\\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Title-R1d.png Petr Beňovský POLYMORPHISM \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM The ability of a solid material to exist in multiple forms or crystal structures known as polymorphs; Polymorphs have different energy of their crystal lattices, and consequently different melting points, solubilities etc. Do not mix up polymorphism with crystal morphology – a compound under different conditions crystallizes in different shapes – habits, but a polymorph is still the same; Pseudopolymorphs – the crystal lattice contains some amount of solvent (solvates, hydrates) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Polymorphs are crystalline materials that have the same chemical composition, but different molecular packing \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM VS. ALLOTROPY ALLOTROPY – the existence of two or more different physical forms of a chemical element; Example – graphite, diamond, fullerene DOES IT MATTER? When Napoleon invaded Russia, the soldiers’ tin buttons disintegrated in the cold. They had to survive the Russian winter with open jackets!! (tin pest) Some say it is only a legend \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Some polymorphs of ice Kurt Vonnegut – Cat’s Cradle - New water modification - Ice Nine – supposedly inspired by Irving Langmuir (General Electric Co.) Ice IX really exists, it is stable at T below 140 K and pressure between 200 – 400 MPa; Ice IX fortunately does not have properties described in the novel! \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM McCrone criterion – Polymorphs differ in crystalline structure, but molecules are identical in liquid and gaseous states; McCrone’s statement – every compound has different polymorphs, and that, in general, the number of forms known for a given compound is proportional to the time and money spent in research on that compound. Polymorphs of cocoa butter \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Monotropic polymorphs Enantiotropic polymorphs – more stable form depends on temperature \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Transition temperature for enantiotropic polymorphs is independent on a solvent; \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM At the transition point of a dimorphic enantiotropic system both polymorphs have the same thermodynamic potential and the same solubility; The transition temperature is only related to the solid lattice structures and therefore independent of the solvent from which the polymorphs are crystallized. \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Metastable zone width is however strongly influenced by selected solvent; Ostwald’s step rule – for several possible polymorphs (in metastable zone) less stable polymorph is formed preferentially; Possible formation of different polymorphs in different solvents; Concomitant polymorphism \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Ostwald’s step rule – graphical description \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Burger (Ramberg) rules Heat of Transition rule -Polymorphs are enantiotropically related if endothermic heat of transition from a lower melting form to a higher melting form is observed; - Heat of Fusion rule -Polymorphic pairs are enantiotropically related if the low melting form has the higher heat of fusion, otherwise they are monotropically related; - Entropy of Fusion rule -Polymorphs are enantiotropically related if the high melting form has the lower entropy of fusion, otherwise they are monotropes; It is recommended to confirm DSC results with experimental microscopic observations, solubility determination or slyrrying; \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Burger (Ramberg) rules Heat of Transition rule \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Disappearing polymorph Ritonavir Case Protease inhibitor for HIV (Abbott, NorvirTM) Chemburkar, S.R. et al Org. Process Res. Dev. 4, 413 (2000) \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Disappearing polymorph Ritonavir Case NDA (New Drug Application) filed in December 1995; Two years after some lots of the product (semisolid gel capsules with Form I) failed a dissolution specification; The new crystal form (Form II) was found; Form II is thermodynamically more stable than Form I Samples of Form II brought to a laboratory to study – within a few days all of the lots of ritonavir turned to Form II; Form I manufacturing failed from this point and “disappeared“ \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Disappearing polymorph Ritonavir Case Causes: •Small amounts of impurity •Residual solvent • Solutions: •Develop new manufacturing process for the preparation of Form I and also Form II; •Develop new formulations with either Form. \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Disappearing polymorph Ritonavir Case Form I Form II \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Disappearing polymorph Ritonavir Case \\DROBO-FS\QuickDrops\JB\PPTX NG\Droplets\LightingOverlay.png Droplets-HD-Content-R1d.png POLYMORPHISM Disappearing polymorph Dunitz, J.D. et al Acc. Chem. Res. 28, 193 (1995) Bučar, D.-K. et al Angew. Chem. Int. Ed. Engl. 54, 6972 (2015)