Computational Crystal Energy Landscapes as an aid to polymorph screening

Transcription

1 Control and Prediction of the rganic Solid State A Basic Technology project of the Research Councils UK Computational Crystal Energy Landscapes as an aid to polymorph screening Sarah (Sally) L Price Department of Chemistry, UCL verview: for details see references on

2 What is the computed crystal energy landscape? Price SL Accounts Chem Res 42:117 v The crystal structures which are sufficiently low in energy to be thermodynamically feasible polymorphs v Within ~ 10 kj mol -1 (?) of most stable v Global minimum predicts THE (thermodynamically most stable) crystal structure v Are local minima possible practically important polymorphs?

3 MU Schmidt 1999 Erice Rarely only one feasible crystal structure Requires a uniquely favourable close packing defining all 3 dimensions C H 3 H H CH 3 2 CH 3 Example with energy gap of ~12 kj mol -1 Pigment Yellow 74 Unique close packed plane Unique stacking from electrostatics

4 More typical: small differences for 3 chiral molecules that spontaneously resolve E. D ria, PG Karamertzanis & SLP, 2010 CG&D 10, v Energy differences all small <1 kcal mol -1 bserved enantiopure P at global min E latt = kj mol -1 Lowest racemic P2 1 /n E latt = kj mol -1 v Racemic structures qualitatively similar to chiral v Even if have a chiral 1D or 2D motif, having packing in 3 rd dimension strongly favouring spontaneous resolution will be unusual

5 Benefits & limitations v Gives range of packing types that are thermodynamically plausible v needs packing analysis v Hydrogen-bond graph sets v XPAC v Compack similarity RMSD n v Within search performed v extent, space groups, Z v Accuracy of energies of static perfect lattice v Missing temperature v Depends on method (Manolis poster)

6 E.g. 5-fluorouracil Form I more stable than form II ~ 550 K with no polymorphic transitions C2/c P-1 Form I Z =4 Lattice Energy / kj mol % of these structures are free energy minima at 310 K P2/c P21 P21/c P Pbcn Pc Pca21 Pna21 Form I In two solvates Form II ,55 1,6 1,65 Density / g cm -3 1,7 1,75 1,8 Form II found experimental search from dry nitromethane Form II & solvate Hulme AT, Tocher DA, SLP, 2005 J. Am Chem Soc, 127, 1116 Karamertzanis PG, Raiteri P, Parrinello M, Leslie M, SLP 2007 J Phys Chem B 112:4298.

7 Why calculate crystal energy landscapes? v to design new molecular materials prior to synthesis v to understand crystallization behaviour of a molecule as a complement to polymorph screening and Quality by Design crystallization processes v target finding new polymorphs (THD or metastable) v to help solve structures from PXRD or other experimental evidence v to see whether disorder may be affecting crystallisation v to understand contrasting crystallisation behaviour of related molecules (see gaga s poster)

8 Interpretation: when low energy structures are similar v if no barrier to rearrangement in nucleating/ growing cluster to most stable form, then only this form will be obtained v if enantiotropic may get polymorphs v if solid state transformations facile may get dynamically averaged structures plastic phases, higher symmetry, methyl rotation,... v may get intrinsic static disorder giving crystal growth reproducibility problems

9 From Eniluracil Crystal Energy Landscape H H H on-polar ribbons Polar ribbons H kj mol -1 Parallel ribbons kj mol -1 PXRD_ kj mol -1 PXRD_2? Anti-parallel ribbons kj mol -1 Also little energy discrimination for the stacking variations for C4 C6H interchange Stacking & interdigitation errors hard to avoid & barrier to correction

10 Experimental: variable disorder in single XRD on 4 crystals Single crystal analysis could be interpreted as polymorphism. P2 1 /n disordered anti-parallel non-polar 0.742(3) 0.705(3) 0.738(3) 0.841(3) Powder patterns are very similar Variable disorder challenging for devising robust production process Simulated PXRD Crystal 4 better R 1 P2 1 Z =2 minor polar Copley RCB, Barnett SA, Karamertzanis PG, Harris KDM, Kariuki BM, Xu MC, ickels EA, Lancaster RW, Price SL Cryst Growth Des 8:3474

11 Site ccupancy Disorder calculations on eniluracil M Habgood R Grau-Crespo & SLP2011 Phys Chem Chem Phys 13, 9590 Energy [kj mol -1 ] Minor component proportion (=τ) Entropic energy (TS ) [kj mol -1 ] A E TS v In 16 molecule supercell, generate all possible configurations v Apply thermodynamics, including configurational entropy, excluding structures unlikely to attach during crystal growth Disorder favoured ~ over observed range See Doris poster for intergrowths

12 Interpretation: when low energy structures are different v nce crystallised, difficulties of solid state transformation may mean that you have practically useful polymorphs v How to experimentally find them? v Are they stable relative to other forms? v May it be impossible to find appropriate conditions?

13 Finding catemeric CBZ V required seeded sublimation suggested by related landscapes CBZ form V CBZ form V DHC form II (seed) Pbca a/å Expt (5) (5) (11) Rigid calc Flexible calc Arlin J-B, Price LS, Price SL, Florence AJ, Chem. Commun., 2011, 47, 7074 b/å c/å

14 Related molecules all have dimer & catemer structures competitive H 2 H 2 H 2 H 2 DHC CYH CYT CBZ dimers form I 1992 form I 2007 form I 2008 form I 2003 chains form II 2006 form II 2008 form II 2008 form II 1987 isostructural relationships form III 2007 form IV :1 CBZ:DHC solid solution 2006 form III 1981 form IV 2002 form V 2011

15 -100 1,1 1,15 1,2 1,25 1,3 1,35 1, Lattice Energy / kj mol Density / g cm -3 bserved Structures Carbamazepine Cyheptamide Cytenamide Dihydrocarbamazepine Lattice energy substitutions in the 8 distinct crystal structure types observed experimentally. Molecule: CBZ, CYH, CYT, DHC

16 Lancaster, RW; Karamertzanis, PG; Hulme, AT; Tocher, DA; Covey, DF; Price, SL, Chem.Commun., 2006, 47, 4921 Finding the right crystallization conditions may be even harder Racemic crystal could not be formed without racemization - or obliging synthetic chemist ther molecules may have less impossible barrier to conformational change

17 Disappearing polymorph of progesterone v Attempts to reproduce form 2 failed v Found concomitantly with form 1 and pregnenolone:progesterone v Form II moderately unstable v Level of pregnenolone too high for impurity stabilization mechanism v 1 mol% ethamindosulphathiazole stabilizes form I sulphathiazole Lancaster RW, Karamertzanis PG, Hulme AT, Tocher DA, Lewis TC, Price SL J Pharm Sci 96: Blagden, R. J. Davey, R. Rowe and R. Roberts, Int. J. Pharm., 1998, 172,

18 50 year old samples from Innsbruck Special thanks to Ulrich Griesser Liquid Chromatography-Mass Spec Form 2 11 impurities total 4.85% Form 1 3 impurities total ~1.5%, Aldrich 1.3% different impurities irreproducible cocktail of impurities needed for long-lived form 2 Lancaster RW, Harris LD, Pearson D 2011 CrystEngComm, 13, 1775

19 The right crystallization experiment cannot be performed because v crystal may be unstable relative to other products, inherent in all possible crystallization experiments v Solvates versus polymorphs v Which, if any, hydrates will crystallise? Predicting hydrate formation of two dihydroxybenzoic acids. Braun DE, Karamertzanis PG, Price SL Chem Commun 47: 5443 v Cocrystals versus components v Salt versus cocrystal ΔpK a <3

20 Cocrystal not found H H Issa SA Barnett, S Mohamed, DE Braun, RCB Copley, DA Tocher, SL Price CrystEngComm ASAP All low energy structures are segregated C C H 3 lowest, next 3 H o cocrystal hydrogen bonds! Could this pack densely?

21 Proton positions matter S Mohammed, DA Tocher & SLP, 2011 Int J Pharm, Experimental salt Hypothetical Cocrystal Disordered proton structure was unique in salt & cocrystal version both low

22 Solid-State Forms of β-resorcylic Acid Braun DE, Karamertzanis PG, Arlin J-B, Florence AJ, Kahlenberg V, Tocher DA, Griesser UJ, Price SL Cryst Growth Des 11, 210 ew polymorph I CSP added confidence to PXRD solution and evidence for proton disorder Similar structures, unlikely to be distinguishable polymorphs

23 Characterising racemic naproxen DE Braun M Ardid-Candel E D ria,pg Karamertzanis J-B Arlin AJ Florence, AG Jones, SLP Cryst. Growth Des., 2011, Racemic structure had to be solved from powder data - confidence from match to global minima + ssmr for Zʹ =1 - other stackings of these layers

24 Energy difference between forms - more challenging than structures ΔH R+S RS cry v 1.5 ± 0.3 kj mol 1 at T~ 156 C by DSC ΔH fus v 2.4 ± 1.0 kj mol 1 T = C from solubilities v -6.1 to -9.2 kj mol 1 at T= 0 K from ΔE latt

25 Interpreting the crystal energy landscape v Polymorphs only occur when barrier to rearrangement to most stable form at nucleation/growth stage v Solid state transformations usually difficult, so kinetically-favoured metastable polymorphs may be trapped. v eed to determine which structures are sufficiently different to be feasible as polymorphs through collaboration with simultaneous experimental screening

26 Where are we now? v Crystal energy landscapes complement crystal engineering and solid form screening, answering What are the alternatives? v likely motifs in solid forms v possible types of disorder v range of possible target structures v Can be calculated with good enough accuracy for increasing range of molecules & multi-component systems.

27 Where do we need to go? CH 3 v To bigger molecules v increased difficulty of changing conformation and packing during crystallisation v To more accurate relevant energies v Plenty of impetus in computational chemistry and from desired applications v eed for more validation data H S S 2 CH 3 DA Bardwell et 40 al Acta Cryst B67, 535. GM Day, CS Adjiman, SLP et 5 al Int J Pharm 418,168

28 Grateful Thanks to v Doris Braun, Matthew Habgood, gaga Uzoh, Louise Price v izar Issa, Gareth Welch, Sharmarke Mohamed v Derek Tocher, Maurice Leslie (ex-cclrc) Bob Lancaster (ex-gsk) v Manolis Vasileiadis, Andrei Kazantsev, Panos Karamertzanis, Costas Pantelides, Claire Adijman (Imperial College) v Alastair Florence, Rajni Miglani, Andrea Johnston, Jean-Baptiste Arlin, Phillipe Fernandes (Strathclyde University) v ther coworkers in CPSS and many collaborators v ther Programs: AJ Stone (Cambridge), H Ammon (Maryland), CCDC v Funding EPSRC (including E-Science), CCDC v Basic Technology Program of RC UK for funding Control and Prediction of the rganic Solid State including Translation funding for Knowledge Transfer in CPSS Industrial Alliance.

29 H 2 Database of computed crystal H structures >150 molecules H 3 C H H 3 C S H H H + H -

30 Basic method for crystal energy landscapes ~ thermodynamically feasible crystal structures v Use quantum mechanics to predict molecular structure and represent the charge distribution within the molecule (repeat with multiple conformers for flexible molecules, using intramolecular energy penalty ΔE intra ) v Use search method to generate plausible crystal structures (~3000 MLPAK or ~10 5 Crystal Predictor for each rigid conformation, or >10 6 for flexible CrystalPredictor) for Z =1,... v Use advanced models of the intermolecular forces (distributed multipoles to represent lone pair & π electron density) to minimize the intermolecular lattice energy U inter of each crystal structure. v Refine conformation within crystal to minimize E latt = U inter + ΔE intra > Basic Crystal (Lattice) Energy Landscape v Estimate lattice modes, elastic tensor & harmonic free energies for rigid molecules and confidence in relative stabilities. v Calculate other properties: PXRD, morphologies Karamertzanis PG, Kazantsev AV, Issa, Welch GWA, Adjiman CS, Pantelides CC, Price SL J Chem Theory Comput 5, 1432

31 Electrostatic potential on the Rearrangement more likely in nucelation Hulme AT, Johnston A, Florence AJ, Fernandes P, Shankland K, Bedford C, Welch GWA, Sadiq G, Haynes DA, Motherwell WDS, Tocher DA, SLP J.Am.Chem.Soc. 2007, 129, blindtest predicted dimers ~ chains invited search for dimer polymorph Screen found plastic phase + chain polymorph (Z =2 arrested crystallisation) & chain solvates Imide can readily rearrange hydrogen bonds to most stable form water-accessible surface Scale ±60 kj/mol chain within computational error Predicted bserved