Isoenergetic Polymorphism: The Puzzle of Tolazamide as a Case Study.

In the present case study of tolazamide we illustrate how many seemingly contradictory results that have been obtained from experimental observations and theoretical calculations can finally start forming a consistent picture: a "puzzle put together". For many years, tolazamide was considered to have no polymorphs. This made this drug substance unique among the large family of sulfonylureas, which was known to be significantly more prone to polymorphism than many other organic compounds. The present work employs a broad and in-depth analysis that includes the use of optical microscopy, single-crystal and powder X-ray diffraction, IR and Raman spectroscopies, DSC, semiempirical PIXEL calculations and DFT of three polymorphs of tolazamide. This case study shows how the polymorphs of a molecular crystal can be overlooked even if discovered serendipitously on one of numerous crystallizations, and how very different molecular packings can be practically isoenergetic but still crystallize quite selectively and transform one into another irreversibly upon heating.

Semi-maleate salts of L- and DL-serinium: the first example of chiral and racemic serinium salts with the same composition and stoichiometry.

L-serinium semi-maleate, (I), and DL-serinium semi-maleate, (II), both C3H8NO3(+)·C4H3O4(-), provide the first example of chiral and racemic anhydrous serine salts with the same organic anion. A comparison of their crystal structures with each other, with the structures of the pure components (L-serine polymorphs, DL-serine and maleic acid) and with other amino acid maleates is important for understanding the formation of the crystal structures, their response to variations in temperature and pressure, and structure-property relationships. As in other known crystal structures of amino acid maleates, there are no direct links between the semi-maleate anions in the two new structures. The serinium cations have different conformations in (I) and (II). In (I), they are linked into infinite chains via hydrogen bonds between carboxylic acid and hydroxy groups. In (II), there are no such chains formed by the serinium cations. In both (I) and (II), there are C2(2)(12) chains consisting of alternating semi-maleate anions and serinium cations. Two types of such chains are present in (I) and (II), termed C2(2)(12) and C2(2)(12)'. In (I), these chains, lying in the same plane, are further linked to each other via hydrogen bonds, whereas in (II) they are not.

A high-pressure single-crystal X-ray diffraction study of potassium guaninate hydrate, K+·C5H4N5O-·H2O.

The crystal structure of potassium guaninate hydrate, K+·C5H4N5O-·H2O, was studied in the pressure range of 1 atm to 7.3 GPa by single-crystal diffraction using synchrotron radiation and a laboratory X-ray diffraction source. Structural strain was compared to that of the same salt hydrate on cooling, and in 2Na+·C5H3N5O2-·7H2O under hydrostatic compression and on cooling. A polymorphic transition into a new, incommensurately modulated, phase was observed at ∼4-5 GPa. The transition was reversible with a hysteresis: the satellite reflections disappeared on decompression to ∼1.4 GPa.

Biochemical Properties of a Promising Milk-Clotting Enzyme, Moose (Alces alces) Recombinant Chymosin.

Moose (Alces alces) recombinant chymosin with a milk-clotting activity of 86 AU/mL was synthesized in the Kluyveromyces lactis expression system. After precipitation with ammonium sulfate and chromatographic purification, a sample of genetically engineered moose chymosin with a specific milk-clotting activity of 15,768 AU/mg was obtained, which was used for extensive biochemical characterization of the enzyme. The threshold of the thermal stability of moose chymosin was 55 °C; its complete inactivation occurred after heating at 60 °C. The total proteolytic activity of moose chymosin was 0.332 A280 units. The ratio of milk-clotting and total proteolytic activities of the enzyme was 0.8. The Km, kcat and kcat/Km values of moose chymosin were 4.7 µM, 98.7 s-1, and 21.1 µM-1 s-1, respectively. The pattern of change in the coagulation activity as a function of pH and Ca2+ concentration was consistent with the requirements for milk coagulants for cheese making. The optimum temperature of the enzyme was 50-55 °C. The introduction of Mg2+, Zn2+, Co2+, Ba2+, Fe2+, Mn2+, Ca2+, and Cu2+ into milk activated the coagulation ability of moose chymosin, while Ni ions on the contrary inhibited its activity. Using previously published data, we compared the biochemical properties of recombinant moose chymosin produced in bacterial (Escherichia coli) and yeast (K. lactis) producers.

From geology to biology: an interdisciplinary course in crystal growth.

This contribution shares experience of teaching an interdisciplinary university course in crystal growth with examples ranging from geology to biology. This is an attempt to combine teaching the basics of the classical and non-classical theories of crystallization with impressive examples of crystals growing around us and in the human body, as well as demonstration of the common phenomena in the growth of minerals in nature, crystalline materials in industry and the laboratory, and biomimetic and stimulus-responsive crystals. Lectures are supported by laboratory exercises. Students can also perform an individual research project and present an oral contribution at a mini-conference. Examples of the topics considered in the course are given, and an extensive list of references to papers and web resources is provided, which may be useful to those who want to implement anything from the authors' experience.

Structure-Based Design, Synthesis, and Biological Evaluation of the Cage-Amide Derived Orthopox Virus Replication Inhibitors.

Despite the fact that the variola virus is considered eradicated, the search for new small molecules with activity against orthopoxviruses remains an important task, especially in the context of recent outbreaks of monkeypox. As a result of this work, a number of amides of benzoic acids containing an adamantane fragment were obtained. Most of the compounds demonstrated activity against vaccinia virus, with a selectivity index SI = 18,214 for the leader compound 18a. The obtained derivatives also demonstrated activity against murine pox (250 ≤ SI ≤ 6071) and cowpox (125 ≤ SI ≤ 3036). A correlation was obtained between the IC50 meanings and the binding energy to the assumed biological target, the p37 viral protein with R2 = 0.60.

A cocrystal of L-ascorbic acid with picolinic acid: the role of O-H...O, N-H...O and C-H...O hydrogen bonds and L-ascorbic acid conformation in structure stabilization.

A new 1:1 cocrystal (L-Asc-Pic) of L-ascorbic acid (vitamin C) with picolinic acid was prepared as a powder and as single crystals. The crystal structure was solved and refined from single-crystal X-ray diffraction (SCXRD) data collected at 293 (2) and 100 (2) K. The samples of the L-Asc-Pic cocrystal were characterized by elemental (HCNS) analysis and titrimetric methods, TG/DTG/DSC, and IR and Raman spectroscopy. The asymmetric unit comprises a picolinic acid zwitterion and an L-ascorbic acid molecule. The stabilization energy of intermolecular interactions involving hydrogen bonds, the vibrational spectrum and the energies of the frontier molecular orbitals were calculated using the GAUSSIAN09 and the CrystalExplorer17 programs. The charge distribution on the atoms of the L-Asc-Pic cocrystal, L-ascorbic acid itself and its 12 known cocrystals (structures from Version 5.40 of the Cambridge Structural Database) were calculated by the methods of Mulliken, Voronoi and Hirshfeld charge analyses (ADF) at the bp86/TZ2P+ level of theory. The total effective charges and conformations of the L-ascorbic acid molecules in the new and previously reported cocrystals were compared with those of the two symmetry-independent molecules in the crystals of L-ascorbic acid. A correlation between molecular conformation and its effective charge is discussed.

A novel crystal form of metacetamol: the first example of a hydrated form.

We report the crystal structure and crystallization conditions of a first hydrated form of metacetamol (a hemihydrate), C8H9NO2·0.5H2O. It crystallizes from metacetamol-saturated 1:1 (v/v) water-ethanol solutions in a monoclinic structure (space group P21/n) and contains eight metacetamol and four water molecules per unit cell. The conformations of the molecules are the same as in polymorph II of metacetamol, which ensures the formation of hydrogen-bonded dimers and R22(16) ring motifs in its crystal structure similar to those in polymorph II. Unlike in form II, however, these dimers in the hemihydrate are connected through water molecules into infinite hydrogen-bonded molecular chains. Different chains are linked to each other by metacetamol-water and metacetamol-metacetamol hydrogen bonds, the latter type being also present in polymorph I. The overall noncovalent network of the hemihydrate is well developed and several types of hydrogen bonds are responsible for its formation.

New 1:1 and 2:1 salts in the `DL-norvaline-maleic acid' system as an example of assembling various crystal structures from similar supramolecular building blocks.

Molecular salts and cocrystals of amino acids have potential applications as molecular materials with nonlinear optical, ferroelectric, piezoelectric, and other various target physical properties. The wide choice of amino acids and coformers makes it possible to design various crystal structures. The amino acid-maleic acid system provides a perfect example of a rich variety of crystal structures with different stoichiometries, symmetries and packing motifs built from the molecular building blocks, which are either exactly the same, or differ merely by protonation or as optical isomers. The present paper reports the crystal structures of two new salts of the DL-norvaline-maleic acid system with 1:1 and 2:1 stoichiometries, namely DL-norvalinium hydrogen maleate, C5H12NO2+·C4H3O4-, (I), and DL-norvalinium hydrogen maleate-DL-norvaline, C5H12NO2+·C4H3O4-·C5H11NO2, (II). These are the first examples of molecular salts of DL-norvaline with an organic anion. The crystal structure of (I) has the same C22(12) structure-forming motif which is common for hydrogen maleates of amino acids. The structure of (II) has dimeric cations. Of special interest is that the single crystals of (I) which are originally formed on crystallization from aqueous solution transform into single crystals of (II) if stored in the mother liquor for several hours.

Crystal structure of a 2:1 co-crystal of meloxicam with acetyl-endi-carb-oxy-lic acid.

The pharmaceutical 2:1 co-crystal of meloxicam [MXM; systematic name: 4-hy-droxy-2-methyl-N-(5-methyl-thia-zol-2-yl)-2H-1,2-benzo-thia-zine-3-carboxamide 1,1-dioxide] with acetyl-enedi-carb-oxy-lic acid (ACA; systematic name: but-2-ynedioic acid), crystallizes with one MXM mol-ecule and half an ACA mol-ecule in the asymmetric unit, C14H13N3O4S2·0.5C4H2O4. The mid-point of the triple bond of ACA is located on an inversion centre. In the crystal, the two stereoisomers of MXM with respect to the N atom of the sulfonamide group are related by the inversion centre. The carbonyl and hy-droxy groups belonging to the MXM mol-ecule are involved in an intra-molecular O-H⋯O hydrogen bond. The structure-forming motif includes two MXM mol-ecules linked via an ACA conformer through N-H⋯O and O-H⋯N hydrogen bonds, similar to MXM co-crystals with other di-carb-oxy-lic acids.

New hydrophobic L-amino acid salts: maleates of L-leucine, L-isoleucine and L-norvaline.

Crystals of maleates of three amino acids with hydrophobic side chains [L-leucenium hydrogen maleate, C6H14NO2(+)·C4H3O4(-), (I), L-isoleucenium hydrogen maleate hemihydrate, C6H14NO2(+)·C4H3O4(-)·0.5H2O, (II), and L-norvalinium hydrogen maleate-L-norvaline (1/1), C5H11NO2(+)·C4H3O4(-)·C5H12NO2, (III)], were obtained. The new structures contain C2(2)(12) chains, or variants thereof, that are a common feature in the crystal structures of amino acid maleates. The L-leucenium salt is remarkable due to a large number of symmetrically non-equivalent units (Z' = 3). The L-isoleucenium salt is a hydrate despite the fact that L-isoleucine is a nonpolar hydrophobic amino acid (previously known amino acid maleates formed hydrates only with lysine and histidine, which are polar and hydrophilic). The L-norvalinium salt provides the first example where the dimeric cation L-Nva...L-NvaH(+) was observed. All three compounds have layered noncentrosymmetric structures. Preliminary tests have shown the presence of the second harmonic generation (SGH) effect for all three compounds.