Conference Agenda

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Session Overview
Poster - 19 Pharmaceutical: Pharmaceutical materials
Tuesday, 17/Aug/2021:
4:40pm - 5:40pm

Session Chair: Nikoletta B. Bathori
Session Chair: Laszlo Fabian


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Poster session abstracts

Radomír Kužel

New salts of levofloxacin with physiochemical, structural and biological Insights

Mayank Joshi1, Indu Verma1, Aakanksha Gulati2, Susmita Rani3, Chesta Budhwar4, Kaisar Raza5, Arunika Mukhopadhaya2, Angshuman Roy Choudhury1

1Department of Chemical Sciences, Indian Institute of Science Education and Research, Mohali, Sector 81, S. A. S. Nagar, Knowledge City, Manauli P. O. Mohali, Punjab, India-140306; 2Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, Sector 81, S. A. S. Nagar, Knowledge City, Manauli P. O. Mohali, Punjab, India-140306; 3MCM DAV College for Women, Sector 36, Chandigarh, U. T., India-160036; 4Department of Chemistry, Indian Institute of Technology, Jodhpur, N.H. 65, Karwar, Rajasthan, India-342037; 5Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Dist. Ajmer, Rajasthan, India-305817

Crystallization of active drug molecules in the presence of various biologically acceptable molecules (acids, bases and amino acids) with the aim of forming a new drug composite has gained immense importance in the last couple of decades [1]. This targeted co-crystallization is exercised to enhance the physical and biological properties of the APIs in the pharmaceutical industry [2]. Low aqueous solubility, poor intrinsic dissolution rate (IDR) and moisture sensitivity of the parent various drug molecules have triggered us to investigate the possibility of formation of novel salts of existing drugs for enhanced physical properties and better biological activity [3]. Levofloxacin (LFX) [4], a broad-spectrum antibiotic suffers from low aqueous solubility and poor IDR. Co-crystallization of LFX with natural organic acids has yielded novel crystalline salts of LFX. Characterization by FTIR, PXRD and DSC confirmed the formation of the new phases and single crystal X-ray diffraction data confirmed the formation of salts as well. Enhanced solubility and IDR of the resultant salts motivated us to conduct in-vitro and in-vivo biological study on selected salts. Minimum inhibitory concentration (MIC) of LFX and salts were determined in E. coli and S. typhimurium. Inhibitory concentration IC50 was determined in S. typhimurium infected Caco-2 cells. Pharmacokinetics parameters and biodistribution study (in heart, liver, kidney and brain) of LFX and selected novel salts using 1 CBM peroral Balb/c mice model was conducted. These salts have shown significant improvement in MIC and IC50 then LFX. So, these salts are more potent then pure drug. These salts are more water soluble and we have seen this effect in the pharmacokinetic parameters like absorbance, plasma half life time, Tmax, Cmax, bioavailability, elimination rate constant and clearance of salts. Significant results of our study will be presented.

[1] Brittain, H. (2012). Cryst. Growth Des. 12, 5823

[2] Jones, W., Motherwell, W. D. S., Trask, A. V. (2006). MRS Bull. 31, 875.

[3] Joshi, M., Choudhury, A. R. (2018). ACS Omega. 3, 2406.

[4] Davis, R.; Bryson, H. M. (1994) Drugs, 47, 677.

Pharmaceutical cocrystallization: polymorphs, salts and cocrystals

Angshuman Roy Choudhury1, Maheswararao karanam1, Mayank Joshi1, Indu Verma1, Aakanksha Gulati2, Chesta Budhwar3, Sushmita Rani4, Aanchal Bhalla4, Pooja Garg5, Arunika Mukhopadhyay2, Kaiser Raza6, Dev Sagarika4

1Department of Chemical Sciences, Indian Institute of Science Education and Research Mohali, Mohali, India; 2Department of Biological Sciences, Indian Institute of Science Education and Research, Mohali, Sector 81, S. A. S. Nagar, Manauli PO, Mohali. Punjab, India. 140306; 3Department of Chemistry, Indian Institute of Technology, Jodhpur, N.H. 65, Karwar, Rajasthan; 4MCM DAV College for Women, Sector 36, Chandigarh, Union Territory, India. 160036; 5Post Graduate Government College, Chandigarh, Union Territory, India. 160011; 6Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Dist. Ajmer, Rajasthan, India. 305817

Pharmaceutical cocrystallization has been an active field of research in the last couple of decades. A large number of research groups have been working in this area and have contributed significantly in the development of new materials derived from known active drug molecules. A number of reviews [1-3] have summarised the contributions of all the major research groups working in the area. In the last decade, our group has been involved in the development of salts and cocrystals of a library of drug molecules, which pose various challenges in formulations due to their poor aqueous solubility and low dissolution rates or high moisture sensitivity. Our experiments on fluconazole, voriconazole, valproic acid, enrofloxacin, lamivudine, amoxapine, levofloxacin, ofloxacin, etc has demonstrated a range of exciting results.

Our efforts in forming cocrystals of fluconazole (antifungal agent) with various monobasic and dibasic acids have resulted into a series of new polymorphs of the parent drug instead of formation of salts or cocrystals [4]. These results highlighted the importance of possible intermolecular interactions between the drug and the conformer in solution. In contrary, voriconazole (antifungal agent) resulted into a cocrystal with a dibasic acid. Valproic acid (mood stabilizing agent), which is liquid at room temperature, is available in the market as a sodium salt, which is highly moisture sensitive and dissolves in moisture soon. Our experiments with valproic acid resulted into stable crystalline salts with a few organic bases. Enrofloxacin, a well-known broad spectrum antibiotic, which also suffers from poor aqueous solubility, has resulted into a series of highly water soluble salts using solvent drop assisted grinding experiments [5].

Amoxapin, a tricyclic antidepressant, also suffers from poor solubility and dissolution rate. Our experiments have resulted into a few stable and highly water soluble salts of amoxapine [6]. Ofloxacin and Levofloxacin were also targeted for the formation of salts with pharmaceutically acceptable organic acids. Novel salts of these drugs were tested for their biological activity and based on enhancement in activity; salts of Levofloxacin were further tested for their activity in animal model as well. Our results indicated that the novel salts of Levofloxacin were more potent than the existing formulations.

Significant results achieve in last 10 years on these drugs from our laboratory will be highlighted in the presentation with special emphasis on their synthesis, characterization, physical and biological (both in-vivo and in-vitro) property studies of novel salts developed in our laboratory.


[1] Brittain, H. (2012). Cryst. Growth Des. 12, 1046.

[2] Brittain, H. (2012). Cryst. Growth Des. 12, 5823.

[3] Brittain, H. (2013). J. Pharm. Sci. 102, 311.

[4] Karanam, M., Dev, S. & Choudhury, A. R. (2012). Cryst. Growth Des. 12, 240.

[5] Karanam, M., & Choudhury, A. R. (2013). Cryst. Growth Des. 13, 1626.

[6] Joshi, M. & Choudhury, A. R. (2018). ACS Omega. 3, 2406.

3D Electron diffraction for the discovery of new crystal forms of APIs

Arianna E. Lanza1, Jason Potticary2, Charlie Hall2, Victoria Hamilton2, Simon R. Hall2, Gustavo Santiso-Quinones1, Gunther Steinfeld1, Eric Hovestreydt1

1ELDICO Scientific AG, 5234 Villigen, Switzerland; 2School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, United Kingdom

Most pharmaceuticals are administered in solid form, therefore extensive research and development efforts are invested to explore the phase diagram of APIs and solid-state formulations. The elucidation of the crystal structure of crystalline forms is the key tool for assessing their applicability, as it allows the rationalization of their relevant physicochemical properties, bioavailability, manufacturing, stability etc. Nonconventional crystallization methods[1] enable to discover new solid forms including polymorphs, cocrystals and solvates, allowing to see even known APIs under a new light. However, these methods can easily lead to nanocrystalline products, which hamper structural elucidation.

3D Electron diffraction (3D ED)[2] has recently emerged as a powerful tool for the discovery of new crystalline forms of pharmaceutical compounds,[3-5] as it allows to bypass many of the common bottlenecks of this process and of the established characterization methods based on x-ray diffraction. Small crystal size, mixture of phases, small product quantities are very frequent obstacles to the structural characterization of APIs that can be easily overcome by 3D ED methods.

Here we showcase how our electron diffractometer, fully dedicated to 3D ED experiments, represents a revolutionary innovation for the discovery of new crystal forms of APIs. Our recent results of representative case studies dealing with challenging pharmaceutical compounds will demonstrate the performances of a dedicated device and how it can meet the growing needs of the crystallographic and pharmaceutical community.

[1] Potticary, J., Hall, C., Hamilton, V., McCabe, J. F. & Hall, S. R. (2020). Cryst. Growth Des. 20, 2877.

[2] Gemmi, M., Mugnaioli, E., Gorelik, T. E., Kolb, U., Palatinus, L., Boullay, P., Hovmöller, S. & Abrahams, J. P. (2019). ACS Cent. Sci. 5, 1315.

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

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

[5] Andrusenko, I., Hamilton, V., Mugnaioli E., Lanza, A., Hall, C., Potticary, J., Hall, S. R. & Gemmi, M. (2019). Angew. Chem. Int. Ed. 58, 10919.

We gratefully acknowledge Dr. Mauro Gemmi and Dr. Iryna Andrusenko (Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Pisa, Italy) for fruitful discussions.

Crystal growth and optical study of thalidomide

Mizuki Kira1, Koichi Tsutao1, Kun Zhang1, Yukana Terasawa1, Norio Shibata2, Toru Asahi3

1Waseda University, Shinjuku-ku, Japan; 2Graduate School of Engineering, Nagoya Institute of Technology, Nagoya, Japan.; 3Research Organization for Nano and Life Innovation, Waseda University, Shinjuku-ku, Japan

Thalidomide (TD) was first developed as a safe sedative hypnotic in 1958 and was prescribed for pregnant women to prevent morning sickness. However, TD was reported to cause the tragic side effect in 1960s: Babies born to mothers who took TD had small limb or malfunctioning organs. Nevertheless, TD has attracted much attention as an indispensable pharmaceutical compound because of its effectiveness in treating intractable diseases. Meanwhile, Blaschke et al. reported that only (S)-isomer of TD caused its teratogenicity [1]. This report has influenced pharmaceutical researchers, and then the importance of studies on chirality of drugs have been recognized. However, subsequent studies revealed facile racemization of TD in the aqueous solution [2, 3], which led us to discuss the interpretation for Blaschke’s report. Since then, many researchers in various scientific fields have been interested in the mechanism of teratogenicity of TD.

In 2010, the molecular target of TD was identified Cereblon (CRBN) [4], which forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 [5]. The structural and biochemical studies on the R- snd S-enantiomers of TD binding to CRBN has been reported, which has revealed that the S-enantiomer exhibits ca.10-fold stronger binding to CRBN compared to the R-enantiomer [6].

Furthermore, the important and significant study on TD have been reported [7, 8], which can demonstrate Blaschke’s report. Meanwhile, experimental results on TD itself in the crystalline state were not sufficiently done. Especially, optical properties in TD crystals were not revealed because of the difficulty in growing the good single crystal. We have succeeded in growing thin single crystals of TD with sublimation methods and studying optical properties in them using the Generalized High Accuracy Universal Polarimeter abbreviated as G-HAUP, which enables us to measure simultaneously linear birefringence (LB), linear dichroism (LD), circular birefringence (CB; optical activity), and circular dichroism (CD) in anisotropic materials [9-11].

We will show wavelength dependencies of anisotropic optical properties; LB, LD, CB, and CD, in TD single crystals.

[1] Blaschke, G., Kraft, HP., Fickentscher, K., Kohler, F. (1979). Arzneimittel-Forschung, 29, 1640-1642.
[2] Nishimura K., Hashimoto, Y., Iwasaki, S. (1994). Chem. Pharm. Bull., 42, 1157-1159.
[3] Knoche, B., Blaschke, G. (1994). J. Chromatogr. A, 666, 235-240.
[4] Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Yamaguchi, Y., Handa, H. (2010). Science, 327, 1345-1350.
[5] Fischer, E. S., et al. (2014). Nature, 512, 49-53.
[6] Mori, T., Ito, T., Liu, S., Ando, H., Sakamoto, S., Yamaguchi, Y., Tokunaga, E., Shibata, N., Handa, H., Hakoshima, T. (2018). Sci. Rep., 8, 1294.
[7] Maeno, M., Tokunaga, E., Yamamoto T., Suzuki, T., Ogino, Y., Ito, E., Shiro, M., Asahi, T., Shibata, N. (2014). Chem. Sci., 6(2), 1043-1048.
[8] Tokunaga, E., Yamamoto, T., Ito, E., Shibata, N. (2018). Sci. Rep., 8, 17131.
[9] Kobayashi, J., Asahi, T., Sakurai, M., Takahashi, M., Okubo, K., Enomoto. Y. (1996). Phys. Rev. B, 53, 11784-11795.
[10] Tanaka, M., Nakamura, N., Koshima, H., Asahi, T. (2012). J. Phys. Appl. Phys., 45, 175303-175311.
[11] Nakagawa, K., Asahi, T. (2019). Sci. Rep., 9, 18453.

Syntesis and charachterization of metallo-drugs with potential use for overweight treatment

Richard Fernando DVries, Stephanny Villamizar-Delgado, Octavio Piñeros, Javier Ellena

Universidad Santiago de Cali, Cali, Colombia

The transition metals, specifically biometals such as Co, Cu, Zn and Ni, are being the target of numerous scientific studies from different branches of chemistry, medicine and pharmacology. These metals are well known to form bonds and interactions with biomolecules. Also, are often responsible for the biological function of biomolecules in the body, are immersed in many biochemical processes essential for life. In addition, these metal cations have a great tendency to form coordination compounds with numerous types of ligands. Into the medical-pharmacological field is the medicinal inorganic chemistry that explores binding agents with therapeutic properties linked to metal cations and their multiple applications.1,2

this work focuses on the synthesis, characterization and structural study of complexes based on metformin and transition metals as Co(II), Cu(II), Ni(II) and Zn(II), in order to propose new therapeutic alternatives, by taking advantage of the characteristics of current drugs in synergy with the activity of metallic cations.3

Effect of grinding procedures on the ritonavir-lopinavir system

Lucas B. M. Pinheiro1, Elizabeth Culbertson2, Gabriel L. B. de Araujo3, Simon Billinge2, Fabio Furlan Ferreira1,4

1Center for Natural and Human Sciences (CCNH), Federal University of ABC (UFABC), Santo André, Brazil; 2Columbia University, New York, USA; 3University of São Paulo, São Paulo, SP, Brazil; 4Nanomedicine Research Unit (NANOMED), Federal University of ABC (UFABC), Santo André, SP, Brazil

Ritonavir is a drug of the protease inhibitor class, marketed by Abbvie- as of 1996 under the name of Norvir® - for the treatment of adult and pediatric patients infected with HIV. Lopinavir is a protease inhibitor drug used in combination with ritonavir in therapy and prevention of HIV infection. Both drugs display polymorphism, which may lead to severe commercial implications for pharmaceutical manufacturing [1]. One way to overcome such problems is the development of amorphous formulations like Kaletra commercial medicine. In this work, we use a ball-mill system and an agate mortar and pestle to obtain individual amorphous ritonavir and lopinavir samples as well as their mixtures. First of all, we identify and characterize the crystal forms present in the raw samples of lopinavir and ritonavir, as well as quantify the mass concentrations of each crystal phase using X-ray powder diffraction and the Rietveld method. Ritonavir tends to recrystallize after some time. On the other hand, the mixture of an already amorphous lopinavir sample with ritonavir seems to facilitate its amorphization. The ball-mill processing of ritonavir and lopinavir together results in the production of unexpected crystalline forms of ritonavir. Pair distribution function (PDF) analysis shows the mixed samples reveal a higher r-dependence of ritonavir up to 2 Å (first two peaks). At the same time, the lopinavir dependence tends to increase for a higher-r signal.

Chaperone Compounds for Co-crystallization of Organics

Fabian Rami1, Tobias Stuerzer2, Clemens Richert1, Martin Adam2

1Universität Stuttgart, Institut für Organische Chemie, Stuttgart, Germany; 2Bruker AXS GmbH, Karlsruhe, Germany

Modern instrumentation and processing techniques enable high-quality 3D structure analysis – including absolute structure determination – often in less than an hour, faster and more comprehensively than many spectroscopic methods can even start to achieve. However, large numbers of small or highly flexible organic molecules remain intractable to even the most sophisticated crystallization methods. Our new set of chemical chaperones for co-crystallization, developed by the University of Stuttgart[1] offers a new alternative to other methods, such as the crystal-sponge approach[2] and can significantly increase the probability of successful crystallization and provide faster access to the absolute 3D structure of an organic analyte:

  • The chaperone method is fast and easy to use
  • Structures in hours rather than weeks
  • Small quantities of analyte required
  • Excellent quality crystals
  • Sample screen of 52 organic compounds
    • Diffraction-quality crystals in 88% of cases
    • High resolution X-ray structures in 77% of cases
    • The chaperone compounds are highly stable
    • 100% analyte occupancy in the crystal guarantees reliable determination of the absolute configuration

We will discuss and demonstrate the features in detail along the diastereomers of Limonene including a demonstration of the crystal growth.

[1] Angew. Chem. Int. Ed. 2020, 59, 15875–15879.

[2] Patent pending.

The "Molecular Grabber" method: Development of another crystalline sponge New idea for structure analysis of compounds using protein

Takashi Matsumoto1, Akihito Yamano1, Ryosuke Nakashima2, Kunihiko Nishino2

1Rigaku Corporation; 2Institute of Scientific and Industrial Research, Osaka University

Molecular structure determination is beneficial for the development of medicines, aroma chemicals, and agrochemicals. Single crystal X-ray diffraction (SC-XRD) analysis is the most powerful technique for molecular structure determination. However, SC-XRD analysis requires good quality crystals.

In fact, the biggest hurdle for SC-XRD analysis is crystallization. Crystallization trials require a large amount of highly purified target compounds. Moreover, good quality crystals for SC-XRD analysis might not be obtained despite performing tedious and time-consuming trials. In this case, we have to abandon the direct structure determination by SC-XRD. As one way to address this situation, Fujita et al. have reported the crystalline sponge method (CS method) for the structure determination of small molecules [1]. However, as with other analysis techniques, the CS method has some limitations.

The CS method utilizes the MOF as the pre-crystallized 'container' for the analytes. The 'container' equips flexible features to fit various analytes and must have enough space to accommodate the wide variety of the molecules. In the latter mean, MOF is a large structure object with three-dimensional networks; thus, the spaces to accommodate are to have limitations in principle.

To overcome the above difficulty, we came to an idea of 'molecular grabber', utilizing protein that has a multisite binding pocket to bind a variety of types of molecules, and having characteristics on easy to crystallize, and resulted crystal gives high-resolution spots.

In this presentation, we will indicate the initial results of the "Molecular Grabber" method, utilizing RamR as the molecular grabber (Fig. 1).

[1] Inokuma, Y., Yoshioka, S., Ariyoshi, J., Arita, T., Hirota, Y., Takada, K., Matsunaga, S., Rissanen, K. & Fujita, M. (2013). Nature 495, 461-467. [2] Matsumoto, T., Nakashima, R., Yamano, A. & Nishino, K. (2019). Biochem. Biophys. Res. Commun. 518, 402-408.

An unexpected and unusually complex Co-Mefenamate with nine octahedrally coordinated crystallographically independent cobalt atoms obtained at room temperature

Graciela C. Díaz de Delgado1, Manuel E. Vivas-Arellano1, Robert A. Toro Hernández2, José Antonio Henao Martínez2, José Miguel Delgado Quiñones1

1Laboratorio de Cristalografía-LNDRX, Departamento de Química, Facultad de Ciencias, Universidad de Los Andes, Mérida, Venezuela; 2Grupo de Investigación en Química Estructural (GIQUE), Escuela de Química, Facultad de Ciencias, Universidad Industrial de Santander, Bucaramanga, Colombia

Mefenamic acid (MefA) is one of the non-steroidal anti-inflammatory drugs (NSAID) commonly used in the treatment of mild to moderate pain. Some of its metal derivatives have shown greater pharmacological activity than mefenamic acid, in addition to fewer side effects of the acid in the digestive tract. With this in mind, it was considered of interest to prepare simple metal complexes of MefA. The reaction of Co(CH3COO)2·4H2O and sodium mefenamate (prepared from NaOH and MefA) in water at ambient conditions, produced a purple precipitate which was filtered and washed with MeOH:water. FT-IR indicated this was a Co-Mefenamic acid derivative. After a solubility study, the product was recrystallized from N,N-dimethylformamide (DMF) by slow evaporation at room temperature. Very small and thin pink needles were obtained after approximately 4 weeks. These crystals were characterized by ATR-IR spectroscopy and single crystal X-ray diffraction. This material crystallizes in a monoclinic P21/c (No. 14) unit cell with an unusually large volume: a = 15.9550(2) Å, b = 33.5553(11) Å, c = 31.6703(10) Å, β = 90.898(2)°, V = 16953.4(8) Å3, Z = 4.

Structure determination and refinement showed a complex structure based on a cluster of nine octahedrally coordinated crystallographically independent cobalt atoms, eight mefenamate ligands, six bridging hydroxyl groups, six DMF molecules, one MeOH, three water molecules, and two carbonato moieties at the core of the cluster. NaCO3 was identified as an impurity in the NaOH used to prepare the Na-Mefenamate reagent. The mefenamate ligands coordinate in a bridging bidentate mode and exhibit intramolecular N—H···O hydrogen bonds. Intermolecular H-bonds occur between carboxylate oxygens, water, DMF, and MeOH molecules. Additional π···π and C—H···π interactions are important in stabilizing the structure. It is worth noting that only three related compounds were found in a search of the CSD. Of them, only one compound (Refcode HAJGIJ) has a similar Co9 core [1].

Nitroxide with diphenylphosphino moiety: synthesis, supramolecular structure, biology and catalysis

Attila Csaba Benyei1, Mostafa Isbera2, Balázs Bognár2, Ferenc Gallyas3,4,6, József Jekő5, Tamás Kálai2

1University of Debrecen Department of Pharmaceutical Chemistry; 2University of Pécs Institute of Organic and Medicinal Chemistry; 3University of Pécs Department of Biochemistry and Medical Chemistry; 4HAS-UP Nuclear-Mitochondrial Interactions Research Group Budapest; 5University of Nyíregyháza Department of Chemistry; 6University of Pécs János Szentágothai Research Center

The coupling of nitroxide and tertiary phosphane moieties offer unique opportunities in synthesis and catalysis as well as in biological effects. Surprisingly, no crystal structure report is found in CSD [1] for tertiary phosphane substituted pyrroline nitroxide. We first reported such structure [2] and synthesis of 3-(diphenylphosphino)-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-1-yloxyl radical, 1, Fig.1., left. Structural data clearly indicate the expected nitroxide radical. Analysis of supramolecular structure gave interesting results (Fig. 1., right). A simple derivative had shown better antiproliferative effect on MDA-MB-231 and MCF-7 human breast cancer lines than MITO-CP indicating the potential of the compound for use in cancer therapy [3]. Moreover, inclusion of phosphane and nitroxide moiety into the same ligand suggest versatile homogeneous catalytic activity by both metal center and ligand assisted mechanisms and they may serve as organocatalysts, too. Further studies to explore these potentials are under way in our laboratories.

Figure 1. ORTEP view of 1 with selected bond length (Å) and angle (°) data (left) and packing diagram (right) showing voids with a small probe.

[1] Groom, C.R., Bruno, I.J., Lightfoot, M.P., Ward, S.C. (2016), Acta Cryst. B72, 171-179 .DOI: 10.1107/S2052520616003954

[2] Isbera, M., Bognár, B. Gallyas, F., Bényei, A. Jekő, J. & Kálai, T. (2021). Molecules, in press. [3] Andreidesz, K.,Szabó, A., Kovács, D., Kőszegi, B.,Vantus, V.B., Isbera, M., Kálai, T., Bognár, Z., Kovács, K., Gallyas, F. (2021). International Journal of Molecular Sciences, submitted for publication

Keywords: IUCr2020; abstracts; template (use Keywords style, Arial 9pt, bold, and separate keywords by semicolons)

This research was funded by the Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the 2020-4.1.1.-TKP2020

New forms of pharmaceutical co-crystals of gefitinib with resorcinol

Parimaladevi Palanisamy

University of Limerick, Castletroy, Ireland

Gefitinib is a chemotherapeutic drug used in the treatment of breast and lung cancer. It is belonging to Biopharmaceutical Classification System II (BCS II) as it is highly permeable and poor soluble drug. The bioavailability of gefitinib is significantly affected by low aqueous solubility of the drug. To overcome this issue, we prepared co-crystals of gefitinib with resorcinol using dry grinding and solution growth method. Crystal structures of newly synthesized co-crystals were analysed by single crystal X-ray diffractometer, and it reveals that gefitinib formed 1:1:1 co-crystal with resorcinol and water. Quantitative analysis intermolecular interactions were studied using Hirschfeld surface and 2D fingerprint plot analysis. Weak molecular interactions like H∙∙∙C, H∙∙∙O, Cl∙∙∙H, F∙∙∙H and N∙∙∙H interactions play a significant role in gefitinib co-crystal formation.

Study in the Solid State, Framework Energy and Crystal Structure by X-Ray Diffraction Techniques of Cetirizine and Levocetirizine Dihydrochloride Used as an Antihistamines

Angie Paola Tamayo Carreño, Robert Antonio Toro Hernández, José Antonio Henao Martínez

Grupo de Investigación en Química Estructural, Universidad Industrial de Santander, Bucaramanga, Colombia

Cetirizine dihydrochloride and levocetirizine are antihistamines of second-generation that block histamine receptors H1, are widely used to treat allergic symptoms. These compounds belong to the class of antihistamines piperazine type and like other second-generation antihistamines, are considered non-sedating [1]. The crystal structure of cetirizine dihydrochloride has been solved and refined using X-ray powder diffraction data and optimized using Density Functional Theory (DFT) techniques. The cetirizine dihydrochloride Fig. 1, crystallized in a monoclinic system and space group P21/n (Nº 14) with parameters a=13,6663(3) Å, b=7,0978(7) Å, c=23,8311(1) Å, β=102, 488(3)°, V=2251,06 Å3 and Z=4. On the other hand, the levocetirizine dihydrochloride Fig. 1, crystallized in a monoclinic system and space group P21 (Nº 4) with parameters a=13,5450(7) Å, b=7,0719(9) Å, c=24,0527(2) Å, β=98, 159(3)°, V=2280,65 Å3 and Z=2. In both crystalline structures there are multiple hydrogen bonds intra and inter molecular, π-interactions and hydrogen-π interactions. The molecular packing and crystal energy are dominated by Van der Waals attractions according to Hirshfeld surfaces. Finally, the crystal structure was optimized with DFT and all non-H bond distances and angles were subjected to restraints, based on a Mercury Mogul Geometry Check of each molecule.

A search in the Cambridge Structural Database (CSD) [2] confirmed the absence of reports for the crystal structure of cetirizine dihydrochloride and levocetirizine. However, there are several reports of cetirizine dihydrochloride and levocetirizine in the PDF-4/Organics database [3] contains four entries PDF 00-058-1973, 00-058-1974 and 00-058-1975, corresponding to unindexed patterns about cetirizine dihydrochloride, dextrocetirizine dihydrochloride and levocetirizine dihydrochloride, respectively; PDF 00-066-1627 corresponding an experimental pattern for cetirizine dihydrochloride, according to this report, it crystallizes in a monoclinic cell with parameters a=24.1256(7) Å, b=7.07588(7) Å, c=13.5196(4) Å β=98.0028(28)° and V=2285.45 Å3 in space group P21/n (Nº14).

Influence of guest lattice solvents on nanomechanical properties of pharmaceutical crystalline solids

Subhrajyoti Bhandary1,2, Pradip Kumar Mondal2, S. R. N. Kiran Mangalampalli3, Upadrasta Ramamurty4, Deepak Chopra2

1Department Of Chemistry, Ghent University, Belgium; 2Department Of Chemistry, INDIAN INSTITUTE OF SCIENCE EDUCATION BHOPAL, India; 3Department of Physics and Nanotechnology, SRM Institute of Science and Technology, Kattankulathur, India; 4School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore

Solvates are ubiquitous in pharmaceutical crystalline solids [1]. Such solvates of a given drug molecule can exhibit different physicochemical properties such as solubility, thermal stability, and mechanical strength [2]. Hence, it is of extreme importance to understand the role of solvent molecules in determining the mechanical properties of the solvates via the nanoindentation technique, especially in view of the manufacturing of pharmaceutical tablets as well as the recent understanding of structure‐property correlations in molecular crystals [3].

The current investigation reveals the role of guest lattice solvents in tailoring nanomechanical responses (hardness and elastic modulus) in different crystalline forms of two pharmaceutically active compounds, in particular with respect to the supramolecular structure and energetics of interaction topology of molecules. The nanomechanical responses of two crystalline phases of a dihydropyrimidine analogue are similar irrespective of the presence (or absence) of the guest dichloromethane lattice solvent [4]. In contrast, the mechanical properties of two differently solvated forms (acetonitrile and DMSO) of the second related compound are anisotropic (Fig. 1). The structural features of all crystalline forms demonstrate that depending on the presence of specific guest solvent molecule and interaction topology of host-guest intermolecular interactions along with their relative orientations in the crystal lattice, majorly decide their nanomechanical properties (hardness and elastic modulus).

Figure 1. Guest solvent-dependence of nanomechanical properties in pharmaceutical crystalline solids.

[1] Griesser, U. J. (2006). The importance of solvates. In Polymorphism in the Pharmaceutical Industry (Ed.: R. Hilfiker), Wiley-VCH: Germany, pp. 211–257.

[2] Brittain, H. G. (2009). Polymorphism in Pharmaceutical Solids, Informa Health-care, NewYork.

[3] Wang, C. & Sun, C. C. (2020). CrystEngComm 22, 1149.

[4] Bhandary, S., Rani, G., Mangalampalli, S. R. N. K., Rao, G. B. D., Ramamurty, U and Chopra, D. (2019). Chem. Asian J. 14, 607.

Keywords: pharmaceutical solvates; nanoindentation; mechanical properties and interaction topology

Photoswitchable dismantlers of biomaterials made of amyloid fibrils.

Przemyslaw Kozminski1, Krzysztof Lyczko1, Zuzana Bednarikova2, Zuzana Gazova2, Imola Wilhelm3, Istvan Krizbai3, Grzegorz Wieczorek4, Dorota Niedzialek4

1Institute of Nuclear Chemistry and Technology, Warsaw, Poland; 2Institute of Experimental Physics, Slovak Academy of Sciences, Kosice, Slovakia; 3nstitute of Biophysics, Biological Research Center, Hungarian Academy of Sciences, Szeged, Hungary; 4Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland

Azobenzene molecules exhibit reversible light-triggered changes in geometrical structure (cis/trans isomerism) and nanoscale mechanical properties. For this reason, they have have been already widely used in materials science to build photo-mechanical responsive systems, incorporated in electronic switchable devices, used for graphene slicing, optical switching and data storage. We have been exploring further the photoresponsive nature of newly designed azobenzene derivatives and exploiting the potential of these smart materials for the generation of novel low-cost relevant molecular machines for biotechnology enabling the control of production/degradation of amyloid-based biomaterials. To this end, we have carefully functionalized azobenzene molecules by properties-by-design approach supported by the state-of-the-art in silico molecular design techniques as well as structure determination by X-ray crystallography. According to our Thioflavin-T Assay and NMR experimental results, the custom-designed azobenzene switches interact with the amyloid assemblies and intercalate between their strands. Stimulation with light, by inducing conformational change of azobenzene molecules, puts mechanical stress on the amyloid strands, eventually dissociating them and, in turn liquidizing the amyloid fibrils. Our in vitro studies of the designed azobenzene derivatives indicate no evidence of their cytotoxicity. Hence, it should be possible, in general, to use them for photo-control amyloid degradation in living systems, which constitutes a big encouragement for designing new azobenzene derivatives for biomedical applications, for example novel therapies against severe infections caused by amyloid biofilm forming bacteria or amyloid associated neurogenerative conditions such as Alzheimer’s disease.

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