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Petr Beňovský
POLYMORPHISM

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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)

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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!

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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

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POLYMORPHISM
Monotropic polymorphs
Enantiotropic polymorphs – more stable form depends on temperature

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POLYMORPHISM
Transition temperature for enantiotropic polymorphs is independent on a solvent;

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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

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POLYMORPHISM
Ostwald’s step rule – graphical description

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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;

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POLYMORPHISM
Burger (Ramberg) rules
Heat of Transition rule

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POLYMORPHISM
Disappearing polymorph
Ritonavir Case
Protease inhibitor for HIV (Abbott, Norvir)
Chemburkar, S.R. et al Org. Process Res. Dev. 4, 413 (2000)

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POLYMORPHISM
Disappearing polymorph
Ritonavir Case
NDA (New Drug Application) filed in December 1995;
Two years after some lots of the product (semisolid 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“

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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.

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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)