finished 2018/08/31 – 2021/09/30
Latvian Council of Science

Crystal engineering of pharmaceutical multicomponent phases for more efficient crystalline phase design

Crystal engineering - design of crystal structures with desired properties, using understanding of intermolecular interactions – can be used as a tool for optimization of properties of pharmaceuticals. Nevertheless, the available knowledge still limits the use of this tool, as there are many aspects of formation of intermolecular interactions in the solid state which are far from being rationalized. One of useful predictions of interest for pharmaceutical systems are formation of multicomponent phases, as these can both be used for improvement of the physical properties as well as appear as complications in the manufacturing. The aim of this research project is to develop general models and approaches for rationalization of formation of multicomponent phases of pharmaceuticals. Several model compounds will be studied, by first performing solid form screening and characterization. Then factors affecting formation of solvates and hydrates of the selected model compounds will be identified, by additionally evaluating the role of association in the solution on the outcome of the crystallization of solvates and hydrates. Additionally, structural factors responsible for formation of solid-solutions in selected systems will be identified to extend the general knowledge on factors determining how molecules assemble in the solid state. As findings of this research would allow easier and more efficient design of pharmaceutical multicomponent phases by enhancing the manufacturing efficiency and reducing the costs associated with the design of the final market form of new solid pharmaceuticals for Latvian pharmaceutical companies, the research corresponds to research priority area of Public health.

Project log

2021/06/01 – 2021/09/30

• Defense of a dissertation Use of powder X-ray diffraction and computational methods for structural characterization of selected highly polymorphic active pharmaceutical solids by the project group member Artis Kons (University of Latvia).
• Exploring the formation of solid solutions between several methyl 4-halogene-(-iodo, -bromo and -chloro)-benzoate analogues.
• Participation in on-line 55th international summer school Erice 2021. Molecular Crystal Engineering organized by the International School of Crystallography (May 31 – June 4) by the PhD student Aija Trimdale.
• Presentation of poster Formation of solid solution in thioxanthone derivative systems exhibiting luminescence properties at 11th Crystal forms at Bologna (Online).
• Presentation of poster Combined Use of Structure Analysis, Studies of Molecular Association in Solution, and Molecular Modelling to Understand the Different Propensities of Dihydroxybenzoic Acids to Form Solid Phases at 11th Crystal forms at Bologna (Online).
• Presentation of both main research directions and the achieved results with talks Solvates of active pharmaceutical ingredients: from challenges to opportunities and Solid solutions for continuous modulation of material properties (both in Latvian) at the Day of New Technologies and Innovations organized by University of Latvia.

2021/03/01 – 2021/05/31

• Participation in on-line courses An Introductory Course to Three-Dimensional Electron Diffraction (3DED) organized by Stockholm University (April 12 – April 15) by the project group members researcher Artis Kons and PhD student Kristaps Saršūns.
• Synthesis, analysis, and structure determination of solid solutions formed by dantrolene and various its analogues.
• Presentation of poster Modulation of Luminescence Spectra Via Solid Solution Formation of thioxanthone Derivatives at 64th International Conference for Students of Physics and Natural Sciences (Online), 11th Belgian Crystallography Symposium (Online), and BCA/BACG Online Joint Spring Meeting 2021 (Online).
• Presentation of an oral lecture Formation of solid solution in xanthone derivative systems exhibiting luminescence properties at BCA/BACG Online Joint Spring Meeting 2021 (Online).
• Presentation of poster Combined use of structure analysis, studies of molecular association in solution and molecular modelling to understand the different propensity of dihydroxybenzoic acids to form solid phases at BCA/BACG Online Joint Spring Meeting 2021 (Online).
• Publication of paper Combined Use of Structure Analysis, Studies of Molecular Association in Solution, and Molecular Modelling to Understand the Different Propensities of Dihydroxybenzoic Acids to Form Solid Phases in Pharmaceutics.

2020/12/01 – 2021/02/28

• Presentation of 3 oral lectures in the 79th Scientific Conference of the University of Latvia (Formation of Solid Solution in Xanthone Derivative Systems Exhibiting Luminescence Properties;Hexamorphism of dantrolene: insight into the crystal structures, stability, and phase transformations;Behavior of dihydroxybenzoic acid molecules in solutions determined using spectroscopic methods and molecular dynamics simulations, and the possible effect of disparities on their propensity to form solid phases).
• Publication of paper Hexamorphism of Dantrolene: Insight into the Crystal Structures, Stability, and Phase Transformations in Crystal Growth & Design.
• Analysis of crystallization products of thioxanthone derivative solid solutions (XRPD, DSC) and measurements of their photoluminescence spectra to test the possible use of solid solutions for modulation of the luminescence spectra.
• Studies on preparation of 3,5-dihydroxybenzoic acid solvate hydrates and pure solvates as well as the conditions for their preparation.
• Crystallographic and thermal characterization of dasatinib solvates.

2020/09/01 – 2020/11/30

• Presentation of poster Computational prediction and experimental confirmation of Solid Solution formation from different nitrobenzoic acid derivatives and their isomers at 61st International Scientific Conference Materials Science and Applied Chemistry (Online) and 2nd International Online Conference on Crystals (Online).
• Presentation of poster Use of Molecular Dynamics Simulations to Investigate the Molecular Association of Dihydroxybenzoic Acids in Solution at 61st International Scientific Conference Materials Science and Applied Chemistry (Online).
• Publication of paper Solid Solutions in the Xanthone–Thioxanthone Binary System: How Well Are Similar Molecules Discriminated in the Solid State? in Crystal Growth & Design.
• Exploring the formation of solid solutions between several thioxanthone derivatives, compounds of particular interest because of their solid-state luminescence properties.
• Study of polymorphs of 2,6-dihydroxybenzoic acid. Solid form synthesis by crystallization and dehydration. Discovery and studies of three new unreported polymorphs.
• Structural and computational analysis of furazidin simple solvates and solvate hydrates.

2020/06/01 – 2020/08/31

• Defense of Master's thesis Studies of the formation of solid solutions of various nitrobenzoic acid derivatives and their isomers by the project group member Kristaps Saršūns (University of Latvia).
• Study on expanding the solid form landscape of dantrolene solvates as well as hydrates via hydration of various dantrolene solvates.
• Participation in on-line summer school Rigaku School for Practical Crystallography (June 1 – June 12) by the project group members PhD students Aija Trimdale and current PhD student Kristaps Saršūns.
• Publication of paper Prediction of Solid Solution Formation among Chemically Similar Molecules Using Calculation of Lattice and Intermolecular Interaction Energy in Key Engineering Materials.
• Publication of paper Computational Study of Association of Dihydroxybenzoic Acids in Solution: Testing the Molecular Self-Association Computational Methodology for Formation of Binary Systems in Key Engineering Materials.
• Publication of paper On the rationalization of formation of solvates: experimental and computational study of solid forms of several nitrobenzoic acid derivatives in Crystal Growth & Design.

2020/03/01 – 2020/05/31

• Presentation of 3 oral lectures in the 78th Scientific Conference of the University of Latvia (Prediction of Solid Solution Formation Among Chemically Similar Molecules Using Calculation of Lattice and Intermolecular Interaction Energy; Decamorphism of R-encenicline hydrochloride; Computational study of association in solution of dihydroxybenzoic acids: use of self-association computational methodology for formation of binary systems).
• Presentation of poster Prediction of Solid Solution Formation Among Chemically Similar Molecules Using Calculation of Lattice and Intermolecular Interaction Energy at 63rd International Conference for Students of Physics and Natural Sciences (Online).
• Supervision of Bachelor's thesis research of Beāte Krūze Preparation and characterization of crystalline phases of two isomeric dihydroxybenzoic acids by the project team members Aija Trimdale and Agris Bērziņš.
• Molecular dynamic simulations on selected dihydroxy benzoic acids to investigate the molecular association in solution.
• Exploration of solvate formation of dasatinib.

2019/12/01 – 2020/02/28

• Structural, experimental and computational study of various solid phases of dantrolene.
• Research visit to Department of Physical Chemistry, Kazan Federal University (Kazan, Russia) to perform flash DSC and solution calorimetry experiments dantrolene and acquire new skills in thermal analysis.
• Analysis of structural aspect, including 2D fingerprint graphs of Hirschfield surfaces and electrostatic potential maps (ESP) of different nitrobenzoic acid derivatives and their isomers for rationalization of the solid-solution formation behaviour.
• Studies of molecular electrostatic potential (ESP) maps of dihydroxybenzoic acids. Spectroscopic studies of solutions of dihydroxybenzoic acids by using ¹H and ¹³C NMR and FT-IR spectroscopy.

2019/09/01 – 2019/11/30

• Exploring the solid-state landscape of dihydroxybenzoic acids by crystallizing from common solvents and exploring the obtained phases. Crystal structure prediction of neat dantrolene polymorphs (in collaboration with Prof. Sally Price, UCL Department of Chemistry).
• Calculations of association of dihydroxybenzoic acids in solution evolving self-association involving evaluation self-association, formation of heterotetramers with water and associates with solvent molecules (bonded exclusively by the carboxyl group).
• Presentation of poster An approach for prediction of solid solution formation possibility of chemically similar molecules using calculation of lattice and intermolecular interaction energy at 60th International Scientific Conference Materials Science and Applied Chemistry (Riga, Latvia).
• Presentation of poster Computational Study of Association of Dihydroxybenzoic Acids in Solution: Testing the Molecular Self-Association Computational Methodology for Formation of Binary Systems at 60th International Scientific Conference Materials Science and Applied Chemistry (Riga, Latvia).
• Participation in Gaussian workshop in Ulm, Germany by acquiring skills in use of ab initio calculations.
• Participation in and organization of international seminar 1st International Seminar on Molecular Crystals (29/11/2019, Riga, Latvia) by giving two oral presentations on the results from the project (Use of computationally obtained association Gibbs energies to substantiate the outcome of the crystallization Polymorphism of R-encenicline Hydrochloride: Access to the Highest Number of Structurally Characterized Packing Polymorphs Using Desolvation of Various Solvates).

2019/06/01 – 2019/08/31

• Presentation of poster Computational prediction and experimental confirmation of Solid Solution formation from different nitrobenzoic acid derivatives at Crystal Forms@Bologna 2019 (Bologna, Italy).
• Presentation of poster Experimental and computational investigation of solid form landscapes of several nitrobenzoic acid derivatives at Crystal Forms@Bologna 2019 (Bologna, Italy).
• Publication of paper Polymorphism of R-encenicline Hydrochloride: Access to the Highest Number of Structurally Characterized Polymorphs Using Desolvation of Various Solvates in Crystal Growth & Design.
• Presentation of poster Polymorphism of R-encenicline Hydrochloride: Access to the Highest Number of Structurally Characterized Polymorphs Using Desolvation of Various Solvates at 32nd European Crystallographic Meeting (Vienna, Austria).
• Calculation of total cell energy and lattice energy of different nitrobenzoic acid derivatives and their isomers: 2-substituted 4-nitrobenzoic acid, 2-substituted 5-nitrobenzoic acid, 4-substituted 3-nitrobenzoic acid and 5-substituted 2-nitrobenzoic acid, where substituents are chlorine and methyl and hydroxyl groups.

2019/03/01 – 2019/05/31

• Preparation of publication describing polymorphs and solvates of R-encenicline hydrochloride. Performing the necessary analysis, characterizations and computational calculations.
• Presentation of poster Structural aspects of formation of solid solutions in different benperidol - droperidol phases at 62nd International Conference for Students – Open Readings (Vilnius, Lithuania).
• Exploring the formation of solid solutions between chemically similar molecules: different pairs of 2-substituted 4-nitrobenzoic acid derivatives, where substituents are chlorine and methyl and hydroxyl groups.
• Structural and physicochemical characterization of the obtained furazidine solvates.
• Exploring the solid-state landscape of dihydroxybenzoic acids by crystallizing from common solvents and exploring the obtained phases.
• Crystallographic and computational analysis of solvate formation of isomers of hloronitrobenzoic acid and 2-substituted 4-nitrobenzoic acids, where substituents are chlorine and methyl and hydroxyl groups.
• Presentation of importance and new possibilities in research of solid forms of pharmaceuticals at Day of New technologies and innovations (University of Latvia).

2018/12/01 – 2019/02/28

• Detailed structural, experimental and computational study of precursor solvates and their respective desolvates of R-encenicline hydrochloride.
• Study of formation of polymorphs and solvates, experimental and computational study of solid forms of different nitrobenzoic acid derivatives and their isomers.
• Screening of mixed solvates of furazidine by crystallizing from solvent mixtures.
• Determining detailed phase diagram for xanthone / thioxanthone system.

2018/08/31 – 2018/11/30

• Exploring the solid-state landscape of R-encenicline hydrochloride by crystallizing from different solvents and exploring the obtained phases, their stability and transformations.
• Research visit to Laboratory of Crystallography, University of Bayreuth (Germany) to perform SCXRD measurements of R-encenicline hydrochloride and acquire new skills in crystallography.
• Exploring experimental and energetic aspects of formation of benperidol – droperidol solid solutions in different phases (ansolvated and solvates).
• Screening of simple solvates of furazidine by crystallizing from pure solvents.
• Exploring formation of solid solutions in xanthone / thioxanthone system.

finished 2017/11/01 – 2020/10/31
European Regional Development Fund

Development of method to control the crystallization of selected pharmaceutical molecules using templates and study of the control mechanism

The aim is to develop a method for controlling the crystallization of solvates and/or polymorphs of selected model pharmaceuticals using templates. This will be achieved using experimental and computational exploration and analysis of solid form landscape of the selected pharmaceuticals, template design based on molecular and crystal structure analysis, experimental verification of the possibilities for the control of crystallization as well as use of multidisciplinary contemporary analytical and computational tools to rationalize the crystallization mechanism at the molecular level.

finished 2017/01/01 – 2019/12/31
'Mikrotikls', Ltd. / University of Latvia Foundation

Development of integrated experimental and computational methods to aid prediction of properties and crystal form diversity of active pharmaceutical ingredients

finished 2014/09/01 – 2015/08/31
European Regional Development Fund

Development of new crystallization and mechanochemical preparation technologies of second-generation tyrosine kinase inhibitor solid forms

finished 2011/07/01 – 2013/12/31
European Regional Development Fund / JSC 'Grindeks'

Active pharmaceutical ingredient crystalline form screening and development of crystallization methods for industry