Abstracts - 5^th October 2004 Pharmaceutical Special Interest Group

Speakers From Left to Right - Front row: Anne Kavanagh (Chair AM), Rebecca Booth, Gareth Lewis, Doug Minick,
Back row: Chris Gilmore, Royston Copley (Chair PM), Ed Collier, Colin Pulham. Inset Chris Hunter.

Abstracts

Hydrate or Anhydrate - That is the Question !
Rebecca Booth - [email protected]

Hydrated crystal structures are frequently found during the development of new drugs. The discovery of a hydrated form, either late in drug development or, worse still, when the drug is on the market, has significant consequences. Some of the problems associated with hydrates and the screening for hydrates will be discussed. Two case studies, theophylline and an AZ compound, will be used to exemplify some of the experimental techniques which can be used to assess the kinetic and thermodynamic stabilities of anhydrous vs hydrated crystal forms.

Crystal Structures from Solution NMR Data
Christopher A. Hunter^a, James McCabe^b Martin J. Packera, Andrea Spitaleri^a

^aUniversity of Sheffield, Brook Hill, Sheffield S3 7HF, United Kingdom
^bAstraZeneca Pharmaceuticals, Silk Road Business Park, Charter Way, Macclesfield, Cheshire SK10 2NA, United Kingdom

NMR methods are widely applied for the determination of the three-dimensional structure of molecules in solution.¹ In recent years, we have developed a quantitative approach to exploiting solution NMR complexation-induced changes in chemical shift (CIS, Δδ ) for structure determination of weakly bound complexes.² This method has potential for investigating the structures of aggregates involved in the nucleation stages of crystallisation. ¹H NMR dilution studies of a series compounds has been carried out, and the limiting complexation-induced changes in chemical shift were used to determine the three-dimensional structure of the dimer element in the initial stages of precipitation. The results show good agreement with the X-ray crystal structures.

C.A. Hunter, M.J. Packer, Chem. Eur. J. 1999, 5, 1891-1897
C.A. Hunter, C.M.R. Low, M.J.Packer, S.E. Spey, J.G. Vinter, M.O. Vysotsky, C. Zonta, Angew. Chem. Int. Engl. Ed. 2001, 40, 2678-2679
A. Spitaleri, C. A. Hunter, J. F. McCabe, M. J. Packer, S. L. Cockcroft, CrystEngComm 2004, in press

Crystal Structure Analysis as an aid to Salt Selection Studies
Gareth R. Lewis, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK

Remacemide was developed as a potential antagonist for epilepsy, Parkinsonism and Huntingon's disease. In this talk the crystal structure of remacemide and six of its salts will be discussed, primarily focussing on an investigation of which H-bond motifs and hydrophobic interactions recur across the structural series.

A Crystallisation / Crystal Engineering Approach To Aid Salt Selection - Anions
Edwin A. Collier¹, Roger J. Davey¹, Ronald J. Roberts² and Simon N. Black³

1. Colloids, Crystals and Interfaces Group, Department of Chemical Engineering, UMIST, P.O. Box 88, Sackville Street, Manchester, M60 1QD, UK
2. Preformulation & Biopharmaceutics, PAR&D, AstraZeneca, Silk Road Business Park, Charter Way, Macclesfield, Cheshire, SK10 2NA, UK
3. Process Engineering Group, PR&D, AstraZeneca, Silk Road Business Park, Charter Way, Macclesfield, Cheshire, SK10 2NA, UK

Salt screening is critical in the drug development process as selection of an appropriate salt form can reduce significantly the time to market of a new pharmaceutical entity. Salt formation is often employed to modify the final drug product, representing a simple chemical modification that can change to advantage the physiochemical, formulation, biopharmaceutical and therapeutic properties of a drug, without varying the basic chemical structure.

This Ph.D. project has applied both classical crystallisation techniques, along with the more modern day supramolecular synthon approach of crystal engineering, to assist in the selection of anions for the formation of novel pharmaceutical salts. Taking the known structure of the hydrochloride salt as a starting point, a further 23 salt forms of the pharmaceutical base (1R, 2S)-(-)-ephedrine have been produced. Optical microscopy confirmed 19 of these forms were crystalline and the crystal structures were subsequently solved. The hydrogen bonding networks for these have been described using Graph set analysis and the structure-property relationships, including morphology, lattice and conformational energy, stability and solubility, evaluated. This has been achieved using molecular modelling, along with a wide variety of analytical techniques such as FTIR, DSC, XRPD, TGA and DVS.

This work augments the conventional salt selection strategy used in the industry. It has provided a starting point for a salt screening strategy, using a theoretical basis for the selection of anions that give the desired physiochemical properties required for a successful new pharmaceutical material. Improved understanding of the reasons for success and failure of the commonly used anions to yield these new crystalline materials by salt formation has also been realised.

High Throughput Crystallography - What to do with 1000 Powder Patterns
Christopher Gilmore,* Gordon Barr and Wei Dong, Department of Chemistry, University of Glasgow, Glasgow, G12 8QQ, Scotland, UK. E-mail: [email protected]

With modern robotic systems and data collection methods, it is quite possible to measure 1000 powder diffraction patterns in a few days, and this is becoming commonplace in some pharmaceutical laboratories where the search for polymorphs and salts is of great importance. The problem arises as to what to do with such data in particular how can it be grouped into classes when there is no database of pure phases, and there may well be mixtures present? We have developed two computer programs to address these issues [1,2] that use techniques of multivariate analysis, and classification to solve these problems. The formalism works as follows:

1. Data are suitably pre-processed with background removal, smoothing via wavelets, and peak searching.
2. Each of the n patterns is correlated with every other pattern using the Pearson and Spearman coefficients to generate an (n xn) correlation matrix.
3. This is used to generate a distance matrix which acts as a source of classification to generate dendrograms, multidimensional metric scaling, silhouettes, fuzzy clusters and minimum spanning trees; these are tools that can partition the data into clusters of related patterns. A typical dendrogram is show below:

Here we have partitioned 21 patterns into 6 clusters containing between 1 and 4 patterns. You can also represent the data in three dimensions using multidimensional metric scaling. Every sphere represents a powder pattern:

[1] Gilmore, C.J., Barr, G. & Paisley, J. (2004). J. Appl. Cryst., in press.
[2] Barr, G. Dong, W. & Gilmore, C.J., (2004). J. Appl. Cryst., in press.

Ab Initio Vibrational Circular Dichroism and Optical Rotation: New Tools for Determining Absolute Configurations
Douglas J. Minick, Randy D. Rutkowske; Luke A. D. Miller
Dept. of Computational, Analytical, and Structural Sciences, GlaxoSmithKline Research, Triangle Park, North Carolina USA

X-ray crystallography remains the definitive tool for assigning the absolute configurations of chiral drug molecules. The number of chiral molecules under investigation by pharmaceutical companies has risen significantly in recent years, however, placing a growing burden on these companies to find alternative techniques for determining this important property. Two chiro-optical techniques, vibrational circular dichroism (VCD) and optical rotation (OR) have emerged as techniques capable of reliably assigning absolute stereochemistries. Yet, these methods have remained on the sideline in most cases, often being treated as curiosities rather than major analytical methods. At GlaxoSmithKline (GSK), we have been performing VCD analyses for over 3 years and have developed a robust method for assigning configurations by this method. More recently, optical rotation has been included in our 'chiral toolbox' as an adjunct to VCD. While both methods remain incomplete, they have been applied successfully in many stereochemical assignments. This talk will include a description of the VCD method currently being practiced at GSK, recent advances in the area of optical rotation analysis, and conclude with an overview of our strategy for combining these chiro-optical methods with X-ray for maximum benefit.

High-pressure recrystallisation - a new method of screening for polymorphs and solvates.
Colin R. Pulham, School of Chemistry, The University of Edinburgh, King's Buildings, West Mains Road, Edinburgh, EH9 3JJ, Scotland, UK. [email protected]

The importance of polymorphism in crystallisation processes is widely recognised and is the subject of intense academic and industrial interest. Although the use of high pressure has been shown by physicists and geologists to be a powerful method for preparing new polymorphs of metals, alloys, ceramics, and minerals, it is only relatively recently that high pressure has been exploited to modify intermolecular interactions in simple molecular compounds. Thus it has been shown that new polymorphs of simple molecular organic and inorganic compounds such as ketones, alcohols, and mineral acids are readily obtained by cooling the liquid compound contained within a diamond-anvil cell under conditions of high pressure. Spectroscopic and structural characterisation of these new polymorphs can then be performed in situ.

Whilst this technique is ideally suited for studying compounds that have normal melting points near or below ambient temperature, it is less useful for compounds with higher melting points, such as pharmaceutical compounds, pigments, or explosives. The problem is exacerbated by the generally steep increase in melting point associated with increasing pressure, with the result that thermal decomposition of the compound occurs well before the onset of melting.

We have overcome this problem by using a solvent so that higher melting compounds are effectively recrystallised from solution at elevated pressures, typically in the range 1-20 kbar. This recrystallisation technique allows us to extend greatly the range of compounds that may be studied and has been used successfully to identify and characterise new polymorphs of phenanthrene and acetamide. A new polymorph of piracetam have also been identified and characterised in this way. The high-pressure recrystallisation technique also provides a route for the preparation and structural characterisation of new solvates of organic compounds. For example, we have identified and characterised a 1:1 methanol solvate of paracetamol [1], a hydrate of parabanic acid [2], and a dihydrate of paracetamol [3].

The technique promises to be a powerful method for the preparation, identification, and characterisation of new polymorphs and solvates of organic compounds such as pharmaceuticals, pigments, and explosives. Its potential as a new method of screening pharmaceutical compounds for polymorphism and solvate formation is being explored and will be reported here.

1. F.P.A. Fabbiani, D.R. Allan, A. Dawson, W. I. F. David, P.A. McGregor, I.D.H. Oswald, S. Parsons and C. R. Pulham, Chem. Commun., (2003), 3004.
2. F.P.A. Fabbiani, D.R. Allan, W.G.Marshall, S. Parsons, C.R. Pulham and R.I. Smith, J. Cryst. Growth, 2004, in press.
3. F.P.A. Fabbiani, D.R. Allan, W.I.F. David, S. Parsons, and C.R. Pulham, CrystEngComm., 2004, in press.