Dr Seishi Shimizu

Overview

Statistical thermodynamics of complex fluids: towards a rational approach to formulation

Solvents are crucial in all chemical, biotechnological, pharmaceutical, biomaterials and food industries: 

• Solubilizing key ingredients is central to product formulation and chemical processes.
• Yet choosing appropriate solvents (or mixtures) often requires extensive trials and errors and is costly.
• Biomolecules exploit solvation for their stability and function.

To exploit solvation to the full, we need to understand its molecular mechanism:

• Solvents associate with solutes in a non-specific and dynamic manner
• Traditional approaches (such as solvent binding model) do not work
• Statistical thermodynamics bridging molecular world with ours is the only reliable guideline from physics laws

Routine experimental data can be surprisingly informative on how molecules work, when assisted by theory:

• Solubilization mechanism can be revealed only from solubility, density and osmotic data
• Why some additives (cosolvents, hydrotropes, entrainers) dramatically increase solubility has been revealed
• How biomolecular stability is affected by osmolytes or flavour molecules can directly come from calorimetry data

To make this possible, we work on:

• Fundamental theory of solvation, adsorption and colloidal interactions using pen and paper
• Experimental work on solubility, densitometry, neutron scattering and biomolecular stability in collaboration with experimentalists
• Industrial collaborations on specific questions

Our present target areas are:

• Hydrotropy and solubilization
• Protein stability and denaturation
• Cellulose dissolution and biomass exploitation
• Colloids, surfactants and interface
• Food science

To find out more, our recent reviews would be useful:

• Formulating rationally via statistical thermodynamics: Shimizu, Curr. Opin. Coll. Interf. Sci. 2020, 48, 53-64.
• A general theory of hydrotropy: Shimizu & Matubayasi, Phys. Chem. Chem. Phys. 2017, 19, 23597.
• Green solution chemistry: Abbott, Booth & Shimizu, Green Chem. 2017, 19, 68-75.
• “Gastrophysics” - food gels and protein stability: Shimizu, Stenner & Matubayasi, Food Hydrocoll. 2017, 62, 128-139.
• Food flavour: Shimizu, Abbott & Matubayasi, Food & Function, 2017, 8, 2999-3009.

Formulation

Formulation science

I am a theorist working very closely with experimentalists and industry.

My research deals with one of the central questions in formulation science, namely how:

A. “transition”, such as solubility, stability, denaturation, sol-gel transition, aggregation, self-association, binding, dispersion, 

can be controlled by adding

B. “cosolvents”, such as hydrotropes, micelles, surfactants, Hofmeister salts, chaotropes, kosmotropes, osmolytes, crowders, inert polymers, denaturants, stabilizers, gelling agents, excipients.

This question is extremely wide in scope, covering diverse types of “transition” (list A and (a)), the wide-ranging “solute” size scales (list A and (b)), and “cosolvents” of varying self-aggregation tendencies (list B and (c)).

A formulator is faced with a need to make many decisions, i.e., to choose

1. the suitable experimental approach(es) out of multitude of candidates that claim to give insight into solution-phase interactions ((a), below),
2. the appropriate theory or model – from several options – to quantify solution-phase interactions ((b), below), and even
3. the correct explanation from mutually contradicting hypotheses that may or may not come with numbers or quantifiable models ((c), below).

Which experiment(s) should be carried out? How should the experiment(s) be analysed to obtain information on interactions taking place in solution? What are the driving forces for solubilization, aggregation, stabilization, and conformational changes?

We have brought in clarity from rigorous statistical thermodynamics. By “rigorous” we do not mean “pages of impenetrable derivations”. Rather, we mean nothing other than the use of its basic principles without any models or assumptions. By “clarity” we mean with regards to:

i. the definition of solute-solvent and solute-cosolvent interactions, in terms of the classical Kirkwood-Buff integrals (KBIs, below), i.e., the increment of water (or cosolvent) molecule from the bulk by the presence of a solute,

and

ii. how i. can be determined from experiments.

For example, calculation of the two KBIs (solute-solvent and solute-cosolvent) requires two independent experiments (as above), such as (a) water activity dependence of the solvation free energy and (b) partial molar volume, or the hydrostatic pressure dependence of the solvation free energy.

Unlike the classical hypotheses, interactions between the species have been defined from a molecular basis and are quantifiable directly from experiments. Many of them did not stand the test of statistical thermodynamics. Here, I wanted to give you a little flavour on how a formulator can work with statistical thermodynamics towards a rational design of experiments and an unambiguous interpretation of the driving forces behind cosolvent effects.

For more details, please refer to our recent reviews.

1. Formulating rationally via statistical thermodynamics: Shimizu,  Opin. Coll. Interf. Sci. 2020, 48, 53-64.
2. A general theory of hydrotropy:Shimizu & Matubayasi,  Chem. Chem. Phys. 2017, 19, 23597.
3. Green solution chemistry:Abbott, Booth & Shimizu, Green Chem. 2017, 19, 68-75.
4. “Gastrophysics” - food gels and protein stability: Shimizu, Stenner & Matubayasi, Food Hydrocoll. 2017, 62, 128-139.
5. Food flavour:Shimizu, Abbott & Matubayasi, Food & Function, 2017, 8, 2999-3009.

This page was based on Reference 1, above.  

I thank Prof Steven Abbott (TCNF Ltd) for fruitful collaboration.

Theory

Theory

I am a theorist who has a keen interest in industrial applications.

Solvation is a driving force and a bottleneck in many industrial processes. Because of its complexity (non-specific and dynamic nature), many traditional models failed.

My goal is to bridge experiments directly to the molecular world. This can be achieved by a rigorous (model-free) approach in statistical thermodynamics.

1. Solvation control, or controlling chemical processes and reactions (a), involving small and large molecules (b), using additives of varying degree of self-association.  See Formulation science tab for details

[Shimizu, Curr. Opin. Coll. Interf. Sci. 2020, 48, 53-64; Shimizu & Matubayasi, J. Phys. Chem. B 2014, 118, 3922-3930; Shimizu, Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 1195-1199.]   

2. Co-operative solubilization theory explains why solubility increases suddenly after certain concentration of hydrotropes and then saturates.

[Shimizu & Matubayasi, Phys. Chem. Chem. Phys. 2016, 25621-25628; 2017, 19: 23597-23605; 2017, 19, 26734-26742; J. Phys. Chem. B 2014, 118, 10515-10524.]

3.Liquid-liquid phase separation and thermodynamic phase stability.

(i) Fluctuations and droplets near the thermodynamic stability limit of multiple-component mixtures involving hydrotropes. This has important applications in surfactant-free solubilization.

[Shimizu & Matubayasi, Phys. Chem. Chem. Phys. 2018, 13777-13784; 2017, 19, 23597-23605.]

(ii) Whether a nanoparticle “dispersion” can be considered a “solution can be judged via experiments from thermodynamic stability condition.

[Shimizu & Matubayasi, J. Coll. Interf. Sci. 2020, 575, 472-479]

4. Phase stability under mesoscale confinement, such as the liquid-liquid phase separation of biomolecules in the cell and the confinement of solution mixtures in nano- and mesoscale.

[Shimizu & Matubayasi, Physica A. 2020, in press.]

I thank Professor Nobuyuki Matubayasi of Osaka University for a fruitful collaboration.  

Experiment

Experiment

Collaboration with experimentalists

I very much enjoy working with experimentalists, always looking for an opportunity to apply my theory, with some occasional stints in the lab (NB: under strict supervision). Here are some examples of our collaborative work.  

(Please refer to overview for my research goal, and to theory for my theoretical contributions.) 

Hydrotropes are very powerful in solubilizing high-value molecules and extracting them. (In collaboration with Steven Abbott TCNF Ltd and University of Aveiro.) 

The Coutinho group (Aveiro, Portugal) successfully confirmed the mechanism of solubilization that we have proposed via statistical thermodynamics!

[Abranches, Benfica, Soares, Sintra, Pires, Pinho, Shimizu & Coutinho, Chem. Comm., 2020, 56, 7143-7146; Soares, Abranches, Sintra, Leal-Duaso, García, Pires, Shimizu, Pinho & Coutinho, ACS Sust. Chem. Eng., 2020, 8, 14, 5742–5749.]

Protic ionic liquids are simple mixtures of acids and tertiary amines, which even a theorist could synthesize (NB: under the strict supervision of my former PhD student, Dr Joshua Reid). 

Photo taken at ISIS Neutron and Muon Source, Rutherford Appleton Laboratory.

They are promising in recycling polymers and textiles. (In collaboration with TWI Ltd, Bioniqs Ltd, Worn Again Ltd and University of Lisbon.)

[Reid, Agapito, Bernardes, Martins, Walker, Shimizu & Minas da Piedade, Phys. Chem. Chem. Phys., 2017, 19, 19928-19936.]

Cellulose solubilization and processing is key to expand the use of cellulose and its recycling. (In collaboration with JAMSTEC, Bioniqs Ltd and Worn Again Ltd). We work on various solvent mixtures that can dissolve cellulose and its analogues, such as aqueous solutions with Lithium ions and protic ionic liquids.

[Nicol, Isobe, Clark & Shimizu, Phys. Chem. Chem. Phys., 2017, 19,23106-23112; Berga, Bruce, Nicol, Holding, Isobe, Shimizu, Walker & Reid, Cellulose, 2020, in press.  Agapito, Bernardes, Martins, Walker, Shimizu & Minas da Piedade, Phys. Chem. Chem. Phys., 2017, 19, 19928-19936.]

Nanoscience. Ionic interactions on a hydrophobic surface are modulated by their sub-nanoscale distance to the surface. This has implications on salt bridges on protein surfaces. (In collaboration with University of Tokyo, NIMS, Nanjing University, Riken, Hokkaido University)

[Chen, Itoh, Masuda, Shimizu, Zhao, Ma, Nakamura, Okuro, Noguchi, Uosaki, Aida, Science, 2015, 348, 555-559]

Protein-protein interaction. Water network around the binding site contribute actively to ligand binding.  Its substantial contribution was evidenced by disrupting it via mutagenesis. (In collaboration with St Jude Children’s Research Hospital, Tennessee, York Chemistry and Biology colleagues).

Darby, Hopkins, Shimizu, Roberts, Brannigan, Turkenburg, Thomas, Hubbard & Fischer, J. Am. Chem. Soc. 2019, 141, 40, 15818–15826.]

Microscopy and biomedical imaging. The real-time motion of a lung cancer cell was observed non-destructively without staining. (In collaboration with RIAT Ltd, University of Tsukuba and Ibaraki University.)

[Shimizu, Saikawa, Uno, Kano, Shimizu, Eur. Phys. J. Appl. Phys., 2020, 91, 30701]

There is a wealth of published data in the literature. Statistical thermodynamics can make the data speak more about the molecular mechanisms. Steven Abbott TCNF Ltd have developed a series of interactive web-based application programs for analysing experimental data using our theory. (In Collaboration with

Food texture and flavour can be understood from the underlying molecular interactions. This is what statistical thermodynamics can do to help experimental measurements to say more about the molecules. (In collaboration with Steven Abbott TCNF Ltd and Osaka University).

[Shimizu, Food Func., 2015, 6, 3228-3235; Shimizu, Abbott & Matubayasi, Food Func., 2017,8, 2999-3009]

Supercritical CO₂ is a useful medium for extracting useful molecules. Because CO2 on its own is a poor solvent, a little bit of additive (called entrainers) is necessary for solubilization. How entrainers work was quantified for the first time. This comes with interactive tools for data analysis. (In collaboration with Steven Abbott TCNF Ltd).

 [Shimizu & Abbott, J. Phys. Chem. B, 2016, 120, 3713-3723]

Protein stability, denaturation, binding, aggregation and allosteric transition in the presence of cosolvents can be rationalized statistical thermodynamically.

[Shimizu, Curr. Opin. Coll. Interf. Sci. 2020, 48, 53-64; Shimizu & Matubayasi, J. Phys. Chem. B 2014, 118, 3922-3930; Shimizu, Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 1195-1199.]   

In addition, we are trying to publish in all branches of chemistry. Wish us good luck.

• Analytical chemistry. Chromatographic determination of solution interactions. (With Steven Abbott TCNF Ltd and Poznan University of Technology). Shimizu, Abbott, Adamska & Voelkel, Analyst, 2019, 144, 1632-1641.
• Organic chemistry. The effect of salts on Diels-Alder reaction. (With Bioniqs, Ltd). Reid, Aquino, Walker, Karadakov & Shimizu, ChemPhysChem, 2019, 20, 1538-1544
• Green Chemistry. Guideline for green hydrotropes. (With Steven Abbott TCNF Ltd). Abbott, Booth & Shimizu, Green Chem., 2017, 19, 68-75.

I would like to thank my experimental collaborators for inspiration, generosity, and patience towards me.

People

Group and collaboration

Group members past and present

• Julie Lynch (PhD student – with Dr Rob McElroy & Dr James Sherwood, 2021-)
• Yueqiang Wang (summer project supervised by Julie Lynch, 2022)
• Ben Williams (MChem, 2022)
• Max Dulson (MChem, 2022)
• William Spencer (BSc in Biochemistry, 2022)
• Olivia Dalby (MChem, 2021)
• Joseph Hurd (MSc in Natural Sciences, 2021 – with Dr John Slattery)
• Glyn Houghton (BSc in Chemistry, 2021)
• Tom Nicol (PhD in Chemistry, 2020 – with Prof James Clark. EPSRC studentship)
• Theodor Rohrkasten (summer project, 2020)
• Dinis Abranches (visiting MSc project student from Aveiro, Portugal, 2020)
• Marianna Mertzanis (MChem, 2018 – with Prof Brendan Keely)
• Kaja Harton (BSc in Biochemistry, 2018)
• Emil Chi (summer project, 2018 & 2019 – with Dr John Slattery. Laidlaw scholarship)
• Joshua Reid (PhD in Chemistry, 2017 – with Dr Adam Walker, TWI Ltd. EPSRC Case studentship)
• Laura Berga (summer project, 2017. Laidlaw scholarship)
• James Perry (BSc in Chemistry, 2016)
• Tom Nicol (MChem, 2015)
• Richard Stenner (MChem, 2015)
• Edd Riley (MChem, 2015)
• Richard Gammons (PhD in Chemistry, 2015 – with Dr John Slattery, Prof Neil Bruce and Prof Simon McQueen-Mason. BBSRC studentship)
• Pedro Aquino (visiting MChem student from Brazil, 2015)
• Edward Matthews (MChem, 2014)
• Mike Everard (MChem, 2014)
• Muhiadin Omar (summer project, 2013)
• Jonathan Booth (MChem, 2012)
• Tim James (MChem, 2011 – with Dr John Slattery)
• Joe Vincent (BSc in Biochemistry, 2010)
• Lawrence Wright (MChem, 2009, with Dr Adam Walker & Dr Guy Hembury, Bioniqs Ltd)
• Marc Sanders (BSc in Biochemistry, 2009, with Dr Adam Walker & Dr Guy Hembury, Bioniqs Ltd)
• Priyanka Kanth Devarakonda (BSc in Biochemistry, 2008)

(I sincerely apologise for any accidental and unintentional errors and omissions.)

Recent co-authors outside York

• Prof Nobuyuki Matubayasi (Osaka, Japan)
• Prof Steven Abbott (TCNF Ltd, Ipswich)
• Prof Joao Coutinho (Aveiro, Portugal)
• Dr Noriyuki Isobe (Japan Agency for Marine-Earth Science and Technology, Japan)
• Prof Simao Pinho (Bragança, Portugal)
• Dr Adam Walker (Bioniqs Ltd & Worn Again Ltd, Nottingham)
• Prof Adam Voelkel (Poznan, Poland)
• Prof Katarzyna Adamska (Poznan, Poland)
• Prof Leandro Martinez (Campinas, Brazil)
• Prof Manuel Minas da Piedade (Lisbon, Portugal)
• Prof Jose Nuno Canongia Lopez (Lisbon, Portugal)
• Prof Nicholas Gathergood (Talinn, Estonia)
• Dr Jens Smiatek (Stuttgart, Germany)
• Prof Paul Smith (Kansas State, USA)
• Dr Yu Kanasaki (Hiroshima, Japan)
• Dr Isao Shimizu (RIAT Ltd, Japan)
• Prof Hideaki Kano (Kyushu, Japan)
• Prof Katsuhiro Uno (Ibaraki, Japan)

Recent York co-authors

• Dr John Slattery
• Professor James Clark
• Dr Peter Karadakov
• Dr Avtar Matharu
• Dr Duncan Macquarrie
• Dr Vitaliy Budarin
• Prof Neil Bruce (Biology)
• Prof Simon McQueen-Mason (Biology)
• Prof Rod Hubbard
• Prof Gavin Thomas (Biology)
• Dr Andrew Hunt
• Dr Tom Farmer

Publications

Publications

My publications

For an up-to-date full list of my publications, please see the York Research database.

Selected publications

• Ensemble transformation in the fluctuation theory
  S Shimizu & N Matubayasi, Physica A, 2022, 585, 126430
• Sorption: a statistical thermodynamic fluctuation theory
  S Shimizu & N Matubayasi, Langmuir, 2021, 37, 7380–7391
• Temperature dependence of sorption
  S Shimizu & N Matubayasi, Langmuir, 2021, 37, 11008–11017
• Thermodynamic stability condition can judge whether a nanoparticle dispersion can be considered a solution in a single phase
  S Shimizu & N Matubayasi, J Coll Interf Sci.,2020, 575, 472-479
• Formulating rationally via statistical thermodynamics 
  S Shimizu, Curr Opin Coll Interf Sci, 2020, 48, 53-64.
• Water Networks Can Determine the Affinity of Ligand Binding to Proteins
  Darby JF, Hopkins AP, Shimizu S, Roberts SM, Brannigan JA, Turkenburg JP, Thomas GH, Hubbard RE, Fischer M., J Am Chem Soc., 2019, 141, 15818-15826
• Statistical thermodynamic foundation for mesoscale aggregation in ternary mixtures 
  S Shimizu & N Matubayasi, Phys Chem Chem Phys, 2018, 20, 13777-13784.
• Hydrotropy and scattering: pre-ouzo as extended near-spinodal region
  S Shimizu and N Matubayasi, Phys Chem Chem Phys., 2017, 19,26734-26742
• Unifying hydrotropy under Gibbs phase rule
  S Shimizu and N Matubayasi, Phys Chem Chem Phys., 2017, 19,23597-23605 
• The origin of cooperative solubilisation by hydrotropes
  S Shimizu and N Matubayasi, Phys Chem Chem Phys., 2016, 18,25621-25628 
• Hydrotrope accumulation around the drug: The driving force for solubilization and minimum hydrotrope concentration for nicotinamide and urea
  J J Booth, M Omar, S Abbott and S Shimizu, Phys Chem Chem Phys., 2015, 17, 8028-8037
• Subnanoscale hydrophobic modulation of salt bridges in aqueous media
  S Chen, Y Itoh, T Masuda, S Shimizu, J Zhao, J Ma, S Nakamura, K Okuro, H Noguchi, K Uosaki and T Aida, Science, 2015, 348, 555-559
• Preferential Solvation: Dividing surface vs excess numbers
  S Shimizu and N Matubayasi,J Phys Chem B., 2014, 118, 3922-3930.
• Hydrotropy: Monomer–micelle equilibrium and minimum hydrotrope concentration
  S Shimizu and N Matubayasi, J Phys Chem B., 2014, 118, 10515-10524.
• The Mechanism of Hydrophobic Drug Solubilization by Small Molecule Hydrotropes
  J J Booth, S Abbott and S Shimizu, J Phys Chem B., 2012, 116, 14915–14921.
• Estimating hydration changes upon biomolecular reactions from osmotic stress, high pressure, and preferential hydration experiments
  S Shimizu, Proc Natl Acad Sci USA, 2004, 101, 1195-1199.

Undergraduate publications

Undergraduates can publish

With their dedication, determination and hard work, undergraduate students have managed to publish their final year and summer projects in peer-reviewed scientific journals.

• James M. Perry, Yu Nagai Kanasaki, Peter B. Karadakov, Seishi Shimizu, “Mechanism of dye solubilization and de-aggregation by urea”, Dyes and Pigments, 193, 109530 (2021).

• Laura Berga, Isobel Bruce,Thomas W. J. Nicol, Ashley J. Holding, Noriyuki Isobe, Seishi Shimizu, Adam J. Walker, Joshua E. S. J. Reid, “Cellulose dissolution and regeneration using a non-aqueous, non-stoichiometric protic ionic liquid system”, Cellulose, 27, 9593–9603 (2020).
• Kaja Harton and Seishi Shimizu, “Response to the “Comments on ‘Statistical thermodynamics of casein aggregation: Effects of salts and water’ [Biophys Chem. 247 (2019) 34–42]””, Biophys. Chem. 256, 106267 (2020).
• Kaja Harton and Seishi Shimizu, “Statistical thermodynamics of casein aggregation: Effects of salts and water”, Biophys. Chem. 247 34–42 (2019).
• Andrew J. Maneffa, Richard Stenner, Avtar S. Matharu, James H. Clark, Nobuyuki Matubayasi and Seishi Shimizu, “Water activity in liquid food systems: A molecular scale interpretation”, Food Chem., 237, 1133-1138 (2019).
• Joshua E. S. J. Reid, Pedro H. G. Aquino, Adam J. Walker, Peter B. Karadakov, and Seishi Shimizu, "Statistical thermodynamics unveils how ions influence an aqueous Diels-Alder reaction", ChemPhysChem, 20, 1538-1544 (2019).
• Steven Abbott, Jonathan J. Booth, and Seishi Shimizu, “Practical molecular thermodynamics for greener solution chemistry”, Green Chemistry, 19,68-75 (2017).
• Seishi Shimizu, Richard Stenner, and Nobuyuki Matubayasi, “Gastrophysics: Statistical thermodynamics of biomolecular denaturation and gelation from the Kirkwood-Buff theory towards the understanding of tofu”, Food Hydrocoll., 62, 128-139 (2017).
• Thomas W. J. Nicol, Nobuyuki Matubayasi, and Seishi Shimizu, “Origin of nonlinearity in phase solubility: Solubilisation by cyclodextrin beyond stoichiometric complexation”,  Chem. Chem. Phys., 18, 15205-15217 (2016). 
• Richard Stenner, Nobuyuki Matubayasi, and Seishi Shimizu, “Gelation of carrageenan: Effects of sugars and polyols”, Food Hydrocoll., 54, 284-292 (2016).
• Jonathan J. Booth, Muhiadin Omar, Steven Abbott, and Seishi Shimizu, S. “Hydrotrope accumulation around the drug: The driving force for solubilization and minimum hydrotrope concentration for nicotinamide and urea”,  Chem. Chem. Phys., 17, 8028-8037 (2015).
• Seishi Shimizu, Jonathan J. Booth, and Steven Abbott, “Hydrotropy: binding models statistical thermodynamics”, Phys. Chem. Chem. Phys., 15, 20625-20632 (2013).
• Jonathan J. Booth, Steven Abbott, and Seishi Shimizu, “Mechanism of Hydrophobic Drug Solubilization by Small Molecule Hydrotropes.”  Phys. Chem. B, 116, 14915-14921 (2012).
• Lawrence Wright, Marc W. Sanders, Lauren Tate, Gayle Fairless, Lorna Crowhurst, Lorna, Neil C. Bruce, Adam J. Walker, Guy A. Hembury, and Seishi Shimizu, “Hydrophilicity, the major determining factor influencing the solvation environment of protic ionic liquids”, Chem. Chem. Phys., 12, 9063-9066 (2010).
• Marc W. Sanders, Lawrence Wright, Lauren Tate, Gayle Fairless, Lorna Crowhurst, Lorna, Neil C. Bruce, Adam J. Walker, Guy A. Hembury, and Seishi Shimizu, “Unexpected Preferential Dehydration of Artemisinin in Ionic Liquids”, Phys. Chem. A, 113, 10143-10145 (2009).