X-Ray Crystallography and Its Role in Understanding The…

J. Indian Inst. Sci. A Multidisciplinary Reviews Journal ISSN: 0970-4140 Coden-JIISAD

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

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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 substances 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 diamond structure that established the role of crystallography 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.

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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. Thus, 1916 and A. W. Hull on iron and various other features that induce chiral- absolute confguration is critical for proper func- materials in 191724 mark the beginning of using ity in organic and inorganic molecules. tioning of biological systems. Since these break- X-ray powder diffraction for material characteri- throughs, the crystal structure of proteins, nucleic zation. For over 50 years, it was primarily used for Absolute confguration: acids, and other biological molecules has been phase identifcation in mineralogy, metallurgy, Spatial arrangement of the atoms of a chiral molecular determined using X-ray crystallography. One of and solid-state chemistry, and its extension to entity (or group) and its ste- the biggest milestones of the 20th century was the more complex problems, such as structure refne- reochemical description, e.g., discovery of the structure of DNA by J. D. Watson ment and structure determination, was limited R or S, referring to Rectus, or Sinister, respectively. and F. H. C. Crick which was based on the diffrac- to only simple high symmetry systems. The pio- tion experiments carried out by R. Franklin.18 neering contributions of H. Rietveld heralded a Watson and Crick were awarded the Nobel Prize paradigm shift by extending the reach of powder in Physiology in 1962, together with M. Wilkins, methods from simple high symmetry structures who had worked with Franklin. The discovery of to complex low symmetry ones. There were a the ‘double helix’ paved the way to macromolecule number of successful attempts to solve new struc- and protein crystallography, essential tools of the tures from powder data by 1970s; however, these biological and medical sciences today. attempts were primarily based on trial-and-error Drug design strongly relies on the use of X-ray methods. Since high-resolution powder diffrac- crystallography. A pharmaceutical company look- tometers, such as synchrotron X-ray and pulsed ing for a new drug to combat a specifc bacterium neutron sources, became available, the feld of or virus frst needs to fnd a small molecule capa- structure determination has transformed from ble of blocking the active proteins (enzymes) that an art to science. The frst challenge in structure are involved in attacking the human cell. Know- determination is to index the diffraction pattern, ing the precise shape of the protein allows scien- but this was conveniently achieved with high- tists to design drug compounds that can clamp resolution data. It was then possible to decom- onto the ‘active’ site on the protein and thereby pose the powder pattern into an approximate disable their harmful activity. With the advent of set of resolved, integrated intensities, so that the powerful X-ray sources (e.g., synchrotrons), new conventional structure-solving tools of the time detectors, new experimental protocols, and the could be applied. This met with a striking suc- development of modern software, the number of cess in the mid-1980s. The unknown structure accurately determined crystal structures of small of iron (III) arsenate (FeAsO4) was solved from and macromolecules has exponentially increased. high-resolution neutron data using direct meth- Currently, the Cambridge Structural Database ods, namely, the Patterson methods.25 So-called (CSD),19 which is the storehouse of small mol- ab initio determination of structures from pow- ecule crystal structures, contains more than der data has become routine in recent years. 750,000 structures, and the Protein Data Bank20 Structure determination from powder X-ray over 105,000 structures of biomacromolecules, diffraction data has potential applications in almost 90% of which were determined by means many important felds where obtaining single of X-ray diffraction. crystals for crystal structure determination is a

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challenging task. For example, the intermedi- and anthracene.26 Powder X-ray diffraction has ates and products of solid-state reactions could also found numerous applications in pharmaceu- be analyzed by powder diffraction for structural ticals.27 Active pharmaceuticals often go through characterization without the need for crystal- a wide range of processes at preformulation and lization. Multi-component crystals of the type formulation stages of drug development. Hence, of pharmaceutical cocrystals are often prepared powder X-ray diffraction plays a key role in the by solid-state techniques and many cocrystals evaluation of stability and possible phase con- can be prepared only by grinding techniques. versions during manufacturing and formulation The microcrystalline powders thus obtained are development. Many a times, solids obtained from generally not suitable for structural characteri- these processes are not subjected to further crys- zation by single-crystal X-ray diffraction. There- tallization and powder diffraction provides the fore, powder X-ray diffraction is an alternative to only possible route for determining the crystal investigate the structural features of cocrystals. structure. Crystal structures of many pharmaceu- For example, K. D. M. Harris and coworkers have tical substances have been determined from pow- demonstrated the use of powder X-ray diffraction der diffraction data—to name a few, polymorphs to determine the crystal structure of a cocrystal of fanaserine, talmisartan, futicasone propionate, involving racemic bis--naphthol, benzoquinone, and tetracaine hydrochloride.

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1.3 Different Solid Forms and Their role Developing a polymorphic form is a promising in Drug Development route as it is the only alternative crystalline form Pharmaceuticals typically consist of one or more in the pure form of drug substance. However, of APIs which are often formulated into a suitable polymorphic variants only show a marginal solu- fnal form comprising inactive ingredients. In the bility improvement and stability is a major con- context of intrinsic value, APIs are the most valu- cern as the metastable (unstable) polymorphs able materials. A majority of drug products in the tend to convert to stable form impacting shelf-life market are developed in the form of solids due to and drug performance. Hydrates and solvates are ease of making and stability advantages. Amongst crystalline solids that contain water and solvents, the various critical issues in drug development, respectively, in the crystal lattice. Though some of tackling poor physicochemical properties, such the existing drug products are developed using as solubility, stability dissolution rate, hygrosco- hydrates or solvates, they are not often regarded picity, and permeability, remain of paramount as preferred solids owing to their low thermal sta- importance. If a particular solid form has any bility, variable stoichiometry, and limited advan- issue(s) with physicochemical properties, drug tages with physicochemical properties. A developers often look for alternative solid forms, pharmaceutical salt is formed when an acidic or such as amorphous forms, polymorphs, salts, basic drug reacts with basic/acidic salt former. solvates/hydrates, and cocrystals.28 The presence of ions in the crystal lattice strongly Crystalline solids have regular arrangement of infuences the physicochemical properties of the molecules with repeating units in three dimen- API, and the salt formation is the most preferred sions, whereas amorphous solids lack long-range route in the development of APIs as drug prod- order (Fig. 3). Amorphous solids display desirable ucts. However, a major setback with salt forma- pharmaceutical properties, such as faster dissolution is that the technique is only applicable to the tion rate and bioavailability than its crystalline APIs, which are ionizable under normal pH con- Bioavailability: It refers to form, but they are not as much frequently mar- ditions. Solid solutions and eutectic composi- the extent and rate at which the active moiety (drug or keted as crystalline solids owing to their poor tions, which are crystalline variable stoichiometry metabolite) enters systemic physical stability and tendency for crystalliza- multi-components and conglomerates of solid circulation, thereby accessing tion.29 Hence, a major fraction of marketed phar- solutions, respectively, are relatively less studied the site of action. Bioavail- ability of a drug is largely maceuticals consists of APIs in crystalline form. in pharmaceuticals but have also been explored determined by the properties These solids can show polymorphism, which is for development of drug products. Over the past of the dosage form, which defned as the ability of a substance to exist in two two decades, cocrystals offered a promising alter- depend partly on its design and manufacture. Differ- or more crystalline phases that have different native route to gain control over physicochemical ences in bioavailability among arrangements of molecules in crystal lattice. properties of APIs by judicious selection of formulations of a given drug can have clinical signifcance; thus, knowing whether drug formulations are equivalent is essential.

Figure 3: Most common solid forms of pharmaceuticals.

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coformers.30 The advantages with cocrystals over its action. Therefore, it is important to under- other traditional solid forms are discussed in the stand the physical description of the API prior to following sections. development of a dosage form. As discussed in the previous section, a given API can form a wide variety of solid forms and each has its own phys- 2 Cocrystals in Pharmaceutical Design icochemical properties, which could impact the 2.1 Modern Drug Development: Need formulation development. Thus, the complex for Better Solid Forms nature of formulation development and manu- From fnding a drug candidate to bringing a drug facturing operations demands a closer look at product to the market, a staggering amount of how the properties of a given drug vary from one Encapsulation: It is a process time is spent in its development. It has been esti- solid form to the other. in which particles of a mated that an average of 12 years is required for substance are surrounded by Pharmaceutical salts are by far the most com- total drug development and it costs about US a coating to give capsules of monly used solid forms for development of drug many useful properties. In $1.5 billion.31 In the process, thousands of com- formulations. It is estimated that approximately pharmaceuticals, encapsula- pounds are computationally screened and tested tion of drug molecules into 50% of drugs contain the active ingredient in salt for their biological activity, and of the 5000– microspheres or nanoparticles form.34 Salt formation has a number of poten- enables controlled drug re- 10,000 compounds that show promise, fve will tial advantages. For example, salts are known lease, taste masking, improv- go to human trials, and only one will fnally ing stability, and protection to improve solubility, dissolution rate, melting become an approved drug. Despite these hard- of protein and peptide from point, photostability, processability, better taste, degradation. ships, if the API identifed as suitable candidate etc. A large number of monographs and books does not offer promising physicochemical prop- highlight the importance of salt formation in erties, such as solubility, stability, and dissolution drug development. Despite widespread applica- rate, it signifcantly impacts drug development tion of salt formation in drug development, the from an economic perspective. It is also to be technique is limited to only APIs that are ioniz- highlighted that despite enormous computational able under normal pH conditions. Many drug and experimental advances, the number of new products and drug substances in the developmen- chemical entities that are used as drug substances tal stages contain APIs that fall into this category. has signifcantly declined. Therefore, modern Therefore, alternative technique such as pharma- drug development is not only focused on the dis- ceutical cocrystallization is important for prob- covery of new chemical entities, but also on ing solid-form diversity of APIs. Cocrystallization exploring ways in which the existing drug sub- scores additional advantages over salt formation stances can be used effectively. Such a repurpos- as it can be applied even to non-ionizable APIs. ing of existing drug substances mainly refers to Pharmaceutical cocrystals are made with cofor- studying the drugs that are already approved to mers that are chosen from the list of Generally treat one disease or condition to see if they are Recognized As Safe (GRAS) chemicals. GRAS safe and effective for treating other diseases.32 Micronization: It is the pro- chemicals are food additives considered safe for Alternatively, it could also mean improvement of 35 cess of reducing the average human consumption and their list constitutes a physicochemical properties of active ingredients diameter of a solid material’s wide range of chemicals like aldehydes, alcohols, particles. The traditional so as to develop better drugs with improved drug carboxylic acids, amides, and sweeteners. There- techniques for micronization performance. This is often carried out by physical focus on mechanical means, fore, the diversity of GRAS chemicals in terms of transformation of an API by making solid disper- such as milling and grinding. their structure and physicochemical properties Micronization is one of the sions, micronization, and amorphous solid forms provides an additional means of selecting a suit- most common techniques of embedded within a polymer matrix.33 An alterna- particle size reduction in drug able coformer for a target change in the API. Over tive approach that has tremendous implication in development. the past decade, alongside other well-known solid drug development is to make novel solid forms of forms, such as salts, polymorphs, and hydrates/ APIs, such as salts, polymorphs, solvates, hydrates, Solid dispersions: It refers solvates, cocrystals have shown immense promise to a group of solid products and cocrystals. Irrespective of the solid form cho- in easing formulation development by addressing consisting of at least two dif- sen for development of a drug, APIs are seldom ferent components, generally the physicochemical problems of APIs. a hydrophilic matrix and a administered alone; rather they are given as part hydrophobic drug. The matrix of formulation in combination with other inac- can be either crystalline or tive substances which aid the development of a 2.2 Impact of cocrystals on drug amorphous. Solid dispersion technique is one of the most suitable formulation for an appropriate mode of development promising techniques for en- administration. While the biological action of the Physicochemical properties of an API differ from hancement of drug solubility drug product depends on the activity of the API, one solid form to the other which is often a con- and dissolution rate conse- quently the bioavailability of its physicochemical properties determine how sequence of the way the API molecules are poorly soluble drugs. well the API is absorbed in the body to perform arranged in the crystal lattice of that solid form.

6 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… its action. Therefore, it is important to under- Hence, selection of a solid form has profound non-obviousness, the physicochemical and phar- stand the physical description of the API prior to implications in clinical, legal, and regulatory per- macokinetic properties of APIs are diffcult to development of a dosage form. As discussed in spective. It has been estimated that approximately predict unless detailed experiments were con- the previous section, a given API can form a wide 80% of the drugs currently under development ducted, (3) utility, the main motivation in the variety of solid forms and each has its own phys- belong to Class II or IV of the biopharmaceutical development of cocrystals is due to their ability to icochemical properties, which could impact the classifcation system (BCS). Poor solubility is the improve the performance of the parent drug. A. formulation development. Thus, the complex characteristic nature of the drugs that fall into V. Trask puts forth the patentability aspects of nature of formulation development and manu- these classes. Drug formulators often rely on pharmaceutical cocrystals.36 With the interest in facturing operations demands a closer look at techniques such as micronization, solid disper- pharmaceutical cocrystals growing, there is a how the properties of a given drug vary from one sion, encapsulation, salt formation, amorphous plethora of patent applications on cocrystals. The Encapsulation: It is a process solid form to the other. forms, etc., for addressing solubility issues. How- potential applications of cocrystals in the devel- in which particles of a substance are surrounded by Pharmaceutical salts are by far the most com- ever, these techniques have inherent drawbacks in opment of drug formulations has been recog- a coating to give capsules of monly used solid forms for development of drug manufacturing and additional risk of stability of nized by several pharmaceutical companies and many useful properties. In formulations. It is estimated that approximately resulting formulations. Cocrystals (Table 1) are many have even recognized the need for their pharmaceuticals, encapsulation of drug molecules into 50% of drugs contain the active ingredient in salt attractive solid forms for addressing solubility screening as part of solid-form screening for microspheres or nanoparticles form.34 Salt formation has a number of poten- issues of BCS Class II and IV drugs. In addition, identifying an optimal solid form for develop- enables controlled drug re- tial advantages. For example, salts are known many solid-state problems such as physical stabil- ment. The importance of pharmaceutical cocrys- lease, taste masking, improving stability, and protection to improve solubility, dissolution rate, melting ity, hygroscopicity, melting point, and dissolution tals has been recognized recently by the US Food of protein and peptide from point, photostability, processability, better taste, rate could be modifed by selecting an appropri- and Drug Administration (FDA, 2011)37 and degradation. etc. A large number of monographs and books ate coformer.28, 30 From an intellectual property European Medicines Agency (EMA, 2014),38 highlight the importance of salt formation in perspective, the emergence of cocrystals as novel which released draft guidelines on the subject of drug development. Despite widespread applica- solid forms provided new avenues for extending regulatory classifcation of pharmaceutical tion of salt formation in drug development, the patent life of parent drugs. Cocrystals that show cocrystals. While FDA classifed pharmaceutical technique is limited to only APIs that are ioniz- improved physicochemical properties satisfy the cocrystals as drug product intermediates and the able under normal pH conditions. Many drug three criteria required for issuing a patent: (1) coformers used to make the cocrystals are defned products and drug substances in the developmen- novelty, every cocrystal is novel as it is not possi- as excipients, EMA defned them as being solid- tal stages contain APIs that fall into this category. ble to predict whether a combination of an API state variants of the APIs, aligning them with Therefore, alternative technique such as pharma- and coformer forms a cocrystal, (2) salts, polymorphs, hydrates, or solvates. The views ceutical cocrystallization is important for prob- ing solid-form diversity of APIs. Cocrystallization scores additional advantages over salt formation Table 1 Milestones in the area of cocrystal research as it can be applied even to non-ionizable APIs. Pharmaceutical cocrystals are made with cofor- Year Milestone mers that are chosen from the list of Generally 1844 Discovery of the frst cocrystal by F. Wöhler involving benzoquinone and hydroquinone (termed as quinhy- Recognized As Safe (GRAS) chemicals. GRAS drone) chemicals are food additives considered safe for 35 1963 First use of the term “cocrystal” by W.R. Lawton and E.F. Lopez for crystalline complexes involving organic human consumption and their list constitutes a amines and bisphenol wide range of chemicals like aldehydes, alcohols, 1974– Several drug–drug molecular complexes (cocrystals) involving antipyrene and salicylic acid, theophylline and carboxylic acids, amides, and sweeteners. There- 91 phenobarbital, pyrimidine and barbituric acid, and sulfaproxyline and caffeine, etc fore, the diversity of GRAS chemicals in terms of 1990 “Rules” of hydrogen bonding proposed by M.C. Etter are useful for predicting hydrogen-bond patterns in their structure and physicochemical properties organic crystals (including cocrystals) provides an additional means of selecting a suit- 1995 Introduction by G.R. Desiraju of the concept of supramolecular synthons in crystal engineering. This has had able coformer for a target change in the API. Over profound impact on the design of cocrystals the past decade, alongside other well-known solid 2004 Seminal feature article by Ö. Almarsson and M.J. Zaworotko in Chemical Communications: Formal begin- forms, such as salts, polymorphs, and hydrates/ ning of the subject of pharmaceutical cocrystals solvates, cocrystals have shown immense promise 2005 An article by M.J. Zaworotko and coworkers that raised, for the frst time, the question: are cocrystals less or in easing formulation development by addressing more prone to polymorphism? the physicochemical problems of APIs. 2007 A comprehensive review by A. V. Trask on patentability aspects of pharmaceutical cocrystals 2009 Indo-US Workshop on pharmaceutical cocrystals and polymorphs 2.2 Impact of cocrystals on drug 2011 US-FDA’s guidance on regulatory classifcation of cocrystals development 2014 EMA’s refection paper on the use of cocrystals in medicinal products Physicochemical properties of an API differ from 2015 Entresto: frst marketed cocrystal post US-FDA’s guidance (2011) on cocrystals that consist of disodium val- one solid form to the other which is often a con- sartan and monosodium sacubitril. The drug was launched by Novartis for the treatment of chronic heart sequence of the way the API molecules are failure arranged in the crystal lattice of that solid form. 2016 US-FDA’s revised guidance on cocrystals, which eases the regulatory burden of pharmaceutical cocrystals

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of the regulatory bodies, in particular FDA, are crystal engineering strategies serve as guiding contrary to what the current understanding of principles for the design of cocrystals. The knowl- the concept of pharmaceutical cocrystals is that edge obtained from the analysis of the crystal the second component in a cocrystal is a pharma- structures deposited in the Cambridge Structural ceutically acceptable coformer. In addition, by Database (CSD) is used in the selection of cofor- classifying them as drug product intermediates, mers for cocrystal formation. A successful cocrys- cocrystals have to comply with additional current tal design demands supramolecular synthons good-manufacturing practice requirements that are observed most frequently between the (cGMPs). Therefore, to address the industry con- functional groups present on the components cerns and also to ease the regulatory burden, the of cocrystals. Hence, the design of cocrystals for FDA has most recently reclassifed them (August a given molecule starts with analyzing the func- 2016) as a special class of solvates in which the tional groups available on that molecule and second component is non-volatile.39 Further- fnding complementary functional groups which more, the FDA made sure that their regulatory would likely form predictable supramolecu- classifcation is similar to that of a polymorph of lar synthons. Thus, the coformer selection in a the API, meaning that cocrystals do not require cocrystal design strategy reinforces a greater role regulatory approvals as is required by a new API of the knowledge of intermolecular interactions or a drug intermediate. which is often drawn from X-ray crystal structure analysis. 2.3 Molecular Insights into Cocrystal Formation 3 Physicochemical Properties Hydrogen bonds: It is an Cocrystals are defned as multi-component crys- of Pharmaceutical Cocrystals attractive interaction between tals composed of two or more solid components Cocrystallization is the result of molecu- a hydrogen atom from a in stoichiometric ratio.40 Non-covalent interac- lar recognition between two or more differ- molecule or a molecular frag- ment X–H in which X is more tions of the type hydrogen bonds are often ent molecules through energetically favorable electronegative than H, and responsible for the association of solid compo- intermolecular interactions. The strength of an atom or a group of atoms nents in a cocrystal. Therefore, knowledge of intermolecular interactions and the way that in the same or a different molecule, in which there is intermolecular interactions between the molecu- the constituents of the cocrystal arranged in the evidence of bond formation. lar components is a prerequisite for a successful crystal lattice determine its physicochemical Hydrogen-bonding rules: cocrystal design. In this regard, G.R. Desiraju’s properties. Hence, it is important that a detailed (1) All good proton donors supramolecular synthon concept41 and M.C. structural analysis is a prerequisite for under- and acceptors are used in Etter’s hydrogen-bonding “rules” 42 provide valu- standing the physicochemical properties, which hydrogen bonding. (2) Six- membered-ring intramolecu- able insights into the association of two or more not only results in structure–property correla- lar hydrogen bonds form in molecules in the crystal lattice. Recurring inter- tion, but also aids in subsequent design of cocrys- preference to intermolecular molecular interactions in a crystal structure are tals for fne-tuning the API properties. Over the hydrogen bonds. (3) The best proton donors and acceptors termed supramolecular synthons and are further past century, single-crystal X-ray diffraction has remaining after intramolecu- classifed into two basic types. One that involves proven to be an important tool for unambigu- lar hydrogen-bond formation the same functional groups is called supramolec- ous determination of crystal structures, and thus, will form intermolecular hydrogen bonds to one ular homosynthon and the one that involves dif- assisted in ground-breaking analysis of material another. These rules correlate ferent but complementary functional groups is properties. With respect to cocrystals, structural functional groups in neutral called supramolecular heterosynthon. As the characterization (a) establishes the reliability of organic molecules with hydrogen-bond patterns in cocrystals are formed due to intermolecular cocrystal design strategy, (b) reveals hydrogen- crystals and useful for selec- interactions between two or more different mole- bond preferences of the functional groups, and tion of suitable coformers for cules, the supramolecular heterosynthons of the (c) provides insights into structure–property the design of cocrystals. type that involve functional groups of different correlation. Supramolecular synthons: molecules play an important role in the design of The existing vast literature on cocrystals pro- Structural units within super- molecules (crystals) that can cocrystals. vides a breadth of knowledge on their diverse be formed and/or assembled Crystal engineering was defned by G. R. applications. These primarily deal with improve- by known or conceivable Desiraju as “the understanding of intermolecu- ment in solubility, dissolution rate, stability, color, synthetic operations involving 28, 30 intermolecular interactions. lar interactions in the context of crystal pack- melting point, mechanical strength, etc. Design of cocrystals generally ing and in the utilization of such understanding Recently, cocrystals have also been found to mod- relies on identifcation of ro- in the design of new solids with desired physical ify properties such as permeability of drugs,44 bust supramolecular synthons 45 between the constituents of and chemical properties” reinforces the molecular explosive nature of energetic materials, non-lin- the cocrystal. recognition between molecules through a knowl- ear optical properties of organic crystals.46 This edge of intermolecular interactions.43 Therefore, section of the review is exclusively focused on

8 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… some properties of cocrystals for which X-ray dif- amounts to excess drug loading. The authors have fraction is instrumental in evaluating the struc- hypothesized that if the weaker hydrogen-bond- ture–property correlations. ing synthons in the crystal structure of SACT are replaced with stronger hydrogen bonds by way of cocrystallization, then the resulting stable cocrys- 3.1 Reduced Solubility of Sulfacetamide tal may be useful to lower the solubility of the for Improved Drug Residence Time parent drug. Crystal structure of the parent SACT Solubility is an important parameter in determin- features self-assembly of the SACT molecules ing the bioavailability of a drug. Pharmaceutical through intermolecular N–H O hydrogen bonds cocrystals have proven to be valuable for address- supported by a single auxiliary··· C–H O interac- ing solubility and dissolution rate issues of several tion. By employing a crystal engineering··· strategy, BCS Class II and IV drug substances, for which the authors have prepared a series of cocrystals low solubility is a serious concern in develop- and analyzed crystal structures and evaluated ment of drug formulations. While a large num- the physicochemical properties. Interestingly, ber of cocrystals have been reported that showed the cocrystals showed low solubility and dissolu- improved solubility of API, attempts to reduce tion rate compared to the parent API. The crystal the solubility of an API through cocrystalliza- structure of sulfacetamide-caffeine (SACT-CAF) tion are seldom reported. One such study that has cocrystal features the SACT molecules propagat- demonstrated the application of cocrystallization ing through stronger heteromeric interactions of technique in controlling the solubility of an API the type N–H O and N–H N hydrogen bonds was reported by A. Nangia and coworkers using and further stabilized··· by C–H··· O interactions an antibiotic, sulfacetamide (SACT).47 SACT is a (Fig. 4). The heteromeric interactions··· afford the commonly prescribed topical antibiotic to treat cocrystal better packing effciency and stronger conjunctivitis and other ocular ailments; how- crystal lattice, which showed lower solubility and ever, its therapeutic effcacy is severely limited by dissolution rate of SACT. It has also been found physiological constraints such as tear fow and that the cocrystal is stable under slurry and accel- refex blinking, and results in considerable drug erated test conditions—a consequence of the loss. Such a limitation necessitates frequent dos- stronger crystal lattice of the cocrystal. The low ing, which is often inconvenient to patients and solubility and good stability of the SACT-CAF

Figure 4: Crystal packing in the parent SACT (a), SACT-CAF cocrystal (b), and comparison of the dis‑ solution rate of cocrystals and the API (c). Reproduced with permission from reference 47. Copyright © 2014, The Royal Society of Chemistry.

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cocrystal could potentially address the poor resi- using a Franz diffusion cell. The solubility and dence time and faster elimination issues of SACT permeability product best represents the impact similar to extended release formulations. of cocrystallization on pharmacokinetic properties of HCT. It has been found that the cocrystals HCT-PPZ and HCT-PCM showed large enhance- 3.2 Improved permeability ment in solubility and fux/permeability com- of hydrochlorothiazide pared to HCT itself (Fig. 5). Notably, HCT-PPZ through cocrystallization cocrystal shows the highest solubility and perme- Permeability across barrier tissue, for instance, ability among all the known HCT cocrystals. The gastrointestinal mucosa, determines absorption diffusion behavior of HCT-MAM, HCT-INZ, and distribution of drugs. To improve perme- and HCT-TMPZ was marginally higher than ability, lipophilic and non-ionizable drugs are that of HCT. The observed improvement in sol- preferred, but such drugs can cause poor solubil- ubility and permeability of the cocrystals is due ity and thus result in low oral absorption. Per- to the disruption of sulfonamide–sulfonamide meability along with solubility may provide an homosynthon in API by the coformer molecules. insightful understanding of bioavailability. The For example, crystal packing of the HCT-PPZ amount of drug transported at the membrane is cocrystal features a 2D bilayer of HCT molecules a function of the concentration gradient. Hence, via N–H O and C–Cl O S interactions, and high-soluble drugs may be absorbed well. The these layers··· bridged through··· = PPZ molecules via diffusion behavior is also dependent on the par- N–H N hydrogen bonds (Fig. 6). The authors ticle size. The in vitro diffusion measurements proposed··· that the higher concentration of cocrys- are commonly performed using parallel artifcial tals in solution leads to amorphous cocrystal membrane permeability assay and Caco-2 cells. formation in solution with moderate or weak Cocrystallization of APIs for improving hydrogen bonds, which could generate high con- aqueous solubility has been a well-established centration gradient at the membrane site. Thus, technique; however, studies on improving drug the resulting high transient concentrations over- permeability through cocrystallization have been come lipophilicity and particle size effects and reported only recently. G. R. Desiraju and cow- provide improved permeation. orkers demonstrated applications of cocrystals in improving the permeability of a BCS Class IV, diuretic drug, hydrochlorothiazide (HCT).48 Five 3.3 Improved Bioavailability of the cocrystals with piperazine (PPZ), picolinamide Muscle Relaxant, Metaxalone (PCM), tetramethylpyrazine (TMPZ), malona- Metaxalone (MTX) is a muscle relaxant used to mide (MAM), or isoniazid (INZ) were prepared relieve discomfort associated with acute and pain- and their solubility and permeability evaluated ful musculoskeletal conditions. Its effects have

Figure 5: Results of permeability studies on HCT and its cocrystals, a cumulative amounts of cocrystals diffused vs time. b Flux/permeability of cocrystals vs time. Reproduced with permission from reference 48. Copyright © 2016, The American Chemical Society.

10 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… been reasoned to depression of central nervous of the MTX. Oxazolidone group of the MTX system.49 MTX is currently available in market as was exploited to form a series of cocrystals with Skelaxin ® in tablets of strengths 400 and 800 mg. dicarboxylic acids such as, succinic acid, fumaric It belongs to Class II drugs of BCS and shows acid, maleic acid, adipic acid, and salicylic acid.51 poor solubility. It has also been reported that the Shown in Fig. 7, the imide–imide dimer synthon oral bioavailability of MTX is greatly infuenced persists in all the cocrystals, which are further by food, which impacts dosing needs of a patient. hydrogen bonded with the coformers via strong The previous attempts to make a suffciently bio- hydrogen bonds. The presence of coformer in available form of MTX have not been successful. the crystal lattice resulted in a signifcant change MTX exists in two polymorphic forms.50 Crys- in the bioavailability of the MTX. Pharmacoki- tal structures of the polymorphs feature distinct netic (PK) studies in beagle dogs using cocrystals hydrogen bonding—one polymorph showing with succinic and fumaric acids revealed higher imide group of the oxazolidone ring to form plasma concentration and the area under the imide–imide catemer synthon and the other curve (AUC) for cocrystals than the MTX. The to form imide–imide dimer synthon (Fig. 7). promising PK properties make the MTX cocrys- Nuformix Limited (UK) has recently pursued tals valuable for development of novel MTX for- cocrystallization route to modify bioavailability mulations and are currently in clinical trials.

Figure 6: Packing of the HCT-PPZ cocrystal: a 2D HCT layers propagated along the ab-plane. b Packing of HCT bilayers through PPZ bridging. Reproduced with permission from reference 48. Copyright © 2016, The American Chemical Society.

Figure 7: Hydrogen bonding in MTX polymorphs and its cocrystals. Notice that the imide–imide dimer synthon is retained in all the crystal structures of the cocrystals. Reproduced with permission from refer‑ ence 50. Copyright © 2011, The American Chemical Society.

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3.4 Improved Photostability in photostability of an antibiotic drug, nitro- of Nitrofurantoin Through furantoin (NF), can be achieved via cocrystalliza- Cocrystallization tion.52, 53 Stability studies on NF powder sample The exposure of photons on pharmaceutical revealed that upon irradiation at 315–400 nm, materials can have destructive effects impact- ~28% of the sample underwent degradation ing quality and effcacy of drug products. As per in a week (Fig. 8). Mechanistically, NF photo- International Conference on Harmonisation degradation was attributed to rapid isomeriza- (ICH) guidelines, photostability testing is an inte- tion at C N bonds and subsequent degradation = gral part of pharmaceutical development process. to 5-nitro-2-furaldehyde and 1-aminohydan- The drug products undergo a variety of complex toin (Fig. 8a). By following a crystal engineer- photochemical reactions depending upon the ing strategy, the authors have made a series of chemical and physical structure of the materials, cocrystals and studied their photostability. As such that the labile functionalities, such as con- shown in Fig. 8b, the cocrystals with coformers, jugated double bonds or aromatic residues con- 4-hydroxybenzamide (4HBAM), 3-aminoben- taining N, S, or O, are prone to photochemical zoic acid (3ABA), 4-aminobenzoic acid (4ABA), degradation. and urea, all degraded to a minor extent (<3%), Applications of cocrystals in modulating except the cocrystal with urea, which showed only photochemical reactivity of pharmaceuticals some degree of stabilization (~17% degraded). have been paid less attention until recently. For Interestingly, under similar experimental con- example, V.R. Vangala and coworkers demon- ditions, photostability of physical mixtures of strated for the frst time that the improvement NF and coformers was similar to NF (26–30%

100

N O N hv 95 O2N O2N O O Anti NH Syn N ed 90 NF O O NF N in 85 HN ma hv Pure NF (β-form) + hv re H2O 80 + H2O O Co-crystals Phys. mix. NF NF-3ABA O NF+3ABA 75 NF-4ABA % NF+4ABA NF-UREA NF+UREA + NH 70 NF-4HBAM NF+4HBAM N O2N CHO O H2N 020406080100 120 140160 180 O 5-nitro-2-furaldehyde 1-aminoimidazolidine-2,4-dione Time (hours) (a) (b)

(c)

Figure 8: a Chemical degradation of nitrofurantoin. Note NF cleavage at azomethine ring, b UV irradiation of pure NF, cocrystals, and NF coformer physical mixture samples up to a week and the photodegrada‑ + tion curves show the enhanced photostability of cocrystals, and c solid-state packing of NF-3ABA (1:1) and note the acid–imide heterosynthon between NF and 3ABA molecules. Reproduced with permission from reference 53. Copyright © 2012, The American Chemical Society.

12 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… degradation), suggesting the potential of cocrys- stronger crystal lattice that hamper the photoi- tallization as a means to control the photodegra- somerization of NF at the C N bond. dation of NF. = The greater photostability of the cocrystals was 3.5 Mechanical Property–Crystal rationalized on the basis of crystal structures. For Structure Correlations in Cocrystals example, NF and 3ABA form planar hydrogen- of Paracetamol bonded sheets in the crystal structure of NF-3ABA Materials undergo deformation on applying cocrystal (Fig. 8c). A closer look into the crystal stress; this includes elasticity, plasticity, viscoelas- structure revealed some important structural fea- ticity, brittle fracture, fragmentation, or a com- tures: (1) the acid group of 3ABA forms an acid– bination of these based on the nature of applied imide heterosynthon (via O–H O and N–H O stress and internal structure of the material. A interactions) with NF, and (2) the··· amine group··· of proper understanding of these mechanical prop- 3ABA forms four strong hydrogen bonds with the erties and material deformation phenomena is remaining hydrogen-bond acceptors of the NF. important for powder compaction and second- The formation of multiple strong hydrogen bonds ary processes such as milling. The previous stud- between the coformer and NF could potentially ies on single-component systems are aimed at hinder the photoisomerization of C N and hence correlating compaction properties and plastic- offer better photostability for the cocrystal.= Simi- ity of materials. The presence of slip planes and larly, greater photostability of the other cocrystals crystallographic planes with weakest interactions could be reasoned to the presence of supramo- or adjacent planes with higher d-spacing in the lecular synthons between NF and coformers and crystal structure affords greater plasticity and

Figure 9: Comparison of compressed tablets and crystal structures of PRA and PRA–oxalic acid cocrys‑ tal. Notice that the perfect layered structure of the cocrystal affords improved tabletability. Reprinted with permission from reference 54. Copyright © 2009 by John Wiley and Sons, Inc.

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better tabletability. Studies concerning mechani- properties of several important APIs. The adopt- cal properties of cocrystals have been conducted ability of cocrystallization technology to a wide only recently. For example, W. Jones and cow- range of APIs, including the ones that are non- orkers have found that the cocrystals of par- ionizable, has tremendous implications in drug acetamol (PRA) showed better tabletability than development. The inherent characteristics of the marketed polymorph.54 Most recently, S. P. cocrystals such as novelty, usefulness, and non- Velaga et al. have demonstrated the relationship obviousness provide additional means for pat- between mechanical properties and crystal struc- enting cocrystals as novel composition of matter. ture in PRA (form I) and its cocrystals.55 Ther- A close inspection of the marketed drugs and modynamically stable Form I of PRA showed their composition revealed that some of them poor tabletability due to high elastic deformation contain the API in cocrystal form. For example, (Fig. 9). However, cocrystals with oxalic acid and well-known drugs such as caffeine citrate, sodium 4,4′-bipyridine, and a salt with HCl displayed valproate–valproic acid, and escitalopram oxa- superior tabletability compared to PRA. The tab- late–oxalic acid, all comply with the cocrystal letability of the substances is shown in the order defnition and marketed even before the concept of: OXA > PRA-HCl PRA-OXA > BPY > PRA- of pharmaceutical cocrystals came to existence.40 BPY. A closer look into≈ the crystal structures of The recognition by US-FDA and EMA has fur- the cocrystals and Form I revealed that the crystal thered the cocrystallization research into a main structure of Form I has no slip plane and con- stream preformulation technique and validated sisted primarily of interlocked PRA molecules the use of cocrystals for drug development. Most held strongly by hydrogen bonds. The rigid recently, US-FDA and EMA approved a cocrys- hydrogen-bonded network affords poor tableting tal hydrate that contains disodium valsartan and properties that resulted in brittleness to the com- monosodium sacubitril (Fig. 10).56 The cocrystal pressed tablets. On the other hand, the cocrystal was developed by Novartis with the trade name with oxalic acid features catemeric arrangement Entresto and is used in the treatment of chronic of oxalic acid and PRA molecules that gener- heart failure. Some other promising cocrystals ate layers parallel to (200) and (100) planes. The that are under late- stage development are: a perfect layered structure of the cocrystal explains drug–drug cocrystal containing a non-steroidal the greater plastic deformation and better tablet- anti-infammatory drug, celcoxib, and an opiod ability. These studies underscore the role of crys- drug, tramadol, which has superior analgesic tal packing and the strength of intermolecular effcacy compared to comparable doses of tram- bonding in determining tablet formation and its adol,57 and a cocrystal of an anti-diabetic drug mechanical strength. ertuglifozin with 5-oxo-proline.58

3.6 Marketability of Cocrystals 4 Conclusions Marketability of a solid form depends on sev- Since its discovery, X-ray crystallography remains eral factors and its promising physicochemical at the forefront of structural characterization of properties are undoubtedly the prime considera- materials. Recent developments such as evolution tion. As detailed in Sects. 3.1–3.5, cocrystals have of synchrotron radiation and structure determi- proved successful in modifying physicochemical nation from X-ray powder diffraction data have

Figure 10: Molecular components of Entresto: disodium valsartan, monosodium sacubitril, and water which has been approved by FDA and EMA recently.

14 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… furthered the applications of X-ray crystallog- API and coformers.59 The recent developments raphy to characterization of a broader range of in cocrystal research suggest reliable pathways to materials. The current ease of structure determi- identify suitable solid forms for development of nation using X-ray crystallography has resulted in novel drug formulations. In this regard, crystal a paradigm shift from simple three-dimensional structures deposited in the CSD serve as valu- structural analysis to correlating material prop- able source of information for the design of func- erties with the crystal structure. A wide range of tional cocrystals. Over the past century, the role material properties have successfully been ration- of X-ray crystallography as a tool to probe the alized on the basis of crystal structure, which not structure and function of materials has greatly only unraveled many scientifc mysteries but also been acknowledged. Prediction of properties of aided rational design of functional materials. In a material based solely on its crystal structure is pharmaceuticals, X-ray crystallography played a an emerging area of research and efforts in this phenomenal role in understanding the properties direction further underscore the importance of of drug molecules, which has several important X-ray crystallography. legal and economic impacts. The emergence of pharmaceutical cocrystals as alternatives to long- Acknowledgements known salts, solvates/hydrates, polymorphs, etc., S. Aitipamula gratefully acknowledges the fnan- has provided additional means of fne-tuning cial support from the Institute of Chemical and physicochemical properties of drug molecules. Engineering Sciences of A*STAR (Agency for Sci- In this regard, structural information-deduced ence, Technology and Research), Singapore. V. R. from X-ray crystal structure analysis provides Vangala thanks the Royal Society of Chemistry breadth of information for judicious selection of for Researcher Mobility Grant (2015/17). coformers for a target change in drug property. Changes in drug properties such as solubility, Received: 14 January 2017 Accepted: 7 February 2017 dissolution rate, physical and chemical stability, permeability, and hygroscopicity have successfully been correlated with the crystal structures of API and its cocrystals. It has been rationalized Open Access: that the coformers that result in signifcant differ- This article is distributed under the terms of ence in the crystal structure of API have profound the Creative Commons Attribution 4.0 Inter- impact on drug properties. Therefore, design of national License (http://creativecommons.org/ pharmaceutical cocrystals demands knowledge licenses/by/4.0/), which permits unrestricted use, of competition among various possible intermo- distribution, and reproduction in any medium, lecular interactions between API and coformers. provided you give appropriate credit to the origi- Despite a signifcant development in the feld nal author(s) and the source, provide a link to of cocrystal design, there remain further chal- the Creative Commons license, and indicate if lenges. 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Srinivasulu Aitipamula is a Scientist in completed M.Sc. from Kakatiya University, Warangal Crystallization and Particle Sciences Divi- (1998) and Ph.D. in crystal engineering (Mentor: Prof. sion at the Institute of Chemical and Engi- Gautam R. Desiraju) from the School of Chemistry, Uni- neering Sciences (ICES) of A*STAR versity of Hyderabad, Hyderabad (2004). Subsequently, he (Agency for Science, Technology and did a brief industrial stint as Research Associate at GVK Research), Singapore. He obtained his Biosciences, Hyderabad (2004–2005) and did post-doctoral Ph.D. in 2006 from the University of Hyderabad (India) research at the University of Iowa, USA (2005–2007) and working with Prof. Ashwini Nangia on structural and ther- University of Minnesota, USA (2007–2009), and worked as mochemical studies of some host–guest systems and poly- Scientist at ICES of A*STAR, Singapore (2009–2014). He is morphs. After a short industrial stint as a Manager-R&D at with the University of Bradford since July 2014. He is the Shasun Research Centre, India, he joined ICES in 2007. He author of nearly 30 publications. His current research is has nearly 50 peer-reviewed publications including two focused on crystal engineering for pharmaceuticals and book chapters. He is currently the guest editor for a special nutraceuticals development, solid forms pre-formulations issue on “Novel pharmaceutical cocrystals and their appli- (cocrystals, polymorphs, salts, and amorphous materials), cations” in the journal Crystals. His research interests crystal structure and pharmaceutical, physicochemical, and include crystal engineering, solid-form screening of active mechanical property understanding, and formulations. pharmaceutical ingredients, and formulation development. http://bradford.ac.uk/life-sciences/pharmacy/our-staff/ venu-vangala.php.

Venu R. Vangala is a Lecturer in Medi- cines Development and Pharmaceutical Science at School of Pharmacy and Medical Sciences, University of Bradford, UK. He

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