More Adventures in Polymorphland

Starring Andreas Lemmerer, Joel Bernstein, Volker Kahlenberg,

Daniel M. Többens, Ulrich Griesser, Saul Lapidus, Peter Stephens, and Catherine Esterhuysen

Chemical Crystallography, Ben-Gurion University of the Negev, Israel and

Institut für Pharmazie, Leopold Franzens Universität Innsbruck, Austria and

Department of Physics & Astronomy, State University of New York, USA and

Department of Chemistry and Polymer Science, University of Stellenbosch, South Africa

present

StarringStarring

A Tale of Two Polymorphic Pharmaceuticals: The Solid State Organic Chemistry of

Persedone and Propyphenazone

Catherine Catherine EsterhuysenEsterhuysen and

Two Molecules with Chronic Multiple Chemical Personality Disorder !

Referee Letter: This is an extremely detailed, thoughtful, careful and well-written manuscript describing experimental work carried out in order to characterize a range of polymorphs which have been known to the scientific community for many decades, but have thus far eluded crystallographic characterization. The manuscript was actually a pleasure to read! The technical quality of the work is outstanding. The level of detail which the authors have included, both in the main body of the manuscript, and in the volume of supporting information, speaks to the quality of their experimental work, and the manuscript is a nice, one-paper distillation of how one can best use a variety of different techniques both to grow, and then characterize, polymorphic compounds. At first glance the manuscript seemed to be far too long and verbose - the Introduction, for example, seems much longer than one would expect - but when one reads the manuscript carefully it is quite clear that everything has its place, the writing flows nicely and, with some small exceptions, the authors do not repeat themselves.

This is an extremely detailed, thoughtful, careful and well-written manuscript This is an extremely detailed, thoughtful, careful and well-written manuscript describing experimental work carried out in order to characterize a range of describing experimental work carried out in order to characterize a range of describing experimental work carried out in order to characterize a range of polymorphs which have been known to the scientific community for many polymorphs which have been known to the scientific community for many decades, but have thus far eluded crystallographic characterization. The decades, but have thus far eluded crystallographic characterization. The manuscript was actually a pleasure to read! The technical quality of the work manuscript was actually a pleasure to read! The technical quality of the work manuscript was actually a pleasure to read! The technical quality of the work is outstanding. The level of detail which the authors have included, both in is outstanding. The level of detail which the authors have included, both in is outstanding. The level of detail which the authors have included, both in the main body of the manuscript, and in the volume of supporting the main body of the manuscript, and in the volume of supporting the main body of the manuscript, and in the volume of supporting

However, this reviewer feels that the length of the manuscript, and the attention to detail which the authors have paid both in their experiments and their reporting, is also the downfall of this manuscript. They have submitted a very detailed solid-state manuscript to a general chemistry journal, which makes this reviewer think they are doing themselves a disservice, in terms of readership. While the initial premise of the manuscript - solving age-old questions - is immediately appealing, the length of the manuscript, and the detail within, will not appeal to non solid state chemists.

However, this reviewer feels that the length of the manuscript, and the attention to detail which the authors have paid both in their experiments and their to detail which the authors have paid both in their experiments and their reporting, is also the downfall of this manuscript. They have submitted a very detailed solid-state manuscript to a general chemistry journal, which makes this detailed solid-state manuscript to a general chemistry journal, which makes this

Recommend Acceptance: D) No *)

Referee Letter: This manuscript is a monumental, impeccable piece of pure and applied chemistry, which ChemEur should be proud to publish as soon as possible. It is one of the very few occasions in which a manuscript meets all the major requirements for publication in top primary literature Journals; depth, originality, general interest to a wide audience.

Importance: A) very important Hypotheses Yes/No: Yes Appropriate Length: Yes Different Journal: Recommend Acceptance: A) Yes, without alterations

This manuscript is a monumental, impeccable piece of This manuscript is a monumental, impeccable piece of pure and applied chemistry, which pure and applied chemistry, which ChemEur should be proud to publish as ChemEur should be proud to publish as ChemEursoon as possible. It is one of the very few occasions in which a soon as possible. It is one of the very few occasions in which a manuscript meets all the major requirements for publication in top manuscript meets all the major requirements for publication in top manuscript meets all the major requirements for publication in top primary literature Journals; depth, originality, general interest to a primary literature Journals; depth, originality, general interest to a primary literature Journals; depth, originality, general interest to a wide audience. wide audience. wide audience.

Recommend Acceptance: A) Yes, without alterations Recommend Acceptance: A) Yes, without alterations Recommend Acceptance: A) Yes, without alterations

On appeal…

Referee Letter: A joint venture resulting in an interesting scientific story. Co-crystals have indeed "undergone a renaissance" in the last years, but this is not unusual in science, and new ways of approaching the subject are now available, as this manuscript clearly shows. The manuscript is well presented, data are carefully analyzed, pleasant and colourful pictures add value and make easier to follow the explanations.

The manuscript is well presented, data are carefully analyzed, pleasant The manuscript is well presented, data are carefully analyzed, pleasant The manuscript is well presented, data are carefully analyzed, pleasant and colourfulcolourfulcolourful pictures add value and make easier to follow the explanations. explanations. explanations.

A joint venture resulting in an interesting scientific story. A joint venture resulting in an interesting scientific story.

Importance: B) important Hypotheses Yes/No: Yes Appropriate Length: Yes Different Journal: Recommend Acceptance: A) Yes, without alterations

Chemistry – A European Journal, 17, 13445-13460 (2011)

Chemical Crystallography, Ben-Gurion University of the Negev, Beersheva, Israel

A.L. goes to Erice

J.B. goes to South Africa

Andreas Lemmerer University of Witwatersrand Johannesburg, South Africa

A.L. goes to Beer Sheva

A.L. spends Christmas 2008 with Mom in Austria

January 2009 – Conflict in the Middle East….

…A.L. and Mom decide not to return to Israel for continuation of holiday

Institut für Pharmazie, Leopold Franzens Universität Innsbruck

Ulrich Griesser

Volker Kahlenberg

Ulrich Griesser agrees to host A.L. in Innsbruck for a couple of weeks

Lodovico Riva de Sanseverino

Professor Maria Kuhnert-Brandstãtter

Wanted to make a

Swiss Patent 1936

The Four Polymorphs of Persedone

N

O O

H

Background Information

•! 3,3-diethylpyridine-2,4(1H,3H)-dione, marketed as Persedone.®

•! Persedone is a sedative and a hypnotic. •! Studied by Artur Burger and Maria Kuhnert-

Brandstätter at the Institut for Pharmakognosie at Universität Innsbruck.

•! It exists in three polymorphic crystalline modifications: Mod I (m.pt. 96°C), II (92°C) and III (87°C)

•! A plastic crystalline phase IV (64°C).

A Controversial Drug •! Uwe Barschel (born 13 May 1944 in Glienicke, died

11 October 1987) was a West German politician (CDU) and from 1982 to 1987 Minister-President in the state of Schleswig-Holstein. He was found dead in the bathtub of his hotel in Geneva.

•! The circumstances of his death are still not entirely clear, and inquiries haven't been able to prove or disprove theories of suicide or murder.

•! The police file says that traces of four compounds were found in his body:

•! Pyrithyldion, Persedon® •! Cyclobarbital, Phanodorm® •! Diphenhydramin, Benadryl® •! Perazin, Taxilan®

A Strong Sedative

Differential Scanning Calorimetry Melting of Persedone I, II and III Melting of Persedone Melting of Persedone Melting of Persedone Melting of Persedone , and Melting of Persedone Melting of Persedone Melting of Persedone Melting of Persedone Melting of Persedone ,

-20

-15

-10

-5

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40 45 50 55 60 65 70 75 80 85 90 95 100

Temperature/°C

Hea

t Flo

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ndo

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cryst. IVIII ! IV

Melting of Persedone IV

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Hea

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m.pt. II

-20

-15

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40 45 50 55 60 65 70 75 80 85 90 95 100

Temperature/°C

Hea

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cryst. IV

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m.pt. IV

Thermodynamic Quantities Modification PYR I PYR II PYR III PYR IV

Melting Point Tonset [°C] 96.0 (±0.1) 91.0 (±0.1) 87.1 (±0.1) 64.1 (±0.3)

Melting Point Tpeak [°C] 96.9 (±0.1) 92.1 (±0.7) 87.8 (±0.2) 64.7 (±0.3)

Heat of fusion [kJ mol-1] 18.8 (±0.4) 21.3 (±0.3) 18.5 (±0.3) 3.5 (±0.1)

Heat of transition [kJ mol-1] - 1.9 (±0.2) - -12.4 (±0.1)

Transition temperature (onset) at °C / ! modification

- 81.3 (±0.8) / ! I

" / ! II

55.2 (±0.3) / ! III

Crystallization Tonset [°C] - - 78-90 62.8 (±0.2)

Heat of crystallization [kJ mol-1] - - -18.0 (±0.7) -3.5 (±0.1)

Density [Mg m-3] 1.217 1.234 1.212 -

96.0 (±0.1) 91.0 (±0.1) 87.1 (±0.1)

18.8 (±0.4) 21.3 (±0.3) 18.5 (±0.3)

64.1 (±0.3)

64.7 (±0.3)

3.5 (±0.1)

Hot Stage Microscopy

Phase Transition from II to I

Modification II from Solution and Commercial Source

Modification I Grown from the Melt

Phase Transition of III to II

Phase Transition of

III to II

Modification III from Rapid Cooling

II

III

II

III

Background Information

•! 1,5-dimethyl-4-(1-methylethyl)-2-phenyl-1,2-dihydro-3H-pyrazol-3-one, also known as isopropylphenazone or propylantipyrine.

•! Propyphenazone is a NSAID, analgesic and antipyretic. •! Studied by Müller and Beer at Pharmazeutische Technologie,

Christian-Albrechts-Universität. •! It exists in three polymorphic crystalline modifications:

Mod I (m.pt. 105.0°C), II (103.5°C) and III (102°C).

The Three Polymorphs of Propyphenazone

Differential Scanning Calorimetry Melting of Propyphenazone

I, II and III

Thermodynamic Quantities

Modification[a] PROP I PROP II PROP III

Melting Point Tonset [°C] 104.1 (±0.1) 102.4 (±0.1) 100.8 (±0.2)

Melting Point Tpeak [°C] 105.0 (±0.2) 103.7 (±0.2) 102.2 (±0.1)

Heat of fusion [kJ mol-1] 22.6 (±0.1) 25.0 (±0.2) -

Density [Mg m-3] 1.127 1.147 -

Energy Temperature Diagram

Problem: No suitable single crystals

A.L. to Stony Brook/Brookhaven Solution: Fly to United States of America

Department of Physics & Astronomy

State University of New York

Peter Stephens Saul Lapidus

First Phase Pure PXRD

Patterns

Isopropylphenazone Form I

0

500

1000

1500

2000

2500

3000

3500

5 7 9 11 13 15 17 19 21 23 25 27 29

2 ThetaC

ount

s

Isopropylphenazone Form II

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5 7 9 11 13 15 17 19 21 23 25 27 29

2 Theta

Cou

nts

Structure Solution of I •! The crystal structure of isopropylphenazone Mod I, C13H18N2O, was solved from

synchrotron X-ray powder diffraction data. The crystallographic data of the compound are: monoclinic unit cell, space group Pc, a = 10.852(1) Å, b = 7.415(1) Å, c = 8.843(1) Å, ! = 107.49(1)°, V = 678.7(1) Å3, Z = 2, Z' = 1.

•! Observed and calculated XRPD pattern, calculated peak positions from the unit cell, and residual difference:

Structure Solution of II •! The crystal structure of Mod II was solved from synchrotron X-ray powder

diffraction data. The crystallographic data of the compound are: monoclinic unit cell, space group P21/c, a = 20.649(1) Å, b = 7.435(1) Å, c = 8.720(1) Å, ! = 95.138(1)°, V = 1350.7(1) Å3, Z = 4, Z' = 1.

•! Observed and calculated XRPD pattern, calculated peak positions from the unit cell, and residual difference:

Hydrogen Bonding of PROP I and II

Packing Differences

of PROP I

and PROP II

Differences Differences Differences

Swiss Patent 1936

The Improvement

•! “Das so gewonnene 2,4-Dioxo-3-3-diäthyl-tetrahydropyridin bildet farblose Kristalle von Schmelzpunkt 98 bis 99°, die sich in warmem Wasser leicht, in kaltem wenig lösen....Mit Pyrazolonderivaten verienigt es sich in molekularem Verhältnis zu gut kristallisierenden beständigen Verbindungen, zum Bespiel mit...1-Phenyl-2,3-dimethyl-4-isopropylpyrazolon (F = 93°). Die neue Verbinding soll als Arzneimittel Verwendung finden, da ihr eine starke Schlafwirkung zukommt.“

•! “The synthesized 3,3-diethyl-2,4(1H,3H)-Pyridinedione crystallizes as colourless crystals with a melting point between 98 and 99°C, which dissolve easily in warm water, less so in cold water…. With Pyrazolone derivatives, stoichiometric molecular complexes are formed, for example with…1,2-dihydro-1,5-dimethyl-4-(1-methylethyl)-2-phenyl-3H-Pyrazol-3-one (MP = 93°C). The new complex [co-crystal] should find application as a pharmaceutical drug, as it has a strong sedative effect.”

Propyphenazone Pyrithyldine II

The Crystals of the Co-crystal

Obtained by slow evaporation from 1:1 stoichiometric solution in 2-butanone

Also by liquid-assisted grinding w/ MeOH

The Structure

Stability of Hydrogen Bonded Interactions

•! Calculated at the M06-2X/6-31+G(d,p) level of theory using Gaussian09 by Dr. Esterhuysen

•! H-bond energies of the dimers of PYR I and II (with H-atom positions optimized) are -66.7 and -67.3 kJ/mol respectively.

•! H-bond energy of PYR III is -35.4 kJ/mol. •! The similar hydrogen bonding patterns of PYR I and II

are reflected in the similar strengths of the hydrogen-bonding interactions between two molecules, whereas the hydrogen-bonding interaction in PYR III is much weaker. Although the molecules undergo other intermolecular interactions in the crystal structure, the hydrogen bonding interaction probably plays the largest role in stabilizing the crystal structure, and can hence explain why PYR III is less stable than PYR II.

Conclusion •! Persedone: The single crystal structures of Mod I and

II have the same hydrogen bonding pattern (dimers) but the relative arrangement of the dimers is different.

•! Persedone: The crystal structure of III is significantly different, featuring 1-D hydrogen bonded chains.

•! Persedone: Mod II is exclusively obtained from solution crystallization, even with additives. However, careful observation, patience and a good hot stage microscopy setup is an alternative to accessing the other modifications.

•! Propyphenazone: Lack of any single crystals is unfortunate and required the expertise of a number of research groups to obtain the 3-D structure of Mod I and II.

Acknowledgements

•! South African National Research Foundation and Oppenheimer Memorial Trust

•! U.S.-Israel Binational Science Foundation

Chemistry – A European Journal, 17, 13445-13460 (2011)