, Joshi AK. Self-microemulsifying drug delivery system (SMEDDS) – challenges and road ahead. Drug Deliv. 2015;22:675–690.
  • Saluja V, Arora S, Goyal S. Self-emulsifying lipid formulation: an overview. Curr Drug Deliv. 2015;12:166–176.
  • Williams HD, Trevaskis NL, Yeap YY, et al. Lipid-based formulations and drug supersaturation: harnessing the unique benefits of the lipid digestion/absorption pathway. Pharm Res. 2013;30:2976–2992.
  • Démuth B, Nagy ZK, Balogh A, et al. Downstream processing of polymer-based amorphous solid dispersions to generate tablet formulations. Int J Pharm. 2015;486:268–286.
  • Sun DD, Lee PI. Crosslinked hydrogels – a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs. Acta Pharm Sin B. 2014;4:26–36.
  • Pawar VK, Singh Y, Meher JG, et al. Engineered nanocrystal technology: in-vivo fate, targeting and applications in drug delivery. J Control Release. 2014;183:51–66.
  • Tarate B, Chavan R, Bansal A. Oral solid self-emulsifying formulations: a patent review. Recent Pat Drug Del Formul. 2014;8:126–143.
  • Li Y, Pang H, Guo Z, et al. Interactions between drugs and polymers influencing hot melt extrusion. J Pharm Pharmacol. 2014;66:148–166.
  • Speybroeck M, Mellaerts R, Martens JA, et al. Ordered mesoporous silica for the delivery of poorly soluble drugs. In: Wilson GC, Crowley JP, editors. Controlled release in oral drug delivery. Boston (MA): Springer US; 2011. p. 203–219.
  • Marthur V, Satrawala Y, Rajput MS. Biopharmaceutical performance and stability of co-crystal. Int J Pharm Frontier Res. 2011;1:135–145.
  • Stappaerts J, Brouwers J, Annaert P, et al. In situ perfusion in rodents to explore intestinal drug absorption: challenges and opportunities. Int J Pharm. 2015;478:665–681.
  • Kostewicz ES, Abrahamsson B, Brewster M, et al. In vitro models for the prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci. 2014;57:342–366.
  • Bevernage J, Brouwers J, Brewster ME, et al. Evaluation of gastrointestinal drug supersaturation and precipitation: strategies and issues. Int J Pharm. 2013;453:25–35.
  • Buckley ST, Frank KJ, Fricker G, et al. Biopharmaceutical classification of poorly soluble drugs with respect to “enabling formulations”. Eur J Pharm Sci. 2013;50:8–16.
  • Gao P, Shi Y. Characterization of supersaturatable formulations for improved absorption of poorly soluble drugs. AAPS J. 2012;14:703–713.
  • Augustijns P, Brewster ME. Supersaturating drug delivery systems: fast is not necessarily good enough. J Pharm Sci. 2012;101:7–9.
  • Newman A, Knipp G, Zografi G. Assessing the performance of amorphous solid dispersions. J Pharm Sci. 2012;101:1355–1377.
  • Williams HD, Trevaskis NL, Charman SA, et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev 2013;65:315–499.
  • Fong SYK, Brandl M, Bauer-Brandl A. Phospholipid-based solid drug formulations for oral bioavailability enhancement: a meta-analysis. Eur J Pharm Sci. 2015;80:89–110.
  • Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–1558.
  • Neyeloff J, Fuchs S, Moreira L. Meta-analyses and Forest plots using a Microsoft excel spreadsheet: step-by-step guide focusing on descriptive data analysis. BMC Res Notes. 2012;5:52.
  • Frank KJ, Westedt U, Rosenblatt KM, et al. What is the mechanism behind increased permeation rate of a poorly soluble drug from aqueous dispersions of an amorphous solid dispersion? J Pharm Sci. 2014;103:1779–1786.
  • Shi C, Tong Q, Fang J, et al. Preparation, characterization and in vivo studies of amorphous solid dispersion of berberine with hydrogenated phosphatidylcholine. Eur J Pharm Sci. 2015;74:11–17.
  • Zhaojie M, Ming Z, Shengnan W, et al. Amorphous solid dispersion of berberine with absorption enhancer demonstrates a remarkable hypoglycemic effect via improving its bioavailability. Int J Pharm. 2014;467:50–59.
  • Ueda K, Higashi K, Limwikrant W, et al. Mechanistic differences in permeation behavior of supersaturated and solubilized solutions of carbamazepine revealed by nuclear magnetic resonance measurements. Mol Pharm. 2012;9:3023–3033.
  • Tsinman O, Tsinman K, Ali S. Excipient update – soluplus: an understanding of supersaturation from amorphous solid dispersions. Drug Dev Deliv. 2015;15:20–26.
  • Beig A, Miller JM, Lindley D, et al. Head-to-head comparison of different solubility-enabling formulations of etoposide and their consequent solubility-permeability interplay. J Pharm Sci. 2015;104:2941–2947.
  • Song WH, Yeom DW, Lee DH, et al. In situ intestinal permeability and in vivo oral bioavailability of celecoxib in supersaturating self-emulsifying drug delivery system. Arch Pharmacal Res. 2013;37:626–635.
  • Kataoka M, Sugano K, Mathews C, et al. Application of dissolution/permeation system for evaluation of formulation effect on oral absorption of poorly water-soluble drugs in drug development. Pharm Res. 2011;29:1485–1494.
  • Zhou H, Wan J, Wu L, et al. A new strategy for enhancing the oral bioavailability of drugs with poor water-solubility and low liposolubility based on phospholipid complex and supersaturated SEDDS. PLoS One. 2013;8:e84530.
  • Nan Z, Lijun G, Tao W, et al. Evaluation of carbamazepine (CBZ) supersaturatable self-microemulsifying (S-SMEDDS) formulation in-vitro and in-vivo. Iran J Pharm Sci. 2012;11:257–264.
  • Bandyopadhyay S, Katare OP, Singh B. Development of optimized supersaturable self-nanoemulsifying systems of ezetimibe: effect of polymers and efflux transporters. Exp Opin Drug Deliv. 2014;11:479–492.
  • Tran TH, Guo Y, Song D, et al. Quercetin-containing self-nanoemulsifying drug delivery system for improving oral bioavailability. J Pharm Sci. 2014;103:840–852.
  • Di Cagno M, Luppi B. Drug “supersaturation” states induced by polymeric micelles and liposomes: a mechanistic investigation into permeability enhancements. Eur J Pharm Sci. 2013;48:775–780.
  • Pu X, Sun J, Han J, et al. Nanosuspensions of 10-hydroxycamptothecin that can maintain high and extended supersaturation to enhance oral absorption: preparation, characterization and in vitro/in vivo evaluation. J Nanoparticle Res. 2013;15:1–13.
  • Ueda K, Higashi K, Yamamoto K, et al. In situ molecular elucidation of drug supersaturation achieved by nano-sizing and amorphization of poorly water-soluble drug. Eur J Pharm Sci. 2015;77:79–89.
  • Nkansah P, Antipas A, Lu Y, et al. Development and evaluation of novel solid nanodispersion system for oral delivery of poorly water-soluble drugs. J Control Release. 2013;169:150–161.
  • Stappaerts J, Geboers S, Snoeys J, et al. Rapid conversion of the ester prodrug abiraterone acetate results in intestinal supersaturation and enhanced absorption of abiraterone: in vitro, rat in situ and human in vivo studies. Eur J Pharm Biopharm. 2015;90:1–7.
  • Balk A, Widmer T, Wiest J, et al. Ionic liquid versus prodrug strategy to address formulation challenges. Pharm Res. 2014;32:2154–2167.
  • Ha ES, Baek IH, Cho W, et al. Preparation and evaluation of solid dispersion of atorvastatin calcium with Soluplus(R) by spray drying technique. Chem Pharm Bull. 2014;62:545–551.
  • Bennett RC, Brough C, Miller DA, et al. Preparation of amorphous solid dispersions by rotary evaporation and KinetiSol dispersing: approaches to enhance solubility of a poorly water-soluble gum extract. Drug Dev Ind Pharm. 2015;41:382–397.
  • Jang D-J, Sim T, Oh E. Formulation and optimization of spray-dried amlodipine solid dispersion for enhanced oral absorption. Drug Dev Ind Pharm. 2013;39:1133–1141.
  • Ranzani LS, Font J, Galimany F, et al. Enhanced in vivo absorption of CB-1 antagonist in rats via solid solutions prepared by hot-melt extrusion. Drug Dev Ind Pharm. 2011;37:694–701.
  • De Jaeghere W, De Beer T, Van Bocxlaer J, et al. Hot-melt extrusion of polyvinyl alcohol for oral immediate release applications. Int J Pharm. 2015;492:1–9.
  • Lohani S, Cooper H, Jin X, et al. Physicochemical properties, form, and formulation selection strategy for a biopharmaceutical classification system class II preclinical drug candidate. J Pharm Sci. 2014;103:3007–3021.
  • Beak I-H, Kim M-S. Improved supersaturation and oral absorption of dutasteride by amorphous solid dispersions. Chem Pharm Bull. 2012;60:1468–1473.
  • Zhang M, Li H, Lang B, et al. Formulation and delivery of improved amorphous fenofibrate solid dispersions prepared by thin film freezing. Eur J Pharm Biopharm. 2012;82:534–544.
  • Chiang P-C, Cui Y, Ran Y, et al. In vitro and in vivo evaluation of amorphous solid dispersions generated by different bench-scale processes, using griseofulvin as a model compound. AAPS J. 2013;15:608–617.
  • DiNunzio JC, Brough C, Miller DA, et al. Fusion processing of itraconazole solid dispersions by kinetisol dispersing: a comparative study to hot melt extrusion. J Pharm Sci. 2010;99:1239–1253.
  • Kojima T, Higashi K, Suzuki T, et al. Stabilization of a supersaturated solution of mefenamic acid from a solid dispersion with EUDRAGIT® EPO. Pharm Res. 2012;29:2777–2791.
  • Kim M-S, Kim J-S, Cho W, et al. Supersaturatable formulations for the enhanced oral absorption of sirolimus. Int J Pharm. 2013;445:108–116.
  • Shah N, Iyer RM, Mair H-J, et al. Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process. J Pharm Sci. 2013;102:967–981.
  • Shi Y, Gao P, Gong Y, et al. Application of a biphasic test for characterization of in vitro drug release of immediate release formulations of celecoxib and its relevance to in vivo absorption. Mol Pharm. 2010;7:1458–1465.
  • Mukherjee T, Plakogiannis FM. Development and oral bioavailability assessment of a supersaturated self-microemulsifying drug delivery system (SMEDDS) of albendazole. J Pharm Pharmacol. 2010;62:1112–1120.
  • Tian X, Dong-Qin Q. Assessment of a supersaturated self-microemulsifying formulation of biphenyl dimethyl dicarboxylate in vitro and in vivo. Chin Pharm J. 2011;46:600–604.
  • Chen Y, Chen C, Zheng J, et al. Development of a solid supersaturatable self-emulsifying drug delivery system of docetaxel with improved dissolution and bioavailability. Biol Pharm Bull. 2011;34:278–286.
  • Lee DH, Yeom DW, Song YS, et al. Improved oral absorption of dutasteride via Soluplus®-based supersaturable self-emulsifying drug delivery system (S-SEDDS). Int J Pharm. 2015;478:341–347.
  • Sha XY, Chen YZ, Wu J, et al. Preparation of paclitaxel supersaturatable self-microemulsifying drug delivery system and its pharmacokinetics in rats. Pharm Care Res. 2011;11:138–140.
  • Thomas N, Richter K, Pedersen TB, et al. In vitro lipolysis data does not adequately predict the in vivo performance of lipid-based drug delivery systems containing fenofibrate. AAPS J. 2014;16:539–549.
  • Chavan RB, Modi SR, Bansal AK. Role of solid carriers in pharmaceutical performance of solid supersaturable SEDDS of celecoxib. Int J Pharm. 2015;495:374–384.
  • Kim M-S, Ha E-S, Choo G-H, et al. Preparation and in vivo evaluation of a dutasteride-loaded solid-supersaturatable self-microemulsifying drug delivery system. Int J Mol Sci. 2015;16:10821–10833.
  • Dash RN, Mohammed H, Humaira T, et al. Solid supersaturatable self-nanoemulsifying drug delivery systems for improved dissolution, absorption and pharmacodynamic effects of glipizide. J Drug Delivery Sci Technol. 2015;28:28–36.
  • Kim M-S. Evaluation of in vitro dissolution and in vivo oral absorption of dutasteride-loaded eudragit E nanoparticles. Drug Res. 2013;63:326–330.
  • Ochi M, Kawachi T, Toita E, et al. Development of nanocrystal formulation of meloxicam with improved dissolution and pharmacokinetic behaviors. Int J Pharm. 2014;474:151–156.
  • Kim M-S, Kim J-S, Park HJ, et al. Enhanced bioavailability of sirolimus via preparation of solid dispersion nanoparticles using a supercritical antisolvent process. Int J Nanomed. 2011;6:2997–3009.
  • Miller MA, DiNunzio J, Matteucci ME, et al. Flocculated amorphous itraconazole nanoparticles for enhanced in vitro supersaturation and in vivo bioavailability. Drug Dev Ind Pharm. 2012;38:557–570.
  • Kim M-S, Baek I-H. Fabrication and evaluation of valsartan–polymer– surfactant composite nanoparticles by using the supercritical antisolvent process. Int J Nanomed. 2014;9:5167–5176.
  • Van Speybroeck M, Mellaerts R, Thi TD, et al. Preventing release in the acidic environment of the stomach via occlusion in ordered mesoporous silica enhances the absorption of poorly soluble weakly acidic drugs. J Pharm Sci. 2011;100:4864–4876.
  • Van Speybroeck M, Mellaerts R, Mols R, et al. Enhanced absorption of the poorly soluble drug fenofibrate by tuning its release rate from ordered mesoporous silica. Eur J Pharm Sci. 2010;41:623–630.
  • Van Speybroeck M, Mols R, Mellaerts R, et al. Combined use of ordered mesoporous silica and precipitation inhibitors for improved oral absorption of the poorly soluble weak base itraconazole. Eur J Pharm Biopharm. 2010;75:354–365.
  • Jia Z, Lin P, Xiang Y, et al. A novel nanomatrix system consisted of colloidal silica and pH-sensitive polymethylacrylate improves the oral bioavailability of fenofibrate. Eur J Pharm Biopharm. 2011;79:126–134.
  • Kim M-S. Soluplus-coated colloidal silica nanomatrix system for enhanced supersaturation and oral absorption of poorly water-soluble drugs. Artif Cells Nanomed Biotechnol. 2013;41:363–367.
  • Rao S, Tan A, Boyd BJ, et al. Synergistic role of self-emulsifying lipids and nanostructured porous silica particles in optimizing the oral delivery of lovastatin. Nanomedicine. 2014;9:2745–2759.
  • Tan A, Davey AK, Prestidge CA. Silica-lipid hybrid (SLH) versus non-lipid formulations for optimising the dose-dependent oral absorption of celecoxib. Pharm Res. 2011;28:2273–2287.
  • Ganesh M, Jeon UJ, Ubaidulla U, et al. Chitosan cocrystals embedded alginate beads for enhancing the solubility and bioavailability of aceclofenac. Int J Biol Macromol. 2015;74:310–317.
  • Childs SL, Kandi P, Lingireddy SR. Formulation of a danazol cocrystal with controlled supersaturation plays an essential role in improving bioavailability. Mol Pharm. 2013;10:3112–3127.
  • Takano R, Takata N, Saito R, et al. Quantitative analysis of the effect of supersaturation on in vivo drug absorption. Mol Pharm. 2010;7:1431–1440.
  • Terebetski JL, Cummings JJ, Fauty SE, et al. Combined use of crystalline sodium salt and polymeric precipitation inhibitors to improve pharmacokinetic profile of ibuprofen through supersaturation. AAPS PharmSciTech. 2014;15:1334–1344.
  • Onoue S, Kojo Y, Suzuki H, et al. Development of novel solid dispersion of tranilast using amphiphilic block copolymer for improved oral bioavailability. Int J Pharm. 2013;452:220–226.
  • Desai S, Disouza J, Sable A, et al. Development of orodispersible tablet of atorvastatin calcium using hot melt extrusion. Drug Deliv Lett. 2015;5:19–30.
  • Mosharraf M, Nyström C. The effect of particle size and shape on the surface specific dissolution rate of microsized practically insoluble drugs. Int J Pharm. 1995;122:35–47.
  • Matteucci ME, Brettmann BK, Rogers TL, et al. Design of potent amorphous drug nanoparticles for rapid generation of highly supersaturated media. Mol Pharm. 2007;4:782–793.
  • Frank KJ, Westedt U, Rosenblatt KM, et al. The amorphous solid dispersion of the poorly soluble ABT-102 forms nano/microparticulate structures in aqueous medium: impact on solubility. Int J Nanomed. 2012;7:5757–5768.
  • Raina SA, Zhang GGZ, Alonzo DE, et al. Enhancements and limits in drug membrane transport using supersaturated solutions of poorly water soluble drugs. J Pharm Sci. 2014;103:2736–2748.
  • Polster CS, Wu S-J, Gueorguieva I, et al. Mechanism for enhanced absorption of a solid dispersion formulation of LY2300559 using the artificial stomach duodenum model. Mol Pharm. 2015;12:1131–1140.
  • Narang AS, Badawy S, Ye Q, et al. Role of self-association and supersaturation in oral absorption of a poorly soluble weakly basic drug. Pharm Res. 2015;32:2579–2594.
  • Williams HD, Sassene P, Kleberg K, et al. Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations. Pharm Res. 2013;30:3059–3076.
  • Qian F, Wang J, Hartley R, et al. Solution behavior of PVP-VA and HPMC-AS-based amorphous solid dispersions and their bioavailability implications. Pharm Res. 2012;29:2766–2776.
  • Do TT, Van Speybroeck M, Mols R, et al. The conflict between in vitro release studies in human biorelevant media and the in vivo exposure in rats of the lipophilic compound fenofibrate. Int J Pharm. 2011;414:118–124.
  • Kanzer J, Hupfeld S, Vasskog T, et al. In situ formation of nanoparticles upon dispersion of melt extrudate formulations in aqueous medium assessed by asymmetrical flow field-flow fractionation. J Pharm Biomed Anal. 2010;53:359–365.
  • Fong SYK, Ibisogly A, Bauer-Brandl A. Solubility enhancement of BCS class II drug by solid phospholipid dispersions: spray drying versus freeze-drying. Int J Pharm. 2015;496:382–391.
  • Shah KB, Patel PG, Khairuzzaman A, et al. An improved method for the characterization of supersaturation and precipitation of poorly soluble drugs using pulsatile microdialysis (PMD). Int J Pharm. 2014;468:64–74.
  • Fong SYK, Martins SM, Brandl M, et al. Solid phospholipid dispersions for oral delivery of poorly soluble drugs: investigation into celecoxib incorporation and solubility-in vitro permeability enhancement. J Pharm Sci. 2016;105:1113–1123.
  • Bevernage J, Brouwers J, Annaert P, et al. Drug precipitation–permeation interplay: supersaturation in an absorptive environment. Eur J Pharm Biopharm. 2012;82:424–428.
  • Mosquera-Giraldo LI, Taylor LS. Glass–liquid phase separation in highly supersaturated aqueous solutions of telaprevir. Mol Pharm. 2015;12:496–503.
  • Yu H, Xia D, Zhu Q, et al. Supersaturated polymeric micelles for oral cyclosporine A delivery. Eur J Pharm Biopharm. 2013;85:1325–1336.
  • Ginski MJ, Polli JE. Prediction of dissolution–absorption relationships from a dissolution/Caco-2 system. Int J Pharm. 1999;177:117–125.
  • Kataoka M, Masaoka Y, Yamazaki Y, et al. In vitro system to evaluate oral absorption of poorly water-soluble drugs: simultaneous analysis on dissolution and permeation of drugs. Pharm Res. 2003;20:1674–1680.
  • Motz SA, Schaefer UF, Balbach S, et al. Permeability assessment for solid oral drug formulations based on Caco-2 monolayer in combination with a flow through dissolution cell. Eur J Pharm Biopharm. 2007;66:286–295.
  • Buch P, Langguth P, Kataoka M, et al. IVIVC in oral absorption for fenofibrate immediate release tablets using a dissolution/permeation system. J Pharm Sci. 2009;98:2001–2009.
  • Miyaji Y, Fujii Y, Takeyama S, et al. Advantage of the dissolution/permeation system for estimating oral absorption of drug candidates in the drug discovery stage. Mol Pharm. 2016;13:1564–1574.
  • Motz AS, Bur M, Schaefer FU, et al. Instrumented in vitro approaches to assess epithelial permeability of drugs from pharmaceutical formulations. In: Ehrhardt C, Kim K-J, editors. Drug absorption studies: in situ, in vitro and in silico models. Boston (MA): Springer US; 2008. p. 430–455.
  • Petrakis O, Vertzoni M, Angelou A, et al. Identification of key factors affecting the oral absorption of salts of lipophilic weak acids: a case example. J Pharm Pharmacol. 2015;67:56–67.
  • Gao Y, Carr RA, Spence JK, et al. A pH-dilution method for estimation of biorelevant drug solubility along the gastrointestinal tract: application to physiologically based pharmacokinetic modeling. Mol Pharm. 2010;7:1516–1526.
  • Stillhart C, Imanidis G, Kuentz M. Insights into drug precipitation kinetics during in vitro digestion of a lipid-based drug delivery system using in-line Raman spectroscopy and mathematical modeling. Pharm Res. 2013;30:3114–3130.
  • Kleppe MS, Forney-Stevens KM, Haskell RJ, et al. Mathematical models to explore potential effects of supersaturation and precipitation on oral bioavailability of poorly soluble drugs. AAPS J. 2015;17:902–917.
  • Charkoftaki G, Dokoumetzidis A, Valsami G, et al. Supersaturated dissolution data and their interpretation: the TPGS–carbamazepine model case. J Pharm Pharmacol. 2011;63:352–361.
  • Woods D, Trewheellar K. Medline and Embase complement each other in literature searches. BMJ. 1998;316:1166–66.
  • Kleijnen J, Knipschild P. The comprehensiveness of Medline and Embase computer searches. Pharm Weekbl. 1992;14:316–320.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.