CF@BO2017 PROGRAMME & ABSTRACTS

CRYSTALLIZATION BY DESIGN BOLOGNA, 4-6 June 2017

This event is organized jointly by:

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Thanks to our SPONSORS

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Welcome to CF@BO2017!

Welcome message from the Chairman of the organizing committee:

The Convention is organized jointly by the group of Molecular Crystal Engineering of the Department of Chemistry Giacomo Ciamician of the University of Bologna and by PolyCrystalLine. The CF@BO series initiated in 2005 becoming, though the years, a traditional occasion for university-industry bi-directional knowledge transfer. This is because CF@BO adopted, since its inception, an unusual format choosing not to be an academic workshop nor an industrial conference. CF@BO is something in between: an open ground where researchers from academy and industry can discuss the state of the art in the investigation and optimization of crystal forms and address intellectual property aspects relevant in the pharmaceutical field. In order to help this dialogue the programme presents contributions from university and public laboratories interspersed with those from industrial environments. Also a whole session focused on patents and intellectual property protection issues is organized on the last day. Moreover, beside fruitful interactions with senior scientists, young scientists will have an overview of the current trends in solid state research and of the open challenges waiting for them. The scientific programme is very dense: 33 presentations in two and a half days and a poster session with about 30 posters. Keeping the time will be very important. Also on behalf of Fabrizia Grepioni, Lucia Maini, of the group of MCE and of the staff of PolyCrystalLine I wish you an enjoyable stay in Bologna and a fruitful and rewarding scientific time at CF@BO.

Dario Braga Chairman

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Program SUMMARY

Sunday 4 June Aula Magna Chemistry Department "G. Ciamician" Via Selmi, 2

12:00 Registration 14:00 Welcome address 14:30 Susan M Reutzel-Edens, Senior Research Advisor, Small Molecule Design & Development

at Eli Lilly and Company Indianapolis, IN USA,

15:00 Michael J. Zaworotko, Rana Saniia and Alankriti Bajpaia, Department of Chemical Sciences and Bernal Institute, University of Limerick, Limerick, Republic of Ireland,

15:30 Judith Aronhime, Senior director solid state characterization TAPI global R&D at Teva

Pharmaceutical Industries Ltd., - 16:00 Jonathan W. Steed, Professor of Chemistry at Durham University,

16:30 Coffee break 17:00 Amy Robertson, Team Manager, Right Particle Team, Chemical Development at

AstraZeneca, 17:30 Juan J. Novoa, Dept. Quimica Fisica & IQTCUB,?Fac. Quimica, Univ. Barcelona,

18:00 Aurora J. Cruz-Cabeza, School of Chemical Engineering and Analytical Science, The

University of Manchester, UK. 18:30 Gérard Coquerel, Normandie Université, Laboratoire SMS-EA3233, Université de Rouen,

Mont Saint Aignan, France, -θ/-θ? X-ray powder diffraction geometry (In-

19:00 Wine and cheese party

Monday 5 June Sala Conferenze Hotel Europa - Via Cesare Boldrini, 11

8:00 Registration 8:30 Walkiria Schlindwein, De Montfort University, Leicester, UK

9:00 Tom Leyssens, Université catholique de Louvain, Belgium -crystallization and

9:30

Ana Kwokal, Technology Lead / API Physical Characterisation at GSK, Hydrate and vice versa; why does it matter for pharmaceuticals and do thermodynamics of crystals relate to their

10:00

Nicholas Blagden, School of Pharmacy, Joseph Banks Laboratories, Green Lane, Lincoln, UK -Leu crystallization.

10:30 Coffee break 11:00 Showcase presentation by PANalytical 11:30

Francesco Amadei, Senior Scientist, Early Pharmaceutics Unit, Head Analytics and Early Formulations Dept. Corporate Preclinical R&D at Chiesi Farmaceutici Spa,

12:00

Alastair Florence, Director of the EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation (CMAC), University of Strathclyde,

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12:30

Alfred Lee, Merck Research Laboratories at Merck Sharpe & Dohme Corp., "Solvates in

13:00 Lunch 14:30 Oertling Heiko, Senior Scientist Flavour Science bei Nestlé, 15:00

Marcus A. Neumann, Avant-garde Materials Simulation, prediction -

15:30

Alessia Bacchi, Università di Parma, Dipartimento di Scienze Chimiche, della Vita e Sostenibilità Ambientale,

16:00 Coffee break 16:30 Showcase presentation by Mettler 17:00

Luc Aerts, UCB Pharma, Belgium

17:30 Ulrich Griesser, University of Innsbruck, Austria, 18:00 Poster Session

Tuesday 6 June Sala Conferenze Hotel Europa - Via Cesare Boldrini, 11

8:00 Registration 8:30 Enrico Modena, Luca Covello, Polycrystalline Spa,

9:00 Franziska Emmerling, Scientist Federal Institute for Materials Research and Testing,

9:30

Neil George, Science and Technology Fellow at Syngenta Crop Protection,

10:00 Susan Bourne, Centre for Supramolecular Chemistry Research, University of Cape Town,

South Africa

10:30 Coffee break 11:00 Showcase presentation by Malvern/Alfatest 11:30 Michael Lange, Physicochemical properties and solid-state selection, Site Operations-

Analytics at Merck Group,

12:00 Teresa Duarte, Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Portugal -

12:30 Philippe Ochsenbein, Researcher at Sanofi-Aventis Montpellier, France

13:00 Showcase presentation by Nordtest 13:30 Lunch 15:00 Joel Bernstein, Global Distinguished Professor of Chemistry at New York University Abu

Dhabi and Shanghai, 15:30 Ilaria Goss, Examiner Directorate at European Patent Office (EPO),

16:00 Jill K. MacAlpine, Partner at Finnegan, Henderson, Farabow, Garrett & Dunner LLP,

16:30 Coffee break and Round Table discussion: The evolution of crystal form protection

Chairman Joel Bernstein 18:00 Dario Braga (University of Bologna) Concluding remarks and Poster Prize

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Sunday 4 June Aula Magna Chemistry Department "G. Ciamician" Via Selmi, 2 12:00 Registration 14:00 Welcome address 14:30 Susan M Reutzel-Edens, Senior Research Advisor, Small Molecule Design & Development at Eli Lilly and Company Indianapolis, IN USA,

ABSTRACT: With the vast majority of small-molecule drugs delivered to patients in solid oral dosage forms, identifying a suitable crystalline form of the active ingredient is the first step taken to transform a molecule to a medicine. Constructing a solid form landscape can be a straightforward task for molecules that crystallize with ease in but a few forms. However, compounds oftentimes exhibit extreme solubility properties, crystallize too slowly (or rapidly) or are chemically unstable, making it difficult to meaningfully survey diverse crystallization conditions. Moreover, the materials generated at small scale and under sub-optimal conditions typical of a polymorph screen may be poorly crystalline, disordered or phase mixtures, all of which complicate form identification. Scale-up of the form hits to

unstable forms that disappear once a more stable form nucleates. All of these factors may confound the generation of a reliable solid form landscape on the timescales of commercial solid form selection, especially when material is in limited supply.

Overcoming the challenges of crystal nucleation and growth reaps dividends in advancing our understanding of how structure and dynamics in real (imperfect) molecular crystals underpin the oftentimes bad behaviors that we observe. In this presentation, the practical challenges in defining a solid form landscape, ensuring that relevant forms are not missed, are highlighted. Crystal structure prediction is explored as a complementary in silico approach to pharmaceutical solid form screening, helping to establish molecular-level understanding of the crystallization behavior of APIs, as well as shown the need for further development.

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15:00 Michael J. Zaworotko, Rana Saniia and Alankriti Bajpaia, Department of Chemical Sciences and Bernal Institute, University of Limerick, Limerick, Republic of Ireland, ABSTRACT: That composition and structure can profoundly impact the bulk properties of crystalline solids has provided impetus for exponential growth in the field of crystal engineering [1] over the past 25 years. Crystalline hydrates and solvates represent classes of multicomponent materials that are long known and are of particular relevance to pharmaceutical science. Indeed, in 1827, H. E. Merck produced morphine, perhaps the first manufactured drug substance, as its sulphate pentahydrate.[2] This drug substance is still manufactured and sold today. However, whereas hydrates and solvates are well-documented, can be readily classified based upon structure and are suitable to serve as the active drug substance in several drug products, there is little in the way of predictability about either the structure or composition of molecular hydrates. This

[3] We have subsequently conducted systematic studies upon crystalline hydrates with emphasis upon (a) methods for hydrate screening and (b) understanding the factors that enable hydrates to be stable vs. anhydrates.[4] We shall present new results that further address hydrate screening methods and our expectation of whether or not hydrates will form. References: [1] (a) G.R. Desiraju, Crystal Engineering: The Design of Organic Solids Elsevier, 1989; (b) B. Moulton, M. J. Zaworotko, Chemical Reviews, 2001, 101, 1629-1658. [2] (a) D.T. Courtwright, Forces of Habit. Drugs and the Making of the Modern World, Harvard Univeristy Press 2001; (b) Merck Co, Merck's 1896 index, New York, 1895. [3] H. D. Clarke, K. K. Arora, H. Bass, P. Kavuru, T. T. Ong, T. Pujari, L. Wojtas, M. J. Zaworotko, Crystal Growth & Design, 2010, 10, 2152-2167. [4] A. Bajpai, H. S. Scott, T. Pham, K. J. Chen, B. Space, M. Lusi, M. L. Perry, M. J. Zaworotko, IUCrJ, 2016, 3, 430-439.

15:30 Judith Aronhime, Senior director solid state characterization TAPI global R&D at Teva Pharmaceutical Industries Ltd., - ABSTRACT: Polymorphism occurrence is frequent in the API (Active Pharmaceutical Ingredient) industry. Several solvates, hydrates and anhydrous forms may be encountered during API development. Their occurrence is dictated by a combination of thermodynamic and kinetic factors which is more obscure than clear. During API development the most frequently encountered polymorphs will be the more stable ones, and the most stable thermodynamic form will be selected as the form of the final API. Consistency of polymorphic form in APIs used in solid pharmaceutical dosage forms is critical in order to assure consistency in biological performance. For this purpose a robust process will be developed and used to consistently produce the API targeted form. It happens sometimes that at some advanced point in development a new crystal form is suddenly encountered, either solvate hydrate or anhydrous. In late stages this sudden appearance can seriously compromise development milestones if a new polymorph target needs to be set for the API. This phenomenon may occur even if a dedicated polymorph search was conducted at the beginning of the development. The reason why a certain polymorph would appear at a late stage of development is not always clear. The present lecture will focus on some recent cases which are reported in the literature. An attempt to find some common features among the cases will be proposed and discussed. 16:00 Jonathan W. Steed, Professor of Chemistry at Durham University,

ABSTRACT: A vast and diverse array of organic compounds and coordination complexes form gels by hierarchical self-assembly either because of hydrophobic effects in water or by more directional interactions such as hydrogen bonding in less polar solvents. Of recent interest is the emergence

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small- -assembly. Particular attractions of LMWGs to the scientific community are the reversible nature of the interactions between the gelator molecules, the wide (essentially unlimited) range of solvents that can be gelled

nality Gels derived from LMWGs have been proposed in a range of applications and include templation of nanoparticles and nanostructures, drug delivery and as crystal growth media. This presentation focuses on the design to targeted supramolecular gels as media for pharmaceutical solid form control. We believe that supramolecular gel phase crystallization offers a versatile and most readily applied innovative crystallization technology in a pharmaceutical screening context. Supramolecular gelators and their gels are easily made, produce large crystals suitable for immediate characterization, are applicable across a very broad range of solvents and their supramolecular nature means that the gelation process is easily reversed by adding competing species without heating (and consequent crystal dissolution) allowing facile isolation of the crystals. Novel crystalline forms discovered using supramolecular gels may then feed into the manufacturing process. Particular gels can exhibit drug-specific molecular recognition that change the polymorphic outcome entirely in ways that can be explicitly understood and designed for. The most spectacular example is the crystallization of the olanzapine precursor ROY from a gel of compound 1 (Scheme 1) which we explicitly designed to have the same peripheral chemical functionality as the ROY molecule itself. Gels of 1 (and ONLY 1) selectively result in the crystallization of the metastable red form of ROY while other gels and a solution control give the thermodynamic yellow form.1

Scheme 1. Crystallization of the Y form of ROY from a toluene gel of a control compound and the metastable R form from a gel of the ROY-mimic gelator 1. The thermodynamic Y form is also obtained from solution under the same conditions. References: [1] J. A. Foster, K. K. Damodaran, A. Maurin, G. M. Day, H. P. G. Thompson, G. J. Cameron, J. C. Bernal and J. W. Steed, Chem. Sci., 2017, 8, 78-84.

16:30 Coffee break 17:00 Amy Robertson, Team Manager, Right Particle Team, Chemical Development at AstraZeneca,

ABSTRACT: Within the pharmaceutical industry in recent years there has been a step-change in the use of crystal structure data. No longer is a crystal structure solely a means of confirming molecular structure or absolute configuration. Through the development of the CCDC data mining tools we can now search commercially available and in-house crystal structure databases for motifs, structure similarity and hydrogen bonds within minutes rather than weeks or months. This enables early risk assessment of forms selected for development, and more focused and effective experimental studies

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to develop crystallization processes. In addition understanding and optimizing of downstream unit operations e.g drying, can be simplified by the use of crystal structure data. The presentation will include examples of how crystal structure data and associated database tools have been used to increase understanding of the crystallization and downstream processing. 17:30 Juan J. Novoa, Dept. Quimica Fisica & IQTCUB, Fac. Quimica, Univ. Barcelona, the mechanism and speed of polymorphic phase transitions: a case example in controlling

ABSTRACT: Despite the continuous progress in the systematic obtention of all the most stable polymorphic forms of any given molecular crystal, both computationally and experimentally, the lack of reliable analytical tools has strongly difficulted a proper assessment of the quality of the results so

ready known

talk we present the obtained on the analysis of bistable molecular crystals, that is, molecular crystals where two of its polymorphs coexist within a given range on temperature, Tl-Th, but reversible interconvert above and below such a range. This results in the presence of a hysteresis loop in the variation of the physical (as, magnetism,

crystals, the variation of temperature induces a switch in the physical properties of the crystal but without hysteresis loop. Finally, other molecular crystals show no changes in in their physical property when temperature is varied. In this talk we present the methodology that has allowed us to rationalize the transformation between two polymorphic forms in terms that allow to explain the presence/absence of bistability between two polymorphs.1,2 As will be shown, the methodology employed to rationalize the presence/absence of bistability is general and can be applied to rationalize any type of polymorphic transformation. References: [1] S. Vela, F. Mota, M. Deumal, R. Suizu, Y. Shuku, A. Mizuno, K. Awaga, M. Shiga, J. J. Novoa and J. Ribas-Arino, Nature Communications, 2014, 5, 4411 [2] S. Vela, M. B. Reardon, C. E. Jakobsche, M. M. Turnbull, J. Ribas-Arino and J. J. Novoa, Chem. Eur. J., 2017, 23, 3479

18:00 Aurora J. Cruz-Cabeza, School of Chemical Engineering and Analytical Science, The University of Manchester, UK. ABSTRACT: In the organic solid state, polymorphism is a common phenomenon. Polymorphs may differ in crystal conformations, symmetries or the interactions governing their crystal structures. Beyond the crystal lattice, polymorphs may also differ in the structures and properties of their surfaces. Whilst the role of crystal surfaces in the kinetics of nucleation and growth of polymorphs is well acknowledged, it is often ignored when it comes to thermodynamics. Crystals obtained by classic crystallization techniques are large molecules sit at the surface. At those length scales, surface effects are so insignificant that they can be safely ignored. However, crystals produced by alternative experimental techniques to crystallisation may be much smaller in size. If the crystallites reach the nano-meter length scales, their thermodynamics can be considerably altered because of surface effects. In this context, we have studied the polymorphism of an aromatic compound with mechanochemistry [1]. Two polymorphs (forms A and B) were discovered and were consistently obtained through variations of the ball-mill grinding conditions. Our investigations show that our milling experiments lead to the thermodynamically stable form. However, the thermodynamically stable form switches from B to A as the size of the crystallites becomes smaller. Molecular modeling confirms that the relative stability of these polymorphs is dependent on crystal size. Equilibrium sizes at the end of the milling

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experiments vary with the milling conditions. We also investigate the effect of solvent concentration and nature on the final equilibrium of ball-mill grinding experiments rather than on the mechanisms of reaction. The thermodynamic considerations here presented are general and must be valid for any milling system, independent of the mechanisms involved in the chemical reaction. References: [1] A. M. Belenguer, G. I. Lampronti, A. J. Cruz-Cabeza, C. A. Hunter, and J. K. M. Sanders, Chem. Sc., 2016, 7, 6617.

18:30 Gérard Coquerel, Normandie Université, Laboratoire SMS-EA3233, Université de Rouen, Mont Saint Aignan, France, -θ/-θ? X-ray powder diffraction geometry (In-situX®) in the

ABSTRACT: The In-situX® is an in-line X-ray diffractometer (XRD) designed for the in-situ identification of solids without any sampling (e.g. pharmaceuticals) during crystallization in suspension. In this report, we describe the set-up and highlight the potential of the technique through several relevant scientific examples. In-situX® technology is also a promising in-line Process Analytical Technology for the monitoring of crystalline states undergoing thermal or humidity stresses.

Schematic view of the reactor and the goniometer geometry.

References: -rays, its applications and

[2] H. Takahashi, S. Iwama, S. Clevers, S. Veesler, G. Polymorphic Transition during Crystallization of Organic Compounds Showing Preferential Enrichment by Means of Temperature-Controlled Video-Microscopy and Time-Resolved X- ystal Growth & Design,

Anal., vol. 112, no. 1, 307 315, Nov. 2012.

19:00 Wine and cheese party

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Monday 5 June Sala Conferenze Hotel Europa - Via Cesare Boldrini, 11 8:00 Registration 8:30 Walkiria Schlindwein, De Montfort University, Leicester, UK

ABSTRACT: The level of interest in the pharmaceutical industry in continuous-manufacturing strategies has increased recently. These strategies can accelerate the full implementation of the QbD paradigm for the next generation of pharmaceutical products. In addition to its flexibility and time and cost-saving features, continuous manufacturing is easily amenable to model predictive design, optimization, and control methods. The example described here is taken from the first practical QbD workshop: development and

developed in collaboration between De Montfort University, GlaxoSmithKline, Leistritz, ColVand manufactured using QbD principles and tools. The main objectives were to demonstrate how to:

Integrate QbD principles in development and manufacture Practice the use of risk assessment tools Understand basics of Design of Experiments Gain process understanding by using in-line monitoring

The target product profile (TPP) requirements were identified based on patients, business and regulatory needs. The OSD selected was an immediate release tablet containing an active pharmaceutical ingredient (API) with poor aqueous solubility, but high permeability (Biopharmaceutical Classification System, BCS Class II). The manufacturing process was based on hot-melt extrusion (HME) with in-line process monitoring using a UV-vis spectrophotometer. The spectral range of the UV-Vis system was from 220 820 nm with resolution of 1 nm. Based on the represent the API concentration if the API is in solution. The maximum concentration of API that will dissolve in the polymer is dependent on the temperature at which both components are being mixed. A change in colour from yellow to orange/red is the result of the deterioration of the API. Using the knowledge acquired during these experiments one can make the following qualitative statements:

A change in chroma represents a variation in API concentration

by another effect that scatters light (e.g. bubbles)

A rapid change in colour/lightness is undesirable. A change in colour from yellow to orange/red is the result of the deterioration of the API due

to excess heat

Operating close to conditions that are difficult to control increases the risk of unstable results In summary, this example nicely illustrates the potential of in-line optical spectroscopy for real-time data generation, measurement of API stability, concentration and solubility. In addition, it is possible to measure feeding accuracy, residence time distribution (RTD), extruder cleaning behaviour (washout phase), temperature/shear stability of Polymer/API against thermal and mechanical energy behaviour, batch to batch or supplier variations of raw materials (old material vs. new material), crystalline and amorphous phases, mapping of the process window and formation of degradation products. The use of QbD methodology and PAT tools for product design and continuous process monitoring in pharmaceutical product manufacture can offer clear advantages to ensure product quality. The case study described here shows how QbD principles and PAT can effectively transform the way pharmaceutical products can be developed and manufactured.

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9:00 Tom Leyssens, Université catholique de Louvain, Belgium -crystallization and its

ABSTRACT: Co-crystals have had considerable attention over the last decade due to their potential as

Even though alternative synthetic methods, such as mechanochemistry or melt crystallization exist for the synthesis of these compounds, solution crystallization remains industrially one of the most accessible routes towards co-crystals. Within the context of this presentation, I will focus on different solution co-crystallization methods which can be used to obtain a robust industrial crystallization process (cooling, evaporative,

be highlighted. A second part of the talk will focus on co-crystallization applications in solution. In this part, the link will be made with co-crystallization thermodynamics and kinetics to get a deeper insight into the possible applications. Initially, we will focus on how co-crystallization can be used to improve the solubility and dissolution profile of an API. We will then use co-crystallization as a separation tool, focusing both on the purification of achiral and chiral compounds.

Figure: Co-crystallization to improve the dissolution profile of an API, and the corresponding thermodynamic/kinetic

diagram.

9:30 Ana Kwokal, Technology Lead / API Physical Characterisation at GSK, vice versa; why does it matter for pharmaceuticals and do thermodynamics of crystals relate to their

ABSTRACT: Hydrate/anhydrate pairs are an interesting case for studying solute-solvent-interactions and thermodynamic stability of crystals vs. their corresponding nuclei. The case of GSK Compound A hydrate, as a pair of its anhydrate form, will be presented, with the focus on their solid state interrelation, reflecting also on the relative stabilities of crystals vs. nuclei. Compound A hydrate is formed from THF solvent, while direct crystallisation from a vast number of organic aqueous solvents was not feasible, unless with high concentration of seed. This is due to the fact that the hydrate is formed via THF solvate, which transforms to hydrate upon drying, by water replacing THF. However, competitive slurry in IPA has shown that Compound A hydrate is thermodynamically more stable than its anhydrate Form 1 pair, at water activity higher than 0.4 (at RT). It is not unusual that certain polymorphs are formed only via desolvation [1], but what is of particular interest in this case is the instability of nuclei in solution compared to the crystal phase. The case will be discussed in the light of molecular cluster [2,3] and nano-size crystal stability [2-4] and the surface effect on cluster stability [5-7]. An industrial perspective will be also given, with the focus on the risks associated with anhydrate/hydrate pair systems and the importance of defining critical quality attributes of product performance.

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References: [1] A. Berzins, E. Skarbulis, and A. Actins, Cryst. Growth Des., 2015, 15, 2337 2351. [2 ]R. B. Hammond, K. Pencheva and K. J. Roberts, J. Phys.Chem. B, 2005, 109, 19550 19552. [3] R. B. Hammond, K. Pencheva and K. J. Roberts, Faraday Discuss., 2007, 136, 91 106. [4] A.M. Belenguer, G.I. Lampronti, A.J. Cruz-Cabeza, C.A. Huntera and J.K. M. Sanders, Chem. Sci., 2016,7, 6617-6627. [5] J.M. Ha, J. H. Wolf, M. A. Hillmyer and M. D. Ward, J. Am.Chem. Soc., 2004, 126, 3382 3383. [6] Q. Jiang and M. D. Ward, Chem. Soc. Rev., 2014, 43, 2066 2079. [7] A. Kwokal Thai T. H. Nguyen, and Kevin J. Roberts. Cryst. Growth Des., 2009, 9, 4324 4334.

10:00 Nicholas Blagden, School of Pharmacy, Joseph Banks Laboratories, Green Lane, Lincoln, UK

- ABSTRACT: The crystallisation of the di-peptide Leu-Leu will be presented. The evidence to date on crystallise-ability of this compound will be presented. The work has focused on the issue of direct crystallisation as a route to purify this material. This direct crystallisation from synthesis approach is counter to the conventional approach to use successive chromatography and thus avoid the resulting high yield loss. The outcome of crystallisation studies has revealed a rich behaviour of outcomes and a broad spectrum of salts to molecular complexes both anhydrous and solvated. Selected highlights of the solid state dosage forms encountered will be presented in the talk. The key point from this work is that multi component factors are the centre of the issues in crystallising this di peptide compound. A considerable amount of crystal growth science has been encountered and the presentation will link to issues around solubility, nucleation and growth. 10:30 Coffee break 11:00 Showcase presentation by PANalytical, platform: the PANalytical solution to cover basic and advanced x-ray scattering application for

11:30 Francesco Amadei, Senior Scientist, Early Pharmaceutics Unit, Head Analytics and Early Formulations Dept. Corporate Preclinical R&D at Chiesi Farmaceutici Spa,

ABSTRACT: The inhaled route of administration is most widely used in the chronic treatment of pulmonary diseases, such as asthma, COPD, cystic fibrosis, pneumonia. The rational for such treatments includes more localized and targeted delivery with minimum systemic exposure. For efficient deposition in the lungs, physical properties of the aerosolized drugs are critical: the particles should have an ideal size and morphology that provide optimal aerodynamic performance.[1] Three main inhalation systems are widely used for pulmonary drugs: nebulizers and pressurized Metered Dose Inhalers (pMDIs) are based on solution/suspension formulations, while Dry Powder Inhalers (DPIs) generate aerosol directly from solid API mixed with solid excipients or carriers. Among the alternative particle engineering technologies available to produce a DPI formulation, the traditional process of blending a micronized crystalline drug (1-5 µm) with larger lactose particles is still the most used approach.[2] The API is usually milled prior to blending, using a jet mill or similar device. The aerodynamic properties of the API particles, their adhesion to the excipient and their stability all impact upon the efficacy of dosing. Therefore, the crystal size, habit, shape and surface of micronised material need to be fully controlled in order to proper tune the aerodynamic properties. Unfortunately, the milling process imparts significant energy to the solid, which can induce localized melting or the formation of amorphous material. Potential undesirable effects of these phenomena are particle aggregation, increased hygroscopicity, and physicochemical instability. In addition, the micronised material should result compatible with the chosen excipients. As a result of all these constraints, the activities for identification of crystalline forms suitable for inhalation should start in earlier phases of drug discovery. It is in fact quite typical perform the first crystallisation screening during the discovery phase, during lead selection or lead optimization, as a

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part of the Screening Cascade of tests for the selection of Candidate Drugs (CD). However, these solid form screenings are generally more complex than for a standard oral development program due to the low amount and suboptimal purity of material generally available at this stage, the high molecular complexity of inhaled drug candidates and the limited number of counterions generally chosen for inhalation.[3] Some case studies will be discussed, showing the challenges the scientists have to face in drug discovery while trying to identify crystalline forms suitable for inhalation. References: [1] Patton, J. S., & Byron, P. R. (2007). Inhaling medicines: delivering drugs to the body through the lungs. Nature Reviews Drug Discovery, 6(1), 67-74. [2] Pilcer, G., & Amighi, K. (2010). Formulation strategy and use of excipients in pulmonary drug delivery. International Journal of Pharmaceutics, 392(1), 1-19. [3] Selby, M. D., de Koning, P. D., & Roberts, D. F. (2011). A perspective on synthetic and solid-form enablement of inhalation candidates. Future medicinal chemistry, 3(13), 1679-1701.

12:00 Alastair Florence, Director of the EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation (CMAC), University of Strathclyde, workf 12:30 Alfred Lee, Merck Research Laboratories at Merck Sharpe & Dohme Corp., "Solvates in

ABSTRACT: Solvates are multi-component crystalline solid adducts in which molecules of the solvent of crystallization are incorporated within the crystal lattice in either non-stoichiometric or stoichiometric amounts. The most common solvate is when the incorporated guest molecule is water in which case the molecular adduct is referred to as a hydrate. Hydrates are frequently encountered in pharmaceutical development as approximately one out of three molecules listed in the European Pharmacopeia can form hydrates. Solvate formation is also quite common but sometimes less studied in early drug development as initial crystallization screening efforts are focused on identification of anhydrous and hydrated forms. Solvates, in this case, are often regarded as a nuisance, however, these molecular adducts can be exploited later to provide enhanced chemical purification, improved product yield and eradicate process-induced disorder in crystalline materials. Application of solvates in drug development will be discussed. Moreover, a case of a late appearing stable solvate in process development will be reviewed. Emphasis will be placed on how thorough understanding of the behavior, stability and interrelationship of the solvating- and non-solvating solid forms are needed to ensure development of robust processes to deliver the target crystalline form. 13:00 Lunch 14:30 Oertling Heiko, Senior Scientist Flavour Science bei Nestlé, ABSTRACT: Ionic cocrystals have recently gained attention as multi-component pharmaceutical materials capable of improving the physicochemical properties of the respective pharmaceutically active compound. Contrastingly, ionic cocrystals between common carbohydrates and alkali or alkaline earth halides have been investigated since the beginning of chemistry. This is well reflected in the multitude of denominations attached to this class of crystalline species over the years, e.g. adducts, binary compounds, complexes, cocrystals, ionic cocrystals or metal organic frameworks. Throughout several centuries, these compounds have been inspected with the specific perspective of contemporary interest. In most cases, they can conveniently be prepared from the ionic salt and the respective neutral carbohydrate via solution crystallization and therefore offer an opportunity for fundamental studies in the fields of crystal engineering and solid state chemistry, bridging traditional organic and inorganic chemistry.[1] An overview will be given on several systems of interest from an applied perspective, with an emphasis on the historic context and evolution of the field. References: [1] H. Oertling, Cryst. Eng. Comm., 18, 1676-1692 (2016).

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15:00 Marcus A. Neumann, Avant-garde Materials Simulation, -

ABSTRACT: Crystal structure prediction is the task of deriving the observable three-dimensional crystal structures of organic molecules from their two-dimensional chemical structure alone. Prediction methods face the mathematical challenge of sampling a search space that grows exponentially with the number of degrees of freedom and the physical challenge of calculating lattice free energy differences with an accuracy that should be better than the order of magnitude of typical lattice energy differences between polymorphs. The state-of-the-art was assessed by a series of blind tests in 1999, 2001, 2004, 2007, 2010 and 2015. In the last three blind tests, the highest success rate was scored with an approach implemented in the computer program GRACE. Dispersion-corrected density functional theory (DFT-D) calculations [1] are used to first generate reference data to which a tailor-made force field is fitted from scratch [2] for every chemical compound under consideration. The tailor-made force field is then used in conjunction with a Monte Carlo parallel tempering algorithm to generate crystal structures that are further optimized at DFT-D level. Statistical control mechanisms ensure that all crystal structures in a user-defined target energy window are found with a user-defined level of confidence. The 2015 blind test [3] has demonstrated the ability of GRACE to perform crystal structure predictions using fully automated workflows, to handle two flexible molecules per asymmetric unit and to predict the crystal structure of the hydrate of a chloride salt. Looking back on more than two dozens of confidential and non-confidential crystal structure prediction studies with GRACE, a picture emerges how crystal structure prediction in an industrial working environment helps rationalize crystallization behavior, understand solid-state forms, solve crystal structures and flag missing more stable forms. The emerging ability to find new crystal forms by rational crystallization experiment design based on the knowledge of the computed crystal energy landscape is illustrated by the example of Dalcetrapib [4]. References: [1] Neumann, M. A. and Perrin, M.-A. J. Phys. Chem. B 109: 15531-15541 (2005) [2] Neumann, M. A. J. Phys. Chem. B 112: 9810-9829 (2008) [3] Reilly, A. M. et al. Acta Cryst. B 72: 439-459 (2016) [4] Neumann, M. A. et al. Nature Communications 6, art7793 (2015)

15:30 Alessia Bacchi, Università di Parma, Dipartimento di Scienze Chimiche, della Vita e Sostenibilità Ambientale, ABSTRACT: We address the problem of stabilizing liquid ingredients in crystalline forms at ambient conditions. One example is nicotine. Nicotine is a toxic alkaloid found in the leaves of the tobacco plants Nicotianatabacum and Nicotianarustica of the family Solanaceae and it is known for being a nootropic stimulant drug. Because of its properties, nicotine has been of commercial interest and employed for widely differing uses such as therapeutic use in treating nicotine dependence or as an insecticide. However nicotine is a liquid, and liquid formulations tend to be essentially less stable than solid forms; in fact most pharmaceutical active ingredients and nutraceutical compounds are manufactured and distributed as crystalline materials and their action involves the delivery of the active molecule by a solubilization process either in the body or in the environment. Nicotine possesses two basic centers, therefore salt formation could be exploited as a well-known method to build a crystalline material from a base; however salification alters the molecular electronic properties, and affords a material sensitive to pH. On the other hand, cocrystallization is considered a smart and dainty way to tune solubility properties of solid phases leaving the molecule chemically unchanged. The design of cocrystals forms of nicotine has been approached by analyzing its molecular electrostatic potential and its full interaction map created with the CCDC-Materials module. An intriguing aspect of nicotine lies in the fact that its crystal structure has never been reported in literature and this peculiarity may be ascribed to the liquid-glass

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transition that occurs when nicotine is supercooled under its melting point (-79°C). Despite nicotine is considered a rigid molecule, its glass forming attitude could be due to a certain extent of conformational variability, which has been assessed by the conformer search of the CCDC software. Based on these considerations, three coformers have been identified and their crystal structure shows that nicotine adapts to the packing features dictated by the coformers.

Figure. Molecular electrostatic potential mapped on the molecular surface of nicotine and one conformer, showing charge complementarity.

16:00 Coffee break & Posters 16:30 Showcase presentation by Mettler 17:00 Luc Aerts, UCB Pharma, Belgium

ABSTRACT: Next to the pure polymorphic forms, an Active Pharmaceutical Ingredient (API) can also crystallize in pseudo-polymorphic forms, such as solvates and hydrates. This presentation will deal with the specific case of hydrates and the complication this might add to pharmaceutical development. Due to the combination of water and the API in one phase, the relative stability of an hydrate with respect to other hydrated states or anhydrous forms is not only dependent on pressure and temperature, but also on relative humidity or water activity. In case the boundary between the hydrate and anhydrous state is close to ambient humidity conditions, neither of both states is fully stable and the system might readily switch from one state to the other with detrimental consequences for solubility, dissolution rate and bioavailability. As in solid state transitions in general, an important aspect to take into account is nevertheless the relative contribution of thermodynamics and kinetics. Some forms might thermodynamically not be stable in a certain condition, but in case a form remains metastable for a sufficiently long period, it can be successfully applied for pharmaceutical development. In all this, besides the behaviour of the pure API, a very important point to watch too is the impact of the drug formulation on the solid state equilibria. Excipients can create a local environment and can, in combination with specific processes applied, affect the (meta)stability of solid forms. The presentation will discuss through a few case studies these different aspects and the sometimes difficult choices to be made during drug development. 17:30 Ulrich Griesser, University of Innsbruck, Austria, ABSTRACT: The potential impact of additional chemical components on the formation (nucleation and growth) as well as the stability of specific polymorphs is well known but is often far from being well understood. Impurities from the chemical synthesis of a compound are probably the most common additives (or admixtures) that may have accidentally caused the formation of new crystalline phases,

- rphs, to stabilize metastable polymorphs, to control the growth (morphology) of crystals or for chiral separations. However, the use of isomorphic additives for the stabilization of a metastable solid state form is rarely addressed in the newer literature. Studies on the phase behavior of admixtures of compounds that are isomorphic and exhibit

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reported for a series of inorganic compounds and many organic substances. The term isopolymorphism describes phase systems where each polymorphous form of one substance is isomorphous to a respective polymorphic form of another substance. Isodimorphism is more specifically used for cases where each compound shows two phases. This presentation discusses examples and applications of isomorphic seeding in order to generate specific solid state forms. Phases produced via this route are usually metastable and can sometimes only be maintained in the presence of traces or higher amounts of the isomorphic component, i.e. as solid solution. The results demonstrate that such techniques enable the generation and stabilization of even highly metastable forms, which would never nucleate in common crystallization experiments. 18:00-19:30 Poster session

Tuesday 6 June Sala Conferenze Hotel Europa - Via Cesare Boldrini, 11 8:00 Registration 8:30 Enrico Modena, Luca Covello, Polycrystalline Spa, ABSTRACT: For solid oral dosage forms solubility represents one of the most important aspects to control, especially for those APIs that show poor water solubility. To enhance the solubility/bioavailability several strategies can be adopted. One approach is the development of a tailor-made formulation to chemically promote the dissolution. Another approach is represented by the modification of the physical properties of the final dosage form (i.e. PSD, crystal form, and crystallinity). Micronization is the most effective and well established process to control PSD, and is aimed to reduce the granulometry of the API in order to maximize the surface area. However, the proper optimization of the crystallization process by defining and controlling its key parameters can offer a reliable alternative, with a cost-saving approach to avoid micronization and the possible issues related (i.e. change of polymorphic form). 9:00 Franziska Emmerling, Scientist Federal Institute for Materials Research and Testing, investigations of mechanochemical syntheses: new i ABSTRACT: Mechanochemistry is increasingly used for synthesizing soft matter materials including metal organic compounds and cocrystals.1,2 The ever-increasing interest in this method is contrasted by a limited mechanistic understanding of the mechanochemical reactivity and selectivity. Time-resolved in situ investigations of milling reactions provide direct insights in the underlying mechanisms.3,4 We recently introduced a setup enabling in situ investigation of mechanochemical reactions using synchrotron XRD combined with Raman spectroscopy (Fig.1a). The specific combination allows to study milling processes comprehensively on the level of the molecular and crystalline structure and thus obtaining reliable data for mechanistic studies. In this talk I will discuss our recent results investigating the formation of (polymorphic) cocrystals.6-7 First investigations of a mechanochemical synthesis under controlled temperature (Fig 2a) which allow determining the activation barrier are presented.8

Furthermore, in situ Raman spectroscopy coupled with thermography revealed a low temperature increase during milling reactions due to the mechanical impact and clear temperature increases as a result of the reaction heat.

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Figure 1: a) Experimental setup for collecting Raman spectra and XRD powder patterns during the mechanochemical synthesis. b) Schematic of in situ monitoring of a mechanochemical reaction under controlled temperature using Raman spectroscopy.

Based on the data, temperature rises as postulated in the magma plasma and hot spot theory can be excluded for soft matter milling syntheses.9 Our results indicate that in situ investigation of milling reactions offer a new approach to tune and optimize mechanochemically synthesized compounds. References: [1] S.L. James et al., Chem. Soc. Rev. 2012, 41, 413-447. [2] A.A.L. Michalchuk, I.A. Tumanov, E.V. Boldyreva, Crystengcomm 2013, 15, 6403-6412. [3] T. Friscic, I. Halasz, P. J. Beldon, A. M. Belenguer, F. Adams, S. A. J. Kimber, V. Honkimaki, R. E. Dinnebier, Nat. Chem. 2013, 5, 66-73. [4] L. Batzdorf, F. Fischer, M. Wilke, K. J. Wenzel, F. Emmerling, Angew. Chem. 2014, 54, 1799-1802. [5] F. Fischer, G. Scholz, S. Benemann, K. Rademann, F. Emmerling, Crystengcomm 2014, 16, 8272-8278. [6] F. Fischer, A. Heidrich, S. Greiser, S. Benemann, K. Rademann, F. Emmerling, Crystal Growth & Design 2016, 16, 1701-1707. [7] F. Fischer, S. Greiser, D. Pfeifer, C. Jager, K. Rademann, F. Emmerling, Angew. Chem. 2016, 55, 14279-14283. [8] F. Fischer, K. J. Wenzel, K. Rademann and F. Emmerling, PCCP 2016, 18, 23320-23325. [9] H. Kulla, M. Wilke, F. Fischer, M. Rollig, C. Maierhofer, F. Emmerling, Chem. Comm. 2017, 53, 1664-1667.

9:30 Neil George, Science and Technology Fellow at Syngenta Crop Protection, and Kinetic Considerations of Solids State Behaviour for the Control of Agrochemical Process and

ABSTRACT: Agrochemical products are often multi-component systems, either as isomers or molecular analogues of a single active ingredient or mixtures of active compounds deliberately combined to achieve a spectrum of activity. Process and product additives and solvents add further complexity in phase behaviour presenting measurement challenges. Rapid and complete crystallisation for productivity, yield, purity and morphology control are often the focus of crystallisation process optimisation. The process must also deliver the physical quality necessary for design of robust formulations. Crystallisation in formulated products often leads to instability, poor flow and poor formulation performance. In contrast to crystallisation for purification purposes, formulation of active compounds generally aims towards minimising crystallisation phenomena. Finding and manufacturing the most thermodynamically stable crystal state is essential to delivering stable formulated products, thereby minimising the driving force for crystallisation in formulation.

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During application of the formulation, however, generation of supersaturation is often inevitable due to temperature, composition changes or solid state transitions. Controlling rates of crystallisation, nucleation and growth, within the formulation is then essential but can often be challenging to measure and control. The presentation discusses application of measurement and modelling tools in an industrial context, the challenges of measurements in multicomponent systems, highlights the importance of the isolation-formulation interface and discusses some approaches to control formulation stability. 10:00 Susan Bourne, Centre for Supramolecular Chemistry Research, University of Cape Town, South Africa ABSTRACT: Supramolecular chemical techniques provide a means to modify properties of solid state forms. These techniques may involve co-crystallization with appropriate co-formers, or the inclusion of the active species in a host matrix. Combined with polymorphic screening, these methods provide opportunities to tune the physical properties of active pharmaceutical ingredients, APIs. While the international disease burden has shifted from premature mortality towards disability, in sub-Saharan Africa, communicable, maternal, nutritional and newborn diseases are still predominant.[1] Communicable diseases of particular concern include malaria, tuberculosis and HIV infection. This presentation will present examples from recent work undertaken in our laboratory on improving the properties of existing and approved APIs through applications of supramolecular chemistry methods. References:

-Available at www.worldbank.org/en/news/feature/2013/09/09

10:30 Coffee break 11:00 Showcase presentation by Malvern/Alfatest - Anne Virden, Product Technical Specialist at Malvern Instruments, -Directed Raman Spectroscopy (MDRS) for the

11:30 Michael Lange, Physicochemical properties and solid-state selection, Site Operations-Analytics at Merck Group, ABSTRACT: In the research of new chemical entities (NCEs), the design of molecules with specific target binding profiles is in focus of the medicinal chemists. Many of these sophisticated substances show weak solubility in biorelevant media leading to insufficient bioavailability. The solid state selection opens a toolbox for enhancement of dissolution profiles, preferably with higher concentration levels by supersaturated systems. In most cases, the drawback is the loss of thermodynamic stability associated with the risk of transitions to more stable forms. The presentation will include an in-house example of a poorly soluble crystalline drug form and the development of its metastable disordered species for use in clinical trials. The talk will encompass the opportunity for a fast track medication, analytical monitoring tools, and importantly, also highlight the risk of loss in stability and challenges for the manufacturing process. 12:00 Teresa Duarte, Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Portugal - ABSTRACT: Polymorphism, the ability of the molecules to adopt different packing arrangements, is a fascinating solid-state phenomenon that has been studied for. However, understanding, predicting, or

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controlling it is quite a challenge! [1,2] Here, we present the results obtained when imidazolium-based room temperature ionic liquids (RTILs) were tested to assess their ability to control molecular polymorphic behavior of gabapentin (GBP), used as a case study. Mixtures of RTILs with distinct cation/anion combinations revealed promising capabilities in directing the crystallization process

isolated. Forms were maintained over time, once they were kept soaked, opening new perspectives for the method presented here. Molecular dynamics (MD) simulations clearly supported the results.

H(acidic(C4/C6mim))···O(carboxylate) interaction between GBP and RTILs drives the formation of Form IV. These results showed th

of avoiding polymorphism. [4] References: [1] Braga, D.; Grepioni, F.; Maini, L.; Polito, M. Struct. [2] Cruz-Cabeza, A. J.; Reutzel-

[4] Martins, I.; Oliveira, M.; Diogo, H., Branco, L., Duarte, M. Teresa, ChemSusChem, 2017, 10, 1360-1363

12:30 Philippe Ochsenbein, Researcher at Sanofi-Aventis Montpellier, France

13:00 Showcase presentation by Nordtest - Anett Kondor, iGC-SEA Product Manager and application Specialist, London, -SEA, an analytical technique to determine batch-to-batch

13:30 Lunch 15:00 Joel Bernstein, Global Distinguished Professor of Chemistry at New York University Abu Dhabi and Shanghai, ABSTRACT: While chemistry is considered to be one of the exact sciences, much of the reasoning in the practice of chemistry is not based on absolutes but rather on general rules and exceptions to those rules. This means that in the practice of their discipline, chemists necessarily

and expert witnesses in patent litigations that necessarily involve technological and scientific issues often including chemistry. As a result of the fuzzy nature of much of chemical logic, accomplished, well established chemists can find themselves on opposite sides of a courtroom, each representing what he or she honestly believes is correct science, even though in terms of the legal question to be

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addressed, they are diametrically opposed. In this talk I will provide examples of these aspects of the relationship between the fuzzy logic of chemistry and the role of expert witnesses in patent litigation. 15:30 Ilaria Goss, Examiner Directorate at European Patent Office (EPO),

ABSTRACT: A number of patent applications and opposition cases in PAOC (Pure and Applied Organic Chemistry, a cluster of the EPO) relate to solid state forms of chemical compounds, in particular of active pharmaceutical ingredients. Chemical compounds can exist in a variety of solid forms including: amorphous solids, polymorphs, solvates including hydrates, salts, and co-crystals. Different solid forms of a compound display unique physicochemical properties which can influence the manufacturability, processing, handling and intended use. For active pharmaceutical ingredients, particularly important are the thermodynamic stability and the bioavailability for poorly water-soluble drugs. Other properties may also be important including chemical stability, filterability or hygroscopicity. In practice, solid state screening seeks to find a form with an optimal balance of desirable properties. Further interest in the subject stems from the fact that solid state form inventions create intellectual property opportunities for originator and generic companies alike. The present presentation aims at offering some guidance for the way how the EPO is dealing with applications relating to solid state inventions. It is particularly focused on polymorphs. 16:00 Jill K. MacAlpine, Partner at Finnegan, Henderson, Farabow, Garrett & Dunner LLP,

ABSTRACT: Patent law pertaining to solid state forms continues to develop in view of scientific advances in the ability to detect, analyze, characterize, and distinguish such forms. General principles of U.S. patent law particularly relevant to claiming solid state forms will be discussed, followed by a focused discussion of the current treatment of such claims by U.S. courts and the U.S. Patent and Trademark Office. Case studies and examples based on publicly available patents, prosecution histories of patent applications, and documents from litigations will be used to highlight issues, considerations, and potential strategies and pitfalls under current U.S. patent law. 16:30 Coffee break and Round Table discussion: The evolution of crystal form protection Chairman Joel Bernstein 18:00 Dario Braga (University of Bologna) Concluding remarks and Poster Prize

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NOTES

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10 things to do in BOLOGNA

1. The main plaza of Bologna is Piazza Maggiore and there is a lot to see here including the Basilica of San Petronio. This church was meant to be the largest church in the world, but when the Vatican caught wind of the construction, they put a halt to that. This Basilica isn't Bologna's main church contrary to popular belief. The actual main church of Bologna is located on the main

enza, Cattedrale di San Pietro.

2. Visit the Basilica di Santo Stefano. The Basilica is a complex of sacred buildings that form the (it has

been recently restored) and is made by Chiesa del Crocifisso, Basilica del Sepolcro, Chiesa di

medieval cloister) and Museo di Santo Stefano.

3. Wander the streets of the Quadrilatero, the medieval market where you can browse through the outside stands and old shops selling all sorts of delicacies.

4. Eat all the Bolognese specialties! Tortellini, sage and butter tortelloni, tagliatelle al ragù, mortadella, crescentine with cold cuts and soft cheese like stracchino and squaquerone; all to be washed down with the local white wine Pignoletto or red Lambrusco.

5. Hike to the top of San Luca under the longest portico in the world: 3,8 km and 666 arcades. The reward is the beautiful sanctuary of the Basilica of San Luca at the top of the hill. One can begin the walk up to the Sanctuary of the Madonna of San Luca at the Meloncello Arch situated along via Saragozza.

6. The towers are one of the main features of Bologna. Between the XII and XIII century many towers were built, but nowadays they are less than twenty. These towers had a military and civil function: they gave prestige to the families which paid for their construction. The two most

7. Visit the Archiginnasio, the first seat of the University of Bologna, the oldest university of the Western world, founded in 1088. Before the Archiginnasio was built between 1562 and 1563, lessons were held in private or rented houses, in religious venues and sometimes on the squares. Make sure you peek inside the gorgeous and fascinating Teatro Anatomico: this is where corpses were dissected for the first scientific studies of the human body.

8. Few people know that Bologna have always been a city of water. The most charming part of this unusual Bologna is discovered by opening a small window located in Via Piella. Other

Oberdan and via Malcontenti. In the Jewish Ghetto, under which flows the Aposa river or between via delle Moline and via Capo di Lucca, you can hear the roar of Salto del Reno river.

9. Visit the Museum of the History of Bologna. Housed inside Palazzo Pepoli, the old residence of one the most important families in medieval Bologna, this museum traces the entire history of Bologna, from the Etruscan settlement known as Felsina to Roman Bononia to the height of its power during the Middle Ages and on through modern times.

10. Stroll the Porticoes. Because Bologna was booming due to its thriving university, extra housing was needed for students. The university was located downtown and instead of building outside the city, Bologna built facades on the front of their buildings into the streets. These student housings were built on the front of already existing buildings with a stipulation that they must be wide and high enough to allow horse carts to pass.

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Thanks to our SPONSORS

This event is organized jointly by: