Polymorphism in material chemistry: an inconvenience or an opportunity?

Transcription

1 ISOF Bologna, 26 nov 2013 Polymorphism in material chemistry: an inconvenience or an opportunity? Massimo Gazzano ISOF CNR, Bologna, Italy A crystal polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two crystalline arrangements of the molecules of that compound in the solid state. McCrone 1965 molecule Polymorph 1 Polymorph 2 Changing the relative position of the molecules, the interactions between them will be different and consequentely also the properties

2 TiO 2 Rutile Tetragonal Density 4.3 Anatase Tetragonal Density 3.9 Different structures: differences in whitening and catalytic properties Paracetamol form I form II F. Grepioni, Workshop Polimorfismo dei farmaci: Fondamenti e Innovazione, Bologna 2007

3 F. Grepioni, Workshop Polimorfismo dei farmaci: Fondamenti e Innovazione, Bologna 2007 L. Yu Acc. Chem. Res., 2010, 43, pp

4 Ritonavir: a case of disappearing polymorph After two-and-a-half years of closely monitored and tested formulation manufacturing, we encountered a new form of ritonavir, a crystal form...previous to [May-June 1998] we had manufactured about 240 batches of ritonavir and none of those batches had ever failed a dissolution test. What has happened is that a new crystal form of ritonavir has appeared. Although it has the same purity, this form has different properties that make it more difficult to formulate. Specifically, the crystalline structure makes ritonavir dissolve more slowly, which affects its bioavailability. This is why all of us at Abbott have been working extremely hard throughout the summer, often around the clock, and sometimes never going home at night. We have been here seven days a week and we will continue to do so. We have canceled vacations and asked our families for their understanding and support. This is not an issue that we take lightly. There were several sub-teams of three to 600 people per team working full time in different areas. We also called on as many resources as we could We tried everything. We conducted countless experiments. We reconditioned our facilities. We rebuilt facilities and new lines. We looked at alternative sites. We visited a number of [other] organizations around the world to see if we could start clean in a new environment free of Form II. End of the story: thermodinamics won. In june 1999 ritonavir was approved a new gelatin-capsule preparation (to be stored in the refrigerator)

5 Ritonavir story remind us two points: (McCrone, 1965) the number of forms known for a given compound is proportional to the time and energy spent in research on that compound. 2 1 Ostwald Rule of stages (1897).in general it is not the most stable but the least stable polymorph that crystallizes first. methylsulfanyl quaterthiophenes: 1st case of conformational polymorphism in oligothiophenes Triclinic form orange G.Barbarella, M.Zambianchi, R.Di Toro, M.Colonna, L.Antolini, A.Bongini, Adv.Mater. (1996), 8, 327 Monoclinic form yellow G.Barbarella, M.Zambianchi, M.del F.Marimon, L.Antolini, A.Bongini, Adv.Mater. (1997), 9, 484

6 β-methylated sexithiophenes Triclinic form Monoclinic form Triclinic Monocl. PL peak 566 nm 535 nm decay monoexp nonexp time 295 ps 120 ps T dep. >380ps no G. Barbarella, M. Zambianchi, L. Antolini, P. Ostoja, P. Maccagnani, A. Bongini, E.A. Marseglia, E. Todesco, G. Gigli, R. Cingolani J.A.C.S. (1999) 121, 8920 thieno (bis) imide derivative time temperature integrator D. Gentili, M. Durso, C. Bettini, I. Manet, M.Gazzano, R. Capelli, M. Muccini, M. Melucci, M. Cavallini Scientific Reports 2013, 3, 2581

7 Can we transfer the metodologies used in Pharmaceutical chemistry to Material chemistry in order to find several phases for a material? to test in advance the more stable phase and the possible presence of polymorphs Polymorph screening, a full study that take into account - Solvent -ph - Temperature - Concentration / sovrasaturation -Solvate forms - Cocrystals -.. Cocrystallization: a possible choice to make solid liquid material and to modulate properties a cocrystal is a crystalline structure made up of two or more components in a definite stoichiometric ratio, where each component is defined as either an atom, ion, or molecule (draft explanation) theophylline benzoic acid

8 Polymorphs of cocrystals cocrystal form II cocrystal form I cocrystal form III Changing the cocrystal former component many cocrystals are possible cocrystal form II cocrystal form I cocrystal form III

9 Keypoints The study of polymorphism is a way to tune the properties of functional molecules Cocrystallization is a further way to modulate properties The functional material molecules should undergo a polymorph screening process We are able to build a polymorphism disctrict in order to test all the new molecules Polymorphs screening Synthetic design Synthetic strategy Device preparation Improoving performance Crystallography Crystal engineering