Conference Agenda

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Session Overview
MS-67: Crystallization mechanisms of small molecule systems
Thursday, 19/Aug/2021:
2:45pm - 5:10pm

Session Chair: Duane Choquesillo-Lazarte
Location: Terrace 2B
100 2nd floor

Invited: Ian Rosbottom (UK)Aurora Cruz-Cabeza (UK)

Session Abstract

For all abstracts of the session as prepared for Acta Crystallographica see PDF in Introduction, or individual abstracts below.

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2:45pm - 2:50pm

Introduction to session

Duane Choquesillo-Lazarte

2:50pm - 3:20pm


Aurora Cruz-Cabeza

University of Manchester, Manchester, United Kingdom

Molecular flexibility has a profound impact on the number of possible ways molecules can pack in the solid state. The phenomenon of Conformational Polymorphism has been well-studied (Cruz-Cabeza, 2014) and recognised to be very common in complex pharmaceuticals (Cruz-Cabeza, 2015).

Perhaps what is less well understood is how molecular flexibility impacts crystallisation. In previous works, we studied the nucleation and growth kinetics of a number of rigid benzoic acid derivatives (Cruz-Cabeza, 2017). We have now studied the nucleation and growth kinetics of a number of flexible benzoic acid derivatives asking the fundamental question “Can Molecular Flexibility Control Crystallisation?” (Tang, 2021). Our kinetic data shows that when the energy barriers for conformational change are small, molecular flexibility is not rate controlling in crystallisation. Aromatic stacking was found, again, to be the key controlling step in the kinetics of crystallisation (Tang, 2021).


Cruz-Cabeza., A.J., and Bernstein, J. (2014). Conformational Polymorphism. Chem. Rev. 114, 2170-2191.

Cruz-Cabeza., A.J., Reutzel-Edens, S.M. and Bernstein, J. (2015). Facts and Fictions about Polymorphs. Chem. Soc. Rev. 44, 8619-8635.

Cruz-Cabeza., A.J., Davey, R.J., Sachithananthan, S.S., Smith, R., Tang, S.K., Vetter, T. and Xiao, Y. (2017). Aromatic Stacking-a key step in nucleation. Chem. Commun. 53, 7905-7908.

Tang, S.K., Davey, R.J., Sacchi, P. and Cruz-Cabeza, A.J. (2021). Can Molecular Flexibility Control Crystallisation? The Case of para substituted benzoic acid. Chem. Sci. accepted.

3:20pm - 3:50pm

Molecular, Solid-State and Surface Structures of the Conformational Polymorphic Forms of Ritonavir in Relation to their Physicochemical Properties

Ian Rosbottom

School of Chemical and Process Engineering, University of Leeds, LS2 9JT


Molecular and crystallographic modelling can be used to de-risk the development of active pharmaceutical ingredients into drug products. Here we present an application of multi-scale modelling workflows to characterise polymorphism in ritonavir with regard to its stability, bioavailability and processing.


Molecular conformation, polarizability and stability are examined using quantum mechanics (QM). Intermolecular synthons, hydrogen bonding, crystal morphology and surface chemistry are modelled using empirical force fields.


The form I conformation is more stable and polarized with more efficient intermolecular packing, lower void space and higher density, however its shielded hydroxyl is only a hydrogen bond donor. In contrast, the hydroxyl in the more open but less stable and polarized form II conformation is both a donor and acceptor resulting in stronger hydrogen bonding and a more stable crystal structure but one that is less dense. Both forms have strong 1D networks of hydrogen bonds and the differences in packing energies are partially offset in form II by its conformational deformation energy difference with respect to form I. The lattice energies converge at shorter distances for form I, consistent with its preferential crystallization at high supersaturation. Both forms exhibit a needle/lath-like crystal habit with slower growing hydrophobic side and faster growing hydrophilic capping habit faces with aspect ratios increasing from polar-protic, polar-aprotic and non-polar solvents, respectively. Surface energies are higher for form II than form I and increase with solvent polarity. The higher deformation, lattice and surface energies of form II are consistent with its lower solubility and hence bioavailability.


Inter-relationship between molecular, solid-state and surface structures of the polymorphic forms of ritonavir are quantified in relation to their physical-chemical properties.

3:50pm - 4:10pm

Bridging the nucleation step – the link of molecular interactions in dilute solutions and the crystal structure

Katharina Edkins

University of Manchester, Manchester, United Kingdom

The solvent influence on crystallisation outcome has been shown in a large number of cases, most often as the observation of different crystal forms crystallising from recrystallization from different solvents. More detailed work has been conducted to investigate solute-solute and solute-solvent interaction in solution with increasing saturation to mimic the crystallisation process, and to understand and use the solvent influence on crystallisation with the ultimate aim to control the crystallisation outcome.[1, 2, 3] However, to date there are contradicting opinions whether solution interaction drives the nucleation of a particular crystal form or if other factors such as the exact nucleation pathway, solvation state of clusters and solute conformations, outweigh the solvent influence.[4]

But can the nucleation step be completely ignored? Our hypothesis is that strong intermolecular interactions in dilute solution are likely to be carried through the nucleation step into the final crystal structure independent from the nucleation pathway followed, and weak interactions are unlikely to survive the nucleation step. Verification of this hypothesis would allow us to directly connect dilute solutions with the crystallisation product, and even allow for prediction of the existence of a particular crystal form before performing crystallisation experiments.

Using a combination of vibrational and nuclear magnetic spectroscopy, X-ray and neutron diffraction and molecular dynamics simulations, I will show the link between solution and solid-state interactions for multi-component crystal forms and how the microscopic structure of the solution can influence the crystallisation outcome.[5]

[1] Davey, R. J., Dent, G., Mughal, R. K., Parveen, S. (2006). Cryst. Growth Des. 6, 1788. [2] Hunter, C. A., McCabe, J. F., Spitaleri, A. (2012). CrystEngComm 14, 7115. [3] Derdour, L., Skliar, D. (2014). Chem. Eng. Sci. 106, 275. [4] Du, W., Cruz-Cabeza, A. J., Woutersen, S., Davey, R. J., Yin, Q. (2015). Chem. Sci. 6, 3515. [5] Jones, C. D., Walker, M., Xiao, Y., Edkins, K. (2019). Chem. Commun. 55, 4865.

4:10pm - 4:30pm

Controlling polymorphism of pharmaceutical cocrystals via polymer assisted cocrystallization in continuous processes

Anna Magdalena Gołkowska, Marta Maria Kozakiewicz, Karol Przemysław Nartowski

Department of Drug Forms Technology, Wroclaw Medical University, Wroclaw, Poland

Pharmaceutical cocrystals are the subject of interest in academic and industrial research as they offer better control over physicochemical, mechanical and pharmacokinetic properties of active pharmaceutical ingredients (API) while their therapeutic activity remains intact. This class of materials, as well as single component pharmaceutical solids, is prone to exhibit the different packing arrangements and molecular conformations within the crystal lattice with the same chemical composition i.e. polymorphism. Hot melt extrusion (HME) is a solvent-free, continuous and scalable technique which makes it an important candidate for the industrial application in a continuous synthesis of pharmaceutical cocrystals. However, processing APIs and coformers with significant difference in their melting temperatures is limited by the possibility of a lower-melting substrate decomposition. As a consequence, reduction of the conversion to a cocrystal during extrusion may be observed.

In this work we used mechanochemical approach to obtain two pharmaceutical cocrystals known to exist in at least two polymorphic forms: theophylline (TP) with benzamide (BZ) [1] and nicotinamide (NCT) with malonic acid (MA) [2] via matrix assisted cocrystallization (MAC) using hot melt extrusion [3] and polymer assisted grinding (POLAG) [4]. The polymers used in the experiments were polyethylene glycol derivatives of different molecular weight (in range from 200 to 20000), Tween® 20 and 80, Span® 80, Brij® 93 and Poloxamers of different HLB values. The milling procedures were performed using a ball-mill (Fritsch Mini-Mill Pulverisette 23) while hot melt extrusion processing was conducted using a co-rotating twin-screw Process 11 extruder (Thermo Fisher Scientific, Karlsruhe, Germany). Structures of the synthesised products were investigated using X-ray powder diffraction (D2 PHASER, Bruker AXS, Karlsruhe, Germany) and Fourier Transform Infrared Spectroscopy (Nicolet 380, Thermo Scientific, USA) whereas phase transitions were assessed using differential scanning calorimetry (DSC 214 Polyma, Netzsch, Germany).

The physical mixture of TP and BZ is difficult to process in the hot melt extrusion process because of the melting temperature difference (mpTP = 273 °C, mpBZ = 128 °C). In case of processing neat mixture of API and coformer, the barrel temperature of 120 °C was necessary to perform a successful cocrystal extrusion whereas the addition of a polymer matrix allowed to decrease the process temperature to 40 °C. In the formulations of higher polymer concentration, i.e. 30% and more, the extrusion led to TP:BZ (1:1) cocrystal form I occurrence while polymer content below 20% resulted in form II cocrystallization. In contrast both polymorphic forms of TP:BZ (1:1) cocrystal were obtained in grinding experiments by neat and liquid assisted grinding as reported previously [1] while all POLAG led exclusively to form I formation. The addition of solid state polymers in a milling procedure accelerated the cocrystallization rate, however, presence of the liquid polymers inhibited cocrystal formation due to both difficulties in mixing or dissolution of one of the components in liquid polymer. Changes in the polymer content and polarity of the matrix (controlled via chain length of polyethylene glycol), did not result in obtaining of TP:BZ (1:1) form II. Furthermore, time required for complete cocrystallization was significantly shorter (3-5 minutes) in the hot melt extrusion as compared to the grinding experiments (40 min). In contrast to TP:BZ cocrystal, the melting temperature of API and coformer of NCT:MA (2:1) cocrystal are significantly closer (mpNCT = 129 °C, mpMA = 135 °C) which simplifies extrusion process. In the examined range of polymer concentrations form I of NCT:MA (2:1) was obtained, similarly grinding of NCT and MA (neat, liquid assisted and polymer assisted grinding) resulted also in form I appearance of NCT:MA (2:1) cocrystal.

Polymers used in matrix assisted techniques can act as cocrystallization rate accelerating agents enabling to obtain higher cocrystal yield. In addition, polymers can act as the functional components of the formulation enabling to tailor important pharmaceutical parameters e.g. tabletability, dissolution rate or release profile. The addition of polymers in continuous cocrystallization via hot melt extrusion allows to reduce the time and temperature of the process enabling processing of thermolabile substances. Furthermore, control over polymorphic outcome enabled selective synthesis of a stable polymorph which prevents unwanted structural changes during formulation and storage of the final product. On these terms matrix assisted cocrystallization, as a modification of hot melt extrusion method, holds a promise in the development of polymorph selective cocrystallization processes.

[1] Fischer, F., Heidrich, A., Greiser, S., Benemann, S., Rademann, K. & Emmerling, F. (2016) Cryst Growth Des. 16, 1701.

[2] Lemmerer, A., Adsmond, D.A., Esterhuysen, C. & Bernstein, J. (2013) Cryst Growth Des. 13, 3935.

[3] Boksa, K., Otte, A. & Pinal, R. (2014) J Pharm Sci. 103, 2904.

[4] Hasa, D., Carlino, E. & Jones, W. (2016) Cryst Growth Des. 16, 1772.

4:30pm - 4:50pm

Crystallization of anionic small molecules with the help of a cation screen

Ekaterina Slyshkina, Jaclyn Parris, Bernhard Spingler

University of Zurich, Zurich, Switzerland

The CSD currently contains more than 1.1 million structures.[1] This impressive number is the result of at least the same number of experiments, which were for the most part all manually set up. There are very few reports about robots that were used to set up crystallization trials for the growth of single crystals of small molecules.[2]

Recently, we have developed an anion screen to crystallize organic [3, 4] and inorganic [5] cations of small molecules from aqueous solutions. For some of these studies [3, 5], we employed robotic systems such as the Crystal Gryphon LCP and the Rock Imager 1000, both of which are well established in protein crystallography [6, 7].

In this presentation, we would like to present our work, which resulted in a cation screen. This screen consists of 96 different aqueous solutions with almost 90 different cations, inorganic and organic ones. There exists a commercial cation screen dedicated exclusively for protein crystallography, but this screen only contains seven different inorganic cations. We will present anions that could be crystallized with the help of this screen and thereby elucidating on the possibilities and limitations of our novel cation screen.

[1] Taylor, R. & Wood, P. A. (2019). Chem. Rev. 119, 9427. [2] Tyler, A. R., Ragbirsingh, R., McMonagle, C. J., Waddell, P. G., Heaps, S. E., Steed, J. W., Thaw, P., Hall, M. J. & Probert, M. R. (2020). Chem 6, 1755. [3] Nievergelt, P. P., Babor, M., Čejka, J. & Spingler, B. (2018). Chem. Sci. 9, 3716. [4] Babor, M., Nievergelt, P. P., Čejka, J., Zvoníček, V. & Spingler, B. (2019). IUCrJ 6, 145. [5] Alvarez, R., Nievergelt, P. P., Slyshkina, E., Müller, P., Alberto, R. & Spingler, B. (2020). Dalton Trans. 49, 9632. [6] Cherezov, V. (2011). Curr. Opin. Struct. Biol. 21, 559. [7] Broecker, J., Morizumi, T., Ou, W.-L., Klingel, V., Kuo, A., Kissick, D. J., Ishchenko, A., Lee, M.-Y., Xu, S., Makarov, O., Cherezov, V., Ogata, C. M. & Ernst, O. P. (2018). Nat. Protoc. 13, 260.

This research was funded by the University of Zurich and the R’Equip programme of the Swiss National Science Foundation (project No. 206021_164018).

4:50pm - 5:10pm

The Future of Co-crystallisation: A New Workflow Based on AI Predictions, the Crystal16 Platform and Electron Diffraction

Danny Stam1,2, Carmen Guguta1, Arianna Lanza2, Gustavo Santiso-Quinones2, Gunther Steinfeld2, Doriana Ungur3, Coca Iordache3, Mihaela Pop3

1Technobis Crystallization Systems B.V., Alkmaar, The Netherlands; 2ELDICO Scientific AG, 5234 Villigen, Switzerland; 3TeraCrystal, Cluj Napoca, Romania

Febuxostat (FB) is a poorly water-soluble BCS class II drug that is used for the treatment of the inflammatory disease arthritis urica (gout). FB has a rich solid form landscape, including many polymorphs, solvates, salts and a few co-crystals [1, 2]. With the aim of improving the aqueous solubility of FB we expanded the search for novel salts and co-crystals by applying modeling techniques followed by directed crystallization experiments. Novel salt and co-crystal forms of FB were obtained in a controlled manner using the Crystal16 platform [3]. Making use of the integrated transmission technology together with 16 parallel reactors at a volume of 1 mL, the Crystal16 easily allows the scientist to assess salt or co-crystal formation.

The salt/co-crystal formation was evidenced by powder X-ray diffraction and differential scanning calorimetry. Aqueous powder dissolution was carried out to determine if solubility improvement is achieved. Within the scope of this workflow, the nanocrystalline powders were not ideal for crystal structure elucidation from powder/single crystal X-ray diffraction but suited for electron diffraction experiments [4 -5 ]. By using a dedicated electron diffractometer [6], the crystalline structures of these materials were easily accessible.

Here we report on the successful crystallization and characterization of pharmaceutical relevant co-crystals using a new workflow: AI (artificial intelligence) predictions [7], the Crystal16 platform and an electron diffractometer.

[1] Maddileti D., Jayabun S. K., Nangia A. (2013) Crystal Growth & Design 13 (7), 3188.
[2] Li L. Y., Du R. K.,. Du Y. L, Zhang C. J., Guan S., Dong C. Z., Zhang L. (2018) Crystals 8 (2), 85.

[3] Li W., de Groen M., Kramer H. J. M., de Gelder R., Tinnemans P., Meekes H., and ter Horst J. H. (2021) Cryst. Growth Des. 21 (1), 112.

[4] Andrusenko I., Potticary J., Hall S. R., Gemmi M. (2020) Acta Cryst. B76, 1036.

[5] Hamilton V., Andrusenko I., Potticiary J., Hall C., Stenner R., Mugnaioli E., Lanza A. E., Gemmi M., Hall S. R.(2020) Cryst. Growth Des. 20, 4731.

[6] ELDICO Scientific AG has developed a dedicated device for electron diffraction experiments. This device, its capabilities, and advantages over (modified)-TEMs will be showcased in this congress too. A scientific publication on a dedicated device for ED experiments is in preparation too.

[7] Devogelaer J.J, Meekes H., Tinnemans P., Vlieg E., de Gelder R. (2020) Angew.Chem. Int.Ed. 59, 21711.

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