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”
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;
Международное сотрудничество:
- Болгария, Юго-Западный Университет “Неофит Рилски”, Благоевград
- Индия, Индийский Институт Химической Технологии (IICT), Hyderabad
- Китай, Университет Сунь Ят-Сена (Гуаньджоу)
- Китай, Таньцзиньский Технологический Унверситет
- Китай, Пекинский Технологический Институт
- Китай, Шанхайский Институт Медицинских Материалов, Китайской Академии Наук (Шанхай)
- ЮАР, Кейптаунский Университет, Химический факультет, Центр Супрамолекулярной химии (Кеуптаун)
- Китай, Университет Сунь Ят-Сена (Гуаньджоу)
- Норвегия, Институт Фармацевтики Университета Тромсё
- Италия, Институт химических наук Университета Болоньи
- Германия, Биомедицинский исследовательский центр (Борстель)
- Германия, Федеральный институт исследования и тестирования материалов (Берлин)
- Финляндия, Институт фармацевтики Университета Хельсинки
- Швеция, Pharmaceutical and Analytical R&D, AstraZeneca R&D, Mölndal
- Шотландия, Институт фармацевтики Университета Глазго
- Дания, Институт физики и химии Южного университета Дании, Оденсе
Российское сотрудничество:
- Институт физиологически активных веществ РАН, Черноголовка
- Институт проблем химической физики РАН, Черноголовка
- Институт общей и неорганической химии РАН, Москва
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.
Нестероидные антиантрогенные соединения
Противотуберкулезные соединения
Антибактериальные
альфа- и бета-адреноблокаторы
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.
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).
