Review
`
`pubs.acs.org/OPRD
`
`Surprises in Crystal Chemistry of Sugars
`Deepak Chopra*
`
`Department of Chemistry, Indian Institute of Science Education and Research Bhopal, ITI (Gas Rahat) Building, Bhopal 462023,
`India
`
`ABSTRACT: The supramolecular chemistry of polyhydroxylated compounds (called carbohydrates) is well established. It
`essentially comprises strong O−H···O and C−H···O H-bonds. The crystallization of these compounds has been carried out
`innumerable times and has resulted in the formation of a single polymorph only. But recent efforts directed toward the structure
`determination and observation of polymorphism in this class of compounds have led to the discovery of new forms of two well-
`known sugar molecules, namely ribose and sucrose. This perspective aims to highlight the significant features associated with this
`novel discovery, with subsequent implications in the biological function of these compounds.
`
`T he importance of polymorphism is of significance from
`
`both an academic and an industrial perspective.1 This field
`has achieved tremendous development and growth in the
`pharmaceutical
`industry, wherein issues
`related to poly-
`morphism are directly interlinked to intellectual property
`rights. In recent years, this physical feature has been observed in
`compounds of significance to the chemical, biological, physical,
`geological, and metallurgical sciences. The role of serendipity
`has played a crucial role in the discovery of different physical
`forms of a given molecule, but the element of design and
`systematic exploration of the phase space has also contributed
`toward the isolation of new crystalline phases. A well-
`documented statement by the late Walter McCrown2 proves
`the fact
`that polymorph formation can accompany any
`molecule. This
`facet was not observed for commonly
`crystallized molecules, namely aspirin, naphthalene, and
`sucrose, which have been crystallised innumerable times. This
`statement has stood the test of time. The case of aspirin was of
`tremendous
`scientific and commercial
`interest, wherein
`Vishweshwar et al. reported the observation of a new form
`for aspirin.3 The identity of the new form was questioned by
`Bond et al.4a The final conclusion reached is that the crystal of
`aspirin, as is the case for several other aspirin crystals, is an
`intergrowth of two “polymorphic domains”.4b Observations on
`aspirin gave the scientific community an opportunity to look at
`polymorphism in compounds wherein new forms have not
`been known for a long time. A very recent example supports
`this observation, wherein Prof Katrusiak’s group in Poland have
`used high pressure techniques to generate in situ a new form of
`the disaccharide (+)-sucrose.5 The presence of O−H···O H-
`bonds, which are ubiquitous in nature, seems to be universally
`in addition to the well documented C−H···O
`prevalent,
`interactions (both intra- and intermolecular) in rigid molecular
`scaffolds of different mono- and disaccharide units, and these
`render stability to the crystal packing. An investigation of the
`Cambridge Structural Database for crystallographic investiga-
`tions, with the search constraints being “molecules containing
`C, H, and O only” and the keyword “carbohydrates”, revealed
`1943 examples.7 In recent times, scientists have been working
`on the origin of the possible formation of sugars on Earth.6 In
`these investigations,
`scientists have performed chemical
`
`reactions under prebiotic conditions to form ribose, which
`constitutes the backbone of RNA. The surprising part is that
`the crystal structure of D-ribose (Figure 1a) had not been
`determined. On most occasions, the crystals obtained were of
`small size, generally twinned and of poor diffraction quality.
`Traditional
`techniques to crystallize D-ribose have failed,
`including a melt procedure for crystallization. It was only in
`2010 that Prof J. Dunitz and co-workers utilized powder
`diffraction techniques along with advanced developments in
`structure solution algorithms (charge flipping methods), using
`high resolution powder X-ray data, which enabled a complete
`structure determination of this compound.8 It was observed in
`the solid state that the asymmetric unit consisted of two
`independent molecules, and the anomeric carbon atom
`contains both a β-pyranose and α-pyranose form. Experiments
`performed on the single crystal grown using zone-melting
`techniques reveal the disordered arrangement of the hydroxyl
`group at the anomeric center, an important observation from
`single crystal data. The surprise observation was the isolation
`and characterization of another form of D-ribose containing
`three independent molecules in the asymmetric unit. The
`questions of relevance are whether it is possible to obtain a third
`form with Z′ = 1, are the hydrogen bonding patterns affected
`because of the disorder at the anomeric center, and third, what is
`the reproducibility in experimental procedures for the formation of
`the observed polymorphs. The first question can be answered by
`predicting crystal structures using programs on theoretical
`crystal structure prediction, which is indeed an area of intense
`computational
`interest. The latter involves detailed exper-
`imentation with the available starting material (it has been
`observed that the source of the compound is important). This
`includes setting up of crystallization screens using different
`solvents (polar, nonpolar, and polar/nonpolar combinations at
`room and low temperature) and also melt crystallization. In
`addition, the role of additives and cocrystallisation procedures
`can also significantly influence the final outcome as regards the
`formation of a given form.
`
`Special Issue: Polymorphism and Crystallization 2013
`
`Received:
`July 22, 2012
`Published: August 29, 2012
`
`© 2012 American Chemical Society
`
`455
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`dx.doi.org/10.1021/op300200v | Org. Process Res. Dev. 2013, 17, 455−456
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`Organic Process Research & Development
`
`Review
`
`Figure 1. Molecular structures of (a) D-ribose and (b) sucrose.
`
`Complementing these significant observations was a very
`recent
`report highlighting polymorphism in (+)-sucrose
`(Figure 1b) generated via in situ crystallization conditions,
`using the techniques of high pressure (>4.8 GPa), performed at
`constant volume and temperature.5 Experimental
`inputs on
`polymorphism in sugars9 and the observation of a phase
`transition in this class of compounds are rare.10 In the last four
`decades,
`the crystallization of sucrose, a disaccharide, has
`resulted in the formation of the monoclinic form only [Form
`I].11 The recently obtained high-pressure Form II also exists in
`monoclinic form but with the unit cell volume reduced by 18
`Å3 and with different lattice parameters when compared to
`Form I.
`It
`is of
`interest
`to note that
`sucrose is a
`conformationally flexible molecule with potential H-bond
`donors and any alteration in the torsion angles with respect
`to the glycosidic linkage can modify the H-bonding patterns
`with concomitant changes in crystal packing. It is of interest to
`compare the salient structural features (in terms of associated
`intra- and intermolecular H-bonds), which are characteristic of
`both the forms of sucrose. Subsequent variations in these are
`reflected in the associated physical properties, such as taste and
`solubility. X-ray diffraction studies were performed on both
`powder samples, and for enhanced accuracy in structure
`refinement, data was also collected on aligned single crystals. It
`has been observed that all the voids present in Form I of
`sucrose collapse in Form II, with subsequent rearrangement of
`the positions of the atoms in molecules into positions which are
`more conducive for hydrogen bonding. It is also to be noted
`that all the existing intermolecular hydrogen bonds in the old
`phase are broken and new ones are formed. The increase in
`pressure obviously results in the increase in the number of O−
`H···O H-bonds and also C−H···O interactions in the crystal
`lattice. In all the above-mentioned cases of investigation, the
`authors have taken advantage of the increased development in
`technology pertaining to detectors and advanced structure
`building and refinement software. Such inputs have contributed
`immensely toward the development of polymorphism.
`Subsequently this structural aspect
`is also related to the
`biological activity of
`the new form of sucrose (sweetener
`properties). “High-pressure” is an important external variable
`which needs to be seriously considered,
`if sucrose is an
`important ingredient which can transform during the stage of
`compaction in drug formulation. To summarise, the phenom-
`enon of polymorphism can surpise any compound wherein new
`crystal forms have not been known, even for decades.
`It is a challenge to generate and characterize unambiguously
`new forms for different compounds, particularly for those
`exhibiting potent biological function. The difficulty also lies in
`successfully reproducing the conditions for
`isolation and
`recovery of new polymorphs. In this regard, generation of
`theoretical crystal structures using crystal structure prediction
`
`packages wherein the energies vary between 0.5 and 2.0 kcal/
`mol can circumvent the problem wherein unusual forms may
`appear
`suddenly. Needless
`to say,
`the phenomenon of
`polymorphism can bring surprises by virtue of the existence
`of “disappearing polymorphs” wherein new forms have a
`transient existence only.12
`■ AUTHOR INFORMATION
`Corresponding Author
`*Fax: (+) 0755-4092392. E-mail: dchopra@iiserb.ac.in.
`Notes
`The authors declare no competing financial interest.
`
`■ ACKNOWLEDGMENTS
`
`D.C. acknowledges IISER Bhopal and the DST fast track
`scheme for facilities and research funding.
`
`■ REFERENCES
`(1) Bernstein, J. Cryst. Growth Des. 2011, 11, 632−650.
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`York, 1965; Vol. 2, pp 725−767.
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`(4) (a) Bond, A. D.; Boese, R.; Desiraju, G. R. Angew. Chem., Int. Ed.
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`(7) All
`the crystal structures were identified by searching the
`Cambridge Structural Database (version 5.32, updates February 2011).
`See: Allen, F. H. Acta Crystallogr. 2002, A58, 380−388.
`(8) Sisak, D.; McCusker, L. B.; Zandomeneghi, G.; Meier, B. H.;
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`(9) (a) Lee, T.; Chang, G.-D. Cryst. Growth. Des. 2009, 9, 3551−
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`Polymorphs and Manufacturing Method Thereof. U.S. Patent No.
`20100317845, 2010. (c) Lee, T.; Chang, G.-D. Method of Obtaining
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`2011.
`(10) (a) Mathlouthi, M.; Benmessaoud, G.; Rogé, B. Food Chem.
`2012, 132, 1630−1637. (b) Shafizadeh, F.; Susott, R. J. Org. Chem.
`1973, 38, 3710−3715.
`(11) (a) Beevers, C. A.; McDonald, T. R. R.; Robertson, J. H.; Stern,
`F. Acta Crystallogr. 1952, 5, 689−690. (b) Jaradat, D. M. M.; Mebs, S.;
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`(12) Dunitz, J. D.; Bernstein, J. Acc. Chem. Res. 1995, 28, 193−200.
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`dx.doi.org/10.1021/op300200v | Org. Process Res. Dev. 2013, 17, 455−456
`
`Merck Exhibit 2181, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`