Polymorph screening: influence of solvents on the rate of solvent-mediated polymorphic transformation.

Solvent-mediated polymorphic transformation is an efficient technique to obtain the most stable polymorph. The rate of solvent-mediated polymorphic transformation of sulfamerazine at 24 degrees C in various solvents and solvent mixtures is controlled by the nucleation rate of the more stable Form II. The transformation rate is generally higher in the solvent giving a higher solubility and is low in the solvent giving a low solubility (8 mmol/L). In these solvents, because of a high interfacial energy, the metastable zone may be wider than the solubility difference between two polymorphs, such that the critical free energy barrier for nucleation cannot be overcome. In addition to the solubility, the strength of the solvent-solute interactions is also important in determining the transformation rate. For sulfamerazine, the transformation rate is lower in the solvent with a stronger hydrogen bond acceptor propensity. Because solubility is higher in the solvent with stronger hydrogen bond acceptor propensity, the balance of solubility and strength of hydrogen bonding interactions between the solute and solvent molecules determines the polymorphic transformation rate. Degree of agitation and temperature also change the polymorphic transformation rate by influencing the crystallization kinetics of the more stable polymorph.

Nuclear magnetic resonance and infrared spectroscopic analysis of nedocromil hydrates.

PURPOSE: Nedocromil sodium (NS), which is used in the treatment of reversible obstructive airway diseases, such as asthma, has been found to exist in the following solid phases: the heptahemihydrate, the trihydrate, a monohydrate, an amorphous phase, which contains variable amounts of water, and a recently discovered methanol + water (MW) solvate. Our aim was to apply 13C solid-state nuclear magnetic resonance (NMR) spectroscopy and solid-state Fourier transform infrared (FTIR) spectroscopy to the study of specific interactions in the various solid forms of NS. METHODS: The 13C solid-state NMR and FTIR spectra of the various solid forms of NS were obtained and were related to the crystal structures of NS, the conformations of the nedocromil anion, and the interactions of the water molecules in these crystals. RESULTS: The 13C solid-state NMR spectrum is sensitive to the conformation of the nedocromil anion, while the solid-state FTIR spectrum is sensitive to interactions of water molecules in the solid state. In NS monohydrate, for which the crystal structure has not yet been solved, and in the amorphous phase, the information about the conformations of the nedocromil anion and the interactions of the water molecules are deduced from the 13C solid-state NMR spectra and solid-state FTIR spectra, respectively. CONCLUSIONS: 13C solid-state NMR spectroscopy and solid-state FTIR spectroscopy are shown to be powerful complementary tools for probing the chemical environment of molecules in the solid state, specifically the conformation of the nedocromil anion and the interactions of water-molecules, respectively.

Cyclical etidronate and calcium carbonate (with citrate) supplementation for osteoporosis unmasking primary hyperparathyroidism.

An 88 year old lady undergoing cyclical etidronate and calcium carbonate (with citrate) therapy for vertebral osteoporosis was found to be symptomatically hypercalcaemic at the end of the first cycle of treatment. She had been previously asymptomatic and normocalcaemic, but was subsequently found to have primary hyperparathyroidism. This condition is most prevalent in postmenopausal females--the same patient group at risk of osteoporosis. Serum calcium should be measured after commencing cyclical etidronate and calcium carbonate. If hypercalcaemia is detected primary hyperparathyroidism should be excluded as an underlying, cause.

Is previous hyperthyroidism still a risk factor for osteoporosis in post-menopausal women?

OBJECTIVE: Hyperthyroidism is a risk factor for osteoporosis, but the relative contributions of the episode of hyperthyroidism and thyroxine replacement for subsequent hyperthyroidism remain uncertain. In this study we have measured bone mineral density (BMD) in post-menopausal women with a previous history of hyperthyroidism, comparing those requiring thyroxine therapy with those remaining euthyroid and with an historical local control population. DESIGN: Cross-sectional study. PATIENTS: One hundred and six post-menopausal women with a previous history of hyperthyroidism. These were divided into four groups: treated with radioiodine, remaining euthyroid (group RU, n = 15); treated with radioiodine, receiving thyroxine for at least 5 years (group RT, n = 46); treated with surgery, remaining euthyroid (group SU, n = 21); treated with surgery, receiving thyroxine for at least 5 years (group ST, n = 24). There were 102 control subjects. MEASUREMENT: Forearm bone mineral density at distal and ultradistal sites as measured by single-photon absorptiometry. RESULTS: Results were expressed as 'Z-scores' i.e. number of standard deviations from the mean of a 5-year age-band from the local control population. Mean Z-scores at distal and ultradistal sites were as follows: -0.61 and -0.81 in group RU; -0.58 and -0.56 in group RT; -0.27 and -0.30 in group SU; -0.81 and -0.57 in group ST. Patients in groups RU, RT and ST but not SU had significantly lower BMD than controls. CONCLUSION: Post-menopausal women with previous hyperthyroidism treated with radioiodine have reduced BMD, whether or not receiving thyroxine. They should be targeted for densitometry and protective therapy with oestrogen should be considered. Those treated with surgery appear to be at less risk; this may be because most are diagnosed and treated whilst premenopausal. Thyroxine may have a deleterious effect in this group; longitudinal studies would provide further clarification.

Crystal structures of a new oral iron chelator, 1,2-dimethyl-3-hydroxy-4-pyridone, and its solvates with acetic acid and formic acid.

The crystal structures of a new oral iron chelator, 1,2-dimethyl-3-hydroxy-4-pyridone (DMHP), and of its 1:1 solvates with formic acid (DMHP,F) and acetic acid (DMHP,A) were determined by single-crystal X-ray diffraction. The data were collected at temperatures of 23 +/- 1 degrees C for DMHP, -64 +/- 1 degrees C for DMHP,F, and -120 +/- 1 degrees C for DMHP,A. The iron chelator DMHP is orthorhombic [Pbca, a = 7.290(5) A, b = 13.046(4) A, c = 13.748(6) A, Z = 8]. The DMHP molecules form centric dimers, each in a 10-membered ring in which the OH group of one molecule is hydrogen-bonded to the CO oxygen of the other [O-H...O; 0.91(4) A, 153(3)degrees, 1.85(4) A]. In each DMHP molecule, the OH group and CO oxygen are insignificantly intramolecularly hydrogen-bonded [O-H...O; 0.91(4) A, 107(3)degrees, 2.33(4) A]. DMHP,F is monoclinic [C2/c, a = 21.825(9) A, b = 3.811(5) A, c = 20.491(6) A, beta = 92.80(3)degrees, Z = 8]. The fundamental intermolecular and insignificant intramolecular hydrogen-bonded dimer structure of DMHP is maintained but is distorted and is supplemented by hydrogen bonds between the CO oxygen of each DMHP molecule and the OH group of one formic acid molecule [O-H...O; 0.99(5) A, 176(3)degrees, 1.53(4) A]. However, the two DMHP and the two formic acid molecules are twisted out of plane like the blades of a four-bladed propeller. DMHP,A is triclinic [P1, a = 8.458(2) A, b = 8.471(2) A, c = 6.986(3) A, alpha = 104.33(2)degrees, beta = 92.57(2)degrees, gamma = 88.78(2)degrees, Z = 2].(ABSTRACT TRUNCATED AT 250 WORDS)