Control and Prediction of the Organic Solid State

A Basic Technology project of the Research Councils UK

Computational Prediction of

Pharmaceutical Crystal Structures -

a severe test of modelling

supramolecular assembly

Sarah (Sally) L Price

Department of Chemistry, UCL www.cposs.org.uk

Contrast Crystals - geological

Durable &

hard as

strong

forces

between

atoms

Grown on

geological

timescales-

10 to 1000

years 2cm

Organic/pharmaceutical and

protein crystals

Often very difficult (impossible?) to get even the

very small crystals needed for solving structures

by diffraction

Compromise strong covalent bonds & weak

intermolecular forces

many

Large crystals parabanic acid ~ 3-5mm

Paracetamol form II

Electron micrograph Protein crystals in 1-2 ml drop

X-ray diffraction gives the atomic

scale model

The Cambridge Crystallographic Database of organic crystal structures has >500,000 entries

Most are the crystal structure of the first crystal found that was suitable for using X-ray diffraction, as chemists used to be only interested in the molecular structure

Much greater resolution in

organics than proteins

No or limited water

Protons often located from

diffraction data

Solving structures from powder

samples increasing

Principles of crystal packing

small molecules to proteins

Close packed

solvent may fill small voids

dynamic water surrounds most protein molecules

Forms hydrogen bonds, p-p stacking, X...X

Intermolecular, more diversity

Intramolecular, amino acids

Conformation vital

~ isolated molecule (Y), some torsions vary

dominant issue & major constraint

Emphasis on inter - vs intra- molecular forces differ

Exercises in prognostication:

Crystal structures and protein folding JD Duntiz & HA Scheraga, 2004 PNAS 101, 14309

global optimisation problems to identify the

structure(s) of lowest potential (or free)

energy

Search challenge

Accuracy of energy evaluation

Kinetic factors ~ preferred pathways to

assembly, may be involved

Objective blind tests “need to be maintained

so they can continue to document progress

and monitor excessive claims”

Polymorphism - a common

phenomenon??

Polymorphism - the ability of a substance to adopt

more than one crystal structure

since different physical properties, now a major

cause for concern when products transform from one

polymorph to another.

•Pigments - change colour.

•Chocolate - need polymorph of

cocoa butter that melts at 37 oC.

• Explosives - change of

polymorphic form leads to

different detonation properties &

industrial accidents.

L. Yu et al. 2000, J. Am. Chem. Soc. 122, 585.

Pharmaceuticals must be

marketed in one controlled

polymorphic form

Change of polymorph changes effective

dose

Want to choose the crystalline form for

optimum properties & control production

Regulatory requirement for

pharmaceuticals that all reasonable

experiments are performed in order to

identify the maximum number of crystalline

forms

Disaster if new polymorph appears during

production or storage, or in rival’s labs

Difficulty in establishing that all

polymorphs are known

McCrone (1963) “the number of

polymorphs of a material depends

on the amount of time and money

spent in research on that

compound”

- Some appear after decades of

crystallisation work on compound

- Some “disappear” after a more stable

polymorph is discovered.

Which drugs may have

undiscovered polymorphs?

1998 Abbott Laboratories anti-HIV drug

Ritonavir produced new polymorph during

manufacture after 2 years

Problem affected plants in different countries

Required reformulation “ Unfortunately, there is nothing we can do today to prevent

a hurricane from striking any community or polymorphism

from striking any drug” Sun, Abbott Laboratories, press conference.

Can we computationally predict whether the drug is

in the polymorphism equivalent of Louisiana or

Hertfordshire, Herefordshire or Hampshire ?

Why calculate crystal energy landscapes?

~ the thermodynamically feasible crystal structures

to confirm that most stable polymorph is known

to design new molecular materials prior to synthesis

to see what structures are plausible undiscovered

polymorphs

Thermodynamics vs. crystallization conditions

(T, P, solvent, supersaturation, impurities, …..)

to help solve structures from powder XRD or other

experimental evidence

as a complement to polymorph screening and “Quality

by Design” crystallization processes in pharmaceutical

development.

2010 5th CCDC Blind Test results –

can we predict a crystal structure?

x/y x = # correct within 3 submitted

y = # groups submitting *own success

Main issue is accuracy of calculating relative energies of

different crystal structures

O

O

NH

N

S

CH3

SO2

CH3

N+ N

-O

O2N

NO2

Cl

Cl

S

Cl

O

N+

N-

CH3

O O

OH

OH

OHHOOC

OH2

Polymorphs 3 and 4

N NH

+

COOH

COO-

A salt

2/15 2/13* 1/13 2/11

2/10* 0 or 2 excl H* /10

Successful approaches to calculating

lattice energy (biological force-fields rarely adequate)

Plane wave density functional theory (i.e. crystal Y) supplemented by empirically damped

-C6/R6 dispersion

Elatt=Eelectronic+Edisp developed by fitting to

crystal structures

Model for intermolecular forces with electrostatic model derived from isolated molecule Y

DEintra from Y

Elatt = Uinter+ DEintra Non-spherical atoms

Use theory of intermolecular forces, moving toward non- empirical models Success in 4th for C6Br2ClFH2

with no experimental input

Neumann, M. A.; Perrin, M. A. J.Phys.Chem.B 2005, 109, 15531

Misquitta AJ, Welch GWA, Stone AJ, Price SL 2008.Chem Phys Lett 456

Rarely only one feasible crystal

structure

O

CH3

N

O2N

N

OH

CH3 O

N

H OCH3

Pigment Yellow 74

Requires a uniquely

favourable close packing

defining all 3 dimensions

Example with energy gap of

~12 kJ mol-1

Unique close packed plane

Unique stacking from

electrostatics

MU Schmidt 1999 Erice

More typical

Cl

BrBr

F

HH

from 2007 blind test

Landscapes will show the

expected hydrogen bond

motifs defining

ribbons/layers

BUT different

•packings of ribbons

•stackings of layers

More predicted

structures than known

polymorphs

Relative energies

sensitive to method

Basic method for crystal energy landscapes ~ thermodynamically feasible crystal structures

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 DEintra)

Use search method to generate plausible crystal structures (~3000 MOLPAK or ~105 CrystalPredictor for each rigid conformation, or >106 for flexible CrystalPredictor) for Z’=1,...

Use advanced models of the intermolecular forces (distributed multipoles to represent lone pair & p electron density) to minimize the intermolecular lattice energy Uinter of each crystal structure.

Refine conformation within crystal to minimize Elatt= Uinter + DEintra

> Basic Crystal (Lattice) Energy Landscape

Estimate lattice modes, elastic tensor & harmonic free energies for rigid molecules and confidence in relative stabilities.

Calculate other properties: PXRD, morphologies

Karamertzanis PG, Kazantsev AV, Issa N, Welch GWA, Adjiman CS, Pantelides CC, Price SL 2009. J Chem

Theory Comput 5, 1432 Price SL, Leslie M, Welch GWA, Habgood M, Price LS, Karamertzanis PG, Day GM

2010. Phys Chem Chem Phys 12:8478-8490.

Why do we overpredict polymorphism ?

1 Neglect of thermal motion

Free energy landscape for benzene has ~ a minimum for each known form in a metadynamics study

Both have many lattice energy minima, and ~ only the observed structures when thermal motion modelled.

Solid state transitions unusually facile for these hydrocarbons

Cyclopentane

C5H10

Torrisi A, Leech CK, Shankland K, David WIF, Ibberson RM, Benet-Buchholz J, Boese R, Leslie M, Catlow CRA,

Price SL 2008. J Phys Chem B 112:3746

MD 30K ~ form III

MD 160K ~ form I

Plastic phases

Raiteri, P. et al. Angew.Chem.,Int.Ed. 2005, 44, 3769

-104

-102

-100

-98

-96

-94

1.55 1.6 1.65 1.7 1.75 1.8

Latt

ice E

nerg

y /

kJ m

ol-

1

Density / g cm-3

C2/c

P-1

P2/c

P21

P21/c

P212121

Pbcn

Pc

Pca21

Pna21

Form I

Form II

Contrast solid state of 5-fluorouracil,

with no polymorphic transitions

Form II found experimental search from dry nitromethane

Form I

Z’=4

Form II &

solvate

In two

solvates

75% of

these

structures

are free

energy

minima at

310 K

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.

Do we need to do Molecular

Dynamics to model thermal motion?

Only if expect facile phase transitions.

Dynamics of nucleation & growth will

determine which structures are observed

Hamad, S, Moon, C, Catlow, CRA, Hulme, AT, SLP, 2006 J. Phys. Chem. B, 110 3323

hydration of

uracil in

water gives

close F···F of

form I

in

nitromethane

get R22 (8) of

form II

Solid-State Forms of b-Resorcylic Acid: How Exhaustive Should a Polymorph Screen Be? Braun DE, Karamertzanis PG, Arlin J-B, Florence AJ, Kahlenberg V, Tocher DA,

Griesser UJ, Price SL 2011 Cryst Growth Des 11: 210-220.

New polymorph I predicted,

Added confidence to PXRD

solution and evidence for proton

disorder

Similar

structures,

unlikely to be

distinguishable

polymorphs

How?

Relative stability?

Catemer polymorph?

Why do we overpredict polymorphism ?

2 The right crystallization

experiment has yet to be performed

Huge range of crystallization methods which have generated new polymorphs

– deliberate to failed cocrystallization

Experimental conditions vary kinetics of nucleation & growth

Can we use crystal energy landscapes to find the right crystallization conditions?

The right crystallization experiment has not yet

been performed on carbamazepine ?

Early predictions of a chain structure

Better methods, modelling flexibility, induction etc

– chains still competitive, also for related molecules

Florence AJ, Johnston A, Price SL, Nowell H, Kennedy AR, Shankland N 2006. J Pharm Sci 95:1918-1930.

Exptal searches are productive

dimers

form II 2008

form I 2008

chains

form IV 2002

form III 1981

form II 1987

form I 2003

form V In prepn

form IV 2010

form III 2007

form II 2006

form I 1992

form II 2008

form I 2007

1:1 CBZ:DHC solid solution 2006

N

O NH2

CBZ

N

O NH2

DHC

O NH2

CYH

O NH2

CYT

isostructural

relationships

Success of catemeric CBZ V

required seeded sublimation

Pbca a/Å b/Å c/Å

Expt 9.1245(5) 10.4518(5) 24.8224(11)

Rigid

prediction

9.3124 10.5979 24.8819

Flex

prediction

9.4816 10.3426 24.7227

DHC form II (seed)

CBZ form V CBZ form V

CBZ form V

Arlin J-B, Price LS, Price SL, Florence AJ, in prepn

Finding the right crystallization

conditions may be even harder

Racemic crystal could not be

formed without racemization

Lancaster, RW; Karamertzanis, PG; Hulme, AT; Tocher, DA; Covey, DF; Price, SL, Chem.Commun., 2006, 47, 4921

- or obliging synthetic chemist

Challenge: what about cases where barrier is high but no so high?

e.g. Changing to an unfavourable conformation – c.f. ritonavir

(Dis)Appearing polymorphs

Only need to nucleate more stable form

once to get seeds

Develop other routes to most stable form

May lead to loss of control of crystallisation

of metastable form

Other forms of seeding/templating May need impurities to producing a polymorph

1 mol% ethamindosulphathiazole stabilizes form I sulphathiazole

Attempts to reproduce form 2 progesterone failed

– could only get moderately unstable samples when

crystallised in presence of pregnenolone

Lancaster RW, Karamertzanis PG, Hulme AT, Tocher DA, Lewis TC, Price SL 2007. J Pharm Sci 96:3419-3431.

N. Blagden, R. J. Davey, R. Rowe and R. Roberts, Int. J. Pharm., 1998, 172, 169-177.

50 year old samples from

Innsbruck

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 CrystEngComm, ASAP

Why do we overpredict polymorphism ?

3 The right crystallization

experiment cannot be performed

Crystal may be unstable relative to other products,

inherent in possible range of crystallization

experiments

Solvates may form

Proton transfer – salt or cocrystal if 0< DpKa <3

Cocrystal may be less stable than components

Why do we overpredict polymorphism ?

4.Plurality of possible structures is

hindering crystallization

Crystallization is difficult

“Commonly found that when good quality large crystals of a substance cannot be grown, the small crystals are poor in quality with substantial mosaic spread” Harding, M. M. J. Synchrotron Radiat. 1996, 3, 250

i.e. structures solved from very small crystals (synchroton) are more likely to be disordered

Can crystal energy landscape can warn of possibilities of disorder = combinations of low energy structures?

Parallel

ribbons

-114.9

kJ mol-1

Anti-parallel

ribbons

-116.1

kJ mol-1

PXRD_2?

-115.5

kJ mol-1

PXRD_1

-116.4

kJ mol-1

From Eniluracil Crystal Energy Landscape

Non-polar ribbons

Also little energy discrimination for the stacking variations for C4O C6H interchange

Stacking & interdigitation errors hard to avoid & barrier to correction

Polar ribbons

N

N

H

H

OO

HH

Experimental: variable disorder in single XRD on

4 crystals

P21/n disordered anti-parallel non-polar

0.742(3) 0.705(3) 0.738(3) 0.841(3)

Crystal 4 better R1 P21 Z’=2 minor polar

Single crystal analysis could be

interpreted as polymorphism.

Powder patterns are very similar

Variable disorder challenging for

devising robust production process

Simulated PXRD

Copley RCB, Barnett SA, Karamertzanis PG, Harris KDM, Kariuki BM, Xu MC, Nickels EA, Lancaster RW, Price SL 2008. Cryst

Growth Des 8:3474

Where are we now?

Crystal energy landscapes complement experiment, providing the alternatives

likely motifs in solid forms

range of possible target structures

possible types of disorder

Can be calculated with “good enough” accuracy for increasing range of molecules & multi-component systems

from aspirin / paracetamol to modern pharmaceuticals

Database of

computed

crystal

structures

>150 molecules

O

OOHH

N

O

NH2

O

N+

H

H

HO-

O

N

NH

SCH3

N

N

CH3

What are the challenges?

Improving accuracy of relative energies

periodic electronic structure DFT+D

non-empirical anisotropic atom-atom potentials

free energies

Understanding limitations of thermodynamic

predictions ~ kinetic factors that lead to

polymorphism

Move to modern pharmaceuticals

Computational efficiency

Grateful Thanks to

Matthew Habgood, Doris Braun, Nizar Issa, Gareth Welch, Sharmarke Mohamed

Derek Tocher, Louise Price, M Leslie (ex-CCLRC) Bob Lancaster (ex-GSK) (UCL)

Andrei Kazantsev, Panos Karamertzanis, Costas Pantelides, Claire Adijman (IC)

Alastair Florence, Andrea Johnston, Jean-Baptiste Arlin, Phillipe Fernandes (SU)

Other coworkers in CPOSS and many collaborators

Other Programs AJ Stone (Cambridge), H Ammon (Maryland), CCDC

Computing infrastructure: National Grid Service (database), HPC(x), UCL

CCDC & CSP community for blind tests

Funding EPSRC (including E-Science)

Basic Technology Program of RC UK for funding Control and Prediction of the Organic Solid State www.cposs.org.uk, including “Translation” funding for Knowledge Transfer in CPOSS Industrial Alliance from April 2008.

CPOSS Open Day, UCL

Wednesday 30 March 2011

10.00, Coffee and registration in the South Cloisters

Introduction and welcome,

Progress in the fifth International Test of Crystal Structure Prediction,

Industrial problems from polymorphism and how we might avoid them, Dr Colin Groom, CCDC

Mapping Crystallization Processes Using In-Situ SSNMR, Dr Colan Hughes, Cardiff University

First and Second Order Transitions: A Re-appraisal, Dr Terry Threlfall, University of Southampton

12.30, Lunch and poster session

2.00, The role of transformations in pharmaceutical crystallization, Prof. Kieran Hodnett, University of

Limerick

GIPAW: a "Bragg's Law" for solid state NMR, Prof. Chris Pickard, UCL

Experimental screening and characterization of solid forms, Prof. Alastair Florence, University of

Strathclyde

3.45, Coffee and poster session cont.

5.00, Removal of posters

Sponsored by CPOSS Industrial Alliance – visit www.cposs.org.uk to register