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| 2. |
- Langefeld, Carl D., et al.
(author)
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Transancestral mapping and genetic load in systemic lupus erythematosus
- 2017
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In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
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Journal article (peer-reviewed)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
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| 6. |
- Croker, D. M., et al.
(author)
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Demonstrating the Influence of Solvent Choice and Crystallization Conditions on Phenacetin Crystal Habit and Particle Size Distribution
- 2015
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In: Organic Process Research & Development. - Washinhton, USA : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 19:12, s. 1826-1836
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Journal article (peer-reviewed)abstract
- Phenacetin was used as a model pharmaceutical compound to investigate the impact of solvent choice and crystallization conditions on the crystal habit and size distribution of the final crystallized product. The crystal habit of phenacetin was explored using crash-cooling crystallization (kinetically controlled) and slow evaporative crystallization (thermodynamically controlled) in a wide range of organic solvents. In general, a variety of needle-type shapes (needles, rods, or blades) were recovered from fast-cooling crystallizations, in contrast to hexagonal blocks obtained from slow evaporative crystallizations. The solubility of phenacetin was measured in five solvents from 10-70 degrees C to allow for the design of larger-scale crystallization experiments. Supersaturation and the nucleation temperature were independently controlled in isothermal desupersaturation experiments to investigate the impact of each on crystal habit and size. The crystal size (needle cross-sectional area) decreased with increasing supersaturation because of higher nucleation rates at higher supersaturation, and elongated needles were recovered: Increasing the nucleation temperature resulted in the production of larger crystals with decreased needle aspect ratios. Antisolvent phenacetin crystallizations were developed for three solvent/antisolvent systems using four different antisolvent addition rates to simultaneously probe the crystal habit and size of the final product. In general, increasing the antisolvent addition rate, associated with increased rate of generation of supersaturation, resulted in the production of shorter needle crystals.
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| 8. |
- O'Mahony, M. A., et al.
(author)
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Investigation into the mechanism of solution-mediated transformation from FI to FIII carbamazepine : The role of dissolution and the interaction between polymorph surfaces
- 2013
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In: Crystal Growth and Design. - : American Chemical Society (ACS). - 1528-7505 .- 1528-7483. ; 13:5, s. 1861-1871
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Journal article (peer-reviewed)abstract
- The solution mediated polymorphic transformation (SMPT) of the pharmaceutical compound carbamazepine was investigated in ethanol. Bulk transformation experiments were performed by monitoring the solution concentration and polymorphic composition over time during the transformation from the metastable FI polymorph to the stable FIII polymorph for a variety of initial conditions. Microscopic techniques, single-crystal X-ray diffraction, and computational methods were used to analyze the transformation. The nucleating behavior of the stable FIII polymorph was a significant factor affecting the transformation time across the range of experiments. The surfaces of the metastable FI particles were responsible for the nucleation of FIII during the transformation. However, no specific lattice matching or epitaxy was conclusively identified. A modest amount of dissolution of the FI particles was found to favor the nucleation of FIII but where extensive dissolution or no significant dissolution occurred this had a negative effect on the nucleation of FIII.
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| 9. |
- O'Mahony, M. A., et al.
(author)
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Measuring the solubility of a quickly transforming metastable polymorph of carbamazepine
- 2013
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In: Organic Process Research and Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 17:3, s. 512-518
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Journal article (peer-reviewed)abstract
- The solubility of the stable FIII polymorph of the pharmaceutical compound carbamazepine was measured by determining its solubility gravimetrically in ethanol and methanol. Where the metastable FI polymorph was suspended in a solution of ethanol, the stable FIII polymorph nucleated immediately, initiating a solution-mediated transformation from FI to FIII. This meant that the FI polymorph was not in thermodynamic equilibrium with the solution as FI was continually dissolving while FIII was growing. We show that the solubility of FI can be accurately measured by in situ microscopy using an adaption of the bracketing method, and the results show that the solubility is close to but higher than the maximum solution concentration reached during the solution mediated transformation from FI to FIII carbamazepine in both solvents. The technique demonstrates a relatively simple and robust method for determining the solubility of a metastable crystalline phase which transforms quickly in solution.
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| 10. |
- O'Mahony, M., et al.
(author)
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Investigating the dissolution of the metastable triclinic polymorph of carbamazepine using in situ microscopy
- 2014
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In: CrystEngComm. - Royal Society of Chemistry (RSC)) : Royal Society of Chemistry (RSC). - 1466-8033. ; 16:20, s. 4133-4141
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Journal article (peer-reviewed)abstract
- Despite a tendency to undergo solution-mediated polymorphic transformation, the dissolution behaviour of the metastable FI (triclinic) polymorph of the pharmaceutical compound carbamazepine (CBZ) was investigated using in situ optical microscopy. Experiments were performed at an undersaturation where single crystals of the metastable FI polymorph dissolved. Dissolution in different solvents was investigated at a constant undersaturation. Separately the sublimation of FI was examined and additionally the dissolution was observed at undersaturations where the more stable FIII polymorph crystallized. The results show that both the dissolution and sublimation of FI occur primarily in the direction of the a-axis of the FI crystal structure where the CBZ molecules are found to stack in this direction. The order for the dissolution rate of FI was acetonitrile ≥ methanol > ethanol. The order of the dissolution rates in each of the solvents is inversely correlated to the viscosity and the binding energy of the solvents with the (100) surface of FI in each of the solvents. This suggests that the rate determining step for the dissolution may be either the diffusion or the detachment of CBZ molecules from the surface of FI. A notable difference in dissolution behaviour is also observed at undersaturations where the more stable FIII polymorph nucleates and grows.
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| 11. |
- Croker, D. M., et al.
(author)
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Isothermal suspension conversion as a route to cocrystal production : One-pot scalable synthesis
- 2014
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In: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 18:8, s. 941-946
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Journal article (peer-reviewed)abstract
- Isothermal suspension conversion is presented as a suitable method for the manufacture of pure cocrystal products once the ternary phase diagram (TPD) for the cocrystal system in the desired solvent is available. One:one and 3:2 cocrystals of p-toluenesulphonamide/triphenylphosphine oxide were produced in acetonitrile and dichloromethane using this method. Eight individual batches of product were prepared with complete conversion to pure product achieved in seven batches. Product recovery (77-99%), reaction conversion (17-89%), and volumetric productivity (0.03-0.63 g/cm(3)) were calculated for each product batch. These parameters are essentially determined by the batch operating mass fraction composition selected from the TPD, allowing for tailoring of processing conditions to suit process requirements and capabilities by careful selection of the optimum operating mass fraction composition.
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| 12. |
- Croker, D. M., et al.
(author)
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Nucleation in the p-toluenesulfonamide/triphenylphosphine oxide co-crystal system
- 2013
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In: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 13:8, s. 3754-3762
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Journal article (peer-reviewed)abstract
- Nucleation has been studied in pure co-crystal and mixed co-crystal phase regions of the ternary phase diagram (TPD) in acetonitrile at 20 C using cooling crystallization experiments. Direct nucleation of each of the co-crystal phases in this system was independently observed in regions of the TPD where each is stable. In mixed regions, regions where either a co-crystal and a coformer, or both co-crystals, are stable, the phase that initially nucleated was a function of the mass composition in that region. The relative amount of each phase nucleating could be controlled by adjusting the relative mass fraction of each component. The kinetic return to equilibrium was also observed as the systems were held over time, with the selected mass fractions always returning to the equilibrium dictated by the TPD after 24 h
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| 13. |
- Croker, D. M., et al.
(author)
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Solution mediated phase transformations between co-crystals
- 2013
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In: CrystEngComm. - : Royal Society of Chemistry. - 1466-8033. ; 15:11, s. 2044-2047
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Journal article (peer-reviewed)abstract
- A solution mediated transformation between two co-crystal phases has been observed for the p-toluensulfonamide-triphenylphosphine oxide co-crystal system. This system has two known co-crystals with 1 : 1 and 3 : 2 stoichiometry respectively, and the ternary phase diagram (TPD) for the system has been determined in acetonitrile previously. By manipulating the solution composition in this solvent to a region of the TPD where the 1 : 1 co-crystal is stable, the 3 : 2 co-crystal could be observed to convert to the 1 : 1 co-crystal. The corresponding transformation was true for the 1 : 1 co-crystal in a region of the TPD where the 3 : 2 co-crystal is stable; the 1 : 1 co-crystal converted to the 3 : 2 co-crystal.
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| 14. |
- Maher, A., et al.
(author)
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Solubility of the metastable polymorph of piracetam (Form II) in a range of solvents
- 2012
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In: Journal of Chemical and Engineering Data. - : American Chemical Society (ACS). - 0021-9568 .- 1520-5134. ; 57:12, s. 3525-3531
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Journal article (peer-reviewed)abstract
- The solid-liquid solubility of the polymorph known as Form II of 2-oxo-1-pyrolidine acetamide (Piracetam) has been determined gravimetrically in different solvents. Form II is the metastable polymorph of piracetam at ambient conditions and has been isolated and characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). Monitoring the solution concentration and the polymorphic composition of the solid phase displayed that this metastable form has a sufficient lifetime when in contact with the solvents to allow measurement of its solubility over the temperature range (278 to 323) K. Four solvents are included: ethanol, 2-propanol, acetone, and 1,4-dioxane. The results show that the solubility of Form II increases with increasing solvent polarity and solvent acidity. Form II has a slightly higher solubility than the stable Form III in all solvents at all temperatures, but the solubility difference is very small. Since Form II is known to transform to Form I below its melting point, a set of regression equations which can be used to extrapolate solubility data to the melting point of Form II were applied to the collected data.
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| 15. |
- Munroe, A., et al.
(author)
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Relative stabilities of the five polymorphs of sulfathiazole
- 2012
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In: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 12:6, s. 2825-2835
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Journal article (peer-reviewed)abstract
- The relative stabilities of the five polymorphs of sulfathiazole have been investigated using solution-based and solid-state methods. In the lower temperature range, the stability order is proposed to be FI < FV < FIV < FII < FIII. FI and FV were identified as the least stable polymorphs below 50 °C using a combination of solubility measurements and isothermal suspension equilibration, with FII, FIII, and FIV displaying very similar stabilities. Between 30 and 50 °C, the stability order was established as FIV < FII < FIII. At 10 °C, FII is still more stable than FIV, but it was not possible to place FIII in relation to these two forms. Above 100 °C, the results from DSC and high-temperature XRD measurements suggest that the stability order changes completely as a result of several enantiotropic transitions. In this upper temperature range, FII and FIII are the least stable forms, with FII being less stable than FIII. The stability order among the remaining three forms is FI < FV < FIV initially, but this reverses with increasing temperature, and as the transition into a melt is approached, a stability order of FII < FIII < FIV < FV < FI is suggested.
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| 16. |
- Munroe, A., et al.
(author)
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Solution-mediated polymorphic transformation of FV sulphathiazole
- 2014
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In: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 14:7, s. 3466-3471
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Journal article (peer-reviewed)abstract
- The solution-mediated polymorphic transformation of FV sulphathiazole was investigated in ethanol at 10 °C. Powder X-ray diffraction (PXRD) identified the transformation product as a mixture of FII and FIV sulphathiazole. This mixture remained stable in solution at 10 °C with agitation for 24 h. In situ temperature controlled optical microscopy enabled visualization of the transformation in real time, allowing elucidation of the transformation mechanism. A modest amount of dissolution of FV sulphathiazole preceded the nucleation of FII and FIV crystals, which were detected simultaneously. Thereafter, these polymorphs grew rapidly. Experimental evidence is presented for a mechanism, whereby nucleation of FII and FIV was initiated on the roughened surface of the dissolving FV crystals, without any indication for a spatially extended structural relationship between the host form V and the nucleating phases. Subsequent growth of FII and FIV crystals consumed the remaining FV crystals completing the dissolution-recrystallization mechanism.
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