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X-Ray Crystallography and Its Role in Understanding The… J. Indian Inst. Sci. A Multidisciplinary Reviews Journal ISSN: 0970-4140 Coden-JIISAD © The Author(s) 2017. X‑Ray Crystallography and its Role in Understanding the Physicochemical Properties of Pharmaceutical Cocrystals Srinivasulu Aitipamula1* and Venu R. Vangala2* REVIEW ARTICLE Abstract | Properties of a matter are intrinsically dependent on the inter‑ nal arrangement of molecules in the solid state. Therefore, knowledge of three-dimensional structure of the matter is a prerequisite for struc‑ ture–property correlations and design of functional materials. Over the past century, X-ray crystallography has evolved as a method of choice for accurate determination of molecular structure at atomic resolution. The structural information obtained from crystallographic analysis paved the way for rapid development in electronic devices, mineralogy, geo‑ sciences, materials science, pharmaceuticals, etc. Knowledge of the structural information of active pharmaceutical ingredients (APIs) is a prerequisite for rational drug design and synthesis of new chemical entities for development as new medicines. Over the past two decades, X-ray crystallography has played a key role in the design of pharmaceu‑ tical cocrystals—crystalline solids containing an API and one or more of pharmaceutically acceptable coformers. These materials have proved X-ray crystallography: An analytical technique used for promising for fne-tuning several important properties of APIs. This short determining the atomic and molecular structure of a crys- review highlights the history of crystallography, early breakthroughs, and tal, in which the crystalline at- the role of crystallography in understanding the physicochemical proper‑ oms cause a beam of incident X-rays to diffract into many ties of pharmaceutical cocrystals. specifc directions. 1 Introduction structure–property correlations.2 For example, *Correspondence: Any matter on the earth is made up of atoms con- the fact that the hardness of diamond and the srinivasulu_aitipamula@ ices.a-star.edu.sg; nected by interatomic bonds. The precise nature brittleness of graphite are due to the different V.G.R.Vangala@bradford. of the interatomic bonds determines the proper- ways that the carbon atoms are arranged in the ac.uk 1 ties of the matter. Curiosity over understanding crystal lattice would not have been revealed unless Crystallization and Particle Sciences, the properties of a material led to investigate how their crystal structures were determined by X-ray Institute of Chemical in different ways the atoms are arranged to form a diffraction. and Engineering certain molecule and intermolecular bonds that Over the past 100 years, diffraction-based Sciences, A*STAR (Agency for Science, connect the molecules to form the solid. In this crystallography has become a mainstream and Technology regard, X-ray crystallography is undoubtedly the powerful experimental tool to determine the and Research), 1 Pesek most comprehensive technique available to deter- three-dimensional structure of small and mac- Road, Jurong Island, 3 Singapore 627833, mine the atomic positions, intermolecular inter- romolecules. Many pioneering works have led Singapore actions, and the overall structure of any molecule to the crystallography to a state where it stands 2 Centre at atomic resolution.1 From the frst use for deter- today as a mature discipline of far-reaching for Pharmaceutical Engineering Science, mination of crystal structure of NaCl, X-ray dif- impact on material characterization and analy- School of Pharmacy fraction has received paramount importance in sis. The emergence of X-ray crystallography and Medical Sciences, many felds of science for understanding the ensued greater understanding of the properties University of Bradford, Bradford BD7 1DP, UK J. Indian Inst. Sci. | VOL xxx:x | xxx–xxx 2017 | journal.iisc.ernet.in 1 3 S. Aitipamula, V. R. Vangala APIs: According to US Food of materials and functioning of biological mol- observe diffraction patterns. Bragg’s law (named and Drug Administration ecules. The structural insights obtained from only after the son, W. L. Bragg) was used to ana- (US-FDA), an API is any crystallographic analysis led to unprecedented lyze the diffraction pattern and their joint and substance or mixture of sub- stances intended to be used developments in electronic devices, mineralogy, independent studies earned the Braggs (father in the manufacture of a drug geosciences, materials science, and pharmaceuti- and son) the Nobel Prize in Physics in 1915. The product and that, when used cals. Knowledge of accurate structural informa- importance and applications of X-ray diffraction in the production of a drug, becomes an active ingredient tion of active pharmaceutical ingredients (APIs) in several scientifc felds have led to the award of in the drug product. Such is a prerequisite for rational drug design and syn- 29 Nobel Prizes so far. The successful inception substances are intended to thesis of new chemical entities for the develop- of crystallography into many scientifc felds has furnish pharmacological 4 activity or other direct effect ment of new medicines. With a focus on the role been recognized by the United Nations, which in the diagnosis, cure, mitiga- of crystallography in modern drug development, declared 2014 as the International Year of Crystal- tion, treatment, or prevention this review is an attempt to highlight the brief lography.8 It is, therefore, important to mention of disease or to affect the structure and function of history of crystallography, early breakthroughs, a few ground-breaking discoveries that furthered the body. and the role of crystallography in understanding the signifcance of crystallography. the physicochemical properties of pharmaceutical After the frst crystal structure of NaCl was cocrystals. determined by X-ray diffraction, it was the dia- mond structure that established the role of crys- tallography in understanding material properties. 1.1 History of X-ray Crystallography The hardness of diamond was established as a The discovery and development of X-ray crystal- repetitive tetrahedral arrangement of carbon lography as a tool for precise analysis of solid- atoms in the crystal lattice (Fig. 1).9, 10 Subse- state matter is the result of many pioneering quent structural determinations included the X-rays: Electromagnetic ra- works. X-rays were discovered by W. C. Röentgen structures of hexamethylenetetramine, quartz, diation of wavelength 0.1–100 in 1895.5 The ability of X-rays to be diffracted Å, produced by bombarding and hexamethylbenzene. It was around late 1920s, by single crystals was demonstrated by M. von a target (generally a metal structural studies on water by W. H. Barnes were such as Cu or Mo) with fast Laue in 1912, which earned him the Nobel Prize instrumental in providing unambiguous insights electrons. for physics in 1914.6 In the subsequent year, W.L. into hydrogen bonding in water crystals.11 Since Bragg formulated the diffraction law famously then, X-ray diffraction has been a reliable tech- Bragg’s law : It refers to the known as Bragg’s law, who demonstrated the simple equation: nλ 2d nique to evaluate the three-dimensional struc- = use of diffraction pattern to determine the crys- sinθ which explains why ture of many other materials including elements, tal structure of NaCl7. His father, W. H. Bragg, the cleavage faces of crystals binary compounds, and even proteins. appear to refect X-ray beams had pioneered the design of instrumentation to at certain angles of incidence (θ, λ), where d is the distance between atomic layers in a crystal and λ is the wavelength of the incident X-ray beam. When X-rays strike a crystal, they will be diffracted only when this equation is satisfed. Figure 1: Diamond (left) and graphite (right), two allotropes of carbon, display distinct physical proper‑ ties, which are rationalized on the basis of crystal structure analysis. Reproduced with permission from reference 10. Copyright © 2006 The Royal Society of Chemistry. 2 1 3 J. Indian Inst. Sci.| VOL xxx:x | xxx–xxx 2017 | journal.iisc.ernet.in X-Ray Crystallography and its Role in Understanding the… The frst X-ray diffraction pictures from a small 1.2 Modern developments: structure hydrated protein, pepsin, were collected by J. D. from powder diffraction Bernal et al. in 1934.12 About 25 years later, crys- Many crystalline solids exist as microcrystal- tal structures of myoglobin and hemoglobin were line powders and making single crystals suitable determined by J. Kendrew et al. in 195813 and M. for structure determination using single-crystal Perutz et al. in 1960,14 respectively, which earned X-ray diffraction technique is a daunting task. them the Nobel Prize in Chemistry in 1962. D.C. In these instances, X-ray powder diffraction pro- Hodgkin solved the structures of a number of bio- vides an alternative tool for characterization of logical molecules, including cholesterol (1937), the crystalline powder materials.21 Over the past penicillin (1949)15, vitamin B12 (1954)16, and century, X-ray powder diffraction has evolved as insulin (1969).8 Her seminal works were recog- one of the most potential characterization tools nized with a Nobel Prize in Chemistry in 1964. for qualitative and quantitative analysis of pow- Chirality is fundamental in biology and drug der materials. The technique is non-destructive Chirality: It is a geometric molecules and has tremendous implications in and has been applied to analyze phase purity of property of some molecules and ions. A chiral molecule/ drug–receptor interactions. The building blocks of a wide range of materials from various disciplines ion is non-superimposable proteins, the naturally occurring amino acids, are such as geology, polymeric, environmental, foren- on its mirror image (Greek: 22 cheir hand). The presence chiral. Milton and coworkers showed that invert- sic, and pharmaceutical sciences (Fig. 2). Semi- = of an asymmetric carbon cen- ing the chirality of an enzyme can lead to a com- nal works of P. Debye and P. Scherrer on LiF in tre is one of several structural 17 23 plete inversion in its enantioselectivity.
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