Laboratory 4-1. Physical Chemistry of Drugs

Scientific direction: 
Design of novel drug forms and biomedical materials
Phone: 
+7 (4932) 533784

Main research themes of the Laboratory:

 

“Development of scientific basis for creation of neurodegenerative and anti-inflammation drug compounds and forms with improved solubility and permeability characteristics”

 

N 01.2.00 950827

 

Head of the Laboratory: Perlovich G.L., PhD, DSc

 

The main problems:

 

In spite of the fact that in many cases affinity to the receptors is obviously a key moment for the potential drug compound candidates, other factors such as solubility, distribution in the immiscible phases, absorption properties, active and passive transport characteristics are also of a great importance for in vivo processes. Unfortunately the above aspects are taking into account only on the final stages of preparation’s screening and design. As a result, the selected candidates possessing the best affinities to the receptors reveal in vitro a wide spectrum of undesirable properties: low solubility in biologically relevant media and extremely poor membrane permeability. Just these points are the serious barriers for the potential candidates («hit-compounds») to become an effective drugs. Even the contemporary advancements of drug substances delivery by means of the complicated pharmaceutical systems can’t compensate the above mentioned limitations. A much more effective and economical way assumes controlling the permeability of the compounds through the different types of membranes on the stages preceding biological and preclinical testing. As a result, not only the facilities economy of highly expensed in-vivo tests occurs, but also the procedure of choosing the «leader-compound» is considerably promoted.

 

To solve the problems in the Laboratory it is carrying out investigations in the following areas:

 

  • Development of drug compounds with neuroprotective and cognitive-stimulating actions;
  • Development of scientific basis for obtaining well soluble drug substances/forms by using cocrystal technology;
  • Development and design of High Throughput Screening (HTS) algorithms of membrane permeability of drug compounds;
  • Impact of structural modification of drug molecules (without disturbing pharmacological site) on ADME characteristics;
  • Polymorphism of drug compounds;
  • Development of drug delivery systems;

 

The studies are conducting:

 

  • Investigation of sublimation processes of drug compounds;
  • X-ray diffraction analysis and theoretical description of crystal lattice energies of molecular crystals;
  • Studying solubility and solvation processes of drug substances in biological relevant mediums;
  • Studying distribution/partitioning processes of drug compounds in the model systems;
  • Design of membranes modeling to the various biological barriers;
  • Investigation and analysis of membrane permeability of drug substances;
  • Studying intermolecular interactions of drugs in biological mediums, crystals and pharmaceutical systems;
  • Development of screening algorithms for obtaining pharmaceutical cocrystals;

 

International collaboration:

  • Institute of Physical Chemistry of Poland Academy of Sciences, Warsaw, Poland.
  • University of Tromsø, Institute of Pharmacy, Breivika, N-9037 Tromsø, Norway.
  • Institute of Chemical Sciences, University of Bologna, 40127 Bologna, Italy.
  • Division of Structural Biochemistry, Research Center Borstel, Leibniz Center for Medicine and Biosciences, Parkallee 1-40, D-23845 Borstel, Germany.
  • Division of Pharmaceutical Technology, Faculty of Pharmacy, P.O. Box 56, FI-00014, University of Helsinki, Finland.
  • Pharmaceutical and Analytical R&D, AstraZeneca R&D Mölndal, 431 83 Mölndal, Sweden. Division of Pharmaceutical Sciences.
  • University of Strathclyde, SIPBS, 27 Taylor Street, Glasgow G4 0NR, Scotland, UK.
  • Institute of Physics and Chemistry, University of Southern Denmark, Campusvej 55, 5230 Odense M., Denmark.

 

 

Russian cooperation:

  • Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Russia.
  • Institute of Problems of Chemical Physics, Russian Academy of Sciences, 142432, Chernogolovka, Russia.
  • Kurnakov's Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 119991, Moscow, Russia.

 

Main classes of the compounds for treating of socially significant diseases – the objects of the laboratory investigations.

 

Compounds for treating of Alzheimer’s disease.

 

Alzheimer’s disease is a common form of dementia disorder, characterized by the progressive decline of memory and highly cerebral functions that in the final analysis leads to the complete degradation of intellectual and cognitive activity. According to the social significance Alzheimer’s disease takes the third place after cancerous and cardiovascular diseases.

Due to the real tendency of constant increasing the percentage of elderly population the search of new approaches aimed on the regeneration and improvement of brain cognitive functions and memory in biological aging and under the different age depended neurodegenerative disorders have been intensified last years. The tendency of screening and creating the positive modulators of NMDA-subtype Glu receptors as the potential cognition enhancers have been intensively developed last time.

 

 

Non-steroidal anti-inflammatory drugs (NSAIDs)

 

Antibiotics

 

Cocrystal Screening

 

In recent years, the development of a pharmaceutical cocrystal has become a novel strategy to improve the solid state properties of an API. Usually, the solubility characteristics improve on the orders and this fact leads to essential reduction of therapeutic doses and, as a consequence, side effects. A cocrystal can be described as a supramolecular system formed by two different molecular entities where, one from the compounds is a poorly soluble API, whereas the second component presents a molecule of well soluble substance, which uptakes by body completely and takes part in enzymatic processes. The second component molecule belongs to GRAS (Generally Regarded As Save) list which includes the compounds recommended for application at pharmaceutical and food industries.

Carried out investigations:

  • Cocrystal screening;
  • Characterization of cocrystal by X-ray diffraction methods;
  • Studying cocrystal solubility processes (kinetic and thermodynamic approaches) and comparison of the obtained characteristics with individual cocrystal components;
  • Parameters searching to obtain thermodynamic stable cocrystals with controlled stoichiometry aimed to scale-up procedure;
  • Membrane permeability of cocrystal and comparison with analogous characteristics of individual components.

 

Investigation of membrane permeability processes

 

Laboratory carries out membrane permeability study and screening API using artificial membranes prepared on basis of phospholipids vesicles with specified function distribution of the size particles. The mentioned phospholipids membranes are a good model describing passive transport processes of gastrointestinal tract. The main advantage of the proposed method is opportunity simulation of both transcellular and paracellular drug delivery pathways.

 

In laboratory it develops algorithms High Throughput Screening (HTS) drug compounds to select substances with optimal permeability characteristics

 

 

Type of carried out investigations:

  • Membrane permeability screening;
  • Database generation which includes permeability coefficients of different class of compounds;
  • Development of correlation models for prediction of compounds with maximal membrane permeability values.

 

Studying solubility processes

 

On the basis of information of pharmaceutical industry about 40 % of development compounds fail to reach the market due to poor pharmaceutical properties as a result of poor solubility, permeability and metabolic stability. Especially these moments lead to essential side effects and reduction of therapeutic effectiveness of drugs. Therefore, solubility screening and prediction of these characteristics for novel compounds is very actual goal for drug design.

 

Low Solubility Drugs in the Market and in the Development Pipeline According to the Biopharmaceutics Classification Systema

 

BCS class

Solubility

Permeability

% drugs on

market

% drugs in

R&D pipeline

I

high

high

35

5 - 10

II

low

high

30

60 - 70

III

high

low

25

5 - 10

IV

low

low

10

10 - 20

aThayer A.M. Finding solutions. Chem. Eng. News 2010, 88 (May 31), 13–18.

 

Comparison of the distribution of drug solubility on the US, GB, ES. JP, and WHO list. [Takagi et al. Mol. Pharm. 2006, 3(6):631–643.]

 

In laboratory it carries out comprehensive investigations of studying API solubility characteristics in various pharmaceutical important solvents.

 

Type of carried out investigations:

 

  • Solubility screening API in aqueous mediums;
  • Solubility of API within the wide temperature interval (15 – 45 °С);
  • Thermodynamic characteristics of API solubility processes;
  • Generation of database including solubility values of the client’s compounds;
  • Making models predicting solubility values of new substances;
  • Studying and analysis of API solubility kinetics;
  • Analysis of the bottom phases and search of appropriate conditions (solvent, experimental time, temperature and so on) for obtaining pharmaceutical important crystallosolvates.

 

Studying Partition/Distribution processes

 

Partition/Distribution coefficients (logP; logD) are important physicochemical characteristics of compounds enabling estimate preferable drug delivery pathways.

 

Used pairs of immiscible solvents:

Model of gastrointestinal tract membranes:

  • Buffer with pH 2.0 / 1-octanol
  • Buffer with pH 7.4 / 1-octanol
  • Water / 1-octanol

 

Model of blood-brain barrier:

  • Buffer with pH 2.0 / n-hexane
  • Buffer with pH 7.4 / n-hexane
  • Water / n-hexane

 

Type of carried out investigations:

  • Partition/Distribution coefficients screening;
  • Database generation which includes partition/distribution coefficients of different class of compounds;
  • Development of correlation models for prediction of partition/distribution coefficients for compounds with specified structures.

 

 

Studying sublimation processes

 

Sublimation of active pharmaceutical ingredient (API) molecular crystals is a key experiment for estimation of crystal lattice energies. Moreover, sublimation characteristics are often used as test parameters for normalization of pair potential function to build theoretical models describing solubility phenomenon. The sublimation properties are usually applied for solubility optimization of new classes of developed compounds and for creation of models predicting these characteristics.

 

In laboratory it carries out comprehensive study of sublimation characteristics of molecular crystals with detail description of thermodynamic properties and structures of the compounds.

 

 

Type of carried out investigations:

  • Temperature dependencies of saturated vapor pressure of API molecular crystals within a wide temperature interval (25 – 200 °С);
  • Conditions screening for monocrystals preparation of the client’s compounds and solving crystal structures by X-ray diffraction methods;
  • Thermodynamic description of sublimation processes of studied API.

 

Polymorphism of molecular crystals

 

Polymorphism may be defined as the ability of a compound to crystallize in two or more crystalline phases with different arrangements and/or conformations of the molecules in the crystal lattice. This broad definition is widely accepted today in crystal engineering, materials science and pharmaceutical development. The existence of polymorphism implies that free energy differences between various forms are small (2-30 kJ mol-1) and that kinetic factors are important during crystal nucleation and growth. Polymorphs are ideal systems to study molecular structure–crystal structure–crystal energy relationships with a minimum number of variables, because differences arise due to molecular conformations, hydrogen bonding, and crystal packing effects but not due to a different chemical species.

 

Polymorphism is more widespread in pharmaceutical solids, with estimates of 30–50% in drug-like molecules, compared to 4–5% polymorphic crystals in the Cambridge Structural Database (CSD). Interest in polymorphism is growing because different solid-state modifications have different physical, chemical and functional properties such as melting point, stability, color, bioavailability, toxicity, pharmacologicalactivity, nonlinear optical response, etc. Polymorph screening is now regarded as an important and routine step in the development of specialty chemicals, drugs and pharmaceuticals.

 

 

Type of carried out investigations:

  • Polymorphs screening of drug compounds;
  • Characterization of polymorphs by X-ray diffraction methods (powder diffraction, single crystal);
  • Studying of thermodynamic stability of polymorphs via DSC and solution calorimetry techniques;
  • Investigating of solubility process of polymorphs (thermodynamic solubility, dissolution rate).
Inventor and patent and licensing work:

Perlovich, G.L.; Manin, A.N.; Manin, N.G.; Surov, A.O.; Voronin, A.P. Co-crystalline form of theophylline with diflunisal or diclofenac. Ref. No: RU 2542100, 20.02.2015.

Perlovich, G.L.; Manin, A.N.; Manin, N.G.; Voronin, A.P. Co-crystalline form of 3-hydroxybenzamide with salicylic acid. Ref. No: RU 2539350, 20.01.2015

Perlovich, G.L.; Manin, A.N.; Manin, N.G.; Surov, A.O.; Voronin, A.P. Co-crystalline form of niflumic acid with isonicotinamide or caffeine. Ref. No: RU 2536484, 27.12.2014

Perlovich, G.L.; Manin, A.N.; Manin, N.G.; Voronin, A.P. Cocrystalline form of fenbufen with pyrazinamide with increased solubility. Ref. No: RU 2521572, 27.06.2014

Perlovich, G.L.; Manin, A.N.; Manin, N.G.; Surov, A.O.; Voronin, A.P. Method for obtaining the co-crystalline form of bicalutamide. Ref. No: RU 2510392, 27.03.2014

 

Perlovich, G.L.; Manin, A.N.; Manin, N.G.; Voronin, A.P. Co-crystalline form of 2-hydroxybenzamide and 4-aminobenzoic acid. Ref. No: RU 2497804, 10.11.2013

Awards:

 

   Award of publishing house “ELSIVER” for the most cited paper in 2004 year published in European Journal of Pharmaceutics and Biopharmaceutics

Award of European Federation for Pharmaceutical Sciences for the Best paper published in European Journal of Pharmaceutics in 2003 year

 

Projects and grants:

Investigations were supported by:

  • The Russian Foundation for Basic Research
  • The Russian Scientific Foundation (№ 14-13-00640)
  • The Federal Agency for Science and Innovations (№ 02.740.11.0857; № 2012-1.4-12-000-1028-6539; № 14.616.21.0027)
  • The basic research programs established by the Presidium of Russian Academy of Sciences “Fundamental Sciences for Medicine”
  • The basic research programs established by the Presidium of Russian Academy of Sciences “Medical and Biomolecular Chemistry”
  • The presidium of Russian Academy of Sciences “Fundamental bases of nanostructures and nanomaterials technologies” (Subprogram: III. Nanobiotechnologies)
  • The Seventh Framework Program of the European Community for Research, Technological Development and Demonstration Activities (IRSES-GA-2009-247500)
  • Found for support of the national science at the nominations: “doctor of science”, “candidate of science”, “PhD student”
  • Bilateral agreements between Russia and:
  • Norway;
  • Italy;
  • Denmark;
  • Finland;
  • China;
Leading researcher
Phd in chemistry
Senior Researcher
Ph.D. student
Ph.D. student
Researcher
Phd in chemistry
Senior researcher
Phd in chemistry
Head of the laboratory
Doctor of сhemical sciences
professor
Researcher
Phd in chemistry
Researcher
Phd in chemistry
Leading researcher
Doctor of сhemical sciences
Lecturer (docent)
Ph.D. student

List of recent publications (2012 – 2015)

 

  1. Perlovich G.L., Ryzhakov A.M., Tkachev V.V., Proshin A.N. Adamantane Derivatives of Sulfonamide Molecular Crystals: Structure, Sublimation Thermodynamic Characteristics, Molecular Packing, Hydrogen Bonds Networks. CrystEngComm (2015) 17 (4), 753 – 763.
  2. Surov A.O., Simagina A.A., Manin N.G., Kuzmina L.G., Churakov A.V., Perlovich G.L. Fenamate Co-crystals with 4,4′-Bipyridine: Structural and Thermodynamic aspects. Crystal Growth & Design. (2015) 15(7), 228-238.
  3. Perlovich G.L., Kazachenko V.P., Strakhova N.N., Raevsky O.A. Impact of Sulfonamide Structure on Solubility and Transfer Processes in Biologically Relevant Solvents. J. Chem. Eng. Data (2014) 59(12), 4217-4226.
  4. Surov A.O., Voronin A.P., Manin A.N., Manin N.G., Kuzmina L.G., Churakov A.V., Perlovich G.L. Pharmaceutical co-crystals of diflunisal and diclofenac with theophylline. Mol. Pharmaceutics. (2014) 11(10), 3707-3715.
  5. Manin A.N., Voronin A.P., Drozd K.V., Manin N.G., Bauer-Brandl A., Perlovich G.L. Cocrystal screening of hydroxybenzamides with benzoic acid derivatives: A comparative study of thermal and solution-based methods. European Journal of Pharmaceutical Sciences (2014) 65, 56–64.
  6. Ol’khovich M.V., Sharapova A.V., Lavrenov S.N., Blokhina S.V., Perlovich G.L. Inclusion complexes of hydroxypropyl-b-cyclodextrin with novel cytotoxic compounds: Solubility and thermodynamic properties. Fluid Phase Equilibria (2014) 384, 68–72.
  7. Manin A.N., Voronin A.P., Manin N.G., Vener M.V., Shishkina A.V., Lermontov A.S., Perlovich G.L. Salicylamide Cocrystals: Screening, Crystal Structure, Sublimation Thermodynamics, Dissolution, and Solid-State DFT Calculations. J. Phys. Chem. B (2014) 118 (24), 6803-6814.
  8. Surov A.O., Solanko K.A., Bond A.D., Bauer-Brandl A., Perlovich G.L. Polymorphism of felodipine co-crystals with 4,4′-bipyridine. CrystEngComm (2014) 16, 6603-6611.
  9. Manin A.N., Voronin A.P., Perlovich G.L. Acetamidobenzoic acid isomers: Studying sublimation and fusionprocesses and their relation with crystal structures. Thermochimica Acta (2014) 583, 72– 77.
  10. Surov A.O., Proshin A.N., Perlovich G.L. Crystal structure analysis and sublimation thermodynamics of bicycle derivatives of a neuroprotector family. Acta Cryst. (2014) B70, 47-53.
  11. Perlovich G.L. Thermodynamic Approaches to the Challenges of Solubility in Drug Discovery and Development. Mol. Pharmaceutics. (2014) 11(1), 1-11.
  12. Perlovich G.L. Thermodynamic approach to improving solubility prediction of co-crystals in comparison with individual poorly soluble components. J. Chem. Thermodynamics (2014), 73, 85-89.
  13. Blokhina S.V., Ol’khovich M.V., Sharapova A.V., Perlovich G.L., Proshin A.N. Vapor pressures and sublimation enthalpies of novel bicyclic heterocycle derivatives. J. Chem. Thermodynamics (2014) 69, 107-111.
  14. Blokhina S.V., Ol’khovich M.V., ., Sharapova A.V., Volkova T.VProshin A.N., Perlovich G.L. Effect of the structure, solid state and lipophilicity on the solubility of novel bicyclic derivatives. J. Chem. Thermodynamics (2014) 78, 152-158.
  15. Blokhina S.V., Volkova T.V., Ol’khovich M.V., Sharapova A.V., Proshin A.N., Perlovich G.L. Solubility and solution thermodynamics of novel bicyclic derivatives of 1,3-selenazine in biological relevant solvents. J. Chem. Eng. Data (2014) 59(7), 2298-2304.
  16. Blokhina S.V., Ol’khovich M.V., Sharapova A.V., Volkova T.V., Proshin A.N., Bachurin S.O., Perlovich G.L. Synthesis, Biological Activity, Distribution and Membrane Permeability of Novel Spiro-thiazines as Potent Neuroprotectors. Eur. J. Med. Chem. (2014) 77, 8-17.
  17. Perlovich G.L., Ryzhakov A.M., Strakhova N.N., Kazachenko V.P., Schaper K.-J., Raevsky O.A. Thermodynamic aspects of solubility and partitioning processes of some sulfonamides in the solvents modeling biological media. J. Chem. Thermodynamics (2014) 69, 56-65.
  18. Surov A.O., Cong Trinh Bui, Proshin A.N., Roussel P., Idrissi A., Perlovich GL. Novel 1,2,4-Thiadiazole Derivatives: Crystal Structure, Conformational Analysis, Hydrogen Bond Networks, Calculations, and Thermodynamic Characteristics of Crystal Lattices. J. Phys. Chem. B (2013) 117, 10414−10429.
  19. Perlovich G.L., Blokhina S.V., Ol’khovich M.V., Sharapova A.V., Proshin A.N. Solubility, Solvation and Distribution of Novel Spiro-Derivatives of 1,3-Thiazine in Aqueous and Organic Solutions. J. Solution Chem. (2013) 42 (10), 2057-2069.
  20. Ol’khovich M.V., Blokhina S.V., Sharapova A.V., Perlovich G.L., Proshin A.N. Thermodynamics of sublimation and solvation for bicyclo-derivatives of 1,3-thiazine. Thermochimica Acta (2013) 569, 61– 65.
  21. Blokhina S.V., Ol’khovich M.V., Sharapova A.V., Proshin A.N., Perlovich G.L. Partition Coefficients and Thermodynamics of Transfer of Novel Drug-like Spiro-derivatives in Model Biological Solutions. J. Chem. Thermodynamics (2013) 61, 11–17.
  22. Perlovich G.L., Ryzhakov A.M., Tkachev V.V., Hansen L.Kr., Raevsky O.A. Sulfonamide Molecular Crystals: Structure, Sublimation Thermodynamic Characteristics, Molecular Packing, Hydrogen Bonds Networks. Crystal Growth & Design. (2013) 13(9):4002-4016.
  23. Perlovich G.L., Kazachenko V.P., Strakhova N.N., Schaper K.-J., Raevsky O.A. Solubility and Transfer Processes of Some Hydrazones in Biologically Relevant Solvents. J. Chem. Eng. Data (2013) 58(9), 2659-2667.
  24. Surov А.O., Solanko K.A., Bond A.D., Bauer-Brandl A., Perlovich G.L. Crystal architecture and physicochemical properties of felodipine solvates. CrystEngComm (2013) 15 (30), 6054 – 6061.
  25. Perlovich G.L., Proshin A.N., Ol’khovich M.V., Sharapova A.V., Lermontov A.S. Novel Spiro-Derivatives of 1,3-Thiazine Molecular Crystals: Structural and Thermodynamic Aspects. Crystal Growth & Design. (2013) 13(2):804-815.
  26.  Manin N.G., Perlovich G.L., Fini A. Thermochemical study of aqueous solutions of lithium diclofenac at 293.15-318.15 K. Russian Journal of Physical Chemistry A, 2013, 87(4), 580-588.
  27. Manin A.N., Voronin A.P., Perlovich G.L. Thermodynamic and structural aspects of hydroxybenzamide molecular crystals study. Thermochimica Acta (2013) 551:57-61.
  28. Perlovich G.L., Blokhina S.V., Manin N.G., Volkova T.V., Tkachev V.V. Polymorphism and Solvatomorphism of Bicalutamide: Thermophysical Study and Solubility. J. Thermal Analysis and Calorimetry (2013) 111:655-662.
  29. Solanko K.A., Surov A.O., Perlovich G.L., Bauer-Brandl A., Bond A.D. Felodipine–diazabicyclo[2.2.2]-octane–water (1/1/1). Acta Cryst. (2012) C68:o1–o3.
  30. Perlovich G.L., Blokhina S.V., Manin N.G., Volkova T.V., Tkachev V.V. Polymorphs and solvates of felodipine: Analysis of crystal structures and thermodynamic aspects of sublimation and solubility processes. CrystEngComm (2012) 14:8577-8588.
  31. Ol’khovich M.V., Sharapova A.V., Blokhina S.V., Perlovich G.L., Proshin A.N. Vapor Pressures and Sublimation Thermodynamic Parameters for Novel Drug-Like Spiro-Derivatives. J. Chem. Eng. Data (2012) 57:3452-3457.
  32. Surov A.O., Solanko K.A., Bond A.D., Perlovich G.L., Bauer-Brandl A. Crystallization and Polymorphism of Felodipine. Crystal Growth & Design. (2012) 12(8):4022-4030.
  33. Blokhina S.V., Ol’khovich M.V., Sharapova A.V., Proshin A.N., Perlovich G.L. Thermodynamics of Solubility Processes of Novel Drug-like Spiro-Derivatives in Model Biological Solutions. J. Chem. Eng. Data (2012) 57(7):1996-2003.
  34. Perlovich G.L., Proshin A.N., Volkova T.V., Petrova L.N., Bachurin S.O. Novel 1,2,4-Thiadiazole Derivatives as Potent Neuroprotectors: Approach to Creation of Bioavailable Drugs. Mol. Pharmaceutics (2012) 9(8):2156-2167.
type:Diffractometers
type:Spectrometers / Spectrophotometers UV and visible region
type:Analyzers
type:Calorimeters
type:Spectrometers / Spectrophotometers UV and visible region
type:Spectrometers / Spectrophotometers UV and visible region