ABSTRACT
The crystallization of metastable crystal polymorphs in polymer matrices has been extensively reported in literature as a possible approach to enhance the solubility of poorly water-soluble drug compounds, yet no clarification of the mechanism of the polymorph formation has been proposed. The current work aims to elucidate the polymorphism behavior of the model compound indomethacin as well as the mechanism of polymorph selection of drugs in semicrystalline systems. Indomethacin crystallized as either the α- or τ-form, a new metastable form, or a mixture of the two polymorphs in dispersions containing different drug loadings in polyethylene glycol, poloxamer, or Gelucire as the result of the variation in the mobility of drug molecules. As a general rule, low molecular mobility of the amorphous drug favors the crystallization into thermodynamically stable forms whereas metastable crystalline polymorphs are preferred when the molecular mobility of the drug is sufficiently high. This rule provides insight into the polymorph selection of numerous active pharmaceutical ingredients in semicrystalline dispersions and can be used as a guide for polymorphic screening from melt crystallization by tuning the mobility of drug molecules. In addition, the drug crystallized faster while the polymer crystallized slower as the drug-loading increased with the maxima of drug crystallization rate in 70% indomethacin dispersion. Increasing the drug content in solid dispersions reduced the τ to α polymorphic transition rate, except for when the more stable form was initially dominant. The segregation of τ and α polymorphs as well as the polymorphic transformation during storage led to the inherent inhomogeneity of the semicrystalline dispersions. This study highlights and expands our understanding about the complex crystallization behavior of semicrystalline systems and is crucial for preparation of solid dispersions with reproducible and consistent physicochemical properties and pharmaceutical performance.
Subject(s)
Drug Carriers/chemistry , Drug Compounding/methods , Indomethacin/chemistry , Calorimetry, Differential Scanning , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Crystallization , Fats/chemistry , Nonlinear Optical Microscopy , Oils/chemistry , Poloxamer/chemistry , Polyethylene Glycols/chemistry , Solubility , Spectroscopy, Fourier Transform Infrared , X-Ray DiffractionABSTRACT
The all-phosphorus analogue of benzene, stabilized as middle deck in triple-decker complexes, is a promising building block for the formation of graphene-like sheet structures. The reaction of [(CpMo)2 (µ,η(6) :η(6)-P6)] (1) with CuX (X=Br, I) leads to self-assembly into unprecedented 2D networks of [{(CpMo)2P6}(CuBr)4 ]n (2) and [{(CpMo)2 P6}(CuI)2]n (3). X-ray structural analyses show a unique deformation of the previously planar cyclo-P6 ligand. This includes bending of one P atom in an envelope conformation as well as a bisallylic distortion. Despite this, 2 and 3 form planar layers. Both polymers were furthermore analyzed by (31)P{(1)H} magic angle spinning (MAS) NMR spectroscopy, revealing signals corresponding to six non-equivalent phosphorus sites. A peak assignment is achieved by 2D correlation spectra as well as by DFT chemical shift computations.
ABSTRACT
An efficient, simplified protocol for solvent-drop assisted co-crystal preparation of ezetimibe (a drug for the treatment of primary hypercholesterolemia) with both imidazole and l-proline has been derived. The structures of the white powders were successfully solved via "NMR crystallography" combining solid-state NMR, powder X-ray diffraction and DFT chemical shift computations. Detailed insights into the likely crystallization mechanism were obtained from competition experiments, where efficient co-crystallization was feasible using ezetimibe monohydrate as precursor indicating that the crystal water acts as "molecular catalyst". It was also found that co-crystallization of imidazole is favored over l-proline, thus suggesting a clear preference of neutral hydrogen bonds compared to charge-assisted motifs.
Subject(s)
Ezetimibe/chemistry , Crystallography, X-Ray , Imidazoles/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Proline/chemistryABSTRACT
ß-sheet-encoded anionic and cationic dendritic peptide amphiphiles form supramolecular copolymers when self-assembled in a 1:1 feed ratio of the monomers. These ampholytic materials have been designed for on-off polymerization in response to pH triggers. The cooperative supramolecular self-assembly process is switched on at a physiologically relevant pH value and can be switched off by increasing or decreasing the pH value.
Subject(s)
Polymers/chemical synthesis , Hydrogen-Ion Concentration , Molecular Structure , Polymers/chemistryABSTRACT
While reacting the sterically demanding triphosphaferrocene [Cp*Fe(η(5)-P3C2Mes2)] () with Cu(i) halides, the sandwich complex undergoes an unprecedented fragmentation into decamethylferrocene, FeX2 (X = Cl, Br, I) and [P3C2Mes2](-) units. Subsequently, these phospholyl ligands act as versatile, negatively charged building blocks for the formation of supramolecular aggregates representing the monomeric, dimeric and polymeric (1D and 2D) coordination compounds [(P3C2Mes2)2{Cu7(CH3CN)7(µ4-X)(µ3-X)2(µ-X)}{Cu2(µ2-X)2X}{Cu(CH3CN)(µ2-X)}]2·6CH3CN (·6CH3CN: X = Cl, ·6CH3CN: X = Br), [(P3C2Mes2)2{Cu(CH3CN)}6(µ-Br)2(µ3-Br)2{Cu(CH3CN)2Br}2]·CH3CN (·CH3CN), [(P3C2Mes2)4{Cu5(CH3CN)5(µ2-Br)}{Cu(CH3CN)2CuBr2}2{Cu(CH3CN)2}]n(+)[CuBr2]n(-)·2CH3CN (·2CH3CN), [(P3C2Mes2){Cu(CH3CN)(µ-I)}4{Cu(CH3CN)3}]·0.5C7H8·2.5CH3CN (·0.5C7H8·2.5CH3CN), [(P3C2Mes2)Cu7(CH3CN)4(µ4-I)2(µ3-I)2(µ-I)2]x·2C7H8 (·2C7H8), [(P3C2Mes2){Cu(CH3CN)3}2{Cu(µ-I)}6]·0.5CH2Cl2·3CH3CN (·0.5CH2Cl2·3CH3CN) and [Cp*Fe(CH3CN)3]n(+)[(P3C2Mes2)2{Cu(CH3CN)2}{Cu(µ-I)}6]n(-)·0.6CH2Cl2 (·0.6CH2Cl2) with rather non-typical structural motifs within the large varieties of copper halide chemistry. Besides the X-ray structural analyses the obtained assemblies were also characterized in solution in which they undergo fragmentation and re-aggregation processes.
ABSTRACT
Polymorphism phenomena in P,P-[3]ferrocenophanes were studied by (31)P and (13)C solid-state NMR spectroscopy and suitable DFT calculations. "No-bond" indirect (31)P(31)P spin-spin coupling constants serve as a rather sensitive tool for the characterization of such systems, particularly since this NMR observable strongly depends on intermolecular PP distances and mutual orientations of the phosphorus lone pairs. Indeed, the structure of a previously unknown pseudo-polymorphism of a P,P-[3]ferrocenophane was determined via the emerging tool kit of "NMR crystallography", where structural inputs and constraints determined by modern solid-state NMR techniques, aided by DFT calculations, are used for faster and more reliable structure solution or refinement of X-ray powder diffraction patterns. Based on this approach it is demonstrated that the observed pseudo polymorphism is related to reversible incorporation of dichloromethane in the crystal structures.