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Ab initio crystal structure determination of two polymorphic modifications of
a local anesthetic agent,Tetracaine Hydrochloride …
Robert J. PapoularLeon Brillouin [email protected]
PPXRD-9 – 23 Feb’ 10 - Hilton Head Island, SC, USA
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This document was presented at PPXRD -Pharmaceutical Powder X-ray Diffraction Symposium
Sponsored by The International Centre for Diffraction Data
This presentation is provided by the International Centre for Diffraction Data in cooperation with the authors and presenters of the PPXRD symposia for the express purpose of educating the scientific community.
All copyrights for the presentation are retained by the original authors.
The ICDD has received permission from the authors to post this material on our website and make the material available for viewing. Usage is restricted for the purposes of education and scientific research.
ICDD Website - www.icdd.comPPXRD Website – www.icdd.com/ppxrd
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With :
APS / ANL Univ. Moscow Univ. Tours
B.H. Toby N.B. Leonidov V. AgafonovJ. Doebbler A.V. Dzyabchenko H. Allouchi
Univ. Rouen
M.-N. Petit
ENSCP, ParisJ.-M. Cense
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What this talk is really about :
Ab initio structure solution
using :
High-resolution XRPD [ indexing ]
Molecular modeling [ starting flexible molecule ]
Direct space methods [ Monte - Carlo ]
Hydrogen bonds [ chemical sense ]
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OVERVIEWMotivation(a) Polymorphism : induced by freeze-drying
known tetracaine HC ŁŁŁŁ unknown leocaine Leonidov (1995)
(b) Anesthetics : local (eyes)(c) Ab Initio structure solution : a textbook example ?
Previous work on TetraCaine HydroChloride [ TCHC ] (a) Giron et al (1997) (b) Nowell et al (2002) (c) Schmidt et al (2006)
Synchrotron X-ray diffraction experiments [ 11-BM @ APS / ANL ]
OUR TALK : Leocaine = Modeling + Indexing + Direct Space Methodswith a twist : Preferred Orientation included in Monte - Carlo
--- Modeling ( One molecule , PMC , four molecules )--- Indexing ( DICVOL : ok ; N-TREOR-09 : perfect )
--- Ab Initio Solving ( FOX ! , EXPO 2009 ? )
Inter- / Intra- molecular H- bonds
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I. MOTIVATION (1) : LEOCAINE , a new effective drug4 / 30
Paper ŁŁŁŁ Patent ŁŁŁŁ Industry
... while the crystal structure remains unknown !
19951995
2005Vestn. Oftalmol.
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I. MOTIVATION (2) : Structure Solving Strategy5 / 30
Preliminarymodeling :
Ab initiosolving :
Postmodeling :
(i) One molecular unitŁ Flexible model
( HyperchemTM )
(ii) Molecular Packing(unit cell known)
ŁŁŁŁ Crystal structureprediction
( PMC , Dzyabchenko )
(i) Direct Methods( Phase Problem )
FAILS !
(ii) Direct SpaceMethods
Monte-Carlo Parallel tempering
( FOX , Favre-Nicolin )
Stability check :Crystal approximated
by a few molecules
( 4 for leocaine )
( HyperchemTM )
(Energy minimization) (Energy minimization)
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II. PREVIOUS WORK (1) : Tetracaine Hydrochloride6 / 30
2 - (dimethylamino)ethyl p - butylaminobenzoate hydrochloride
Novell et al
NJC (2002)
Inter-molecularH - bonds
ab initiofromXRPD
[ DASH ]
TriclinicP -1
V = 822 Å3
C15H25N2O2+Cl-
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II. PREVIOUS WORK (2) : Tetracaine Hydrochloride7 / 30
• Giron et al
TCHC polymorphism ( DSC , HT XRPD )J. Therm. Anal. (1997)6 anhydrous crystalline forms … 2 stable at T = 300 K.
• Schmidt et al
TCHC mod.4 ( SXD ) Pharmaceutical Research (2005)Polymorphism caused by conformal flexibility of the molecules …
• Hamaed et al
TCHC ( SXD, 35Cl NMR )JACS (2008)
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II. Our Experiments (1) : Sample characterization 8 / 30
• Electron microscopy ( SEM )
• Raman spectroscopy ( FTR )
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II. Our Experiments (2) : High-resolution Synchrotron XRPD9 / 30
11-BM beamline @ APS / ANL ( Argonne , USA)
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II. Our Experiments (3) : High-resolution Synchrotron data10 / 30
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III. Our Structure Solutions (1) : INDEXING with N-TREOR-0911 / 30
Tetracaine(TCHC)
Leocainepoly # 1
Leocainepoly # 2
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III. Our Structure Solutions (1) : INDEXING with N-TREOR-0911 / 30
Tetracaine(TCHC)
Leocainepoly # 1
Leocainepoly # 2
13.6923 8.5669 7.4002 98.778 90.853 106.211 Novell et al (2002)
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III. Our Structure Solutions (1) : INDEXING with N-TREOR-0911 / 30
Tetracaine(TCHC)
Leocainepoly # 1
Leocainepoly # 2
13.6923 8.5669 7.4002 98.778 90.853 106.211 Novell et al (2002)
P 21 / c
P 21 / c
P -1
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III. Our Structure Solutions (2): Flexible molecular model12 / 30
forTetracaine
( Novell , NJC, 2002 )
Quantum-MechanicalSemi-Empirical Methods :
AM1 PM3 ZNDO (best)
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III. Our Structure Solutions (3): Flexible molecular model13 / 30
forLeocaine
2 more
experimental
models
Tetracaine(TCHC)
XRPD (Novell,2002)
Tetracaine(TCHC)
SXD (2010)
[ IL MILIONE ]
_diffrn_radiation_monochromator graphite_diffrn_radiation_source 'fine-focus sealed tube'_diffrn_radiation_type MoK\a_diffrn_radiation_wavelength 0.71073_diffrn_reflns_av_R_equivalents 0.0513_diffrn_reflns_av_sigmaI/netI 0.0884_diffrn_reflns_limit_h_max 9_diffrn_reflns_limit_h_min -9_diffrn_reflns_limit_k_max 11_diffrn_reflns_limit_k_min -9_diffrn_reflns_limit_l_max 17_diffrn_reflns_limit_l_min -17_diffrn_reflns_number 5899_diffrn_reflns_theta_full 27.44_diffrn_reflns_theta_max 27.44_diffrn_reflns_theta_min 3.39
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III. Our Structure Solutions (3): Flexible molecular model13 / 30
forLeocaine
2 more
experimental
models
Tetracaine(TCHC)
XRPD (Novell,2002)
Tetracaine(TCHC)
SXD (2010)
[ IL MILIONE ]
_diffrn_radiation_monochromator graphite_diffrn_radiation_source 'fine-focus sealed tube'_diffrn_radiation_type MoK\a_diffrn_radiation_wavelength 0.71073_diffrn_reflns_av_R_equivalents 0.0513_diffrn_reflns_av_sigmaI/netI 0.0884_diffrn_reflns_limit_h_max 9_diffrn_reflns_limit_h_min -9_diffrn_reflns_limit_k_max 11_diffrn_reflns_limit_k_min -9_diffrn_reflns_limit_l_max 17_diffrn_reflns_limit_l_min -17_diffrn_reflns_number 5899_diffrn_reflns_theta_full 27.44_diffrn_reflns_theta_max 27.44_diffrn_reflns_theta_min 3.39
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III. Our Structure Solutions (4) : Theoretical Crystal Model14 / 30
PMC :Packing ofMolecules
in Crystals( Dzyabchenko , 2008 )Russ. J. Phys. Chem.
ŁŁŁŁ minimizes the energyof the lattice
ŁŁŁŁ requires :• the unit cell• a rigid molecular model
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III. Our Structure Solutions (5) : SOLVING THE STRUCTURE !15 / 30
OUR STRATEGY :
(i) Fine-tune the solving procedure on a known case :
( Tetracaine Hydrochloride )
(ii) Transpose it to cases of similar complexity :
The two new polymorphs ( Leocaine )
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III. Our Structure Solutions (6) : SOLVING THE STRUCTURE !16 / 30
EXPO-2009 ?
(i) DIRECT METHODS [ Phase problem ] FAIL
WHY : Not enough triplets / quartets …… in the Lebail- extracted F(hkl)’s
(ii) SIMULATED ANNEALING FAILS ( for now … )
WHY : Preferred Orientation not yet included …… in the Monte-Carlo search
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III. Our Structure Solutions (7) : SOLVING THE STRUCTURE !17 / 30
FOX ! ( Favre-Nicolin , Cerny )
J. Appl. Cryst. 2002
WHAT : DIRECT SPACE METHODS
HOW : Monte-Carlo Parallel Tempering+
Relaxed Flexible Molecular Model
WHY : Preferred Orientation IS included …… in the Monte-Carlo search
WORKS WITH TETRACAINE ŁŁŁŁ WE TRY IT ON LEOCAINE
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III. Our Structure Solutions (8) : A TYPICAL FOX SCREEN18 / 30
Key part : Preferred Orientation
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III. Our Structure Solutions (9) : FOX solutions for LEO19 / 30
Polymorph # 1 Polymorph # 2
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III. Our Structure Solutions (10) : FOX solutions for LEO20 / 30
Polymorph # 1 Polymorph # 2
… after GSAS refinement
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III. Our Structure Solutions (11) : FOX solutions for LEO21 / 30
Polymorph # 1 : GSAS-fit diffraction data
Rwp = 0.139
Rp = 0.104
156 variables
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III. Our Structure Solutions (12) : FOX solutions for LEO22 / 30
Polymorph # 2 : GSAS-fit diffraction data
Rwp = 0.168
Rp = 0.131
144 variables
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III. Our Structure Solutions (13) : FOX solutions for LEO23 / 30
Polymorph # 1 Polymorph # 2versus
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III. Our Structure Solutions (14) : Do they make sense ?24 / 30
Polymorph # 1 PMC / THEORY
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III. Our Structure Solutions (15) : Do they make sense ?25 / 30
LEO Polymorph # 1
TETRACAINE
MOGUL[ CCDC ]
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III. Our Structure Solutions (16) : Are they stable ?26 / 30
LEOCAINE polymorph # 1
Hyperchem / PM3
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III. Our Structure Solutions (17) : Are they stable ?27 / 30
LEOCAINE polymorph # 2
Hyperchem / PM3
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III. Our Structure Solutions (18): Intramolecular H-bonds ?28 / 30
( 2000 )Leocaine : poly # 1
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CONCLUSION Freeze-drying TCHC generates a new unknow polymorph:
Leocaine #1
Leocaine #1 exposure to intense X-ray beams [ synchrotron , 27 keV ]produces a second new polymorph: Leocaine #2
Structure solution with :Index [ N-TREOR-09 / EXPO-2009 ] ; Solve [ FOX ] ; Refine [ GSAS ]
FOX requires a flexible molecular model:(i) Molecular Modeling (ii) XRPD [ TCHC , 2002 ] (iii) SXD [ TCHC ]
Why FOX works better than EXPO-2009 on Leocaine …… Preferred Orientation is included in the Monte-Carlo search
Next : observe Leocaine #1 ŁŁŁŁ Leocaine #2 transition in situ
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THANK YOU :
Prof. Carmelo GIACOVAZZO : IC-CNR, U. Bari, ItalyN-TREOR-09 EXPO-2009 IL MILIONE
Free Web resources : GSAS [ R. Von Dreele ]FOX [ V. Favre-Nicolin ]
MERCURY [ CCDC ]
Last but not least :
ICDD staff : Newton Square, PA, USAmy participation …
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