Rationalization of the Color Properties of Fluorescein in the Solid State: A Combined Computational and Experimental Study

Fluorescein is known to exist in three tautomeric forms defined as quinoid, zwitterionic, and lactoid. In the solid state, the quinoid and zwitterionic forms give rise to red and yellow materials, respectively. The lactoid form has not been crystallized pure, although its cocrystal and solvate forms exhibit colors ranging from yellow to green. An explanation for the observed colors of the crystals is found using a combination of UV/Vis spectroscopy and plane‐wave DFT calculations. The role of cocrystal coformers in modifying crystal color is also established. Several new crystal structures are determined using a combination of X‐ray and electron diffraction, solid‐state NMR spectroscopy, and crystal structure prediction (CSP). The protocol presented herein may be used to predict color properties of materials prior to their synthesis.     

差示扫描量热法(DSC)定量测试阿德福韦酯晶型的研究

红外光谱（FTIR）和x-射线衍射（XRD）测试表明阿德福韦酯药物具有A、E2种晶型．利用差示扫描量热法（DSC）对阿德福韦酯药物的不同晶型进行了定量测试方法的研究,该方法的依据是药物的不同晶型具有不同的熔点和熔融热焓,根据熔融热焓的量可以定量测试药物中某种晶型的含量,为指导生产工艺研究和产品品质的判断提供快速准确及有效的测试方法。     

Polymorphs of Aspirin – Solid-state IR-LD spectroscopic and quantitative determination in solid mixtures

Solid-state linear-dichroic infrared (IR-LD) spectroscopy, using an orientation technique as a suspension in nematic liquid crystal, has been carried out of Aspirin polymorphs (forms I and II). Reducing-difference procedure for polarized IR-spectra interpretation has been applied for structural analysis of both modifications and the data have been compared with known crystallographic ones. A vibration assignment of forms I and II has been included and on this basis, a quantitative determination by FT-IR spectra for form I in mixtures with second one has been presented, using intensity ratio of 1606 cm⁻¹ peak (characteristic for both forms) to 599 cm⁻¹ one (attributed to form I). The obtained reliability is 99.78%.     

晶型转变对尼龙11分子链运动的影响

Two crystal forms (α and δ′ form) of nylon 11 were prepared by melting, ice water bath quenching and annealing. The characteristic of chain movement of two forms was investigated using dielectric relaxation spectroscopy in the frequency range from 42 Hz to 5 MHz. The dielectric temperature spectra at different frequencies show that the primary α relaxation corresponding to the chain segment movement is located at higher temperature in α form, indicating the chain segment movement is restricted after δ′→α crystal transition. The activation energy of secondary β relaxation remained almost unchanged for two forms, but the relaxation time was longer and the relaxation strength was weaker for α form, confirming that the local relaxation was also restricted to some extent after δ′→α crystal transition.     

Configuration-Controlled Crystal and/or Gel Formation of Protected d-Glucosamines Supported by Promiscuous Interaction Surfaces and a Conformationally Heterogeneous Solution State

The configuration-dependent self-association mode of the two anomers of O-Ac,N-Fmoc-d -glucosamine, a foldamer building block, leading to gel and/or single crystal formation is described. The β-anomer of the sugar amino acid ( 2 ) forms a gel from various solvents (confirmed by SEM, rheology measurements, NMR, and ECD spectroscopy), whereas the α-anomer ( 1 ) does not form a gel with any solvent tested. Transition from the solution state to a gel is coupled to a concurrent shift of the Fmoc-groups: from a freely rotating (almost symmetrical) to a specific, asymmetric orientation. Whereas the crystal structure of the α-anomer is built as an evenly packed 3D system, the β-anomer forms a looser superstructure of well-packed 2D layers. Modeling indicates that in the lowest energy, but scarcely sampled conformer of the β-anomer, the Fmoc-group bends above the sugar moiety, stabilized by intramolecular CH↔π interactions between the aromatic rings. It is concluded that possessing an extended and promiscuous interaction surface and a conformationally heterogeneous solution state are among the basic requirements of gel formation for a candidate molecule.     

Analysis of crystallization behavior and crystal modifications of poly(butylene‐2,6‐naphthalene dicarboxylate)

Information on the crystalline structure and the properties of poly(butylene‐2,6‐naphthalene dicarboxylate) (PBN) has not been well reported until now, but it is known that there are two different crystal modifications in PBN, as follows: one is formed in isotropic samples by annealing (α form); another appears by annealing with tension (β form). The relation between the crystal modifications and the kinetics of isothermal crystallization for PBN was investigated using in‐situ Fourier transform infrared spectroscopy (FTIR) and wide‐angle X‐ray diffraction (WAXD). The melting behavior of each crystalline form was also studied by means of FTIR and differential scanning calorimetry (DSC) measurements. From the analysis of the melt‐crystallized PBN specimens, the two crystalline forms coexisted in the isotropic samples melt‐crystallized at 230°C, but only the α crystal modification was observed in the films annealed at lower temperatures. In addition, it was revealed that, at 230°C, the β modification was formed only in the primary crystallization process. © 1999 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 37: 561–574, 1999     

A Dicobalt Complex with an Unsymmetrical Quinonoid Bridge Isolated in Three Units of Charge: A Combined Structural, (Spectro)electrochemical,Magnetic and Spectroscopic Study

Quinonoid ligands are excellent bridges for generating redox‐rich dinuclear assemblies. A large majority of these bridges are symmetrically substituted, with examples of unsymmetrically substituted quinonoid bridges being extremely rare. We present here a dicobalt complex in its various redox states with an unsymmetrically substituted quinonoid bridging ligand. Two homovalent forms and one mixed‐valent form have been isolated and characterized by single crystal X‐ray diffraction. The complex displays a large comproportionation constant for the mixed‐valent state which is three orders of magnitude higher than that observed for the analogous complex with a symmetrically substituted bridge. Results from electrochemistry, UV/Vis/NIR spectroelectrochemistry, SQUID magnetometry, multi‐frequency EPR spectroscopy and FIR spectroscopy are used to probe the electronic structures of these complexes. FIR provides direct evidence of exchange coupling. The results presented here display the advantages of using an unsymmetrically substituted bridge: site specific redox chemistry, high thermodynamic stabilization of the mixed‐valent form, isolation and crystallization of various redox forms of the complex. This work represents an important step on the way to generating heterodinuclear complexes for use in cooperative catalysis.     

The Richest Collection of Tautomeric Polymorphs: The Case of 2‐Thiobarbituric Acid

Five new polymorphs and one hydrated form of 2‐thiobarbituric acid have been isolated and characterised by solid‐state methods. In both the crystalline form II and in the hydrate form, the 2‐thiobarbituric molecules are present in the enol form, whereas only the keto isomer is present in crystalline forms I (reported in 1967 by Calas and Martinex), III , V and VI . In form IV , on the other hand, a 50:50 ordered mixture of enol/keto molecules is present. All new forms have been characterised by single‐crystal X‐ray diffraction, 1D and 2D (¹H, ¹³C, and ¹⁵N) solid‐state NMR spectroscopy, Raman spectroscopy and X‐ray powder diffraction at variable temperature. It has been possible to induce keto–enol conversion between the forms by mechanical methods. The role of hydrogen‐bond interactions in determining the relative stability of the polymorphs and as a driving force in the conversions has been ascertained. To the best of the authors’ knowledge, the 2‐thiobarbituric family of crystal forms represents the richest collection of examples of tautomeric polymorphism so far reported in the literature.     

Fourier transform infrared spectroscopy supported by multivariate statistics in compatibility study of atenolol with excipients

The objective of this study was to use Fourier transform infrared spectroscopy (FTIR) and multivariate statistics to investigate compatibility/incompatibility of atenolol as a representative of active pharmaceutical ingredients and excipients, such as β-cyclodextrin, methylcellulose, starch and chitosan, when used in solid dosage formulations. Two-component physical mixtures consisting of atenolol and selected excipients were studied by FTIR spectroscopy and two methods of multivariate statistical analysis – principal component analysis (PCA) and cluster analysis (CA), which were used as a supplementary tool for interpretation of the FTIR spectra. Taking into account variability explained by the first two principal components, the results of PCA were visualized in the form of a bi-dimensional scatterplot. A lack of interaction was confirmed by two distinct clusters created by both atenolol and a particular excipient with their mixtures. In the case of CA, lack of interaction between both ingredients was also indicated by two large clusters at a level of 33 or 66% of the maximum distance. The results of the investigations show that with the exception of β-cyclodextrin, the remaining excipients are compatible with atenolol. These findings were confirmed by complementary methods, such as differential scanning calorimetry, thermogravimetry and X-ray powder diffraction.     

Aggregation of 2‐Aminobenzimidazole—A Combined Experimental and Theoretical Investigation

An investigation of 2‐aminobenzimidazole was carried out by calculations at HF, MP2, and DFT levels of theory and also by UV and IR spectroscopy. The quantum chemical calculations predict a full shift of the equilibrium towards the amino form, but the absorption spectra in different solvents distinctly show a two‐component equilibrium system. Examination of possible equilibria in solution shows that an equilibrium between two dimeric forms of the amino tautomer of 2‐aminobenzimidazole explains the spectral observations.     

Physico-chemical Characterization of Hydrated and Anhydrous Crystal Forms of Amlodipine Besylate

The antihypertensive drug substance amlodipine besylate crystallizes in two stable crystal forms, an anhydrate and a hitherto unknown monohydrate. Both forms have been characterized by thermal analysis, X-ray powder diffractometry, FTIR- and FT Raman spectroscopy. Moisture sorption- and desorption investigations reveal their unusual physical stability in a broad range of relative humidities. The monohydrate forms an isomorphic dehydrate upon dehydration, which was elucidated by variable temperature X-ray powder diffractometry. Physico-chemical properties as well as relative stabilities of the crystal forms are described and discussed based on a comprehensive analytical identification, and enable an estimation of practical relevance for manufacturing of amlodipine besylate solid dosage forms. This revised version was published online in August 2006 with corrections to the Cover Date.     

Physico-chemical characterization of an active pharmaceutical ingredient

The physico-chemical properties and polymorphism of a new active pharmaceutical ingredient entity has been analyzed and the gain of knowledge during the chemical development of the substance is described. Initial crystallization revealed an anhydrous crystal form with good crystallinity and a single, sharp DSC melting peak at 171°C and a straightforward development of this crystal form seemed possible. However, during polymorphism screening, new crystalline forms were detected that were often analyzed as mixtures of crystal forms. The process of characterization and identification of the different crystalline forms and its thermodynamical relationship has been supported by a combination of experimental and computational work including determination of the three-dimensional structures of the crystal forms. The crystal structure of one polymorphic form was solved by single crystal X-ray structure analysis. Unfortunately, Mod B resisted in formation of suitable single crystals, but its structure could be solved by high resolution powder diffraction data analysis using synchrotron radiation. Calculation of the theoretical X-ray powder diffraction pattern from three dimensional crystal coordinates allowed an unambiguous identification of the different crystalline forms. Two polymorphic crystal forms of the API-CG3, named Mod A and Mod B, are enantiotropic whereas Mod B is the most stable polymorph at room temperature up to about 50°C and Mod A at temperatures above 50°C. The mechanism of the solid-solid transition can be explained by analyzing the molecular packing information gained from the single crystal structures. A third crystalline form with the highest melting peak turned out to be not a polymorphic or pseudopolymorphic crystal modification of our API-CG3 but a chemically different substance. This revised version was published online in July 2006 with corrections to the Cover Date.     

Thin‐Film Properties of DNA and RNA Bases: A Combined Experimental and Theoretical Study

The structures of the DNA and RNA bases cytosine, uracil, and thymine in thin films with a nominal film thickness of about 20 nm are studied by using X‐ray photoemission spectroscopy (XPS) and Fourier‐transform infrared spectroscopy. The molecules are evaporated in situ from powder on a gold foil. The experimental results indicate that cytosine is composed of two energetically close tautomeric forms, whereas uracil and thymine exist in only one tautomeric form. Additionally, quantum chemical calculations are performed to complement the experimental results. The relative energies of the tautomeric forms of cytosine, uracil, and thymine are calculated using Hartree–Fock (HF), density functional theory (DFT), and post‐HF methods. Furthermore, the assignment of the XPS spectra is supported by using simple model considerations employing Koopmans ionization energies and Mulliken net atomic charges.     

How do Pseudoenantiomers Structurally Differ in the Gas Phase? An IR/UV Spectroscopy Study of Jet‐Cooled Hydroquinine and Hydroquinidine

The gas‐phase structures of the cinchona alkaloids, hydroquinine and its pseudoenantiomer hydroquinidine, are studied in a supersonic expansion by means of laser‐induced fluorescence and IR/UV double‐resonance spectroscopy. Vibrational spectroscopy combined with density functional calculations show that the conformational properties of the two pseudoenantiomers are identical. In both cases, they exist in two isoenergetic forms, with similar IR spectra. Both conformers are similar to the most stable cis‐γ‐open form of quinine; they differ from each other by the position of the ethyl substituent attached to the quinuclidine ring. Further differences between the two conformers are observed in the laser‐induced fluorescence spectrum. The first electronic transition is characterized by time‐dependent density functional theory and RI‐cc2 calculations, and is of ππ* nature. The results described here emphasize the role of the ethyl substituent in the structural differences between pseudoenantiomers of cinchona alkaloids.     

A caged lanthanide complex as a paramagnetic shift agent for protein NMR

A lanthanide complex, named CLaNP (caged lanthanide NMR probe) has been developed for the characterisation of proteins by paramagnetic NMR spectroscopy. The probe consists of a lanthanide chelated by a derivative of DTPA (diethylenetriaminepentaacetic acid) with two thiol reactive functional groups. The CLaNP molecule is attached to a protein by two engineered, surface-exposed, Cys residues in a bidentate manner. This drastically limits the dynamics of the metal relative to the protein and enables measurements of pseudocontact shifts. NMR spectroscopy experiments on a diamagnetic control and the crystal structure of the probe-protein complex demonstrate that the protein structure is not affected by probe attachment. The probe is able to induce pseudocontact shifts to at least 40 A from the metal and causes residual dipolar couplings due to alignment at a high magnetic field. The molecule exists in several isomeric forms with different paramagnetic tensors; this provides a fast way to obtain long-range distance restraints.     

Keto/enol tautomerism in phenylpyruvic acids: structure of the o-nitrophenylpyruvic acid

The synthesis of a tautomeric keto/enol mixture of o-nitrophenylpyruvic acid followed the acid hydrolysis of the azlactone of o-nitrobenzaldehyde was carried out. The structures of the two tautomeric forms were assigned by NMR spectroscopy. X-ray diffraction of a single crystal revealed that the crystalline form corresponds to the keto tautomer. Quantum mechanics calculations in the gas phase confirmed the experimental findings in solution.     

Tetrazene–Characterization of Its Polymorphs

The reinvestigation of tetrazene single crystalline material by means of X-ray methods resulted in a slightly different structure when compared to previously published data. Reaction conditions responsible for different crystalline modification formation were investigated. Newly described C form was found to be the primary reaction product and the combined action of temperature and the presence of water over time is required for the transition to the A form. Both forms were described by X-ray powder diffraction. Tetrazene was also subjected to infrared and Raman spectroscopy, which allowed differentiating between the forms. The molecule was isotopically labeled with ¹⁵N atoms at two different locations (ring and nitrogen sidechain) and employed in assigning vibrational modes to the resulting bands. Differences between sensitivities to mechanical stimuli of the two modifications were investigated and found industrially insignificant. In the same vein, the performance of either modification in primer composition and primer was identical.     

Kinetic and thermodynamic stability of cluster compounds under heating

A new polymorphic form of Norfloxacin has been identified and fully characterized by a variety of methods including powder X-ray diffraction, vibrational spectroscopy (IR and Raman), thermal analysis (DSC and TG), SEM and solid-state NMR spectroscopy. The relationship between the new form C and the previously known forms A and B have been studied. Moreover, the crystal structure of the known form A has been solved by single-crystal methods.     

Three polymorphic forms of the co-crystal 4,4'-bipyridine/pimelic acid and their structural, thermal, and spectroscopic characterization

Three crystal forms of the co-crystal 4,4'-bipy/pimelic acid (bipy: bipyridine), [NH(4)C(5)-C(5)H(4)N][HOOC(CH(2))(5)COOH], have been prepared and their relationship investigated by single-crystal X-ray diffraction, variable-temperature X-ray powder diffraction, differential scanning calorimetry and solid-state NMR spectroscopy. Both X-ray and NMR spectroscopic results indicate that no proton transfer takes place, that is, the three crystal forms are true co-crystals of neutral molecules. Forms I and II both convert into Form III at high temperature, Forms II and III being the thermodynamically stable forms at room and high temperature, respectively.     

Vibrational spectra and conformational isomerism of 2-phenoxy-5,6-benz-1,3,2-dioxaphosphepins

Conclusions Using vibrational spectroscopy methods in different aggregate states and solutions with variation of the polarity of the medium, we have studied 2-phenoxy-5,6-benz-1,3,2-dioxaphosphepin and its oxo, thio, and seleno analogs. In the liquid and solutions, they exist as a conformational equilibrium of three forms: two chair forms, differing in the orientation of the phenoxyl radical, and a twist form. The population of the twist form is no more than 25%. The content of the chair conformers is determined by the solvent. In the crystal, all the compounds have the chair form with axial phenoxyl group.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 844–849, April, 1989.