The selection of polymers suitable for the formulation of supersaturating drug-delivery systems is imperative to improve the solubility, thermodynamic stability, precipitation inhibition ability, and bioavailability of drugs in vivo. However, a detailed molecular-level understanding of finding the right drug–polymer combination in the aqueous medium is still ambiguous and often selected based on the trial procedure. Here, we have employed sum frequency generation vibrational spectroscopy (SFG-VS) to probe the impact of drug–polymer interactions on the interfacial water structure at the model biorelevant medium (BM) interface to extract better insights into the molecular system. We investigated two different polymers, Eudragit EPO (E-EPO) and polyvinylpyrrolidone K30 (P-K30), resulting in a considerable difference in the supersaturation limits of the atorvastatin calcium (ATC), the model drug molecule in the BM solution. The solubility study suggests an ∼42 times enhancement in the solubility of ATC drug with the presence of E-EPO polymer and merely an ∼2.6 times enhancement for polymer P-K30. Interestingly, SFG spectroscopic studies showed that E-EPO supports a substantial orientational ordering of the interfacial water molecules with the signature of strongly hydrogen (H)-bonded water molecules. An opposite trend is witnessed for the P-K30 polymer with less preferential ordering and weakly H-bonded water molecules at the air–BM interface. The microscopic insights from the SFG spectroscopy, in correlation with the observations on drug solubility, present a new potential approach for probing drug–polymer interactions. The implementation of SFG vibrational spectroscopy can be beneficial in selecting suitable polymers to adopt better strategies for bioavailability enhancement in drug formulation development.
REFERENCES
1.
B.
Rana
, D. J.
Fairhurst
, and K. C.
Jena
, “Investigation of water evaporation process at air/water interface using hofmeister ions
,” J. Am. Chem. Soc.
144
, 17832
–17840
(2022
).2.
E.
Brini
, C. J.
Fennell
, M.
Fernandez-Serra
, B.
Hribar-Lee
, M.
Lukšič
, and K. A.
Dill
, “How water’s properties are encoded in its molecular structure and energies
,” Chem. Rev.
117
, 12385
–12414
(2017
).3.
J.
Westergren
, L.
Lindfors
, T.
Höglund
, K.
Lüder
, S.
Nordholm
, and R.
Kjellander
, “In silico prediction of drug solubility: 1. Free energy of hydration
,” J. Phys. Chem. B
111
, 1872
–1882
(2007
).4.
F.
Höök
, B.
Kasemo
, M.
Grunze
, and S.
Zauscher
, “Quantitative biological surface science: Challenges and recent advances
,” ACS Nano
2
, 2428
–2436
(2008
).5.
H. D.
Williams
, N. L.
Trevaskis
, S. A.
Charman
, R. M.
Shanker
, W. N.
Charman
, C. W.
Pouton
, and C. J. H.
Porter
, “Strategies to address low drug solubility in discovery and development
,” Pharmacol. Rev.
65
, 315
–499
(2013
).6.
K.
Meister
, S.
Strazdaite
, A. L.
DeVries
, S.
Lotze
, L. L. C.
Olijve
, I. K.
Voets
, and H. J.
Bakker
, “Observation of ice-like water layers at an aqueous protein surface
,” Proc. Natl. Acad. Sci. U. S. A.
111
, 17732
–17736
(2014
).7.
F.-G.
Wu
, P.
Yang
, C.
Zhang
, X.
Han
, M.
Song
, and Z.
Chen
, “Investigation of drug–model cell membrane interactions using sum frequency generation vibrational spectroscopy: A case study of chlorpromazine
,” J. Phys. Chem. C
118
, 17538
–17548
(2014
).8.
N.
Dhopatkar
, A. P.
Defante
, and A.
Dhinojwala
, “Ice-like water supports hydration forces and eases sliding friction
,” Sci. Adv.
2
, e1600763
(2016
).9.
S.
Sun
, A. M.
Sendecki
, S.
Pullanchery
, D.
Huang
, T.
Yang
, and P. S.
Cremer
, “Multistep interactions between Ibuprofen and lipid membranes
,” Langmuir
34
, 10782
–10792
(2018
).10.
J.
Grdadolnik
, F.
Merzel
, and F.
Avbelj
, “Origin of hydrophobicity and enhanced water hydrogen bond strength near purely hydrophobic solutes
,” Proc. Natl. Acad. Sci. U. S. A.
114
, 322
–327
(2017
).11.
D.
Ben-Amotz
, “Hydration-shell vibrational spectroscopy
,” J. Am. Chem. Soc.
141
, 10569
–10580
(2019
).12.
J. D.
Cyran
, M. A.
Donovan
, D.
Vollmer
, F.
Siro Brigiano
, S.
Pezzotti
, D. R.
Galimberti
, M.-P.
Gaigeot
, M.
Bonn
, and E. H. G.
Backus
, “Molecular hydrophobicity at a macroscopically hydrophilic surface
,” Proc. Natl. Acad. Sci. U. S. A.
116
, 1520
–1525
(2019
).13.
D.
Tomar
, S.
Chaudhary
, and K. C.
Jena
, “Self-assembly of L-phenylalanine amino acid: Electrostatic induced hindrance of fibril formation
,” RSC Adv.
9
, 12596
–12605
(2019
).14.
K.
Sensui
, T.
Tarui
, T.
Miyamae
, and C.
Sato
, “Evidence of chemical-bond formation at the interface between an epoxy polymer and an isocyanate primer
,” Chem. Commun.
55
, 14833
–14836
(2019
).15.
K.
Aoki
, K.
Shiraki
, and T.
Hattori
, “Salt effects on the picosecond dynamics of lysozyme hydration water investigated by terahertz time-domain spectroscopy and an insight into the Hofmeister series for protein stability and solubility
,” Phys. Chem. Chem. Phys.
18
, 15060
–15069
(2016
).16.
J.
Wang
, S. M.
Buck
, and Z.
Chen
, “The effect of surface coverage on conformation changes of bovine serum albumin molecules at the air–solution interface detected by sum frequency generation vibrational spectroscopy
,” Analyst
128
, 773
–778
(2003
).17.
N. W.
Ulrich
, J. N.
Myers
, and Z.
Chen
, “Characterization of polymer/epoxy buried interfaces with silane adhesion promoters before and after hygrothermal aging for the elucidation of molecular level details relevant to adhesion
,” RSC Adv.
5
, 105622
–105631
(2015
).18.
D. B.
Warren
, H.
Benameur
, C. J. H.
Porter
, and C. W.
Pouton
, “Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: A mechanistic basis for utility
,” J. Drug Targeting
18
, 704
–731
(2010
).19.
K.
Vithani
, V.
Jannin
, C. W.
Pouton
, and B. J.
Boyd
, “Colloidal aspects of dispersion and digestion of self-dispersing lipid-based formulations for poorly water-soluble drugs
,” Adv. Drug Delivery Rev.
142
, 16
–34
(2019
).20.
A.
Elkhabaz
, D. E.
Moseson
, J.
Brouwers
, P.
Augustijns
, and L. S.
Taylor
, “Interplay of supersaturation and solubilization: Lack of correlation between concentration-based supersaturation measurements and membrane transport rates in simulated and aspirated human fluids
,” Mol. Pharm.
16
, 5042
–5053
(2019
).21.
P.
Gao
and Y.
Shi
, “Characterization of supersaturatable formulations for improved absorption of poorly soluble drugs
,” AAPS J.
14
, 703
–713
(2012
).22.
J. M. M.
Salmani
, H.
Lv
, S.
Asghar
, and J.
Zhou
, “Amorphous solid dispersion with increased gastric solubility in tandem with oral disintegrating tablets: A successful approach to improve the bioavailability of atorvastatin
,” Pharm. Dev. Technol.
20
, 465
–472
(2015
).23.
J.
Brouwers
, M. E.
Brewster
, and P.
Augustijns
, “Supersaturating drug delivery systems: The answer to solubility-limited oral bioavailability?
,” J. Pharm. Sci.
98
, 2549
–2572
(2009
).24.
L.
Hu
, D.
Gu
, Q.
Hu
, Y.
Shi
, and N.
Gao
, “Investigation of solid dispersion of atorvastatin calcium in polyethylene glycol 6000 and polyvinylpyrrolidone
,” Trop. J. Pharm. Res.
13
, 835
–842
(2014
).25.
X.
Wu
, L. R.
Whitfield
, and B. H.
Stewart
, “Atorvastatin transport in the Caco-2 cell model: Contributions of P-glycoprotein and the proton-monocarboxylic acid co-transporter
,” Pharm. Res.
17
, 209
–215
(2000
).26.
S.
Sunnam
, I.
Sodhi
, P.
Joshi
, S. K.
Samal
, and A. T.
Sangamwar
, “Correlating precipitation inhibition efficacy of EUD EPO and PVP K30 on supersaturated solution of atorvastatin calcium with Caco-2 permeability enhancement
,” J. Drug Delivery Sci. Technol.
57
, 101692
(2020
).27.
X.
Wei
and Y. R.
Shen
, “Motional effect in surface sum-frequency vibrational spectroscopy
,” Phys. Rev. Lett.
86
, 4799
–4802
(2001
).28.
E.
Tyrode
, C. M.
Johnson
, A.
Kumpulainen
, M. W.
Rutland
, and P. M.
Claesson
, “Hydration state of nonionic surfactant monolayers at the liquid/vapor interface: Structure determination by vibrational sum frequency spectroscopy
,” J. Am. Chem. Soc.
127
, 16848
–16859
(2005
).29.
J. E.
Patterson
, “The nonresonant sum-frequency generation response: The not-so-silent partner
,” J. Chem. Phys.
161
, 60901
(2024
).30.
K. C.
Jena
and D. K.
Hore
, “Water structure at solid surfaces and its implications for biomolecule adsorption
,” Phys. Chem. Chem. Phys.
12
, 14383
–14404
(2010
).31.
D.
Tomar
, B.
Rana
, and K. C.
Jena
, “The structure of water–DMF binary mixtures probed by linear and nonlinear vibrational spectroscopy
,” J. Chem. Phys.
152
, 114707
(2020
).32.
Q.
Du
, R.
Superfine
, E.
Freysz
, and Y. R.
Shen
, “Vibrational spectroscopy of water at the vapor/water interface
,” Phys. Rev. Lett.
70
, 2313
–2316
(1993
).33.
D. E.
Gragson
, B. M.
McCarty
, and G. L.
Richmond
, “Ordering of interfacial water molecules at the charged air/water interface observed by vibrational sum frequency generation
,” J. Am. Chem. Soc.
119
, 6144
–6152
(1997
).34.
B.
Rana
, D. J.
Fairhurst
, and K. C.
Jena
, “Ion-specific water–macromolecule interactions at the air/aqueous interface: An insight into hofmeister effect
,” J. Am. Chem. Soc.
145
, 9646
–9654
(2023
).35.
S.
Chaudhary
, H.
Kaur
, H.
Kaur
, and K. C.
Jena
, “Recognition of bovine hemoglobin protein on molecularly imprinted polymer surfaces using nonlinear vibrational spectroscopy
,” Appl. Phys. Lett.
123
, 033703
(2023
).36.
H.
Kaur
, D.
Tomar
, H.
Kaur
, B.
Rana
, S.
Chaudhary
, and K. C.
Jena
, “Sum-frequency generation vibrational spectroscopy: A nonlinear optical tool to probe the polymer interfaces
,” in Advances in Spectroscopy: Molecules to Materials
, edited by D. K.
Singh
, S.
Das
, and A.
Materny
(Springer
, 2019
), Vol. 236
, pp. 39
–55
.37.
E.
Jantratid
and J.
Dressman
, “Biorelevant dissolution media simulating the proximal human gastrointestinal tract: An update
,” Dissolution Technol.
16
, 21
–25
(2009
).38.
M.
Sovago
, R. K.
Campen
, H. J.
Bakker
, and M.
Bonn
, “Hydrogen bonding strength of interfacial water determined with surface sum-frequency generation
,” Chem. Phys. Lett.
470
, 7
–12
(2009
).39.
N. N.
Casillas-Ituarte
, K. M.
Callahan
, C. Y.
Tang
, X.
Chen
, M.
Roeselová
, D. J.
Tobias
, and H. C.
Allen
, “Surface organization of aqueous MgCl2 and application to atmospheric marine aerosol chemistry
,” Proc. Natl. Acad. Sci. U. S. A.
107
, 6616
–6621
(2010
).40.
E. A.
Raymond
and G. L.
Richmond
, “Probing the molecular structure and bonding of the surface of aqueous salt solutions
,” J. Phys. Chem. B
108
, 5051
–5059
(2004
).41.
D.
Wu
, Y.
Guo
, G.
Liu
, and G.
Zhang
, “Investigation of the interfacial water structure on poly[2-(dimethylamino)ethyl methacrylate] at the air/water interface by sum frequency generation vibrational spectroscopy
,” Chin. Sci. Bull.
57
, 984
–991
(2012
).42.
X.
Pan
, F.
Yang
, S.
Chen
, X.
Zhu
, and C.
Wang
, “Cooperative effects of zwitterionic–ionic surfactant mixtures on the interfacial water structure revealed by sum frequency generation vibrational spectroscopy
,” Langmuir
34
, 5273
–5278
(2018
).43.
M.
Sovago
, R. K.
Campen
, G. W. H.
Wurpel
, M.
Müller
, H. J.
Bakker
, and M.
Bonn
, “Vibrational response of hydrogen-bonded interfacial water is dominated by intramolecular coupling
,” Phys. Rev. Lett.
100
, 173901
(2008
).44.
W.
Gan
, D.
Wu
, Z.
Zhang
, R.-R.
Feng
, and H.-F.
Wang
, “Polarization and experimental configuration analyses of sum frequency generation vibrational spectra, structure, and orientational motion of the air/water interface
,” J. Chem. Phys.
124
, 114705
(2006
).45.
N.
Ji
, V.
Ostroverkhov
, C. S.
Tian
, and Y. R.
Shen
, “Characterization of vibrational resonances of water-vapor interfaces by phase-sensitive sum-frequency spectroscopy
,” Phys. Rev. Lett.
100
, 096102
(2008
).46.
C. S.
Tian
and Y. R.
Shen
, “Sum-frequency vibrational spectroscopic studies of water/vapor interfaces
,” Chem. Phys. Lett.
470
, 1
–6
(2009
).47.
J. A.
Mondal
, V.
Namboodiri
, P.
Mathi
, and A. K.
Singh
, “Alkyl chain length dependent structural and orientational transformations of water at alcohol–water interfaces and its relevance to atmospheric aerosols
,” J. Phys. Chem. Lett.
8
, 1637
–1644
(2017
).48.
C.
Dutta
, A.
Svirida
, M.
Mammetkuliyev
, M.
Rukhadze
, and A. V.
Benderskii
, “Insight into water structure at the surfactant surfaces and in microemulsion confinement
,” J. Phys. Chem. B
121
, 7447
–7454
(2017
).49.
J. A.
Mondal
, S.
Nihonyanagi
, S.
Yamaguchi
, and T.
Tahara
, “Three distinct water structures at a zwitterionic lipid/water interface revealed by heterodyne-detected vibrational sum frequency generation
,” J. Am. Chem. Soc.
134
, 7842
–7850
(2012
).50.
J. A.
Fournier
, C. T.
Wolke
, C. J.
Johnson
, M. A.
Johnson
, N.
Heine
, S.
Gewinner
, W.
Schöllkopf
, T. K.
Esser
, M. R.
Fagiani
, H.
Knorke
, and K. R.
Asmis
, “Site-specific vibrational spectral signatures of water molecules in the magic H3O+(H2O)20 and Cs+(H2O)20 clusters
,” Proc. Natl. Acad. Sci. U. S. A.
111
, 18132
–18137
(2014
).51.
S.
Saha
, S.
Roy
, M.
Pandiyathuray
, and J. A.
Mondal
, “Polyatomic iodine species at the air-water interface and its relevance to atmospheric iodine chemistry: An HD-VSFG and Raman-MCR study
,” J. Phys. Chem. A
123
, 2924
–2934
(2019
).52.
S.
Strazdaite
, J.
Versluis
, E. H. G.
Backus
, and H. J.
Bakker
, “Enhanced ordering of water at hydrophobic surfaces
,” J. Chem. Phys.
140
, 054711
(2014
).53.
Z.
Chen
, Y.
Shen
, and G. A.
Somorjai
, “Studies of polymer surfaces by sum frequency generation vibrational spectroscopy
,” Annu. Rev. Phys. Chem.
53
, 437
–465
(2002
).54.
A. D.
Curtis
, A. R.
Calchera
, M. C.
Asplund
, and J. E.
Patterson
, “Observation of sub-surface phenyl rings in polystyrene with vibrationally resonant sum-frequency generation
,” Vib. Spectrosc.
68
, 71
–81
(2013
).55.
K. A.
Becraft
, F. G.
Moore
, and G. L.
Richmond
, “In-situ spectroscopic investigations of surfactantadsorption and water structure at the CaF2/aqueous solution interface
,” Phys. Chem. Chem. Phys.
6
, 1880
–1889
(2004
).56.
A. V.
Benderskii
and K. B.
Eisenthal
, “Aqueous solvation dynamics at the anionic surfactant air/water interface
,” J. Phys. Chem. B
105
, 6698
–6703
(2001
).57.
M. D.
Baer
, I.-F. W.
Kuo
, D. J.
Tobias
, and C. J.
Mundy
, “Toward a unified picture of the water self-ions at the air–water interface: A density functional theory perspective
,” J. Phys. Chem. B
118
, 8364
–8372
(2014
).58.
S.
Kaur
, D.
Tomar
, M.
Chaudhary
, B.
Rana
, H.
Kaur
, V.
Nigam
, and K. C.
Jena
, “Interfacial molecular structure of phosphazene-based polymer electrolyte at the air-aqueous interface using sum frequency generation vibrational spectroscopy
,” J. Phys.: Condens. Matter
36
, 105001
(2023
).59.
K. S.
Gautam
, A. D.
Schwab
, A.
Dhinojwala
, D.
Zhang
, S. M.
Dougal
, and M. S.
Yeganeh
, “Molecular structure of polystyrene at air/polymer and solid/polymer interfaces
,” Phys. Rev. Lett.
85
, 3854
–3857
(2000
).60.
R. I.
Moustafine
, T. V.
Kabanova
, V. A.
Kemenova
, and G.
Van den Mooter
, “Characteristics of interpolyelectrolyte complexes of eudragit E100 with eudragit L100
,” J. Controlled Release
103
, 191
–198
(2005
).61.
Y.
Borodko
, S. E.
Habas
, M.
Koebel
, P.
Yang
, H.
Frei
, and G. A.
Somorjai
, “Probing the interaction of poly(vinylpyrrolidone) with platinum nanocrystals by UV−Raman and FTIR
,” J. Phys. Chem. B
110
, 23052
–23059
(2006
).62.
J. C.
Conboy
, M. C.
Messmer
, and G. L.
Richmond
, “Investigation of surfactant conformation and order at the Liquid−Liquid interface by total internal reflection sum-frequency vibrational spectroscopy
,” J. Phys. Chem.
100
, 7617
–7622
(1996
).63.
T. D.
Ambagaspitiya
, D. J. C.
Garza
, A.
Zuercher
, and K. L.
Asetre Cimatu
, “Investigating the self-assembly of pH-sensitive switchable diamine surfactant using sum frequency generation spectroscopy and molecular dynamics simulations
,” J. Chem. Phys.
161
, 164709
(2024
).64.
A. G.
Lambert
, P. B.
Davies
, and D. J.
Neivandt
, “Implementing the theory of sum frequency generation vibrational spectroscopy: A tutorial review
,” Appl. Spectrosc. Rev.
40
, 103
–145
(2005
).65.
S.
Ye
, P.
Majumdar
, B.
Chisholm
, S.
Stafslien
, and Z.
Chen
, “Antifouling and antimicrobial mechanism of tethered quaternary ammonium salts in a cross-linked poly(dimethylsiloxane) matrix studied using sum frequency generation vibrational spectroscopy
,” Langmuir
26
, 16455
–16462
(2010
).© 2025 Author(s). Published under an exclusive license by AIP Publishing.
2025
Author(s)
You do not currently have access to this content.
