Polymorphism in material chemistry: an inconvenience or an opportunity?

Massimo GazzanoISOF – CNR, Bologna, Italy

ISOF Bologna, 26 nov 2013

massimo.gazzano@isof.cnr.it

A crystal polymorph is a solid crystalline phase of a givencompound resulting from the possibility of at least twocrystalline arrangements of the molecules of thatcompound in the solid state. McCrone 1965

molecule

Polymorph 1

Polymorph 2

Changing the relative position of the molecules, the interactionsbetween them will be different and consequentely also the properties

TiO2

Rutile TetragonalDensity 4.3

Anatase TetragonalDensity 3.9

Different structures: differences in whitening and catalytic properties

Paracetamol

F. Grepioni, Workshop ‘Polimorfismo dei farmaci: Fondamenti e Innovazione’, Bologna 2007

form I

form II

F. Grepioni, Workshop ‘Polimorfismo dei farmaci: Fondamenti e Innovazione’, Bologna 2007

L. Yu Acc. Chem. Res., 2010, 43, pp 1257–1266

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 hardthroughout 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 approveda new gelatin-capsule preparation (to be stored in the refrigerator)

Ostwald Rule of stages (1897)

….in general it is not the most stable but the least stable polymorph that crystallizes first.

(McCrone, 1965)…the number of forms known for a given compound is proportional to the time and energy spent in research on that compound.

Ritonavir story remind us two points:

1

2

G.Barbarella, M.Zambianchi, R.Di Toro, M.Colonna, L.Antolini, A.Bongini, Adv.Mater. (1996), 8, 327

Triclinic form orange

G.Barbarella, M.Zambianchi, M.del F.Marimon,L.Antolini, A.Bongini, Adv.Mater. (1997), 9, 484

Monoclinic form yellow

methylsulfanyl quaterthiophenes: 1st case of conformational polymorphism in oligothiophenes

β-methylated sexithiophenes

Triclinic form Monoclinic form

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

Triclinic

566 nm

monoexp

295 ps

>380ps

Monocl.

535 nm

nonexp

120 ps

no

PL peak

decay

time

T dep.

D. Gentili, M. Durso, C. Bettini, I. Manet, M.Gazzano, R. Capelli,M. Muccini, M. Melucci, M. Cavallini Scientific Reports 2013, 3, 2581

time temperature integrator

thieno (bis) imide derivative

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

-…..

Can we transfer the metodologies used in Pharmaceutical chemistry to Material chemistry in order to find several phases for a material?

Cocrystallization: a possible choice to make solid‘liquid material’ and to modulate properties

a cocrystal is a crystalline structure made up of twoor more components in a definite stoichiometric ratio, where each component is defined as either an atom, ion, or molecule (draft explanation)

theophylline benzoic acid

Polymorphs of cocrystals

cocrystal form I

cocrystal form II

cocrystal form III

Changing the ‘cocrystal former’ componentmany cocrystals are possible

cocrystal form I

cocrystal form II

cocrystal form III

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

Device preparation Improoving performance

Polymorphs screening

CrystallographyCrystal engineering

Synthetic strategySynthetic design