Supramolecular Pharmacy
8. Polymorphism
Ondřej Jurček
1
Crystallization techniques and quality crystals
2https://www.unifr.ch/chem/de/assets/public/PDFWordDocuments/Guide%20for%20crystallization.pdf
Crystal Structure Determination
3
• Unit cell determination, the smallest imaginary 3D
unit in which the atoms are placed and multiplying
this unit will build the whole macroscopic crystal
• Unit cell is defined by axes a, b, c, and angles α,
β, γ – volume of unit cell
• Due to crystal symmetry seven types of primitive
unit cells can exist
Book: Analytical methods in supramolecular chemistry, 2nd edition, Wiley, Kari Rissanen – chapter Crystallography and crystal engineering, book edited by C. Schalley
Polymorphism
4
• Polymorphism is the ability of a chemical compound to exist in more than one crystal
packing arrangement in the solid state and hence exhibit different packing of the
molecules and generally different crystal unit cell dimensions
• Formation of polymorphism can be influenced by solvent, temperature, humidity and
the presence of seeds or additives, or crystallization method
• Solid crystals can also change form, sometime irreversibly, as a function of
temperature, pressure, humidity changes or just time
• The first description of polymorphism was made in 1832 by
Friedrich Wöhler (the father of organic synthesis) and
Justus von Liebig when they examined crystallization of
benzamide - it initially forms silky needle-shaped crystals on
cooling an aqueous solution but over time these turn into
rhombic crystals (there are three polymorphs in the end as
found later)
Polymorph properties
5
• Different polymorphs exhibit different physical properties such as electrical or
thermal conductivity, filtering, drying, flow, tableting, dissolution and processing
characteristics and hence can have different bioavailability
• Ostwald’s step rule conceived by Wilhelm Ostwald states that it is the least stable
polymorph that crystallizes first with increasingly more stable forms crystallizing out
in next steps
E. H. Lee Asian J. Pharm. Sci. 2014, 9, 163-175.
Polymorphism – Legal Issues
• Great impact in pharmacy - particular crystal form of API (polymorph) can be
separately patented as distinct inventions next to patent of API development
• If particular polymorphs are patented after the original API patent then upon the expiry
of the API patent, rival generic drug companies are prevented from marketing their
own versions of the drug
• Conversely, if a rival discovers a new solid form of an API they can separately patent
this new polymorph and secure exclusive rights over other companies when the API
patent expires
• Ranitidine hydrochloride (Zantac) a stomach acid production
inhibitor was discovered 1976, came to market 1981
• GlaxoSmithKline defended its patent for the polymorph type
II of ranitidine hydrochloride against competitors when the
patent on polymorph type I had expired
• 2019-2020 – N-nitrosodimethylamine (NDMA) found as
impurity, cancerogenic compound, withdrawal from market
Polymorphism
7
• Walter McCrone once famously said ‘every compound has different polymorphic
forms, 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’
• ROY (5-methyl-2-[(nitrophenyl)amino]-3-thiophenecarbonitrile) = 10 polymorphs
Red-Orange-Yellow
Rohani et al. Curr. Med. Chem. 2009, 16, 884-905 & Wikipedia.
Polymorphism
8
• The term pseudopolymorph is a
synonym for hydrate (when the cocrystallized
guest is water) or solvate
(when the guest is a solvent molecule
other than water). Pseudopolymorphs are
also sometimes referred to as
solvatomorphs.
• Packing polymorphism ×
conformational polymorphism
• Concomitant polymorphs – a solid
crystalline phase of a given compound
resulting from at least two crystalline
arrangements of the molecules of that
compound in the solid state
• Disappearing polymorphism
• Supramolecular polymorphism
packing
polymorphism
Concomitant polymorphs
9
• The first recognized example of a polymorphic organic substance was also an
example with concomitant polymorphs (Wöhler+Liebig, 1832) – dimorphism of
benzamide
Bernstein et al. Angew. Chem. Int. Ed. 1999, 38, 3440-3461.
Disappearing polymorphism
10
• Seemingly stable crystal structure is suddenly unable to be produced, instead
transforming into a polymorph, or differing crystal structure with the same chemical
composition, during nucleation
• Paroxetin, rotigotine, progesterone, beta-melibiose, xylitol, etc.
a) Dunitz et al. Acc. Chem. Res. 1995, 28, 193—200; b) Bučar et al. Angew. Chem. Int. Ed. 2015, 54, 6972 –6993.
Disappearing polymorphism - Case of Ritonavir
11
• Abbott Laboratories introduced the anti-AIDS (later anti-COVID-19) drug ritonavir in
1996
• 18 months on the market a previously unknown
more stable polymorph II was suddenly detected
during manufacture (reason unknown, subtle
alteration in manufacturing conditions or even
seeding by microscopic particles of the second
polymorph) and it became major
• New form was only half as soluble as the first and
so was also the bioavailability
• Disappearing polymorph (loss of 250 mil. USD) → refrigerated gelcap with predissolved
mixture of both
• In 2000 - tablet formulation of lopinavir/ritonavir (Kaletra)
• In 2010 - tablets produced in a solid dispersion by melt-extrusion were found to
remain in form I
Supramolecular isomerism (polymorphism)
12
• Defined by Zaworotko: „existence of more than one type of network
superstructure for the same molecular building blocks“
• Related to structural isomerism at the molecular level
Crystallization
13Zhou et al. CrystEngComm 2017, 19, 1143-1155.
Crystallization of polymorphs
14
• Polymorph screening is conducted by crystallizing substances from a single or
mixed solvent via cooling crystallization, evaporation, or antisolvent crystallization
using a set of 96 solvents
• 15 categories using cluster statistical analysis where solvent parameters such as
hydrogen-bond acceptor/donor propensity, polarity/dipolarity, dipole moment,
dielectric constant, etc. are variables
• Heating and cooling rates, crystallization temperature, evaporation rate, the degree
of supersaturation, the rate of agitation, pH of the media can affect crystallization
• High throughput screening approach is adopted with multiple crystallization wells
reflecting systematic variation of solvent, supersaturation etc. followed by rapid
in situ technique such as Raman spectroscopy
E. H. Lee Asian J. Pharm. Sci. 2014, 9, 163-175.
Polymorphism transitions
15
• Two types of polymorphous transition:
i) enantiotropic – characterized by transformation temperature TA→B, it is
often reversible and well-defined,
ii) monotropic – has no TA→B, polymorph transition pass over liquid phase
(crystallization from a different solvent)
• Pharmaceutics are often undergoing monotropic transformation
• Uncontrolled transition might happen during final crystallization of API,
long-lasting standing of the product in the parent solution, during drying,
micronization, tablet pressing, during wet granulation, or even in the tablet
during storing
• Seeding can help in control of polymorphism
Analysis of Polymorphs
16
• Obvious change of properties of crystalline materials, e.g., color, solubility, melting
point, etc.
• Differential scanning calorimetry
• Thermogravimetry
• Vibrational spectroscopy (IR, Raman)
• Single crystal X-ray diffraction
• Powder X-ray diffraction
• Solid state magic angle spinning NMR
• Polarised optical hot-stage microscopy
• Neutron diffraction
Phenobarbital Nicotinamide
a) Brog et al. RSC Adv. 2013, 3, 16905; b) Bernstein et al. Angew. Chem. Int. Ed. 1999, 38, 3440-3461.
Paracetamol
Analysis of Polymorphs
17E. H. Lee Asian J. Pharm. Sci. 2014, 9, 163-175.
Polymorphism in pharma companies
18
• Polymorph screening must undergo every new API
• For pharmaceutical companies, the problem of polymorphism is rather a
blocking than a creative element. Sometimes the differences between two
polymorphs are tiny and tiny are the differences in properties (e.g.,
polymorphs of aspirin - acetylsalycilic acid).
• Polymorphism is closely watched by regulatory authorities and no
pharmaceutical manufacturer can afford to ignore it.
Shtukenberg et al. Cryst. Growth Des. 2017, 17, 6, 3562–3566.
Probucol and Succinobucol: Example from our Lab
Succinobucol
• LDL reduction effect
• anti-inflammatory
• antioxidant
• anti-restenotic
• antihyperglycemic effects
probucol
succinobucol
19
Succinobucol re-crystallization
Jurček et al. J. Pharm. Sci. 2012, 101(5), 1794.
B C D E
A
A
B
THF/hexane
THF/hexane hexane/pe/ether MeOH/ACN/water CHCl3/ACN
ea/hexane p-xylene water/MeOH
ether/pe
ACN
EtOH
ether/hexane DCM/ACNTHF/hexane
Crystallization of crude product
Column chromatography Recrystallization
20
5 different crystalline
solids were obtained
where 4 different
polymorphs of
succinobucol were
found
succinobucol
probucol
Succinobucol polymorphism studies
Jurček et al. J. Pharm. Sci. 2012, 101(5), 1794.
21
Powder X-ray diffraction (PXRD)
4 8 12 16 20 24 28
Intensity(counts)
2 (°)
F
D
C
B
A
Aged (1-1.5 year)
B=C+D C+D→C+A
A
C→A
E→E+A
Fresh
Succinobucol polymorphism studies
Differential scanning calorimetry (DSC)
Aged (1-1.5 year)Fresh
Jurček et al. J. Pharm. Sci. 2012, 101(5), 1794.
Thermogravimetry (TGA)
Succinobucol polymorphism studies
Jurček et al. J. Pharm. Sci. 2012, 101(5), 1794.
23
A
B as a mixture of C and D
C
D
E
liquid 13C NMR
Solid state nuclear magnetic resonance (ssNMR)
1 4 17
5
6,10
16,18
7,9 15,19
814 11
HO
S S
O
O
OH
O
1
2
3
4
5
6
7
8
9
1011
12 13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
13C
Succinobucol polymorphism studies
Jurček et al. J. Pharm. Sci. 2012, 101(5), 1794.
24
Infrared (IR) spectroscopy
Succinobucol polymorphism studies
Jurček et al. J. Pharm. Sci. 2012, 101(5), 1794.
25
Single crystals X-ray diffraction (SCXRD)
Polymorph D
Overlap of polymorphs C and D
Polymorph D
Succinobucol conjugation with steroids
• Probucol, succinobucol, and phytosterol derivatives
a) Jurček et al. J. Pharm. Sci. 2012, 101(5), 1794; b) Jurček et al. Molecules 2011, 16, 9404-9420; c) Ikonen et al. J. Mol. Struct. 2012, 1011, 25–33.
Phytosterols
• lowering of cholesterol serum
level (especially LDL), block
cholesterol absorption
• aiming of the drug into
hepatopancreatic system
+
Succinobucol
• LDL reduction effect
• anti-inflammatory
• antioxidant
• antirestenotic
• antihyperglycemic effects
Succinobucol-sterol conjugates
27a) Jurček et al. Molecules 2011, 16, 9404-9420; b) Ikonen et al. J. Mol. Struct. 2012, 1011, 25–33.
In the next class…
Porous solid materials, Metal-Organic Frameworks (MOFs)
Thank you for your attention!