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Dr. Wei Wu has received awards from many national societies for the originality and quality of his projects. He has authored 70 peer-reviewed papers in international journals.",coeditorOneBiosketch:"A pioneering researcher in obstetrics and holder of three registered patents. Dr. Qiuqin Tang's research interests include genetic and epigenetic risk factors of reproductive and developmental health. She has authored over 20 papers in international journals.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"178661",title:"Dr.",name:"Wei",middleName:null,surname:"Wu",slug:"wei-wu",fullName:"Wei Wu",profilePictureURL:"https://mts.intechopen.com/storage/users/178661/images/system/178661.jpeg",biography:"Dr. Wei Wu is an associate professor and associate department\nchair in the Department of Toxicology, Nanjing Medical University, China, where he received his Ph.D. in Toxicology in 2012.\nHe was a guest researcher at the National Institute of Environmental Health Sciences (NIEHS) between 2017 and 2018. Dr.\nWu is a member of different national and international societies\nin the fields of human reproduction and toxicology and has\nreceived awards from many national societies for the originality and quality of his\nprojects. Dr. Wu has authored seventy-three peer-reviewed papers in international\njournals. He has edited four books and collaborated on ten others as well as seventeen patents and in the organization of three international conferences. He is a\nreviewer for ninety-eight journals.",institutionString:"Nanjing Medical University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"Nanjing Medical University",institutionURL:null,country:{name:"China"}}}],coeditorOne:{id:"184798",title:"Ms.",name:"Qiuqin",middleName:null,surname:"Tang",slug:"qiuqin-tang",fullName:"Qiuqin Tang",profilePictureURL:"https://mts.intechopen.com/storage/users/184798/images/13334_n.jpg",biography:"Qiuqin Tang is an attending doctor of The Women’s Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital). Her research interests include genetic and epigenetic risk factors of reproductive and developmental health. She has authored over 20 papers in international journals such as EBioMedicine, Clinical Epigenetics, Molecular Human Reproduction, Scientific Reports, and European Journal of Endocrinology. She has collaborated in four books and three patents. 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He is also the headmaster of the Family Planning Centre and Gynecological Cytology\nLaboratory at the same university. Dr. Tsikouras is a fellow of the\nInternational Academy of Clinical and Applied Thrombosis/Hemostasis. His scientific activities focus on paediatric and adolescence medicine, gynecological oncology, high-risk pregnancies. He is a reviewer for several international journals and has numerous scientific publications to his credit, including papers and book chapters. 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He\nis currently a professor in the Gynecology and Obstetrics Faculty\nof Medicine, University of Kiel, Germany, and honorary doctor\nat the Democritus University of Thrace, Alexandroupoli University Hospital He previously served as chief of the Department\nof Gynecology and Obstetrics at University Hospital RWTH Aachen,\nGermany. Dr. Rath is a reviewer for numerous journals and chief editor of Geburtshilfe und Frauenheilkunde (GebFra). 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1. Introduction: historical perspective
The intrinsic awareness in structure-properties relationship of solids was firstly introduced on the study of minerals and inorganic compounds and has been preserved over time [1]. Within this frame, the first step on the polymorphism phenomenon was unknowingly given by Klaproth [2] in 1788 identifying three different crystalline phases of calcium carbonate (calcite, vaterite and aragonite). In 1819, Mitscherlich commenced his research on phosphates and arsenates of potassium (KH2PO4 and KH2AsO4) and established their complete morphological similarity, noting that they crystallize in similar forms. His subsequent results with the corresponding potassium salts (NH4H2PO4 and NH4H2AsO4) confirmed that observation and led him to pose that there do exist bodies of dissimilar chemical composition having the same crystalline form. He not only recovered the work of Whollaston with orthorhombic carbonates and sulfates of barium, strontium and lead, who already noticed this phenomenon in 1812 but also, extended to rhombohedral carbonates of calcium, magnesium, iron and manganese, and to sulfates of iron, copper, zinc, magnesium, nickel and cobalt. Curiously, he also evinced the basis of seeding at realizing that having two substances both able to crystallize in various forms, the presence of one during the crystallization of the other will force the crystallization of the latter in the same form. Then, he moved to Stockholm with Berzelius with whom he delved deeply into phosphates and arsenates and forged the concept of isomorphism. Last but not least, he reported two distinct crystallized forms of sulfur in 1826 demonstrating a clear case of an element which could be made to crystallize in two different systems of symmetry at will, by merely changing the crystallization conditions. Therefore, Mitscherlich was identified as the one who took the first step towards the rise of polymorphism [3]. Shortly after, in 1824, the contradictory results garnered by Liebig [4] and Wöhler [5] during their research on silver fulminate and silver cyanate triggered the conflict which led them to be colleagues and to pose the following dilemma: can two compounds with the same composition have different physical properties?. Their results evinced two Ag salts with the same composition but different physical properties, which did not go unnoticed by Wöhler’s master Berzelius, who merged these results with those of Mitscherlich. It is unclear who was the first to conceive the notion of polymorphism but this crucial period of 1820–1832 was mainly drawn by Mitscherlich [6, 7, 8] who shed light on this phenomenon, even though the concept was still vague. It was during these years when Berzelius [9] proposed the concept of isomerism (1831–1832) and it took until 1832 for Wöhler and Liebig [10] to report the first case of polymorphism in an organic compound. The awareness of isomerism set the beginning of structural chemistry, broadening the knowledge and understanding of organic structures.
Since observation was the essential tool to identify polymorphism, this research drastically changed with the accessibility and wide spreading use of the microscope, but it was not until 1839 when Frankenheim [11] introduced the first principles defining polymorphism and a postriori, Mallard [12] set the structural basis of polymorphism in 1876, relating differences in physical properties with different arrangements. One of the most remarkable contribution during this period was the “Rule of steps” or “Law of successive reactions” from Ostwald [13] in 1897. He pointed that during a succession of polymorphic forms, those appeared later are generally more stable. Despite not being considered a rule, it is still valid as a general observation. But the two major queries raised by Buerger and Bloom [14] in 1937 were still unanswered: what causes the formation of different phases of a substance and which factors determine them?.
The narrow link between crystallography and polymorphism was forged by Tamman [15] in 1926 and settled with the first polymorphic X-ray crystal structure determination of an organic compound, resorcinol, published by Robertson and Ubbelohde [16] in 1939. Despite this achievement, the next decades passed without a better understanding of polymorphism, being underrated until 1965 when McCrone [17] conducted a comprehensive study in which he defined a polymorph as: “a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of the molecules of that compound in the solid state” and published a review in 1969 about the importance of such phenomenon in the pharmaceutical outlook [18]. Since the introduction of the term allotrope by Berzelius in 1841, Polymorphism had been taken with allotropy on the same meaning. But, it was not until the 1990s, when Sharma [19] and Reinke [20] set the differences between them: polymorphism occurs in chemical compounds while allotropy occurs in chemical elements. This work was crowned a posteriori by Dunitz’s [21, 22] crystal description contribution.
In the 1970s, the works of Schmidt [23] and Paul and Curtin [24, 25] grounded the flourish of solid-state chemistry and precede the breakthrough of conceiving polymorphism. They served as inspiration to Bernstein and Desiraju, who laid the foundation for recent supramolecular chemistry. In 1978, Bernstein [26] changed the landscape of polymorphism by rationalizing the study of crystal packing forces on molecular conformations of polymorphs and later in 1990, together with Etter [27, 28, 29, 30], applied their graph set descriptors and provide guidelines to understand polymorphic transformations [31]. Bernstein compiled most of this historical results in his book “Polymorphism in Molecular Crystals”, which the authors encourage reading [32]. Likewise, Desiraju achieved substantial progress in this field during his studies of structure-properties relationship of organic solids mainly of pharmaceutical interest, emphasizing and aiming its importance in this industry as reflected in his book “Crystal Engineering: A Textbook” [33]. Both channeled their polymorphism vision in terms of supramolecular chemistry.
During 1990s, computational chemistry went hand in hand, achieving methodologies capable to reproduce experimental results and enabling even crystal structure predictions. The first attainment was obtained by using Williams’ software [34] that met the main handicap hitherto, the identification of lattice energy minimums. Subsequent years, many computational approaches were developed facing with computer-generated structures for prediction, to the extent that in 1999 a collaborative workshop held at the Cambridge Crystallographic Data Centre (CCDC) [35] brought together the benchmark computational groups of this period to provide an objective assessment of the possibilities of crystal structure prediction. The results gathered in this event were clearly summarized a posteriori in a paper published by Lommerse [36]. Further advances on prediction methods accuracy as well as the implementation of Density Functional Theory (DFT) and Machine Learning (ML) can be found in Spark’s review [37].
Despite the basis of polymorphism were already defined at the end of the twentieth century, the increasing advances on X-ray diffraction techniques and crystallization methods afforded the determination and analysis of metal–organic structures, especially coordination polymers. Polymorphism of metal–organic complexes was still unexplored and these new class of materials, from which polymorphic structures grew exponentially, required classification and awareness. This impasse was encouraged by renowned researchers as Sharma [38], Ciani [39], Rogers [40] and Zaworotko [41]. In this regard, the same Zaworotko was who published a review in 2001 emphasizing the difference between polymorphism and supramolecular isomerism and underlined the link between them in organic and metal–organic networks [42].
2. Types and borders: from organic to metal–organic
During the early stages of polymorphism, the lack of crystallographic tools conditioned the understanding and therefore, classification of the different polymorphic forms, but the exponential advances in this field provided perhaps too many concurrent data to bring it together and form a unique mindset. It was not until 1965 when McCrone [17] gathered the knowledge hitherto and set a more excluding definition of polymorphism. The inclusion or not of hydrated forms and solvates have been discussed since the rise of polymorphism, but be that as it may, he ventured to propose their exclusion from polymorphic forms and to avoid the use of pseudopolymorphism to define them. This assertion was underpinned by Bernstein [32] in 2002, even if actually it is a wide spread term, probably because of its acceptance by the pharmaceutical industry [43] from its regulatory and patentability point of view. Since the aim of this chapter is not about pseudopolymorphs we therefore, decided to exclude this term to refer to solvates and hydrates, which can lead to undesirable misunderstandings. In 2012, Desiraju, Karpinski, Thaper and Zaworotko [44] defined cocrystals as solids that are crystalline single-phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. As well as salts that are any of numerous compounds that result from replacement of part or all of the acid hydrogen of an acid by a metal or a radical acting like a metal; an ionic or electrovalent crystalline solid. Instead, solvates have one component, commonly a solvent, which is liquid by itself and hydrates are a particular case of solvates, containing water as solvent. A deeper discussion on pseudopolymorphism can be found in references [45, 46, 47].
Until the beginning of the twenty-first century, the polymorphs’ classification was settled from the perspective of crystal packing forces and introduced conformational and packing polymorphism to sort the examples hitherto. Coordination polymers are infinite repeating coordination entities composed of organic molecules serving as linkers and metal ions as nodes [48]. Their main classification is based on dimensionality which is the number of directions in which the array is extended. Therefore, they can be divided into one-, two- or three-dimensional. The rise of this field befell in 1961 when Bailar [49] firstly introduced the term coordination polymers. Distinction between polymorphs and other forms as solvates, hydrates or cocrystals in organic structures was well defined, but in the case of metal–organic structures, in particular coordination polymers, this classification was not sufficient.
Numerous structures which were not truly polymorphs (solvent molecules were present in the lattice), but neither were solvates, started to rise at the end of the twentieth century. This new domain required the borders to be clarified and established. Yet, these rigid structures were thought to be less disposed to suffer structural variations but some examples were gathered in works of Janiak [50] with Zn(II) poly(pyrazolyl)borates, Ciani [39] with Ag(I) and 4-cyanopyridine, Zaworotko [41, 51] with Co(II) and pyridyl containing linkers, Ripmeester [52] with Cu(II) and a diketone and Rogers [40] with Hg(II) and tetrapyridylporphyrines. Thus, supramolecular isomerism was invoked to merge those different types of structures (mainly coordination polymers) assembled from identical building blocks. In this impasse, Zaworotko [42] strongly contributed to shed light upon this ambiguity in his review of 2001. He defined supramolecular isomerism as “…the existence of more than one type of network superstructure for the same molecular building blocks…” and pointed that polymorphs are a particular case of supramolecular isomers “…polymorphs can therefore be regarded as being supramolecular isomers of one another but the reverse is not necessarily the case”. This assertion should be clear before classifying metal–organic structures.
Henceforth, supramolecular isomerism was divided into structural (regarding the formation of different networks inter alia ladder, brickwall, 3D frame, herringbone, bilayer or Lincoln logs), conformational (relying on the flexibility of the ligands) and a new class named catenane (promoted by interpenetration), being polymorphic forms a certain condition of them. A schematic representation highlighting such division is depicted in Figure 1. At that time, structural isomerism was focused on the particular case of architectural isomers [41], understood as variations of the connectivity of the ligands between two structures, sharing the same composition as a result of ligand conformations [53]. In particular, to those cases in which the accommodation of different solvent guest molecules promoted the change in the spatial disposition of the organic linkers.
Figure 1.
Schematic representation of the structural relationship between the different architectures among organic and metal–organic compounds.
In this direction, Robin and Fromm [48] in 2006 described supramolecular isomerism as the ability of a substance to arrange into one or several network superstructures by different molecular or supramolecular assemblies with the inherent condition that organic linkers and metal ion remain the same and this metal ion retains an equal coordination sphere. They also reported several examples of a new subclass of structural supramolecular isomers named as ring opening. Recently, Zhou [54] has provided the specific term framework isomers to define supramolecular isomerism in MOFs, in which solvent occluded molecules are trivial.
3. Thermodynamic vs. kinetic factors: formation and transformation of polymorphs
A brief summary of fundamental thermodynamics principles is required prior to understand their relevance on polymorphism. Despite ideal systems are not viable, the definition of boundaries within this phenomenon based on simple laws could be achieved with a sufficient accuracy to be useful. It is essential to stress that the result of any structural change will be reflected as a change on the properties of the system. Since energy changes are empirically measurable, they are a pragmatic way to face polymorphism and led these energy differences to be a useful descriptor. The identification of the relative intensities within the different forms of energy displays whether exchanges of energy between two polymorphs will occur. Remarkably, this allows to induce energetic modifications, by an external stimulus, only on a selected form of energy to establish relationships in a linear manner.
The quantity of energy a system exchanges with environs is named enthalphy and is referred to as H. Taking a chemical reaction as the case study, the character of the energetics involved in it, is represented as the enthalpy of reaction, which is the difference in enthalpies between products and reactants. This concept is useful to determine the direction in which energy will flow but such information is not conclusive to establish spontaneity. Hence the introduction of the notion of entropy (S) is essential. It is a way to represent the organization of a system approached as the degree of disorder and it is measured in terms of entropy changes of the system. Using both terms, Gibbs free energy (G) provides further insights into spontaneity at constant temperature and pressure.
To understand the relative stability of the different polymorphs within a given system as well as their transformations, the energy/temperature diagrams (E/T) introduced by Buerger in 1951 [55] are the most valuable approach, being capable to encapsulate much data in a single representation. It is based on the G equation:
G=H−TSE1
As a general representation, the diagram on Figure 2a displays how these terms evolve at increasing temperature. Since the term TS is more significantly affected by temperature than H, its effect on G becomes intense as the temperature of the system raises and thus, G of the system tends to decrease. The energy of a transformation undergone within a polymorphic system, under conditions of constant temperature and pressure, are defined by:
Figure 2.
(a) Progression of the terms G, S, TS and H at increasing temperature. (b) Representation of the evolution of H and G variables in a dimorphic system (polymorphs A and B) at increasing temperature.
ΔG=ΔH−TΔSE2
Within a series of polymorphic forms their crystal lattices are unique per se, so despite their G at a certain temperature could be equal (isoenergetic forms), the values of H and S will be different (Figure 2b). If isoenergetic forms are present, there is a crossing point between the two G value curves in the E/T diagram, named transition point (t.p.), which to be useful is to be placed below the melting point (m.p.). In such a scenario, if the formation of these polymorphs is allowed by kinetic factors, both forms coexist and can be formed as concomitant polymorphs (vide infra in Section 5).
For instance, considering a case study as the one represented in Figure 2b, containing two polymorphic forms (dimorphic) named as A and B, a brief analysis of this E/T diagram can provide some useful data. Below the t.p. (blue region) form A is the most thermodynamically stable as its lower G value states. Within this region, its transformation into form B is related to an increase in H and it is defined as an endothermic transition. At the t.p. both forms have the same G (ΔG = 0), which applied to Eq. (2) is set that ΔH = TΔS, where ΔH = HB-HA and ΔS = SB-SA. All these equations allow to quantify the entropic change of a polymorphic transformation once the enthalpic variation ΔHt,B↔A is experimentally determined (see Section 4.1). Above the t.p. (green region), within this range of temperature and before the change of state at the m.p., form B is the thermodynamically stable and therefore, transformation from A to B is associated with a decrease in H (exothermic process). After defining these borders, one can infer the proper conditions in which the formation of one polymorph is favored instead of the other.
Considering that theoretical thermodynamic relations applied to systems undergoing phase transformation are bounded by experimental data, more empirical concepts were developed to better represent these changes. Consequently, the terms Enantiotropism and Monotropism were defined to meet this requirement. The former refers to those systems presenting a reversible transformation before the m.p. when heated above or cooled below the t.p. Contrarily, Monotropism sets that only one polymorph is the more thermodynamically stable over the entire range of temperatures until the m.p. Both examples are illustrated in Figure 3a and b, respectively.
Figure 3.
E/T diagrams of (a) enantiotropic and (b) monotropic dimorphic systems.
The incorporation of energetics associated with the liquid state into the E/T diagram, enthalpy (Hliq) and free energy (Gliq), ease to parse their behavior and classification. If the crossing points between the Gliq curve and the G curves of both A and B are after the t.p., they are said to be enantiotropes. The absence of crossing points between A and B before their m.p. classify them as monotropes. The terms ΔHf,B and ΔHf,A are the energy that B or A require to change into liquid state, respectively.
Burger and Ramberger [56] in 1979, pioneered in the development of many experimental rules to empirically establish the nature of this relationship between polymorphic forms and their applicability was exemplified with 113 substances [57]. All giving fundamental knowledge to determine the proper conditions to control their formation: Heat-of-transition, Heat-of-fusion, Entropy-of-fusion, Phase transformation reversibility, Enthalpy of sublimation, Heat-capacity, Infrared, Solubility and Density rules. Among them, the most applied are Heat-of-transition and Heat-of-fusion rules. The former being based on using Differential Scanning Calorimetry (DSC) to identify the endothermic or exothermic character of the transition. If this rule cannot be applied, Heat-of-fusion rule, which rely on the determination of the m.p., states that the relation is enantiotropic when the higher melting polymorph has the lower enthalpy of fusion while monotropic systems are defined by the higher melting polymorph having the higher enthalpy of fusion. Detailed explanation on the application of them could be found in Burger publication [57] or in the more recent Brittain’s review [58].
Crystallization is the process related with nucleation and growth of a crystal structure. This process is, in principle, directed by thermodynamic factors that tend to reach the structure with a lower lattice energy. However, the crucial stage is supersaturation which is determined by kinetics, in particular, by the rate of nucleation and thus, the first structure to be formed is the one with preferred nucleation. Therefore, a metastable form can grow despite being unfavored by thermodynamic factors. Subsequently, this form can be converted into a more thermodynamically stable by solution or solid state-mediated phase transformation. This successive phase change was identified and proposed as the Law of States by Ostwald [13].
To avoid common mistakes in ascribing the nature of the nucleation process, Mullin [59] divided it into primary, in which any crystalline matter is directing the process, and secondary, pertaining to the circumstances of nucleation generated in the vicinity of crystals, previously nucleated or intentionally placed, a methodology known as seeding (vide infra in Section 4.2). Furthermore, secondary nucleation can be classified as homogeneous if it is spontaneous or heterogeneous if it is induced by foreign particles.
Solid-state phase transformations are usually promoted by an external stimulus in the form of mechanical work or temperature. They are thought to be related with intrinsic defects, whether coming from the original structure or being caused by mechanical stress, which commence and propagate the formation of the new phase. The most studied transformations are those based on order–disorder changes, mainly promoted by temperature variations. Disordering processes arise from increasing temperature whereas ordering processed are observed at decreasing temperature. An excellent analysis of such phenomena with the most relevant examples were summarized by Dunitz and Bernstein [60].
The reversibility of these changes could not be evident or even accessible since hysteresis plays a crucial role. It is the lagging of the transition behavior respect to the applied stimulus. Therefore, it is possible to need heating or cooling beyond the t.p. to let the phase change occurs and even with the sufficient high degree of hysteresis is conceivable to avoid transformation [61]. Although ideal reversibility is often desired, control of hysteresis [62] also leads to unique properties [63], often advantageous to the application of these materials, only achievable by a precedent transformation. Hysteresis phenomenon is associated to structural fatigue [64, 65, 66], which means the rise of structural changes in the crystalline material as dislocations as well as to a different nucleation with different energy barriers from one to another [67]. Further concerns regarding the basis of this topic can be addressed reading Flanagan’s publication [68].
Overall, since crystallization is a competitive process between minimizing lattice energy (thermodynamic) and reaching supersaturation (kinetic), the achievement of non-minimal energetically stable forms allows to the transformation into lower energetic forms after reaching the activation barrier.
4. Strategies to identify and achieve polymorphs and the influence on their properties
4.1 Identification of polymorphs
The identification of polymorphism had been, in the vast majority of cases, a matter of chance, but this all changed as a result of the efforts of many scientists in the field. The first tool of recognition was visual observation inasmuch as it was the most affordable and accessible technique. Since it is not a strict approach, however, it is often useful to detect anomalies. In particular, observation of crystalline materials through optical microscopy can allow to differentiate between two crystal habits (their characteristic external shape), because this shape is governed by its molecular packing and intermolecular interactions (internal structure). Notwithstanding that more than a century has passed, it is still a routinely used technique, even if optical microscopy is being superseded by Scanning Electron Microscopy (SEM), which allows more accurate surface topology and morphology analysis. The closely related Transmission Electron Microscopy (TEM) was not appropriate for this kind of materials even given its uniqueness. It could collect structural and dynamic data from single crystals in a bulk powder and therefore, have remarkable benefits compared to any other. Unfortunately, the high energy applied to the samples caused strong damages precluding their characterization. Over years, researchers intended to reduce the applied voltage, seeking for this technique to be applicable by minimizing sample damage and improving cameras and detector technologies. This was especially aimed to the study of metal organic frameworks (MOFs), one of the most emerging topics with fundamental need to understand structure-properties relationship. Hence, breakthrough developments in characterization techniques as cryogenic-TEM (cryo-TEM) [69] and High-Resolution TEM (HR-TEM) [70] paved the way to structural features at the nanometric scale as well as recent improvements for in situ measurements inter alia hot stage TEM, liquid cell TEM (LCTEM) [71] or environmental TEM (ETEM) [72] enabled to observe the dynamics of these systems. Advanced 3-dimensional electronic techniques as automated electron diffraction tomography (ADT) [73] and Rotation Electron Diffraction (RED) [74] were able to gather sufficient data for ab initio structure elucidation and thus succeeded where conventional diffraction techniques failed [75].
Despite all these advances, the most valuable technique has been and remains, single-crystal X-ray diffraction (SC-XRD). Only neutron diffraction is tantamount, being capable to collect specific and accurate data of atomic positions, bond distances, and angles [76]. Thus, serving as a complementary technique to SC-XRD. However, one must consider the possibility of temperature driven single-crystal to single-crystal transformations since a growing number of examples have been reported in the literature. Careful inspection of temperature effects on the sample is to be required. The generally used condition in SC-XRD is about 100 K which can undergo the phase transformation. If such events are not assured, one could fail at drawing conclusions of property changes from structural differences.
Although SC-XRD provides complete information about atom positions and structural packing, the growth of suitable crystals for structure determination is sometimes a laborious and very time-consuming task or even not attainable. Often, but nowadays less and less, it is not thought to be part of the endeavors of a chemist. That is why structural studies goes hand in hand with Powder X-Ray diffraction (PXRD), which is in many cases more available and can reflect any structural difference between SC-XRD and the bulk powder. But one must not forget that after ensuring no phase transformation, SC-XRD and neutron diffraction are the unique unambiguous techniques while the rest requires to be combined to successfully identify polymorphism. Recent advances in diffraction methodologies have enabled to improve PXRD characterization. For instance, variable temperature-PXRD and variable temperature-SC-XRD not only ease to determine differences in crystalline materials but also allow to trace phase transformations being subject to temperature changes.
Solid-state spectroscopic techniques are also a complementary tool during the identification of structural differences. Sometimes these changes are not evident but, in many cases, subtle structure modifications are reflected in the spectra. The most marked differences observable by Fourier Transformation Infrared Spectroscopy-Attenuated Total Reflectance (FTIR-ATR) [77] or Raman spectroscopies [78] usually appears in the fingerprint region since it is unique for a substance. In the case of polar molecules, transitions associated with rotation can be measured in absorption or emission by microwave or far infrared spectroscopies [79]. Also solid-state Nuclear Magnetic Resonance (SS-NMR) [80] as well as solid-state Ultraviolet–Visible absorption (SS-UV–Vis) [81] and fluorescence [82] have proven to be fruitful techniques to identify polymorphism and phase transformations. The recording of SS-NMR data can be improved by using Schaefer and Stejskal [83] experiments, in which high power heteronuclear decoupling, cross polarization (CP) and magic-angle spinning (MAS) are combined. Careful attention should be paid during MAS since the required high spinning rates generate mechanical stress and local heating, thus favoring conditions for transformations. Isotopomeric polymorphs [84] have also been identified, albeit in a lesser extent.
Solid-state Electron spin resonance (ESR) also known as Electron Paramagnetic Resonance (EPR) can be used only for materials containing paramagnetic metal ions or structures in which those metal ions have been embedded. Copper(II) but also cobalt(II) are the archetypal metals for this technique and there already exist examples incorporating Cu(II) into the structures of templated materials [85]. More sophisticated variations include variable-temperature magnetic-susceptibility and variable-temperature solid-state EPR measurements. An increasingly common strategy combines them in the study of single-ion magnets (SIMs), a type of single-molecule magnets (SMMs). This EPR analysis is not easily available since it is preferably implemented with a synchrotron radiation source [86]. The magnetic evaluation of SIMs is performed in solid state so the structural differences between polymorphic forms promoted by conformational changes could lead to a dramatic alteration of the magnetic properties [87]. This effect is marked in Clathrochelates, a special class of structurally rigid cage metal complexes [88].
Last but not least, thermoanalytical techniques inter alia hot stage microscopy (also known as thermal microscopy), Thermogravimetric analysis (TGA), Differential Thermal Analysis (DTA) and Differential Scanning Calorimetry (DSC), are widely used to characterize both polymorphism as well as phase transformation phenomena. They are usually combined to maximize the efficiency of the data collection as TG-DTA or DSC-TGA, among others.
During hot stage microscopy, the sample is subjected to heating and cooling processes under polarized light. It provides m.p. data as well as, if it occurs, the reversible or irreversible character of the transition. TGA method is used to determine the thermal stability of the products and as previously mentioned, it is commonly combined with DTA. By the use of a thermobalance, it is capable to measure weight losses during temperature changes. It is especially useful to determine desolvation temperatures and thermal stability ranges but it is less accurate to quantify these transitions. The most appropriate technique to track phase transformations with quantitative data is DSC.
DSC is routinely used to measure the difference in the amount of heat required to increase the temperature of the sample respect to a reference. It is divided into power compensation DSC and heat-flux DSC methods. The quantification of the ΔHt,B↔A enables to identify its exo- or endothermic character, as well as the determination of reversible or not transitions provides essential data about the enantiotropic or monotropic behavior. DSC has not been deeply exploited yet for metal–organic materials but this practice is inevitably set to change. In particular, it is increasingly used in the study of breathing metal–organic frameworks (MOFs) [89] or solid-state phase transformations in Zeolitic imidazolate frameworks (ZIFs) [90].
Evidence of polymorphism can also be confirmed by nanoindentation or by optical properties as refractive index (n) or the identification of an interference figure caused by birefringence, which is the presence of different n and mainly depends on crystallographic orientations [91]. Once polymorphism has been identified and characterized, the proper conditions to isolate or to only reach one polymorphic form are to be established, avoiding the presence of mixtures and undesired products.
4.2 Screening and isolation of polymorphic forms
There are significant factors determining the formation of polymorphs inter alia molecular structure, chemical composition, energetic differences and experimental conditions (solvent, additives, pH, temperature and pressure). What should be clear is that the different polymorphic forms of a given structure can be selectively reach either by crystallization from the melt or solution, or by solid-state transformation. Crystallization approach has been the most widely studied heretofore but awareness of hitherto ignored solid-state transformations has led to value their tantamount importance. The solution-mediated approach is based on the proper adjustment of the crystallization process and involves much more control of the polymorphs forming conditions. Instead, the advances in solid-state characterization techniques have triggered a significant increase of polymorphism studies allowing traceability of such conversions. This is especially the case of coordination polymers and MOFs, optimal materials for polymorphism study because of their flexibility and capability to accommodate structural modifications without the breaking of bonds.
The first step in polymorphs screening is to determine the phase space of a substance and the boundaries of stability for the different forms as well as identifying, if it is the case, interconversion. Defining the most stable phase is recommended since, unless modulating external factors dictate otherwise, that form would be the result. The occurrence of polymorphs and their transformations are confined to what is known as occurrence domains that encompass all the conditions in which the targeted crystal forms originate. Early studies carried out by Sato [92] on stearic acid delved deeply into the dependence of temperature and supersaturation on solvent polarity. Is in those regions with domain overlap where polymorphic transformations can occur, bearing in mind that the domain is not unique for one crystallographic form.
The many attempts to control the formation of a desired form have supplied us of a vast number of methods to selectively achieve it through crystallization or solid-state phase transformation. Most of the old and recent methods have been compiled in Figure 4. Further details about fundamental crystallization methods are found in Hulliger’s review [93].
Figure 4.
Classification of the different methods to achieve polymorphic forms by crystallization or transformation.
Over all of the difficulties of achieving isolated polymorphs, to identify the conditions to reach isolated forms is an essential task. When dealing with a polymorphic mixture scenario, the initial way of facing it, is the use of common crystallization methods as those mentioned before. However, crystallization of less stable forms is often intricated and therefore, it requires the design of more robust strategies inter alia high-pressure crystallization, spray-drying, crystallization from a melt or crystallization from a quenched amorphous phase. They give sometimes satisfactory results, but their major drawback is the lack of control in the formation of a single product. Hence, the use of additives and substrates was implemented as template though a limited triumph, considering that only thermodynamic aspects are contemplated and kinetic factors have a determinant role in nucleation. Subsequent methods as application of external fields, surface templating, selective nucleation by supersaturation control and nucleation temperature or seeding experiments emerged, but there is still a need for their improvement.
It is nevertheless important to note again that MOF materials are themselves appropriate candidates for filing structural modifications, since the predefined preferences of the organic linkers combined with those of the metal ions result in a restricted range of potential structures. This is strongly reflected in the common formation of isostructural products although they combine different linkers and metal ions. Such a controllable way of structure design is therefore adequate to identify new strategies for the isolation of different crystalline phases. Currently, throughout all the advances in MOFs design, polymorphism and isomerism awareness has driven the seeking of selective crystalline phase formation methods. For instance, in the case of mixed-metal MOFs, in which the addition of more than one metal ion disrupts the predefined structural formation, the selective phase formation has been achieved by the incorporation of guiding organic linkers or even metal ions to template the structural assembly. There was already consciousness of polymorphism and isomorphism in chromium(III) terephthalate MOFs [94], but the strategies to reach them were lacking. In 2018, Bureekaew [95] controlled the formation of this family of MOFs by using iron(III) metal-cationic competition, which served as modulator during crystallization. Likewise, Užarevic [85] demonstrated a rapid and selective way of controlling polymorphism in this family of MOFs by a mechanochemical approach using additives.
4.3 Properties
Become aware of a difference in the properties of a unique sample or two sample which in principle, are to be identical is the commencement of most polymorphism studies. One important aspect to be considered, sometimes careless, is the manipulation of the samples before the measurements. It is widely reported that a routinely sample treatment as grinding can undergone phase transformation. Even this subtle stimulus can provoke changes in the sample with the consequent incongruent results, thus hampering their correct analysis. These changes produced by polymorphic modifications could range from slight differences to dramatic alterations of the target properties and those which have raised more interest are listed in Figure 5.
Figure 5.
Properties likely to be altered by polymorphic modifications.
5. The special cases: concomitant, vanishing (or disappearing) and intergrowth polymorphism
The terms Vanishing or disappearing polymorphs were renowned during the second half of the twentieth century by referring to the evolving nature of some crystal forms over time that caused their unrepeatability. In the course of the subsequent years, researchers realized that every crystal form can be repeated being the finding of the proper conditions (control over nucleation and crystal growth) the main trouble.
Within the polymorphism landscape, the presence of mixtures of crystalline phases has brought a profound attention whereby, many efforts were devoted to the understanding of such circumstances. Reproducibility and purity have always been a requisite for chemists, so such demonstration of lack of control led them to seek to comprehend and identify the source of these phenomena. These two closely related special cases, named as Concomitant and Vanishing polymorphs, refers to a condition describing all the forms involved. Concomitant polymorphs are those simultaneously formed at the exactly same conditions. This assertion is not trivial since many factors contribute to the crystallization process. The case of vanishing or disappearing polymorphs describes the formation of a metastable phase which undergoes transformation into a more thermodynamically stable one. This phenomenon is quite thorny since as mentioned, reproducibility of the results is often intricated. Such conversions can be found by redissolution of the former crystal or in solid-state. In the solution-mediated process, the formation and disappearing of a metastable product can be quenched by seeding. A crucial statement is to be noted, once seeds of one polymorph are formed, the other form will no longer be formed. By using this criterion, seeding crystallites of the desired polymorph will lead to the growth of its crystals, even though it is a metastable form [60]. This method allows to avoid both undesirable cases, concomitancy and vanishing, if phase-pure materials are to be achieved. Vanishing by solid-state transformations is even less evident, indeed, any slight appliance of an external stimuli can promote this phase change and routinely sample treatments required for many characterization techniques as grinding, milling or pressure and temperature changes could be sufficient to trigger it. Both phenomena have probably been less reported than occurs and just a curious point is that the first recognized example of polymorphism in an organic substance described by Wöhler [10] the dimorphism of benzamide, that was also the first precedent of concomitancy.
The critical point describing concomitant and vanishing polymorphs is based on the same kinetic/thermodynamic factors, better understandable by the mentioned E/T plots and promoted by the kinetic govern. In fact, concomitancy is dependent on where from the diagram the polymorphs are growing. Having this data, one can also design a strategy to favor the nucleation of one polymorphic form instead of the other.
Identification of concomitant polymorphs is as always, initially assessed by visual recognition. Thus far, careful inspection during hot-stage microscopy has been the most reliable method. Differences in crystal habit and variable melting point suggesting crystalline mixtures could provide a clue as to trace concomitancy. Also broadening signals in solid-state NMR or FTIR-ATR may be a symptom of this.
Reported cases of vanishing polymorphs in metal–organic compounds are in large part still unfathomed. The phenomenon of concomitant polymorphs is equally meager being only few examples reported hitherto. Oliver [96] in 2012 reported the special case of two Cd(II) coordination polymers concomitantly formed from which the less stable form was subsequently identified as a disappearing polymorph. Both products crystallize in the monoclinic crystal system but the stable form (2) exhibited a C2/c space group and bigger unit cell parameters than the vanishing form (1), which displayed a P2/c space group. Their main dissimilarity was the slightly different orientation of the dipicolinate ligands (Figure 6), which improved the inter-chain π···π interactions in the structure of the stable form and provoked a different packing.
Figure 6.
(a) Overlapping representation of the two Cd(II) polymeric chains in the two polymorphs. Different disposition of dipicolinate ligands: front chain (1) and back chain in dark (2). (b) c axis view of the packing of the less stable form 1 and (c) a axis view of the packing of the more stable form 2 [96].
In the case of organic structures, several examples can be found in literature. Chalcones are a class of natural products widely used in medicinal chemistry. For instance, the (E)-3′-dimethylamino-nitrochalcone has demonstrated concomitant polymorphism, easily detectable by the different colors associated to each form [97].
In spite of topologically flexible MOFs as ZIFs and other azolates are prone to manifest polymorphism, the scarce monitoring of in situ structure formation thwart its recognition. An example of concomitant polymorphism has been recently reported by Sánchez and Fernández [98] with two Pt(II) metallosupramolecular polymers. Both products were formed by self-assembly of monomeric units but differed in presenting slipped or pseudoparallel packings. In 2020, a new study from Hanusa and Friščić [99] identified the presence of a disappearing polymorph during the formation of two different Hg(II) imidazolate (Hg(Im)2) phases, synthesizing a new layered structure (sql) with the consequent disappearing of a previously reported interpenetrated dense phase (dia) Hg(Im)2 [100]. Both forms exhibited an orthorhombic crystal system but having evident structural differences driven by an agostic interaction (C-H··Hg) in the sql form. The dia-Hg(Im)2 contained tetrahedral Hg(II) nodes in a Pbca space group and cell parameters of a = 14.5899(3) Å; b = 10.8076(2) Å; c = 9.8200(2) Å while the sql-Hg(Im)2 form presented a tetrahedral see-saw geometry in the space group P21212, with a = 9.4089(4) Å, b = 7.6414(3) Å, c = 5.3625(2) Å. The transient nature of the dia form was tracked by PXRD during the mechanochemical synthesis of sql form, being inaccessible to reach dia form as a final product.
Intergrowth polymorphism was firstly reported by Bond, Boese and Desiraju [101] in 2007 during a study about the doubtful crystalline forms of aspirin and the related difficulties of its structural refinement. It was conceived to refer to the existence of distinct structural domains within a single crystal of a compound. When analyzing the one-dimensionally diffuse diffraction data, using Bürgi [102] method, they noticed some diffuse streaks between the Bragg reflections. Considering the reported results of Bürgi, this would be associated with the presence of a less ordered domain. Careful inspection of such results led them to identify two differently ordered domains in the same crystal of aspirin. They also demonstrated by a nanoindentation study in 2014, a bimodal mechanical response depending on which of the crystal faces were measured [103]. From the metal–organic perspective, there had already been examples reported by Ciani of coordination polymers of cobalt(II) intergrowth supramolecular isomers [104] and copper (II) intergrowth polymorphs [105] due to the presence of conformational non-rigid linkers.
6. Interest of polymorphism in organic and metal–organic structures
Polymorphism has an implicit interest since it represents a special situation for the study of structure-properties relationship with limited number of variables as well as provides essential information to understand and control the crystalline inception. The special case of concomitant polymorphs, is in turn, an even more worthwhile situation. From a unique reaction, one could establish direct relations between structure modifications and properties. They are also benchmark products for computational analysis as well as for verification of structure-prediction softwares. All this beneficial knowledge can be fruitfully employed throughout the industrial and academic landscape.
6.1 Industrial interest
In the industrial field, stability and purity are mandatory equal for organic and metal–organic materials. Properties of organic solids reflected in their processability and storage as well as solubility and dissolution rates are directly related with bioavailability of a drug and hence are of prime interest to the pharmaceutical industry. For instance, an important concern in the manufacturing, storage and transport of energetic materials is that polymorphic modifications alter the energetics and safety risks associated to them. A representative case is 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX), in which higher compact crystal packings lead to the safer form [106]. In addition, polymorphism has relevant commercial impact in the patenting of drugs [107] as in the renowned case of Ranitidine, a drug for the treatment of stomach and intestines ulcers. The subsequent discovery of the polymorphic form 2, having an easier manufacturing procedure, after the patenting of form 1, originated a lengthy court process [108]. Concomitant polymorphs are regularly found in industrial precipitation processes in the pharmaceutical and fine-chemicals sectors as in the case of L-histidine, to which anti-solvent crystallization became an inevitable proceeding [109]. Coordination polymers has special interest for waste water treatment, protective coatings and fluorescent chemosensors [110]. For instance, in MOFs the thermo-mechanical stability is crucial to move towards the industrial segment. Among the most promising applications, those of industrial interest are adsorption, separation, purification and catalysis. They are being exhaustively tested to supersede, by improved performance, the extensively exploited zeolitic molecular sieves, activated carbon and base metal oxides [111]. Furthermore, ZIFs materials have exhibited remarkable efficiency in separation of olefin/paraffin mixtures [112] and emerged as appropriate candidates to adsorb and retain radioactive iodine [113]. All of these applications depend on the structural arrangement of the materials and thus, control over crystal structure formation is imperative.
6.2 Academic interest
The interest of polymorphism in coordination polymers lies on the always present structure-properties relationship. The exact control of their structural arrangement is reflected in the achievement of the desired chemical and physical properties. Despite being known as promising functional materials their modular nature can result in polymorphic forms and thus, hampering their application. This is emphasized in applications demanding a high selectivity as enantiomeric separation, gas storage, sensing, molecular recognition, ionic exchange [114], heterogeneous catalysis [115] or non-linear optics. The rise of MOFs, a remarkable case of ordered coordination polymers with potential voids and permanent porosity was driven by the breakthrough of the archetypal MOF-5 [116]. Their main attribute is the controlled porosity to which the formation of cages allows their controlled use in such applications. Currently research is devoted to study structural transformations in Zr-based MOFs. Also a particular family of MOFs essentially constructed with zinc(II) or cobalt(II) metal ions, the Zeolitic Imidazolate Frameworks (ZIFs), have been explored for their superior thermal and chemical stability but as zeolites, the ZIF family displays rich polymorphism [117]. The Zn(Im)2 itself can accommodate 18 polymorphic forms, being essential towards its application the finding of controlled synthesis as the recently established template-mediated route [118]. As afore mentioned, there has been evidence in the recent cases of Cd(II) coordination polymers or especially in the ZIF material dia-Hg(Im)2 of the undesirable scenario of vanishing polymorphs. In the latter case, the formation of the more stable form has hampered the obtention of the 3D structure being superseded by the new layered sql-Hg(Im)2. These examples demonstrate the dormant resemblance of metal–organic materials with such well known phenomenon in organic compounds. Another important subject are phthalocyanines, being copper phthalocyanine the model compound. They revolutionized color printing offering a better economic remedy but facing polymorphic troubles since their discovery. Subtle alterations of their crystal packing which is based on π···π interactions, acutely influences the absorption properties with the consequent color change from blue to red [119]. Intergrowth polymorphism and intergrowth supramolecular isomerism in coordination polymers has also been promoted by flexible linkers and several examples have been reported hitherto mainly with d10 metal ions [120]. This ability to present different properties available in a single crystal open new possibilities for materials design.
7. Conclusions
The perspective of polymorphism was primarily based on organic substances until the beginning of the twenty-first century. The increasing advances on solid state characterization, especially in situ measurements, benefited the rise of metal–organic structure and its awareness on polymorphic modification. Currently, the ease of tracking structural transformations of dynamic materials has brought to promising insights into the understanding and control of polymorphism.
Acknowledgments
J.P. acknowledges financial support from the CB615921 project, the CB616406 project from “Fundació La Caixa” and the 2017SGR1687 project from the Generalitat de Catalunya. F.S.F. acknowledges the PIF pre-doctoral fellowship from the Universitat Autònoma de Barcelona.
\n',keywords:"polymorphism, pseudopolymorphism, solvates, transition metals, organic linkers, crystal structures",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/76025.pdf",chapterXML:"https://mts.intechopen.com/source/xml/76025.xml",downloadPdfUrl:"/chapter/pdf-download/76025",previewPdfUrl:"/chapter/pdf-preview/76025",totalDownloads:202,totalViews:0,totalCrossrefCites:1,totalDimensionsCites:1,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:44,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"February 8th 2021",dateReviewed:"March 1st 2021",datePrePublished:"April 8th 2021",datePublished:"March 30th 2022",dateFinished:"March 30th 2021",readingETA:"0",abstract:"The chapter presented hereafter, outlines the narrow link between chemistry and crystallography that impelled the identification of polymorphism and provided a priceless grounding to understand structure-properties relationship. It was initially conceived for organic substances but actually embraced by metal–organic products, especially in the study of coordination polymers. All of the technologic advances have provided profound insights on the control of crystal structures formation revealing that any applied stimulus over a substance can undergo a structural transformation. This has led to the implementation of several methodologies in the industrial and academic segment shedding light on the source of hitherto, not well understood results.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/76025",risUrl:"/chapter/ris/76025",book:{id:"10504",slug:"crystallization-and-applications"},signatures:"Francisco Sánchez-Férez and Josefina Pons",authors:[{id:"344057",title:"Dr.",name:"Josefina",middleName:null,surname:"Pons",fullName:"Josefina Pons",slug:"josefina-pons",email:"josefina.pons@uab.es",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Autonomous University of Barcelona",institutionURL:null,country:{name:"Spain"}}},{id:"344064",title:"Mr.",name:"Francisco",middleName:null,surname:"Sánchez-Férez",fullName:"Francisco Sánchez-Férez",slug:"francisco-sanchez-ferez",email:"francisco.sanchez.ferez@uab.cat",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Autonomous University of Barcelona",institutionURL:null,country:{name:"Spain"}}}],sections:[{id:"sec_1",title:"1. Introduction: historical perspective",level:"1"},{id:"sec_2",title:"2. Types and borders: from organic to metal–organic",level:"1"},{id:"sec_3",title:"3. Thermodynamic vs. kinetic factors: formation and transformation of polymorphs",level:"1"},{id:"sec_4",title:"4. Strategies to identify and achieve polymorphs and the influence on their properties",level:"1"},{id:"sec_4_2",title:"4.1 Identification of polymorphs",level:"2"},{id:"sec_5_2",title:"4.2 Screening and isolation of polymorphic forms",level:"2"},{id:"sec_6_2",title:"4.3 Properties",level:"2"},{id:"sec_8",title:"5. The special cases: concomitant, vanishing (or disappearing) and intergrowth polymorphism",level:"1"},{id:"sec_9",title:"6. Interest of polymorphism in organic and metal–organic structures",level:"1"},{id:"sec_9_2",title:"6.1 Industrial interest",level:"2"},{id:"sec_10_2",title:"6.2 Academic interest",level:"2"},{id:"sec_12",title:"7. 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Chemistry Department, Autonomous University of Barcelona, Barcelona, Spain
Chemistry Department, Autonomous University of Barcelona, Barcelona, Spain
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1. Introduction: historical perspective
The intrinsic awareness in structure-properties relationship of solids was firstly introduced on the study of minerals and inorganic compounds and has been preserved over time [1]. Within this frame, the first step on the polymorphism phenomenon was unknowingly given by Klaproth [2] in 1788 identifying three different crystalline phases of calcium carbonate (calcite, vaterite and aragonite). In 1819, Mitscherlich commenced his research on phosphates and arsenates of potassium (KH2PO4 and KH2AsO4) and established their complete morphological similarity, noting that they crystallize in similar forms. His subsequent results with the corresponding potassium salts (NH4H2PO4 and NH4H2AsO4) confirmed that observation and led him to pose that there do exist bodies of dissimilar chemical composition having the same crystalline form. He not only recovered the work of Whollaston with orthorhombic carbonates and sulfates of barium, strontium and lead, who already noticed this phenomenon in 1812 but also, extended to rhombohedral carbonates of calcium, magnesium, iron and manganese, and to sulfates of iron, copper, zinc, magnesium, nickel and cobalt. Curiously, he also evinced the basis of seeding at realizing that having two substances both able to crystallize in various forms, the presence of one during the crystallization of the other will force the crystallization of the latter in the same form. Then, he moved to Stockholm with Berzelius with whom he delved deeply into phosphates and arsenates and forged the concept of isomorphism. Last but not least, he reported two distinct crystallized forms of sulfur in 1826 demonstrating a clear case of an element which could be made to crystallize in two different systems of symmetry at will, by merely changing the crystallization conditions. Therefore, Mitscherlich was identified as the one who took the first step towards the rise of polymorphism [3]. Shortly after, in 1824, the contradictory results garnered by Liebig [4] and Wöhler [5] during their research on silver fulminate and silver cyanate triggered the conflict which led them to be colleagues and to pose the following dilemma: can two compounds with the same composition have different physical properties?. Their results evinced two Ag salts with the same composition but different physical properties, which did not go unnoticed by Wöhler’s master Berzelius, who merged these results with those of Mitscherlich. It is unclear who was the first to conceive the notion of polymorphism but this crucial period of 1820–1832 was mainly drawn by Mitscherlich [6, 7, 8] who shed light on this phenomenon, even though the concept was still vague. It was during these years when Berzelius [9] proposed the concept of isomerism (1831–1832) and it took until 1832 for Wöhler and Liebig [10] to report the first case of polymorphism in an organic compound. The awareness of isomerism set the beginning of structural chemistry, broadening the knowledge and understanding of organic structures.
Since observation was the essential tool to identify polymorphism, this research drastically changed with the accessibility and wide spreading use of the microscope, but it was not until 1839 when Frankenheim [11] introduced the first principles defining polymorphism and a postriori, Mallard [12] set the structural basis of polymorphism in 1876, relating differences in physical properties with different arrangements. One of the most remarkable contribution during this period was the “Rule of steps” or “Law of successive reactions” from Ostwald [13] in 1897. He pointed that during a succession of polymorphic forms, those appeared later are generally more stable. Despite not being considered a rule, it is still valid as a general observation. But the two major queries raised by Buerger and Bloom [14] in 1937 were still unanswered: what causes the formation of different phases of a substance and which factors determine them?.
The narrow link between crystallography and polymorphism was forged by Tamman [15] in 1926 and settled with the first polymorphic X-ray crystal structure determination of an organic compound, resorcinol, published by Robertson and Ubbelohde [16] in 1939. Despite this achievement, the next decades passed without a better understanding of polymorphism, being underrated until 1965 when McCrone [17] conducted a comprehensive study in which he defined a polymorph as: “a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of the molecules of that compound in the solid state” and published a review in 1969 about the importance of such phenomenon in the pharmaceutical outlook [18]. Since the introduction of the term allotrope by Berzelius in 1841, Polymorphism had been taken with allotropy on the same meaning. But, it was not until the 1990s, when Sharma [19] and Reinke [20] set the differences between them: polymorphism occurs in chemical compounds while allotropy occurs in chemical elements. This work was crowned a posteriori by Dunitz’s [21, 22] crystal description contribution.
In the 1970s, the works of Schmidt [23] and Paul and Curtin [24, 25] grounded the flourish of solid-state chemistry and precede the breakthrough of conceiving polymorphism. They served as inspiration to Bernstein and Desiraju, who laid the foundation for recent supramolecular chemistry. In 1978, Bernstein [26] changed the landscape of polymorphism by rationalizing the study of crystal packing forces on molecular conformations of polymorphs and later in 1990, together with Etter [27, 28, 29, 30], applied their graph set descriptors and provide guidelines to understand polymorphic transformations [31]. Bernstein compiled most of this historical results in his book “Polymorphism in Molecular Crystals”, which the authors encourage reading [32]. Likewise, Desiraju achieved substantial progress in this field during his studies of structure-properties relationship of organic solids mainly of pharmaceutical interest, emphasizing and aiming its importance in this industry as reflected in his book “Crystal Engineering: A Textbook” [33]. Both channeled their polymorphism vision in terms of supramolecular chemistry.
During 1990s, computational chemistry went hand in hand, achieving methodologies capable to reproduce experimental results and enabling even crystal structure predictions. The first attainment was obtained by using Williams’ software [34] that met the main handicap hitherto, the identification of lattice energy minimums. Subsequent years, many computational approaches were developed facing with computer-generated structures for prediction, to the extent that in 1999 a collaborative workshop held at the Cambridge Crystallographic Data Centre (CCDC) [35] brought together the benchmark computational groups of this period to provide an objective assessment of the possibilities of crystal structure prediction. The results gathered in this event were clearly summarized a posteriori in a paper published by Lommerse [36]. Further advances on prediction methods accuracy as well as the implementation of Density Functional Theory (DFT) and Machine Learning (ML) can be found in Spark’s review [37].
Despite the basis of polymorphism were already defined at the end of the twentieth century, the increasing advances on X-ray diffraction techniques and crystallization methods afforded the determination and analysis of metal–organic structures, especially coordination polymers. Polymorphism of metal–organic complexes was still unexplored and these new class of materials, from which polymorphic structures grew exponentially, required classification and awareness. This impasse was encouraged by renowned researchers as Sharma [38], Ciani [39], Rogers [40] and Zaworotko [41]. In this regard, the same Zaworotko was who published a review in 2001 emphasizing the difference between polymorphism and supramolecular isomerism and underlined the link between them in organic and metal–organic networks [42].
2. Types and borders: from organic to metal–organic
During the early stages of polymorphism, the lack of crystallographic tools conditioned the understanding and therefore, classification of the different polymorphic forms, but the exponential advances in this field provided perhaps too many concurrent data to bring it together and form a unique mindset. It was not until 1965 when McCrone [17] gathered the knowledge hitherto and set a more excluding definition of polymorphism. The inclusion or not of hydrated forms and solvates have been discussed since the rise of polymorphism, but be that as it may, he ventured to propose their exclusion from polymorphic forms and to avoid the use of pseudopolymorphism to define them. This assertion was underpinned by Bernstein [32] in 2002, even if actually it is a wide spread term, probably because of its acceptance by the pharmaceutical industry [43] from its regulatory and patentability point of view. Since the aim of this chapter is not about pseudopolymorphs we therefore, decided to exclude this term to refer to solvates and hydrates, which can lead to undesirable misunderstandings. In 2012, Desiraju, Karpinski, Thaper and Zaworotko [44] defined cocrystals as solids that are crystalline single-phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. As well as salts that are any of numerous compounds that result from replacement of part or all of the acid hydrogen of an acid by a metal or a radical acting like a metal; an ionic or electrovalent crystalline solid. Instead, solvates have one component, commonly a solvent, which is liquid by itself and hydrates are a particular case of solvates, containing water as solvent. A deeper discussion on pseudopolymorphism can be found in references [45, 46, 47].
Until the beginning of the twenty-first century, the polymorphs’ classification was settled from the perspective of crystal packing forces and introduced conformational and packing polymorphism to sort the examples hitherto. Coordination polymers are infinite repeating coordination entities composed of organic molecules serving as linkers and metal ions as nodes [48]. Their main classification is based on dimensionality which is the number of directions in which the array is extended. Therefore, they can be divided into one-, two- or three-dimensional. The rise of this field befell in 1961 when Bailar [49] firstly introduced the term coordination polymers. Distinction between polymorphs and other forms as solvates, hydrates or cocrystals in organic structures was well defined, but in the case of metal–organic structures, in particular coordination polymers, this classification was not sufficient.
Numerous structures which were not truly polymorphs (solvent molecules were present in the lattice), but neither were solvates, started to rise at the end of the twentieth century. This new domain required the borders to be clarified and established. Yet, these rigid structures were thought to be less disposed to suffer structural variations but some examples were gathered in works of Janiak [50] with Zn(II) poly(pyrazolyl)borates, Ciani [39] with Ag(I) and 4-cyanopyridine, Zaworotko [41, 51] with Co(II) and pyridyl containing linkers, Ripmeester [52] with Cu(II) and a diketone and Rogers [40] with Hg(II) and tetrapyridylporphyrines. Thus, supramolecular isomerism was invoked to merge those different types of structures (mainly coordination polymers) assembled from identical building blocks. In this impasse, Zaworotko [42] strongly contributed to shed light upon this ambiguity in his review of 2001. He defined supramolecular isomerism as “…the existence of more than one type of network superstructure for the same molecular building blocks…” and pointed that polymorphs are a particular case of supramolecular isomers “…polymorphs can therefore be regarded as being supramolecular isomers of one another but the reverse is not necessarily the case”. This assertion should be clear before classifying metal–organic structures.
Henceforth, supramolecular isomerism was divided into structural (regarding the formation of different networks inter alia ladder, brickwall, 3D frame, herringbone, bilayer or Lincoln logs), conformational (relying on the flexibility of the ligands) and a new class named catenane (promoted by interpenetration), being polymorphic forms a certain condition of them. A schematic representation highlighting such division is depicted in Figure 1. At that time, structural isomerism was focused on the particular case of architectural isomers [41], understood as variations of the connectivity of the ligands between two structures, sharing the same composition as a result of ligand conformations [53]. In particular, to those cases in which the accommodation of different solvent guest molecules promoted the change in the spatial disposition of the organic linkers.
Figure 1.
Schematic representation of the structural relationship between the different architectures among organic and metal–organic compounds.
In this direction, Robin and Fromm [48] in 2006 described supramolecular isomerism as the ability of a substance to arrange into one or several network superstructures by different molecular or supramolecular assemblies with the inherent condition that organic linkers and metal ion remain the same and this metal ion retains an equal coordination sphere. They also reported several examples of a new subclass of structural supramolecular isomers named as ring opening. Recently, Zhou [54] has provided the specific term framework isomers to define supramolecular isomerism in MOFs, in which solvent occluded molecules are trivial.
3. Thermodynamic vs. kinetic factors: formation and transformation of polymorphs
A brief summary of fundamental thermodynamics principles is required prior to understand their relevance on polymorphism. Despite ideal systems are not viable, the definition of boundaries within this phenomenon based on simple laws could be achieved with a sufficient accuracy to be useful. It is essential to stress that the result of any structural change will be reflected as a change on the properties of the system. Since energy changes are empirically measurable, they are a pragmatic way to face polymorphism and led these energy differences to be a useful descriptor. The identification of the relative intensities within the different forms of energy displays whether exchanges of energy between two polymorphs will occur. Remarkably, this allows to induce energetic modifications, by an external stimulus, only on a selected form of energy to establish relationships in a linear manner.
The quantity of energy a system exchanges with environs is named enthalphy and is referred to as H. Taking a chemical reaction as the case study, the character of the energetics involved in it, is represented as the enthalpy of reaction, which is the difference in enthalpies between products and reactants. This concept is useful to determine the direction in which energy will flow but such information is not conclusive to establish spontaneity. Hence the introduction of the notion of entropy (S) is essential. It is a way to represent the organization of a system approached as the degree of disorder and it is measured in terms of entropy changes of the system. Using both terms, Gibbs free energy (G) provides further insights into spontaneity at constant temperature and pressure.
To understand the relative stability of the different polymorphs within a given system as well as their transformations, the energy/temperature diagrams (E/T) introduced by Buerger in 1951 [55] are the most valuable approach, being capable to encapsulate much data in a single representation. It is based on the G equation:
G=H−TSE1
As a general representation, the diagram on Figure 2a displays how these terms evolve at increasing temperature. Since the term TS is more significantly affected by temperature than H, its effect on G becomes intense as the temperature of the system raises and thus, G of the system tends to decrease. The energy of a transformation undergone within a polymorphic system, under conditions of constant temperature and pressure, are defined by:
Figure 2.
(a) Progression of the terms G, S, TS and H at increasing temperature. (b) Representation of the evolution of H and G variables in a dimorphic system (polymorphs A and B) at increasing temperature.
ΔG=ΔH−TΔSE2
Within a series of polymorphic forms their crystal lattices are unique per se, so despite their G at a certain temperature could be equal (isoenergetic forms), the values of H and S will be different (Figure 2b). If isoenergetic forms are present, there is a crossing point between the two G value curves in the E/T diagram, named transition point (t.p.), which to be useful is to be placed below the melting point (m.p.). In such a scenario, if the formation of these polymorphs is allowed by kinetic factors, both forms coexist and can be formed as concomitant polymorphs (vide infra in Section 5).
For instance, considering a case study as the one represented in Figure 2b, containing two polymorphic forms (dimorphic) named as A and B, a brief analysis of this E/T diagram can provide some useful data. Below the t.p. (blue region) form A is the most thermodynamically stable as its lower G value states. Within this region, its transformation into form B is related to an increase in H and it is defined as an endothermic transition. At the t.p. both forms have the same G (ΔG = 0), which applied to Eq. (2) is set that ΔH = TΔS, where ΔH = HB-HA and ΔS = SB-SA. All these equations allow to quantify the entropic change of a polymorphic transformation once the enthalpic variation ΔHt,B↔A is experimentally determined (see Section 4.1). Above the t.p. (green region), within this range of temperature and before the change of state at the m.p., form B is the thermodynamically stable and therefore, transformation from A to B is associated with a decrease in H (exothermic process). After defining these borders, one can infer the proper conditions in which the formation of one polymorph is favored instead of the other.
Considering that theoretical thermodynamic relations applied to systems undergoing phase transformation are bounded by experimental data, more empirical concepts were developed to better represent these changes. Consequently, the terms Enantiotropism and Monotropism were defined to meet this requirement. The former refers to those systems presenting a reversible transformation before the m.p. when heated above or cooled below the t.p. Contrarily, Monotropism sets that only one polymorph is the more thermodynamically stable over the entire range of temperatures until the m.p. Both examples are illustrated in Figure 3a and b, respectively.
Figure 3.
E/T diagrams of (a) enantiotropic and (b) monotropic dimorphic systems.
The incorporation of energetics associated with the liquid state into the E/T diagram, enthalpy (Hliq) and free energy (Gliq), ease to parse their behavior and classification. If the crossing points between the Gliq curve and the G curves of both A and B are after the t.p., they are said to be enantiotropes. The absence of crossing points between A and B before their m.p. classify them as monotropes. The terms ΔHf,B and ΔHf,A are the energy that B or A require to change into liquid state, respectively.
Burger and Ramberger [56] in 1979, pioneered in the development of many experimental rules to empirically establish the nature of this relationship between polymorphic forms and their applicability was exemplified with 113 substances [57]. All giving fundamental knowledge to determine the proper conditions to control their formation: Heat-of-transition, Heat-of-fusion, Entropy-of-fusion, Phase transformation reversibility, Enthalpy of sublimation, Heat-capacity, Infrared, Solubility and Density rules. Among them, the most applied are Heat-of-transition and Heat-of-fusion rules. The former being based on using Differential Scanning Calorimetry (DSC) to identify the endothermic or exothermic character of the transition. If this rule cannot be applied, Heat-of-fusion rule, which rely on the determination of the m.p., states that the relation is enantiotropic when the higher melting polymorph has the lower enthalpy of fusion while monotropic systems are defined by the higher melting polymorph having the higher enthalpy of fusion. Detailed explanation on the application of them could be found in Burger publication [57] or in the more recent Brittain’s review [58].
Crystallization is the process related with nucleation and growth of a crystal structure. This process is, in principle, directed by thermodynamic factors that tend to reach the structure with a lower lattice energy. However, the crucial stage is supersaturation which is determined by kinetics, in particular, by the rate of nucleation and thus, the first structure to be formed is the one with preferred nucleation. Therefore, a metastable form can grow despite being unfavored by thermodynamic factors. Subsequently, this form can be converted into a more thermodynamically stable by solution or solid state-mediated phase transformation. This successive phase change was identified and proposed as the Law of States by Ostwald [13].
To avoid common mistakes in ascribing the nature of the nucleation process, Mullin [59] divided it into primary, in which any crystalline matter is directing the process, and secondary, pertaining to the circumstances of nucleation generated in the vicinity of crystals, previously nucleated or intentionally placed, a methodology known as seeding (vide infra in Section 4.2). Furthermore, secondary nucleation can be classified as homogeneous if it is spontaneous or heterogeneous if it is induced by foreign particles.
Solid-state phase transformations are usually promoted by an external stimulus in the form of mechanical work or temperature. They are thought to be related with intrinsic defects, whether coming from the original structure or being caused by mechanical stress, which commence and propagate the formation of the new phase. The most studied transformations are those based on order–disorder changes, mainly promoted by temperature variations. Disordering processes arise from increasing temperature whereas ordering processed are observed at decreasing temperature. An excellent analysis of such phenomena with the most relevant examples were summarized by Dunitz and Bernstein [60].
The reversibility of these changes could not be evident or even accessible since hysteresis plays a crucial role. It is the lagging of the transition behavior respect to the applied stimulus. Therefore, it is possible to need heating or cooling beyond the t.p. to let the phase change occurs and even with the sufficient high degree of hysteresis is conceivable to avoid transformation [61]. Although ideal reversibility is often desired, control of hysteresis [62] also leads to unique properties [63], often advantageous to the application of these materials, only achievable by a precedent transformation. Hysteresis phenomenon is associated to structural fatigue [64, 65, 66], which means the rise of structural changes in the crystalline material as dislocations as well as to a different nucleation with different energy barriers from one to another [67]. Further concerns regarding the basis of this topic can be addressed reading Flanagan’s publication [68].
Overall, since crystallization is a competitive process between minimizing lattice energy (thermodynamic) and reaching supersaturation (kinetic), the achievement of non-minimal energetically stable forms allows to the transformation into lower energetic forms after reaching the activation barrier.
4. Strategies to identify and achieve polymorphs and the influence on their properties
4.1 Identification of polymorphs
The identification of polymorphism had been, in the vast majority of cases, a matter of chance, but this all changed as a result of the efforts of many scientists in the field. The first tool of recognition was visual observation inasmuch as it was the most affordable and accessible technique. Since it is not a strict approach, however, it is often useful to detect anomalies. In particular, observation of crystalline materials through optical microscopy can allow to differentiate between two crystal habits (their characteristic external shape), because this shape is governed by its molecular packing and intermolecular interactions (internal structure). Notwithstanding that more than a century has passed, it is still a routinely used technique, even if optical microscopy is being superseded by Scanning Electron Microscopy (SEM), which allows more accurate surface topology and morphology analysis. The closely related Transmission Electron Microscopy (TEM) was not appropriate for this kind of materials even given its uniqueness. It could collect structural and dynamic data from single crystals in a bulk powder and therefore, have remarkable benefits compared to any other. Unfortunately, the high energy applied to the samples caused strong damages precluding their characterization. Over years, researchers intended to reduce the applied voltage, seeking for this technique to be applicable by minimizing sample damage and improving cameras and detector technologies. This was especially aimed to the study of metal organic frameworks (MOFs), one of the most emerging topics with fundamental need to understand structure-properties relationship. Hence, breakthrough developments in characterization techniques as cryogenic-TEM (cryo-TEM) [69] and High-Resolution TEM (HR-TEM) [70] paved the way to structural features at the nanometric scale as well as recent improvements for in situ measurements inter alia hot stage TEM, liquid cell TEM (LCTEM) [71] or environmental TEM (ETEM) [72] enabled to observe the dynamics of these systems. Advanced 3-dimensional electronic techniques as automated electron diffraction tomography (ADT) [73] and Rotation Electron Diffraction (RED) [74] were able to gather sufficient data for ab initio structure elucidation and thus succeeded where conventional diffraction techniques failed [75].
Despite all these advances, the most valuable technique has been and remains, single-crystal X-ray diffraction (SC-XRD). Only neutron diffraction is tantamount, being capable to collect specific and accurate data of atomic positions, bond distances, and angles [76]. Thus, serving as a complementary technique to SC-XRD. However, one must consider the possibility of temperature driven single-crystal to single-crystal transformations since a growing number of examples have been reported in the literature. Careful inspection of temperature effects on the sample is to be required. The generally used condition in SC-XRD is about 100 K which can undergo the phase transformation. If such events are not assured, one could fail at drawing conclusions of property changes from structural differences.
Although SC-XRD provides complete information about atom positions and structural packing, the growth of suitable crystals for structure determination is sometimes a laborious and very time-consuming task or even not attainable. Often, but nowadays less and less, it is not thought to be part of the endeavors of a chemist. That is why structural studies goes hand in hand with Powder X-Ray diffraction (PXRD), which is in many cases more available and can reflect any structural difference between SC-XRD and the bulk powder. But one must not forget that after ensuring no phase transformation, SC-XRD and neutron diffraction are the unique unambiguous techniques while the rest requires to be combined to successfully identify polymorphism. Recent advances in diffraction methodologies have enabled to improve PXRD characterization. For instance, variable temperature-PXRD and variable temperature-SC-XRD not only ease to determine differences in crystalline materials but also allow to trace phase transformations being subject to temperature changes.
Solid-state spectroscopic techniques are also a complementary tool during the identification of structural differences. Sometimes these changes are not evident but, in many cases, subtle structure modifications are reflected in the spectra. The most marked differences observable by Fourier Transformation Infrared Spectroscopy-Attenuated Total Reflectance (FTIR-ATR) [77] or Raman spectroscopies [78] usually appears in the fingerprint region since it is unique for a substance. In the case of polar molecules, transitions associated with rotation can be measured in absorption or emission by microwave or far infrared spectroscopies [79]. Also solid-state Nuclear Magnetic Resonance (SS-NMR) [80] as well as solid-state Ultraviolet–Visible absorption (SS-UV–Vis) [81] and fluorescence [82] have proven to be fruitful techniques to identify polymorphism and phase transformations. The recording of SS-NMR data can be improved by using Schaefer and Stejskal [83] experiments, in which high power heteronuclear decoupling, cross polarization (CP) and magic-angle spinning (MAS) are combined. Careful attention should be paid during MAS since the required high spinning rates generate mechanical stress and local heating, thus favoring conditions for transformations. Isotopomeric polymorphs [84] have also been identified, albeit in a lesser extent.
Solid-state Electron spin resonance (ESR) also known as Electron Paramagnetic Resonance (EPR) can be used only for materials containing paramagnetic metal ions or structures in which those metal ions have been embedded. Copper(II) but also cobalt(II) are the archetypal metals for this technique and there already exist examples incorporating Cu(II) into the structures of templated materials [85]. More sophisticated variations include variable-temperature magnetic-susceptibility and variable-temperature solid-state EPR measurements. An increasingly common strategy combines them in the study of single-ion magnets (SIMs), a type of single-molecule magnets (SMMs). This EPR analysis is not easily available since it is preferably implemented with a synchrotron radiation source [86]. The magnetic evaluation of SIMs is performed in solid state so the structural differences between polymorphic forms promoted by conformational changes could lead to a dramatic alteration of the magnetic properties [87]. This effect is marked in Clathrochelates, a special class of structurally rigid cage metal complexes [88].
Last but not least, thermoanalytical techniques inter alia hot stage microscopy (also known as thermal microscopy), Thermogravimetric analysis (TGA), Differential Thermal Analysis (DTA) and Differential Scanning Calorimetry (DSC), are widely used to characterize both polymorphism as well as phase transformation phenomena. They are usually combined to maximize the efficiency of the data collection as TG-DTA or DSC-TGA, among others.
During hot stage microscopy, the sample is subjected to heating and cooling processes under polarized light. It provides m.p. data as well as, if it occurs, the reversible or irreversible character of the transition. TGA method is used to determine the thermal stability of the products and as previously mentioned, it is commonly combined with DTA. By the use of a thermobalance, it is capable to measure weight losses during temperature changes. It is especially useful to determine desolvation temperatures and thermal stability ranges but it is less accurate to quantify these transitions. The most appropriate technique to track phase transformations with quantitative data is DSC.
DSC is routinely used to measure the difference in the amount of heat required to increase the temperature of the sample respect to a reference. It is divided into power compensation DSC and heat-flux DSC methods. The quantification of the ΔHt,B↔A enables to identify its exo- or endothermic character, as well as the determination of reversible or not transitions provides essential data about the enantiotropic or monotropic behavior. DSC has not been deeply exploited yet for metal–organic materials but this practice is inevitably set to change. In particular, it is increasingly used in the study of breathing metal–organic frameworks (MOFs) [89] or solid-state phase transformations in Zeolitic imidazolate frameworks (ZIFs) [90].
Evidence of polymorphism can also be confirmed by nanoindentation or by optical properties as refractive index (n) or the identification of an interference figure caused by birefringence, which is the presence of different n and mainly depends on crystallographic orientations [91]. Once polymorphism has been identified and characterized, the proper conditions to isolate or to only reach one polymorphic form are to be established, avoiding the presence of mixtures and undesired products.
4.2 Screening and isolation of polymorphic forms
There are significant factors determining the formation of polymorphs inter alia molecular structure, chemical composition, energetic differences and experimental conditions (solvent, additives, pH, temperature and pressure). What should be clear is that the different polymorphic forms of a given structure can be selectively reach either by crystallization from the melt or solution, or by solid-state transformation. Crystallization approach has been the most widely studied heretofore but awareness of hitherto ignored solid-state transformations has led to value their tantamount importance. The solution-mediated approach is based on the proper adjustment of the crystallization process and involves much more control of the polymorphs forming conditions. Instead, the advances in solid-state characterization techniques have triggered a significant increase of polymorphism studies allowing traceability of such conversions. This is especially the case of coordination polymers and MOFs, optimal materials for polymorphism study because of their flexibility and capability to accommodate structural modifications without the breaking of bonds.
The first step in polymorphs screening is to determine the phase space of a substance and the boundaries of stability for the different forms as well as identifying, if it is the case, interconversion. Defining the most stable phase is recommended since, unless modulating external factors dictate otherwise, that form would be the result. The occurrence of polymorphs and their transformations are confined to what is known as occurrence domains that encompass all the conditions in which the targeted crystal forms originate. Early studies carried out by Sato [92] on stearic acid delved deeply into the dependence of temperature and supersaturation on solvent polarity. Is in those regions with domain overlap where polymorphic transformations can occur, bearing in mind that the domain is not unique for one crystallographic form.
The many attempts to control the formation of a desired form have supplied us of a vast number of methods to selectively achieve it through crystallization or solid-state phase transformation. Most of the old and recent methods have been compiled in Figure 4. Further details about fundamental crystallization methods are found in Hulliger’s review [93].
Figure 4.
Classification of the different methods to achieve polymorphic forms by crystallization or transformation.
Over all of the difficulties of achieving isolated polymorphs, to identify the conditions to reach isolated forms is an essential task. When dealing with a polymorphic mixture scenario, the initial way of facing it, is the use of common crystallization methods as those mentioned before. However, crystallization of less stable forms is often intricated and therefore, it requires the design of more robust strategies inter alia high-pressure crystallization, spray-drying, crystallization from a melt or crystallization from a quenched amorphous phase. They give sometimes satisfactory results, but their major drawback is the lack of control in the formation of a single product. Hence, the use of additives and substrates was implemented as template though a limited triumph, considering that only thermodynamic aspects are contemplated and kinetic factors have a determinant role in nucleation. Subsequent methods as application of external fields, surface templating, selective nucleation by supersaturation control and nucleation temperature or seeding experiments emerged, but there is still a need for their improvement.
It is nevertheless important to note again that MOF materials are themselves appropriate candidates for filing structural modifications, since the predefined preferences of the organic linkers combined with those of the metal ions result in a restricted range of potential structures. This is strongly reflected in the common formation of isostructural products although they combine different linkers and metal ions. Such a controllable way of structure design is therefore adequate to identify new strategies for the isolation of different crystalline phases. Currently, throughout all the advances in MOFs design, polymorphism and isomerism awareness has driven the seeking of selective crystalline phase formation methods. For instance, in the case of mixed-metal MOFs, in which the addition of more than one metal ion disrupts the predefined structural formation, the selective phase formation has been achieved by the incorporation of guiding organic linkers or even metal ions to template the structural assembly. There was already consciousness of polymorphism and isomorphism in chromium(III) terephthalate MOFs [94], but the strategies to reach them were lacking. In 2018, Bureekaew [95] controlled the formation of this family of MOFs by using iron(III) metal-cationic competition, which served as modulator during crystallization. Likewise, Užarevic [85] demonstrated a rapid and selective way of controlling polymorphism in this family of MOFs by a mechanochemical approach using additives.
4.3 Properties
Become aware of a difference in the properties of a unique sample or two sample which in principle, are to be identical is the commencement of most polymorphism studies. One important aspect to be considered, sometimes careless, is the manipulation of the samples before the measurements. It is widely reported that a routinely sample treatment as grinding can undergone phase transformation. Even this subtle stimulus can provoke changes in the sample with the consequent incongruent results, thus hampering their correct analysis. These changes produced by polymorphic modifications could range from slight differences to dramatic alterations of the target properties and those which have raised more interest are listed in Figure 5.
Figure 5.
Properties likely to be altered by polymorphic modifications.
5. The special cases: concomitant, vanishing (or disappearing) and intergrowth polymorphism
The terms Vanishing or disappearing polymorphs were renowned during the second half of the twentieth century by referring to the evolving nature of some crystal forms over time that caused their unrepeatability. In the course of the subsequent years, researchers realized that every crystal form can be repeated being the finding of the proper conditions (control over nucleation and crystal growth) the main trouble.
Within the polymorphism landscape, the presence of mixtures of crystalline phases has brought a profound attention whereby, many efforts were devoted to the understanding of such circumstances. Reproducibility and purity have always been a requisite for chemists, so such demonstration of lack of control led them to seek to comprehend and identify the source of these phenomena. These two closely related special cases, named as Concomitant and Vanishing polymorphs, refers to a condition describing all the forms involved. Concomitant polymorphs are those simultaneously formed at the exactly same conditions. This assertion is not trivial since many factors contribute to the crystallization process. The case of vanishing or disappearing polymorphs describes the formation of a metastable phase which undergoes transformation into a more thermodynamically stable one. This phenomenon is quite thorny since as mentioned, reproducibility of the results is often intricated. Such conversions can be found by redissolution of the former crystal or in solid-state. In the solution-mediated process, the formation and disappearing of a metastable product can be quenched by seeding. A crucial statement is to be noted, once seeds of one polymorph are formed, the other form will no longer be formed. By using this criterion, seeding crystallites of the desired polymorph will lead to the growth of its crystals, even though it is a metastable form [60]. This method allows to avoid both undesirable cases, concomitancy and vanishing, if phase-pure materials are to be achieved. Vanishing by solid-state transformations is even less evident, indeed, any slight appliance of an external stimuli can promote this phase change and routinely sample treatments required for many characterization techniques as grinding, milling or pressure and temperature changes could be sufficient to trigger it. Both phenomena have probably been less reported than occurs and just a curious point is that the first recognized example of polymorphism in an organic substance described by Wöhler [10] the dimorphism of benzamide, that was also the first precedent of concomitancy.
The critical point describing concomitant and vanishing polymorphs is based on the same kinetic/thermodynamic factors, better understandable by the mentioned E/T plots and promoted by the kinetic govern. In fact, concomitancy is dependent on where from the diagram the polymorphs are growing. Having this data, one can also design a strategy to favor the nucleation of one polymorphic form instead of the other.
Identification of concomitant polymorphs is as always, initially assessed by visual recognition. Thus far, careful inspection during hot-stage microscopy has been the most reliable method. Differences in crystal habit and variable melting point suggesting crystalline mixtures could provide a clue as to trace concomitancy. Also broadening signals in solid-state NMR or FTIR-ATR may be a symptom of this.
Reported cases of vanishing polymorphs in metal–organic compounds are in large part still unfathomed. The phenomenon of concomitant polymorphs is equally meager being only few examples reported hitherto. Oliver [96] in 2012 reported the special case of two Cd(II) coordination polymers concomitantly formed from which the less stable form was subsequently identified as a disappearing polymorph. Both products crystallize in the monoclinic crystal system but the stable form (2) exhibited a C2/c space group and bigger unit cell parameters than the vanishing form (1), which displayed a P2/c space group. Their main dissimilarity was the slightly different orientation of the dipicolinate ligands (Figure 6), which improved the inter-chain π···π interactions in the structure of the stable form and provoked a different packing.
Figure 6.
(a) Overlapping representation of the two Cd(II) polymeric chains in the two polymorphs. Different disposition of dipicolinate ligands: front chain (1) and back chain in dark (2). (b) c axis view of the packing of the less stable form 1 and (c) a axis view of the packing of the more stable form 2 [96].
In the case of organic structures, several examples can be found in literature. Chalcones are a class of natural products widely used in medicinal chemistry. For instance, the (E)-3′-dimethylamino-nitrochalcone has demonstrated concomitant polymorphism, easily detectable by the different colors associated to each form [97].
In spite of topologically flexible MOFs as ZIFs and other azolates are prone to manifest polymorphism, the scarce monitoring of in situ structure formation thwart its recognition. An example of concomitant polymorphism has been recently reported by Sánchez and Fernández [98] with two Pt(II) metallosupramolecular polymers. Both products were formed by self-assembly of monomeric units but differed in presenting slipped or pseudoparallel packings. In 2020, a new study from Hanusa and Friščić [99] identified the presence of a disappearing polymorph during the formation of two different Hg(II) imidazolate (Hg(Im)2) phases, synthesizing a new layered structure (sql) with the consequent disappearing of a previously reported interpenetrated dense phase (dia) Hg(Im)2 [100]. Both forms exhibited an orthorhombic crystal system but having evident structural differences driven by an agostic interaction (C-H··Hg) in the sql form. The dia-Hg(Im)2 contained tetrahedral Hg(II) nodes in a Pbca space group and cell parameters of a = 14.5899(3) Å; b = 10.8076(2) Å; c = 9.8200(2) Å while the sql-Hg(Im)2 form presented a tetrahedral see-saw geometry in the space group P21212, with a = 9.4089(4) Å, b = 7.6414(3) Å, c = 5.3625(2) Å. The transient nature of the dia form was tracked by PXRD during the mechanochemical synthesis of sql form, being inaccessible to reach dia form as a final product.
Intergrowth polymorphism was firstly reported by Bond, Boese and Desiraju [101] in 2007 during a study about the doubtful crystalline forms of aspirin and the related difficulties of its structural refinement. It was conceived to refer to the existence of distinct structural domains within a single crystal of a compound. When analyzing the one-dimensionally diffuse diffraction data, using Bürgi [102] method, they noticed some diffuse streaks between the Bragg reflections. Considering the reported results of Bürgi, this would be associated with the presence of a less ordered domain. Careful inspection of such results led them to identify two differently ordered domains in the same crystal of aspirin. They also demonstrated by a nanoindentation study in 2014, a bimodal mechanical response depending on which of the crystal faces were measured [103]. From the metal–organic perspective, there had already been examples reported by Ciani of coordination polymers of cobalt(II) intergrowth supramolecular isomers [104] and copper (II) intergrowth polymorphs [105] due to the presence of conformational non-rigid linkers.
6. Interest of polymorphism in organic and metal–organic structures
Polymorphism has an implicit interest since it represents a special situation for the study of structure-properties relationship with limited number of variables as well as provides essential information to understand and control the crystalline inception. The special case of concomitant polymorphs, is in turn, an even more worthwhile situation. From a unique reaction, one could establish direct relations between structure modifications and properties. They are also benchmark products for computational analysis as well as for verification of structure-prediction softwares. All this beneficial knowledge can be fruitfully employed throughout the industrial and academic landscape.
6.1 Industrial interest
In the industrial field, stability and purity are mandatory equal for organic and metal–organic materials. Properties of organic solids reflected in their processability and storage as well as solubility and dissolution rates are directly related with bioavailability of a drug and hence are of prime interest to the pharmaceutical industry. For instance, an important concern in the manufacturing, storage and transport of energetic materials is that polymorphic modifications alter the energetics and safety risks associated to them. A representative case is 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX), in which higher compact crystal packings lead to the safer form [106]. In addition, polymorphism has relevant commercial impact in the patenting of drugs [107] as in the renowned case of Ranitidine, a drug for the treatment of stomach and intestines ulcers. The subsequent discovery of the polymorphic form 2, having an easier manufacturing procedure, after the patenting of form 1, originated a lengthy court process [108]. Concomitant polymorphs are regularly found in industrial precipitation processes in the pharmaceutical and fine-chemicals sectors as in the case of L-histidine, to which anti-solvent crystallization became an inevitable proceeding [109]. Coordination polymers has special interest for waste water treatment, protective coatings and fluorescent chemosensors [110]. For instance, in MOFs the thermo-mechanical stability is crucial to move towards the industrial segment. Among the most promising applications, those of industrial interest are adsorption, separation, purification and catalysis. They are being exhaustively tested to supersede, by improved performance, the extensively exploited zeolitic molecular sieves, activated carbon and base metal oxides [111]. Furthermore, ZIFs materials have exhibited remarkable efficiency in separation of olefin/paraffin mixtures [112] and emerged as appropriate candidates to adsorb and retain radioactive iodine [113]. All of these applications depend on the structural arrangement of the materials and thus, control over crystal structure formation is imperative.
6.2 Academic interest
The interest of polymorphism in coordination polymers lies on the always present structure-properties relationship. The exact control of their structural arrangement is reflected in the achievement of the desired chemical and physical properties. Despite being known as promising functional materials their modular nature can result in polymorphic forms and thus, hampering their application. This is emphasized in applications demanding a high selectivity as enantiomeric separation, gas storage, sensing, molecular recognition, ionic exchange [114], heterogeneous catalysis [115] or non-linear optics. The rise of MOFs, a remarkable case of ordered coordination polymers with potential voids and permanent porosity was driven by the breakthrough of the archetypal MOF-5 [116]. Their main attribute is the controlled porosity to which the formation of cages allows their controlled use in such applications. Currently research is devoted to study structural transformations in Zr-based MOFs. Also a particular family of MOFs essentially constructed with zinc(II) or cobalt(II) metal ions, the Zeolitic Imidazolate Frameworks (ZIFs), have been explored for their superior thermal and chemical stability but as zeolites, the ZIF family displays rich polymorphism [117]. The Zn(Im)2 itself can accommodate 18 polymorphic forms, being essential towards its application the finding of controlled synthesis as the recently established template-mediated route [118]. As afore mentioned, there has been evidence in the recent cases of Cd(II) coordination polymers or especially in the ZIF material dia-Hg(Im)2 of the undesirable scenario of vanishing polymorphs. In the latter case, the formation of the more stable form has hampered the obtention of the 3D structure being superseded by the new layered sql-Hg(Im)2. These examples demonstrate the dormant resemblance of metal–organic materials with such well known phenomenon in organic compounds. Another important subject are phthalocyanines, being copper phthalocyanine the model compound. They revolutionized color printing offering a better economic remedy but facing polymorphic troubles since their discovery. Subtle alterations of their crystal packing which is based on π···π interactions, acutely influences the absorption properties with the consequent color change from blue to red [119]. Intergrowth polymorphism and intergrowth supramolecular isomerism in coordination polymers has also been promoted by flexible linkers and several examples have been reported hitherto mainly with d10 metal ions [120]. This ability to present different properties available in a single crystal open new possibilities for materials design.
7. Conclusions
The perspective of polymorphism was primarily based on organic substances until the beginning of the twenty-first century. The increasing advances on solid state characterization, especially in situ measurements, benefited the rise of metal–organic structure and its awareness on polymorphic modification. Currently, the ease of tracking structural transformations of dynamic materials has brought to promising insights into the understanding and control of polymorphism.
Acknowledgments
J.P. acknowledges financial support from the CB615921 project, the CB616406 project from “Fundació La Caixa” and the 2017SGR1687 project from the Generalitat de Catalunya. F.S.F. acknowledges the PIF pre-doctoral fellowship from the Universitat Autònoma de Barcelona.
\n',keywords:"polymorphism, pseudopolymorphism, solvates, transition metals, organic linkers, crystal structures",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/76025.pdf",chapterXML:"https://mts.intechopen.com/source/xml/76025.xml",downloadPdfUrl:"/chapter/pdf-download/76025",previewPdfUrl:"/chapter/pdf-preview/76025",totalDownloads:202,totalViews:0,totalCrossrefCites:1,dateSubmitted:"February 8th 2021",dateReviewed:"March 1st 2021",datePrePublished:"April 8th 2021",datePublished:"March 30th 2022",dateFinished:"March 30th 2021",readingETA:"0",abstract:"The chapter presented hereafter, outlines the narrow link between chemistry and crystallography that impelled the identification of polymorphism and provided a priceless grounding to understand structure-properties relationship. It was initially conceived for organic substances but actually embraced by metal–organic products, especially in the study of coordination polymers. All of the technologic advances have provided profound insights on the control of crystal structures formation revealing that any applied stimulus over a substance can undergo a structural transformation. This has led to the implementation of several methodologies in the industrial and academic segment shedding light on the source of hitherto, not well understood results.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/76025",risUrl:"/chapter/ris/76025",signatures:"Francisco Sánchez-Férez and Josefina Pons",book:{id:"10504",type:"book",title:"Crystallization and Applications",subtitle:null,fullTitle:"Crystallization and Applications",slug:"crystallization-and-applications",publishedDate:"March 30th 2022",bookSignature:"Youssef Ben Smida and Riadh Marzouki",coverURL:"https://cdn.intechopen.com/books/images_new/10504.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83969-317-5",printIsbn:"978-1-83969-316-8",pdfIsbn:"978-1-83969-318-2",isAvailableForWebshopOrdering:!0,editors:[{id:"311698",title:"Dr.",name:"Youssef",middleName:null,surname:"Ben Smida",slug:"youssef-ben-smida",fullName:"Youssef Ben Smida"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"344057",title:"Dr.",name:"Josefina",middleName:null,surname:"Pons",fullName:"Josefina Pons",slug:"josefina-pons",email:"josefina.pons@uab.es",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Autonomous University of Barcelona",institutionURL:null,country:{name:"Spain"}}},{id:"344064",title:"Mr.",name:"Francisco",middleName:null,surname:"Sánchez-Férez",fullName:"Francisco Sánchez-Férez",slug:"francisco-sanchez-ferez",email:"francisco.sanchez.ferez@uab.cat",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Autonomous University of Barcelona",institutionURL:null,country:{name:"Spain"}}}],sections:[{id:"sec_1",title:"1. Introduction: historical perspective",level:"1"},{id:"sec_2",title:"2. Types and borders: from organic to metal–organic",level:"1"},{id:"sec_3",title:"3. Thermodynamic vs. kinetic factors: formation and transformation of polymorphs",level:"1"},{id:"sec_4",title:"4. Strategies to identify and achieve polymorphs and the influence on their properties",level:"1"},{id:"sec_4_2",title:"4.1 Identification of polymorphs",level:"2"},{id:"sec_5_2",title:"4.2 Screening and isolation of polymorphic forms",level:"2"},{id:"sec_6_2",title:"4.3 Properties",level:"2"},{id:"sec_8",title:"5. The special cases: concomitant, vanishing (or disappearing) and intergrowth polymorphism",level:"1"},{id:"sec_9",title:"6. Interest of polymorphism in organic and metal–organic structures",level:"1"},{id:"sec_9_2",title:"6.1 Industrial interest",level:"2"},{id:"sec_10_2",title:"6.2 Academic interest",level:"2"},{id:"sec_12",title:"7. 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Nature. 1999;402:276-9.'},{id:"B117",body:'Widmer RN, Lampronti GI, Chibani S, Wilson CW, Anzellini S, Farsang S, et al. Rich Polymorphism of a Metal-Organic Framework in Pressure-Temperature Space. J Am Chem Soc. 2019;141:9330-7.'},{id:"B118",body:'Tu M, Kravchenko DE, Xia B, Rubio-Giménez V, Wauteraerts N, Verbeke R, et al. Template-mediated control over polymorphism in the vapor-assisted formation of zeolitic imidazolate framework powders and films. Angew Chemie Int Ed. 2021;60:1-7.'},{id:"B119",body:'Erk, Peter; Hengelsberg H.Applications of Phthalocyanines. In: The Porphyrin Handbook. Kadish KM, Smith KM, Guilard R, editors. San Diego, California, USA: Academic Press; 2003. p. 118-22.'},{id:"B120",body:'Caradoc-Daviesa PL, Hanto LR, Henderson W. Coordination polymers and isomerism; a study using silver(I) and a π-stacked ligand. J Chem Soc Dalt Trans. 2001;2749-55.'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Francisco Sánchez-Férez",address:null,affiliation:'
Chemistry Department, Autonomous University of Barcelona, Barcelona, Spain
Chemistry Department, Autonomous University of Barcelona, Barcelona, Spain
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Synthetic RNA and DNA molecules allow scalable, rapid, and cell-free production of vaccines in response to an emerging disease such as the current COVID-19 pandemic. The development process begins with laboratory transcription of sequences encoding antigens, which are then formulated for delivery. The various potent of RNA over live and inactivated viruses are proven by advances in delivery approaches. These vaccines contain no infectious elements nor the risk of stable integration with the host cell genome compared to conventional vaccines. Conventional mRNA-based vaccines transfer genes of interest (GOI) of attenuated mRNA viruses to individual host cells. Synthetic mRNA in liposomes forms a modern, refined sample, resulting in a safer version of live attenuated RNA viruses. Self-amplifying RNA (saRNA) is a replicating version of mRNA-based vaccines that encode both (GOI) and viral replication machinery. saRNA is required at lower doses than conventional mRNA, which may improve immunization. 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These Terms and Conditions outline the rules and regulations pertaining to the use of IntechOpen’s website www.intechopen.com and all the subdomains owned by IntechOpen located at 5 Princes Gate Court, London, SW7 2QJ, United Kingdom.
',metaTitle:"Terms and Conditions",metaDescription:"These terms and conditions outline the rules and regulations for the use of IntechOpen Website at https://intechopen.com and all its subdomains owned by Intech Limited located at 7th floor, 10 Lower Thames Street, London, EC3R 6AF, UK.",metaKeywords:null,canonicalURL:"/page/terms-and-conditions",contentRaw:'[{"type":"htmlEditorComponent","content":"
1. Terms
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By accessing the website at www.intechopen.com you are agreeing to be bound by these Terms of Service, all applicable laws and regulations, and agree that you are responsible for compliance with any applicable local laws. Use and/or access to this site is based on full agreement and compliance of these Terms. All materials contained on this website are protected by applicable copyright and trademark laws.
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The following terminology applies to these Terms and Conditions, Privacy Statement, Disclaimer Notice, and any or all Agreements:
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“Client”, “Customer”, “You” and “Your” refers to you, the person accessing this website and accepting the Company’s Terms and Conditions;
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“The Company”, “Ourselves”, “We”, “Our” and “Us”, refers to our Company, IntechOpen;
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“Party”, “Parties”, or “Us”, refers to both the Client and ourselves, or either the Client or ourselves.
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All Terms refer to the offer, acceptance, and consideration of payment necessary to provide assistance to the Client in the most appropriate manner, whether by formal meetings of a fixed duration, or by any other agreed means, for the express purpose of meeting the Client’s needs in respect of provision of the Company’s stated services/products, and in accordance with, and subject to, the prevailing laws of the United Kingdom.
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Any use of the above terminology, or other words in the singular, plural, capitalization and/or he/she or they, are taken as interchangeable.
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2. License
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Unless otherwise stated, IntechOpen and/or its licensors own the intellectual property rights for all materials on www.intechopen.com. All intellectual property rights are reserved. You may view, download, share, link and print pages from www.intechopen.com for your own personal use, subject to the restrictions set out in these Terms and Conditions.
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3. Cookies
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We employ the use of cookies. By using the IntechOpen website you consent to the use of cookies in accordance with IntechOpen’s Privacy Policy. Most modern day interactive websites use cookies to enable the retrieval of user details for each visit. On our site, cookies are predominantly used to enable functionality and ease of use for those visiting the site.
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In no circumstances shall IntechOpen or its suppliers be liable for any damages (including, without limitation, damages for loss of data or profit, or due to business interruption) arising out of the use, or inability to use, the materials on IntechOpen's websites, even if IntechOpen or an IntechOpen authorized representative has been notified orally or in writing of the possibility of such damage. Some jurisdictions do not allow limitations on implied warranties, or limitations of liability for consequential or incidental damages; consequently, these limitations may not apply to you.
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5. Accuracy of Materials
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Intechopen.com website content and services are provided on an "AS IS" and an "AS AVAILABLE" basis. Material appearing on www.intechopen.com could include minor technical, typographical, or photographic errors. IntechOpen may make changes to any material contained on its website at any time without notice.
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6. Links
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IntechOpen has no formal affiliation to any external sites that link to www.intechopen.com, unless otherwise specifically stated. As such, it is not responsible for content that appears on any such sites. The inclusion of any link to IntechOpen does not imply endorsement by IntechOpen. Use of any such linked website is done solely at the user's own discretion.
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We reserve the right of ownership over our entire website www.intechopen.com, and all contents. By using our services, you agree to remove all links to our website immediately upon request. We also reserve the right to amend these Terms and Conditions and our linking policy at any time. By continuing to link to our website, you agree to be bound to, and abide by, these linking Terms and Conditions.
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If you find any link on our website, or any linked website, objectionable for any reason, please Contact Us. We will consider all requests to remove links but will have no obligation to do so.
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7. Frames
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Without prior approval and express written permission, you may not create frames around our web pages or use other techniques that alter in any way the visual presentation or appearance of our website.
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8. Modifications
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IntechOpen may revise its Terms of Service for its website at any time without notice. By using this website, you are agreeing to be bound by the current version of all Terms at the time of use.
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9. Governing Law
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These Terms and Conditions are governed by and construed in accordance with the laws of the United Kingdom and you irrevocably submit to the exclusive jurisdiction of the courts in London, United Kingdom.
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Croatian version of Terms and Conditions available here
By accessing the website at www.intechopen.com you are agreeing to be bound by these Terms of Service, all applicable laws and regulations, and agree that you are responsible for compliance with any applicable local laws. Use and/or access to this site is based on full agreement and compliance of these Terms. All materials contained on this website are protected by applicable copyright and trademark laws.
\n\n
The following terminology applies to these Terms and Conditions, Privacy Statement, Disclaimer Notice, and any or all Agreements:
\n\n
“Client”, “Customer”, “You” and “Your” refers to you, the person accessing this website and accepting the Company’s Terms and Conditions;
\n\n
“The Company”, “Ourselves”, “We”, “Our” and “Us”, refers to our Company, IntechOpen;
\n\n
“Party”, “Parties”, or “Us”, refers to both the Client and ourselves, or either the Client or ourselves.
\n\n
All Terms refer to the offer, acceptance, and consideration of payment necessary to provide assistance to the Client in the most appropriate manner, whether by formal meetings of a fixed duration, or by any other agreed means, for the express purpose of meeting the Client’s needs in respect of provision of the Company’s stated services/products, and in accordance with, and subject to, the prevailing laws of the United Kingdom.
\n\n
Any use of the above terminology, or other words in the singular, plural, capitalization and/or he/she or they, are taken as interchangeable.
\n\n
2. License
\n\n
Unless otherwise stated, IntechOpen and/or its licensors own the intellectual property rights for all materials on www.intechopen.com. All intellectual property rights are reserved. You may view, download, share, link and print pages from www.intechopen.com for your own personal use, subject to the restrictions set out in these Terms and Conditions.
\n\n
3. Cookies
\n\n
We employ the use of cookies. By using the IntechOpen website you consent to the use of cookies in accordance with IntechOpen’s Privacy Policy. Most modern day interactive websites use cookies to enable the retrieval of user details for each visit. On our site, cookies are predominantly used to enable functionality and ease of use for those visiting the site.
\n\n
4. Limitations
\n\n
In no circumstances shall IntechOpen or its suppliers be liable for any damages (including, without limitation, damages for loss of data or profit, or due to business interruption) arising out of the use, or inability to use, the materials on IntechOpen's websites, even if IntechOpen or an IntechOpen authorized representative has been notified orally or in writing of the possibility of such damage. Some jurisdictions do not allow limitations on implied warranties, or limitations of liability for consequential or incidental damages; consequently, these limitations may not apply to you.
\n\n
5. Accuracy of Materials
\n\n
Intechopen.com website content and services are provided on an "AS IS" and an "AS AVAILABLE" basis. Material appearing on www.intechopen.com could include minor technical, typographical, or photographic errors. IntechOpen may make changes to any material contained on its website at any time without notice.
\n\n
6. Links
\n\n
IntechOpen has no formal affiliation to any external sites that link to www.intechopen.com, unless otherwise specifically stated. As such, it is not responsible for content that appears on any such sites. The inclusion of any link to IntechOpen does not imply endorsement by IntechOpen. Use of any such linked website is done solely at the user's own discretion.
\n\n
We reserve the right of ownership over our entire website www.intechopen.com, and all contents. By using our services, you agree to remove all links to our website immediately upon request. We also reserve the right to amend these Terms and Conditions and our linking policy at any time. By continuing to link to our website, you agree to be bound to, and abide by, these linking Terms and Conditions.
\n\n
If you find any link on our website, or any linked website, objectionable for any reason, please Contact Us. We will consider all requests to remove links but will have no obligation to do so.
\n\n
7. Frames
\n\n
Without prior approval and express written permission, you may not create frames around our web pages or use other techniques that alter in any way the visual presentation or appearance of our website.
\n\n
8. Modifications
\n\n
IntechOpen may revise its Terms of Service for its website at any time without notice. By using this website, you are agreeing to be bound by the current version of all Terms at the time of use.
\n\n
9. Governing Law
\n\n
These Terms and Conditions are governed by and construed in accordance with the laws of the United Kingdom and you irrevocably submit to the exclusive jurisdiction of the courts in London, United Kingdom.
\n\n
Croatian version of Terms and Conditions available here
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Shohel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"974",title:"Signal Processing",slug:"applied-mathematics-signal-processing",parent:{id:"163",title:"Applied Mathematics",slug:"applied-mathematics"},numberOfBooks:2,numberOfSeries:0,numberOfAuthorsAndEditors:68,numberOfWosCitations:36,numberOfCrossrefCitations:33,numberOfDimensionsCitations:62,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicId:"974",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editedByType:"Edited by",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5411",title:"Fourier Transforms",subtitle:"High-tech Application and Current Trends",isOpenForSubmission:!1,hash:"5c45d1a91daef66093a42a82448a70f0",slug:"fourier-transforms-high-tech-application-and-current-trends",bookSignature:"Goran S. 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The hydration processes of biopolymers have been extensively studied in the past 20 years with reference to a considerable variety of models and concepts. In all recent works, a distinction is made between intracellular water that maintains the ordinary liquid state (bulk water) and water ordered in extended hydrogen‐bonded lattices at the surface and structured in the internal grooves of macromolecules (hydration water) in dependence on the chemical properties of the macromolecule surface. FTIR spectroscopy has been implemented in this field both for the sensitivity in the conformational analysis of biological macromolecules and the reliability in the investigation of the water network. A perturbation technique such as dehydration‐rehydration treatment modifies the macromolecule structure and water distribution. It was applied to two structurally different proteins: lysozyme, a globular (α + β) protein and collagen, a fibrous protein characterized by the triple helix structure. Submitted to the treatment both of them display irreversible conformational changes.",book:{id:"5411",slug:"fourier-transforms-high-tech-application-and-current-trends",title:"Fourier Transforms",fullTitle:"Fourier Transforms - High-tech Application and Current Trends"},signatures:"Maria Grazia Bridelli",authors:[{id:"108760",title:"Dr.",name:"Maria Grazia",middleName:null,surname:"Bridelli",slug:"maria-grazia-bridelli",fullName:"Maria Grazia Bridelli"}]},{id:"74096",doi:"10.5772/intechopen.94521",title:"Time Frequency Analysis of Wavelet and Fourier Transform",slug:"time-frequency-analysis-of-wavelet-and-fourier-transform",totalDownloads:1162,totalCrossrefCites:6,totalDimensionsCites:8,abstract:"Signal processing has long been dominated by the Fourier transform. However, there is an alternate transform that has gained popularity recently and that is the wavelet transform. The wavelet transform has a long history starting in 1910 when Alfred Haar created it as an alternative to the Fourier transform. In 1940 Norman Ricker created the first continuous wavelet and proposed the term wavelet. Work in the field has proceeded in fits and starts across many different disciplines, until the 1990’s when the discrete wavelet transform was developed by Ingrid Daubechies. While the Fourier transform creates a representation of the signal in the frequency domain, the wavelet transform creates a representation of the signal in both the time and frequency domain, thereby allowing efficient access of localized information about the signal.",book:{id:"10065",slug:"wavelet-theory",title:"Wavelet Theory",fullTitle:"Wavelet Theory"},signatures:"Karlton Wirsing",authors:[{id:"325178",title:"Dr.",name:"Karlton",middleName:null,surname:"Wirsing",slug:"karlton-wirsing",fullName:"Karlton Wirsing"}]},{id:"52810",doi:"10.5772/65776",title:"Study of Green Nanoparticles and Biocomplexes Based on Exopolysaccharide by Modern Fourier Transform Spectroscopy",slug:"study-of-green-nanoparticles-and-biocomplexes-based-on-exopolysaccharide-by-modern-fourier-transform",totalDownloads:2e3,totalCrossrefCites:2,totalDimensionsCites:6,abstract:"The intention of this chapter is to contribute in clarification of nanoparticle synthesis and biocomplexes based on exopolysaccharide, green synthetic method development, their physico‐chemical characterization by modern spectroscopy, as well as testing of their antimicrobial activity. Silver nanoparticles of polysaccharide type have scientific interest, but practical importance too, because of their application in pharmaceutical and cosmetic product development due to proven antimicrobial and antioxidant activities. On the other hand, the biocomplexes based on exopolysaccharides are important in treatment of biometal deficiency in human and veterinary medicine, as well as in metal ion transporting in organism. Despite a number of studies of this kind of complexes, the investigations of effect of their structure to pharmaco‐biological activity are still interesting. It is important that question of interaction between reducing and stabilizing agents with metal ions is still opened. In this respect, the presented chapter offers further progress in the examination of silver nanoparticles and cobalt biocomplex synthesis with dextran oligosaccharides and its derivatives (such as dextran sulfate and carboxymethyl dextran). The complex structure, spectroscopic characterization, and the spectra‐structure correlation have been analyzed by different Fourier transform infrared (FTIR) spectroscopic techniques combined with energy‐dispersive X‐ray (EDX), X‐ray diffraction (XRD), scanning electron microscopy (SEM), and surface plasmon resonance UV‐Vis methods.",book:{id:"5411",slug:"fourier-transforms-high-tech-application-and-current-trends",title:"Fourier Transforms",fullTitle:"Fourier Transforms - High-tech Application and Current Trends"},signatures:"Goran S. Nikolić, Milorad D. Cakić, Slobodan Glišić, Dragan J.\nCvetković, Žarko J. Mitić and Dragana Z. Marković",authors:[{id:"23261",title:"Prof.",name:"Goran",middleName:"S.",surname:"Nikolic",slug:"goran-nikolic",fullName:"Goran Nikolic"},{id:"195519",title:"Dr.",name:"Milorad",middleName:null,surname:"Cakic",slug:"milorad-cakic",fullName:"Milorad Cakic"},{id:"195520",title:"MSc.",name:"Slobodan",middleName:null,surname:"Glišić",slug:"slobodan-glisic",fullName:"Slobodan Glišić"},{id:"195521",title:"Prof.",name:"Dragan",middleName:"J.",surname:"Cvetkovic",slug:"dragan-cvetkovic",fullName:"Dragan Cvetkovic"},{id:"195522",title:"Dr.",name:"Žarko",middleName:null,surname:"Mitić",slug:"zarko-mitic",fullName:"Žarko Mitić"},{id:"195523",title:"MSc.",name:"Dragana",middleName:null,surname:"Marković-Nikolić",slug:"dragana-markovic-nikolic",fullName:"Dragana Marković-Nikolić"}]},{id:"53388",doi:"10.5772/66107",title:"Fourier Transform Hyperspectral Imaging for Cultural Heritage",slug:"fourier-transform-hyperspectral-imaging-for-cultural-heritage",totalDownloads:1772,totalCrossrefCites:1,totalDimensionsCites:6,abstract:"Hyperspectral imaging is a technique of analysis that associates to each pixel of the image the spectral content of the radiation coming from the scene. This content can be helpful to recognize the chemical nature of the materials within the scene or to calculate their colours under particular conditions. Different solutions of hyperspectral imager have been realized with different spatial resolution, spectral resolution and range in the electromagnetic spectrum. In particular, improving the spectral resolution allows discriminating smaller features in the spectrum and the unambiguous detection of the absorption bands characteristic of superficial materials. Hyperspectral imagers based on interferometers have the advantage of having a spectral resolution that can be varied according to the needs by changing the optical path delay of the interferometer. A spectrum for each pixel is obtained with an algorithm based on the Fourier transform of the calibrated interferogram. We present the results of the application of a hyperspectral imager based on Fabry‐Perot interferometers to the field of cultural heritage. On different artworks, the hyperspectral imager has been used for pigment recognition, for colour rendering elaborations of the image with different light sources or standard illuminants and for calculating the chromatic coordinates useful for specific purposes.",book:{id:"5411",slug:"fourier-transforms-high-tech-application-and-current-trends",title:"Fourier Transforms",fullTitle:"Fourier Transforms - High-tech Application and Current Trends"},signatures:"Massimo Zucco, Marco Pisani and Tiziana Cavaleri",authors:[{id:"20909",title:"Dr.",name:"Marco Q.",middleName:null,surname:"Pisani",slug:"marco-q.-pisani",fullName:"Marco Q. Pisani"},{id:"20910",title:"Dr.",name:"Massimo E.",middleName:null,surname:"Zucco",slug:"massimo-e.-zucco",fullName:"Massimo E. Zucco"},{id:"194761",title:"Dr.",name:"Tiziana",middleName:null,surname:"Cavaleri",slug:"tiziana-cavaleri",fullName:"Tiziana Cavaleri"}]},{id:"53524",doi:"10.5772/66733",title:"Fourier Analysis for Harmonic Signals in Electrical Power Systems",slug:"fourier-analysis-for-harmonic-signals-in-electrical-power-systems",totalDownloads:4493,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"The harmonic content in electrical power systems is an increasingly worrying issue since the proliferation of nonlinear loads results in power quality problems as the harmonics is more apparent. In this paper, we analyze the behavior of the harmonics in the electrical power systems such as cables, transmission lines, capacitors, transformers, and rotating machines, the induction machine being the object of our study when it is excited to nonsinusoidal operating conditions in the stator winding. For this, a model is proposed for the harmonic analysis of the induction machine in steady‐state regimen applying the Fourier transform. The results of the proposed model are validated by experimental tests which gave good results for each case study concluding in a model proper for harmonic and nonharmonic analysis of the induction machine and for “harmonic” analysis in an electrical power system.",book:{id:"5411",slug:"fourier-transforms-high-tech-application-and-current-trends",title:"Fourier Transforms",fullTitle:"Fourier Transforms - High-tech Application and Current Trends"},signatures:"Emmanuel Hernández Mayoral, Miguel Angel Hernández López,\nEdwin Román Hernández, Hugo Jorge Cortina Marrero, José\nRafael Dorrego Portela and Victor Ivan Moreno Oliva",authors:[{id:"187793",title:"Dr.",name:"Emmanuel",middleName:null,surname:"Hernández",slug:"emmanuel-hernandez",fullName:"Emmanuel Hernández"},{id:"202757",title:"Dr.",name:"Miguel Angel",middleName:null,surname:"Hernández López",slug:"miguel-angel-hernandez-lopez",fullName:"Miguel Angel Hernández López"},{id:"202758",title:"Dr.",name:"Hugo Jorge",middleName:null,surname:"Cortina Marrero",slug:"hugo-jorge-cortina-marrero",fullName:"Hugo Jorge Cortina Marrero"},{id:"202759",title:"Dr.",name:"Edwin Román",middleName:null,surname:"Hernández",slug:"edwin-roman-hernandez",fullName:"Edwin Román Hernández"},{id:"202760",title:"Dr.",name:"Victor Iván Moreno",middleName:null,surname:"Oliva",slug:"victor-ivan-moreno-oliva",fullName:"Victor Iván Moreno Oliva"},{id:"202761",title:"Dr.",name:"José Rafael Dorrego",middleName:null,surname:"Portela",slug:"jose-rafael-dorrego-portela",fullName:"José Rafael Dorrego Portela"}]}],mostDownloadedChaptersLast30Days:[{id:"74096",title:"Time Frequency Analysis of Wavelet and Fourier Transform",slug:"time-frequency-analysis-of-wavelet-and-fourier-transform",totalDownloads:1162,totalCrossrefCites:6,totalDimensionsCites:8,abstract:"Signal processing has long been dominated by the Fourier transform. However, there is an alternate transform that has gained popularity recently and that is the wavelet transform. The wavelet transform has a long history starting in 1910 when Alfred Haar created it as an alternative to the Fourier transform. In 1940 Norman Ricker created the first continuous wavelet and proposed the term wavelet. Work in the field has proceeded in fits and starts across many different disciplines, until the 1990’s when the discrete wavelet transform was developed by Ingrid Daubechies. While the Fourier transform creates a representation of the signal in the frequency domain, the wavelet transform creates a representation of the signal in both the time and frequency domain, thereby allowing efficient access of localized information about the signal.",book:{id:"10065",slug:"wavelet-theory",title:"Wavelet Theory",fullTitle:"Wavelet Theory"},signatures:"Karlton Wirsing",authors:[{id:"325178",title:"Dr.",name:"Karlton",middleName:null,surname:"Wirsing",slug:"karlton-wirsing",fullName:"Karlton Wirsing"}]},{id:"74032",title:"Wavelets for EEG Analysis",slug:"wavelets-for-eeg-analysis",totalDownloads:1157,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"This chapter introduces the applications of wavelet for Electroencephalogram (EEG) signal analysis. First, the overview of EEG signal is discussed to the recording of raw EEG and widely used frequency bands in EEG studies. The chapter then progresses to discuss the common artefacts that contaminate EEG signal while recording. With a short overview of wavelet analysis techniques, namely; Continues Wavelet Transform (CWT), Discrete Wavelet Transform (DWT), and Wavelet Packet Decomposition (WPD), the chapter demonstrates the richness of CWT over conventional time-frequency analysis technique e.g. Short-Time Fourier Transform. Lastly, artefact removal algorithms based on Independent Component Analysis (ICA) and wavelet are discussed and a comparative analysis is demonstrated. The techniques covered in this chapter show that wavelet analysis is well-suited for EEG signals for describing time-localised event. Due to similar nature, wavelet analysis is also suitable for other biomedical signals such as Electrocardiogram and Electromyogram.",book:{id:"10065",slug:"wavelet-theory",title:"Wavelet Theory",fullTitle:"Wavelet Theory"},signatures:"Nikesh Bajaj",authors:[{id:"326400",title:"Dr.",name:"Nikesh",middleName:null,surname:"Bajaj",slug:"nikesh-bajaj",fullName:"Nikesh Bajaj"}]},{id:"53524",title:"Fourier Analysis for Harmonic Signals in Electrical Power Systems",slug:"fourier-analysis-for-harmonic-signals-in-electrical-power-systems",totalDownloads:4493,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"The harmonic content in electrical power systems is an increasingly worrying issue since the proliferation of nonlinear loads results in power quality problems as the harmonics is more apparent. In this paper, we analyze the behavior of the harmonics in the electrical power systems such as cables, transmission lines, capacitors, transformers, and rotating machines, the induction machine being the object of our study when it is excited to nonsinusoidal operating conditions in the stator winding. For this, a model is proposed for the harmonic analysis of the induction machine in steady‐state regimen applying the Fourier transform. The results of the proposed model are validated by experimental tests which gave good results for each case study concluding in a model proper for harmonic and nonharmonic analysis of the induction machine and for “harmonic” analysis in an electrical power system.",book:{id:"5411",slug:"fourier-transforms-high-tech-application-and-current-trends",title:"Fourier Transforms",fullTitle:"Fourier Transforms - High-tech Application and Current Trends"},signatures:"Emmanuel Hernández Mayoral, Miguel Angel Hernández López,\nEdwin Román Hernández, Hugo Jorge Cortina Marrero, José\nRafael Dorrego Portela and Victor Ivan Moreno Oliva",authors:[{id:"187793",title:"Dr.",name:"Emmanuel",middleName:null,surname:"Hernández",slug:"emmanuel-hernandez",fullName:"Emmanuel Hernández"},{id:"202757",title:"Dr.",name:"Miguel Angel",middleName:null,surname:"Hernández López",slug:"miguel-angel-hernandez-lopez",fullName:"Miguel Angel Hernández López"},{id:"202758",title:"Dr.",name:"Hugo Jorge",middleName:null,surname:"Cortina Marrero",slug:"hugo-jorge-cortina-marrero",fullName:"Hugo Jorge Cortina Marrero"},{id:"202759",title:"Dr.",name:"Edwin Román",middleName:null,surname:"Hernández",slug:"edwin-roman-hernandez",fullName:"Edwin Román Hernández"},{id:"202760",title:"Dr.",name:"Victor Iván Moreno",middleName:null,surname:"Oliva",slug:"victor-ivan-moreno-oliva",fullName:"Victor Iván Moreno Oliva"},{id:"202761",title:"Dr.",name:"José Rafael Dorrego",middleName:null,surname:"Portela",slug:"jose-rafael-dorrego-portela",fullName:"José Rafael Dorrego Portela"}]},{id:"53366",title:"New Spectral Applications of the Fourier Transforms in Medicine, Biological and Biomedical Fields",slug:"new-spectral-applications-of-the-fourier-transforms-in-medicine-biological-and-biomedical-fields",totalDownloads:2340,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"This chapter reviews some recent spectral applications of the Fourier transform techniques as they are applied in spectroscopy. An overview about Fourier transform spectroscopy (FTS) used like a powerful and sensitive tool in medical, biological, and biomedical analysis is provided. The advanced spectroscopic techniques of FTS, such as Fourier transform visible spectroscopy (FTVS), Fourier transform infrared-attenuated total reflectance (FTIR-ATR), Fourier transform infrared-photoacoustic spectroscopy (FTIR-PAS), Fourier transform infrared imaging spectroscopy (FTIR imaging), and their biomedical applications are described. A special attention has been paid to the description of the FTVS method of commercial quantum dots like an innovative and reliable technique used in the field of nanobiotechnology.",book:{id:"5411",slug:"fourier-transforms-high-tech-application-and-current-trends",title:"Fourier Transforms",fullTitle:"Fourier Transforms - High-tech Application and Current Trends"},signatures:"Anca Armăşelu",authors:[{id:"189080",title:"Dr.",name:"Anca",middleName:null,surname:"Armăşelu",slug:"anca-armaselu",fullName:"Anca Armăşelu"}]},{id:"53419",title:"Fourier Transform Infrared Spectroscopy in the Study of Hydrated Biological Macromolecules",slug:"fourier-transform-infrared-spectroscopy-in-the-study-of-hydrated-biological-macromolecules",totalDownloads:2442,totalCrossrefCites:3,totalDimensionsCites:15,abstract:"The interaction between biological macromolecules (proteins, nucleic acids, lipids and other biomolecules in the cell) and environmental water is an important determining factor in their conformational properties, stability and function. The hydration processes of biopolymers have been extensively studied in the past 20 years with reference to a considerable variety of models and concepts. In all recent works, a distinction is made between intracellular water that maintains the ordinary liquid state (bulk water) and water ordered in extended hydrogen‐bonded lattices at the surface and structured in the internal grooves of macromolecules (hydration water) in dependence on the chemical properties of the macromolecule surface. FTIR spectroscopy has been implemented in this field both for the sensitivity in the conformational analysis of biological macromolecules and the reliability in the investigation of the water network. A perturbation technique such as dehydration‐rehydration treatment modifies the macromolecule structure and water distribution. It was applied to two structurally different proteins: lysozyme, a globular (α + β) protein and collagen, a fibrous protein characterized by the triple helix structure. Submitted to the treatment both of them display irreversible conformational changes.",book:{id:"5411",slug:"fourier-transforms-high-tech-application-and-current-trends",title:"Fourier Transforms",fullTitle:"Fourier Transforms - High-tech Application and Current Trends"},signatures:"Maria Grazia Bridelli",authors:[{id:"108760",title:"Dr.",name:"Maria Grazia",middleName:null,surname:"Bridelli",slug:"maria-grazia-bridelli",fullName:"Maria Grazia Bridelli"}]}],onlineFirstChaptersFilter:{topicId:"974",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:8,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:286,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:106,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:9,numberOfPublishedChapters:101,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"
\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems. \r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.
",coverUrl:"https://cdn.intechopen.com/series/covers/25.jpg",latestPublicationDate:"April 13th, 2022",hasOnlineFirst:!1,numberOfPublishedBooks:1,editor:{id:"197485",title:"Dr.",name:"J. Kevin",middleName:null,surname:"Summers",slug:"j.-kevin-summers",fullName:"J. Kevin Summers",profilePictureURL:"https://mts.intechopen.com/storage/users/197485/images/system/197485.jpg",biography:"J. Kevin Summers is a Senior Research Ecologist at the Environmental Protection Agency’s (EPA) Gulf Ecosystem Measurement and Modeling Division. He is currently working with colleagues in the Sustainable and Healthy Communities Program to develop an index of community resilience to natural hazards, an index of human well-being that can be linked to changes in the ecosystem, social and economic services, and a community sustainability tool for communities with populations under 40,000. He leads research efforts for indicator and indices development. Dr. Summers is a systems ecologist and began his career at the EPA in 1989 and has worked in various programs and capacities. This includes leading the National Coastal Assessment in collaboration with the Office of Water which culminated in the award-winning National Coastal Condition Report series (four volumes between 2001 and 2012), and which integrates water quality, sediment quality, habitat, and biological data to assess the ecosystem condition of the United States estuaries. He was acting National Program Director for Ecology for the EPA between 2004 and 2006. He has authored approximately 150 peer-reviewed journal articles, book chapters, and reports and has received many awards for technical accomplishments from the EPA and from outside of the agency. Dr. Summers holds a BA in Zoology and Psychology, an MA in Ecology, and Ph.D. in Systems Ecology/Biology.",institutionString:null,institution:{name:"Environmental Protection Agency",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"38",title:"Pollution",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",isOpenForSubmission:!0,annualVolume:11966,editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",slug:"ismail-m.m.-rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",biography:"Ismail Md. Mofizur Rahman (Ismail M. M. Rahman) assumed his current responsibilities as an Associate Professor at the Institute of Environmental Radioactivity, Fukushima University, Japan, in Oct 2015. He also has an honorary appointment to serve as a Collaborative Professor at Kanazawa University, Japan, from Mar 2015 to the present. \nFormerly, Dr. Rahman was a faculty member of the University of Chittagong, Bangladesh, affiliated with the Department of Chemistry (Oct 2002 to Mar 2012) and the Department of Applied Chemistry and Chemical Engineering (Mar 2012 to Sep 2015). Dr. Rahman was also adjunctly attached with Kanazawa University, Japan (Visiting Research Professor, Dec 2014 to Mar 2015; JSPS Postdoctoral Research Fellow, Apr 2012 to Mar 2014), and Tokyo Institute of Technology, Japan (TokyoTech-UNESCO Research Fellow, Oct 2004–Sep 2005). \nHe received his Ph.D. degree in Environmental Analytical Chemistry from Kanazawa University, Japan (2011). He also achieved a Diploma in Environment from the Tokyo Institute of Technology, Japan (2005). Besides, he has an M.Sc. degree in Applied Chemistry and a B.Sc. degree in Chemistry, all from the University of Chittagong, Bangladesh. \nDr. Rahman’s research interest includes the study of the fate and behavior of environmental pollutants in the biosphere; design of low energy and low burden environmental improvement (remediation) technology; implementation of sustainable waste management practices for treatment, handling, reuse, and ultimate residual disposition of solid wastes; nature and type of interactions in organic liquid mixtures for process engineering design applications.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",slug:"zinnat-ara-begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",biography:"Zinnat A. Begum received her Ph.D. in Environmental Analytical Chemistry from Kanazawa University in 2012. She achieved her Master of Science (M.Sc.) degree with a major in Applied Chemistry and a Bachelor of Science (B.Sc.) in Chemistry, all from the University of Chittagong, Bangladesh. Her work affiliations include Fukushima University, Japan (Visiting Research Fellow, Institute of Environmental Radioactivity: Mar 2016 to present), Southern University Bangladesh (Assistant Professor, Department of Civil Engineering: Jan 2015 to present), and Kanazawa University, Japan (Postdoctoral Fellow, Institute of Science and Engineering: Oct 2012 to Mar 2014; Research fellow, Venture Business Laboratory, Advanced Science and Social Co-Creation Promotion Organization: Apr 2018 to Mar 2021). The research focus of Dr. Zinnat includes the effect of the relative stability of metal-chelator complexes in the environmental remediation process designs and the development of eco-friendly soil washing techniques using biodegradable chelators.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null},{id:"39",title:"Environmental Resilience and Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",isOpenForSubmission:!0,annualVolume:11967,editor:{id:"137040",title:"Prof.",name:"Jose",middleName:null,surname:"Navarro-Pedreño",slug:"jose-navarro-pedreno",fullName:"Jose Navarro-Pedreño",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRAXrQAO/Profile_Picture_2022-03-09T15:50:19.jpg",biography:"Full professor at University Miguel Hernández of Elche, Spain, previously working at the University of Alicante, Autonomous University of Madrid and Polytechnic University of Valencia. Graduate in Sciences (Chemist), graduate in Geography and History (Geography), master in Water Management, Treatment, master in Fertilizers and Environment and master in Environmental Management; Ph.D. in Environmental Sciences. His research is focused on soil-water and waste-environment relations, mainly on soil-water and soil-waste interactions under different management and waste reuse. His work is reflected in more than 230 communications presented in national and international conferences and congresses, 29 invited lectures from universities, associations and government agencies. Prof. Navarro-Pedreño is also a director of the Ph.D. Program Environment and Sustainability (2012-present) and a member of several societies among which are the Spanish Society of Soil Science, International Union of Soil Sciences, European Society for Soil Conservation, DessertNet and the Spanish Royal Society of Chemistry.",institutionString:"Miguel Hernández University of Elche, Spain",institution:null},editorTwo:null,editorThree:null},{id:"40",title:"Ecosystems and Biodiversity",coverUrl:"https://cdn.intechopen.com/series_topics/covers/40.jpg",isOpenForSubmission:!0,annualVolume:11968,editor:{id:"209149",title:"Prof.",name:"Salustiano",middleName:null,surname:"Mato",slug:"salustiano-mato",fullName:"Salustiano Mato",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLREQA4/Profile_Picture_2022-03-31T10:23:50.png",biography:"Salustiano Mato de la Iglesia (Santiago de Compostela, 1960) is a doctor in biology from the University of Santiago and a Professor of zoology at the Department of Ecology and Animal Biology at the University of Vigo. He has developed his research activity in the fields of fauna and soil ecology, and in the treatment of organic waste, having been the founder and principal investigator of the Environmental Biotechnology Group of the University of Vigo.\r\nHis research activity in the field of Environmental Biotechnology has been focused on the development of novel organic waste treatment systems through composting. The result of this line of work are three invention patents and various scientific and technical publications in prestigious international journals.",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorTwo:{id:"60498",title:"Prof.",name:"Josefina",middleName:null,surname:"Garrido",slug:"josefina-garrido",fullName:"Josefina Garrido",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRj1VQAS/Profile_Picture_2022-03-31T10:06:51.jpg",biography:"Josefina Garrido González (Paradela de Abeleda, Ourense 1959), is a doctor in biology from the University of León and a Professor of Zoology at the Department of Ecology and Animal Biology at the University of Vigo. She has focused her research activity on the taxonomy, fauna and ecology of aquatic beetles, in addition to other lines of research such as the conservation of biodiversity in freshwater ecosystems; conservation of protected areas (Red Natura 2000) and assessment of the effectiveness of wetlands as priority areas for the conservation of aquatic invertebrates; studies of water quality in freshwater ecosystems through biological indicators and physicochemical parameters; surveillance and research of vector arthropods and invasive alien species.",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorThree:{id:"464288",title:"Dr.",name:"Francisco",middleName:null,surname:"Ramil",slug:"francisco-ramil",fullName:"Francisco Ramil",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003RI7lHQAT/Profile_Picture_2022-03-31T10:15:35.png",biography:"Fran Ramil Blanco (Porto de Espasante, A Coruña, 1960), is a doctor in biology from the University of Santiago de Compostela and a Professor of Zoology at the Department of Ecology and Animal Biology at the University of Vigo. His research activity is linked to the taxonomy, fauna and ecology of marine benthic invertebrates and especially the Cnidarian group. Since 2004, he has been part of the EcoAfrik project, aimed at the study, protection and conservation of biodiversity and benthic habitats in West Africa. He also participated in the study of vulnerable marine ecosystems associated with seamounts in the South Atlantic and is involved in training young African researchers in the field of marine research.",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}}},{id:"41",title:"Water Science",coverUrl:"https://cdn.intechopen.com/series_topics/covers/41.jpg",isOpenForSubmission:!0,annualVolume:11969,editor:{id:"349630",title:"Dr.",name:"Yizi",middleName:null,surname:"Shang",slug:"yizi-shang",fullName:"Yizi Shang",profilePictureURL:"https://mts.intechopen.com/storage/users/349630/images/system/349630.jpg",biography:"Prof. Dr. Yizi Shang is a pioneering researcher in hydrology and water resources who has devoted his research career to promoting the conservation and protection of water resources for sustainable development. He is presently associate editor of Water International (official journal of the International Water Resources Association). He was also invited to serve as an associate editor for special issues of the Journal of the American Water Resources Association. He has served as an editorial member for international journals such as Hydrology, Journal of Ecology & Natural Resources, and Hydro Science & Marine Engineering, among others. He has chaired or acted as a technical committee member for twenty-five international forums (conferences). Dr. Shang graduated from Tsinghua University, China, in 2010 with a Ph.D. in Engineering. Prior to that, he worked as a research fellow at Harvard University from 2008 to 2009. 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The combination of electronics and computer science with biology and medicine has improved patient diagnosis, reduced rehabilitation time, and helped to facilitate a better quality of life. Nowadays, all medical imaging devices, medical instruments, or new laboratory techniques result from the cooperation of specialists in various fields. The series of Biomedical Engineering books covers such areas of knowledge as chemistry, physics, electronics, medicine, and biology. 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Dr. Koprowski has authored more than a hundred research papers with dozens in impact factor (IF) journals and has authored or co-authored six books. Additionally, he is the author of several national and international patents in the field of biomedical devices and imaging. Since 2011, he has been a reviewer of grants and projects (including EU projects) in biomedical engineering.",institutionString:null,institution:{name:"University of Silesia",institutionURL:null,country:{name:"Poland"}}},subseries:[{id:"7",title:"Bioinformatics and Medical Informatics",keywords:"Biomedical Data, Drug Discovery, Clinical Diagnostics, Decoding Human Genome, AI in Personalized Medicine, Disease-prevention Strategies, Big Data Analysis in Medicine",scope:"Bioinformatics aims to help understand the functioning of the mechanisms of living organisms through the construction and use of quantitative tools. The applications of this research cover many related fields, such as biotechnology and medicine, where, for example, Bioinformatics contributes to faster drug design, DNA analysis in forensics, and DNA sequence analysis in the field of personalized medicine. Personalized medicine is a type of medical care in which treatment is customized individually for each patient. Personalized medicine enables more effective therapy, reduces the costs of therapy and clinical trials, and also minimizes the risk of side effects. Nevertheless, advances in personalized medicine would not have been possible without bioinformatics, which can analyze the human genome and other vast amounts of biomedical data, especially in genetics. The rapid growth of information technology enabled the development of new tools to decode human genomes, large-scale studies of genetic variations and medical informatics. The considerable development of technology, including the computing power of computers, is also conducive to the development of bioinformatics, including personalized medicine. In an era of rapidly growing data volumes and ever lower costs of generating, storing and computing data, personalized medicine holds great promises. Modern computational methods used as bioinformatics tools can integrate multi-scale, multi-modal and longitudinal patient data to create even more effective and safer therapy and disease prevention methods. Main aspects of the topic are: Applying bioinformatics in drug discovery and development; Bioinformatics in clinical diagnostics (genetic variants that act as markers for a condition or a disease); Blockchain and Artificial Intelligence/Machine Learning in personalized medicine; Customize disease-prevention strategies in personalized medicine; Big data analysis in personalized medicine; Translating stratification algorithms into clinical practice of personalized medicine.",annualVolume:11403,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/7.jpg",editor:{id:"351533",title:"Dr.",name:"Slawomir",middleName:null,surname:"Wilczynski",fullName:"Slawomir Wilczynski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035U1loQAC/Profile_Picture_1630074514792",institutionString:null,institution:{name:"Medical University of Silesia",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"5886",title:"Dr.",name:"Alexandros",middleName:"T.",surname:"Tzallas",fullName:"Alexandros Tzallas",profilePictureURL:"https://mts.intechopen.com/storage/users/5886/images/system/5886.png",institutionString:"University of Ioannina, Greece & Imperial College London",institution:{name:"University of Ioannina",institutionURL:null,country:{name:"Greece"}}},{id:"257388",title:"Distinguished Prof.",name:"Lulu",middleName:null,surname:"Wang",fullName:"Lulu Wang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRX6kQAG/Profile_Picture_1630329584194",institutionString:null,institution:{name:"Shenzhen Technology University",institutionURL:null,country:{name:"China"}}},{id:"225387",title:"Prof.",name:"Reda",middleName:"R.",surname:"Gharieb",fullName:"Reda Gharieb",profilePictureURL:"https://mts.intechopen.com/storage/users/225387/images/system/225387.jpg",institutionString:"Assiut University",institution:{name:"Assiut University",institutionURL:null,country:{name:"Egypt"}}}]},{id:"8",title:"Bioinspired Technology and Biomechanics",keywords:"Bioinspired Systems, Biomechanics, Assistive Technology, Rehabilitation",scope:'Bioinspired technologies take advantage of understanding the actual biological system to provide solutions to problems in several areas. Recently, bioinspired systems have been successfully employing biomechanics to develop and improve assistive technology and rehabilitation devices. The research topic "Bioinspired Technology and Biomechanics" welcomes studies reporting recent advances in bioinspired technologies that contribute to individuals\' health, inclusion, and rehabilitation. Possible contributions can address (but are not limited to) the following research topics: Bioinspired design and control of exoskeletons, orthoses, and prostheses; Experimental evaluation of the effect of assistive devices (e.g., influence on gait, balance, and neuromuscular system); Bioinspired technologies for rehabilitation, including clinical studies reporting evaluations; Application of neuromuscular and biomechanical models to the development of bioinspired technology.',annualVolume:11404,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/8.jpg",editor:{id:"144937",title:"Prof.",name:"Adriano",middleName:"De Oliveira",surname:"Andrade",fullName:"Adriano Andrade",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRC8QQAW/Profile_Picture_1625219101815",institutionString:null,institution:{name:"Federal University of Uberlândia",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"49517",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Tsunashima",fullName:"Hitoshi Tsunashima",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYTP4QAO/Profile_Picture_1625819726528",institutionString:null,institution:{name:"Nihon University",institutionURL:null,country:{name:"Japan"}}},{id:"425354",title:"Dr.",name:"Marcus",middleName:"Fraga",surname:"Vieira",fullName:"Marcus Vieira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003BJSgIQAX/Profile_Picture_1627904687309",institutionString:null,institution:{name:"Universidade Federal de Goiás",institutionURL:null,country:{name:"Brazil"}}},{id:"196746",title:"Dr.",name:"Ramana",middleName:null,surname:"Vinjamuri",fullName:"Ramana Vinjamuri",profilePictureURL:"https://mts.intechopen.com/storage/users/196746/images/system/196746.jpeg",institutionString:"University of Maryland, Baltimore County",institution:{name:"University of Maryland, Baltimore County",institutionURL:null,country:{name:"United States of America"}}}]},{id:"9",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. Finally, the tissue engineering subcategory will support topics such as the fundamentals of stem cells and progenitor cells and their proliferation, differentiation, bioreactors for three-dimensional culture and studies of phenotypic changes, stem and progenitor cells, both short and long term, ex vivo and in vivo implantation both in preclinical models and also in clinical trials.",annualVolume:11405,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/9.jpg",editor:{id:"126286",title:"Dr.",name:"Luis",middleName:"Jesús",surname:"Villarreal-Gómez",fullName:"Luis Villarreal-Gómez",profilePictureURL:"https://mts.intechopen.com/storage/users/126286/images/system/126286.jpg",institutionString:null,institution:{name:"Autonomous University of Baja California",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"35539",title:"Dr.",name:"Cecilia",middleName:null,surname:"Cristea",fullName:"Cecilia Cristea",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYQ65QAG/Profile_Picture_1621007741527",institutionString:null,institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"40735",title:"Dr.",name:"Gil",middleName:"Alberto Batista",surname:"Gonçalves",fullName:"Gil Gonçalves",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYRLGQA4/Profile_Picture_1628492612759",institutionString:null,institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}},{id:"211725",title:"Associate Prof.",name:"Johann F.",middleName:null,surname:"Osma",fullName:"Johann F. 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