| 1. |
- Heffernan, C., et al.
(författare)
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Extraction and Purification of Curcuminoids from Crude Curcumin by a Combination of Crystallization and Chromatography
- 2017
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Ingår i: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 21:6, s. 821-826
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Tidskriftsartikel (refereegranskat)abstract
- In this work a method is developed for the extraction and purification of the three curcuminoids, curcumin (CUR), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC), from commercially available crude curcumin. In a previous publication the extraction of pure curcumin by repeated crystallization has been described. The focus of this paper is on the following chromatographic treatment of the mother liquor from the crystallization to obtain pure DMC and BDMC and to increase the yield of pure CUR. In the chromatographic process, a mixture of chloroform and methanol is used as the mobile phase, and silica gel is used as the stationary phase. Each fraction isolated in the chromatographic process was characterized by high-performance liquid chromatography (HPLC) and mass spectrometry (LC-MS) techniques, and the pure CUR, DMC, and BDMC solid phases were fully characterized by powder Xray diffraction (PXRD), differential scanning calorimetry (DSC), and thermal gravimetric analysis (TGA). Stability studies were performed on the purified curcuminoids where the degradation products were observed and analyzed by HPLC/LC-MS. Overall, the combined purification method recovered from the crude: 88.5%, 79.7%, and 68.8% of CUR, DMC, and BDMC, respectively, in highly pure form CUR (100%), DMC (98.6%), and BDMC (98.3%).
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| 2. |
- Hodnett, B. K., et al.
(författare)
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The SSPC : Leading the way for next-generation medicines manufacture
- 2015
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Ingår i: European Pharmaceutical Review. - : Russell Publishing. - 1360-8606. ; 20:4, s. 33-37
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Tidskriftsartikel (refereegranskat)abstract
- The Synthesis and Solid State Pharmaceutical Centre (SSPC), a global hub of pharmaceutical process innovation and advanced manufacturing, is funded by Science Foundation Ireland (SFI) and Industry, and represents a unique collaboration between 22 industry partners, nine research performing organisations and 12 international academic collaborators (Figure 1; page 34). It is a €42 million state-industry investment, which supports a globally-leading research team of 38 investigators, 34 post-doctoral researchers and 60 PhD candidates. As the largest research collaboration in Ireland and one of the largest globally within the pharmaceutical area, the SSPC transcends company and academic boundaries (Figure 2; page 34). Its role is to link experienced scientists and engineers in academia and the pharmaceutical industry, to address critical research challenges and to deliver industry-relevant solutions, which result in job growth and retention within the pharmaceutical industry.
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| 3. |
- Hu, Y., et al.
(författare)
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Solid-state transformations of sulfathiazole polymorphs : The effects of milling and humidity
- 2013
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Ingår i: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 13:8, s. 3404-3413
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Tidskriftsartikel (refereegranskat)abstract
- The effect of milling on the transitions of sulfathiazole polymorphs in the absence and presence of solvent and excipients was monitored by X-ray powder diffraction (XRPD), attenuated total reflectance infrared (ATR-IR), and near-infrared (NIR) spectroscopy. Sulfathiazole forms FII-FV undergo a transformation toward the metastable FI, which involves an intermediate amorphous stage upon milling at ambient temperature. Milling the commercial form (FC) with catalytic amounts of solvent converts it to pure FIV or to mixtures of FI and FIV depending on the solvent used. Pure FIV can be easily prepared from FC by this method. The physical stability of nonmechanically activated pure sulfathiazole forms in the presence of different levels of relative humidity (RH) was also investigated. At low RH, all sulfathiazole forms are kinetically stable, but at RH levels above 70% FII, FC and FIV remain stable, while FI and FV transform to mixtures of FII and FIV without any apparent change in the external form of the crystals. Comilling FC with a range of excipients gave results that depended on the excipient used, and comilling with cellulose gave samples that had an amorphous content that was stable at 10% RH for at least nine months at ambient temperature.
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| 4. |
- Croker, D. M., et al.
(författare)
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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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Ingår i: Organic Process Research & Development. - Washinhton, USA : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 19:12, s. 1826-1836
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Heffernan, C., et al.
(författare)
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Effects of structurally - related impurities on the crystal growth of curcumin spherulites
- 2022
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Ingår i: CrystEngComm. - : Royal Society of Chemistry (RSC). - 1466-8033. ; 24:28, s. 5156-5169
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Tidskriftsartikel (refereegranskat)abstract
- The crystal growth of curcumin in pure propan-2-ol and in this solvent containing two structurally related impurities, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), has been investigated by seeded isothermal desupersaturation experiments at 283, 293 and 308 K. In situ attenuated total reflectance UV-visible spectroscopy and focused beam reflectance measurement were used as process analytical technologies to monitor the solution concentration over time and to track the particle counts. Both impurities are found to slow down the growth of curcumin spherulites. The product particles collected after growth in the presence of the impurities present a rougher and more porous surface appearance in comparison to curcumin crystalline material grown in pure solutions. A detailed analysis of the powder X-ray diffraction patterns along with compositional analysis by high performance liquid chromatography of grown crystals reveals that impurities are not incorporated into the solid phase except at the highest impurity concentrations explored. By molecular modelling it is shown that the influence of impurities on the diffractograms of the material grown at high impurity concentrations is consistent with the formation of a solid solution. By fitting the Birth and Spread theory to the experimental growth data it is found that the interfacial energy for growth in the presence of the impurities is higher than that for growth of curcumin in the absence of impurities. Two scenarios are envisaged explaining the results. The first is that 3-D nucleation occurs on the impurity encumbered CUR crystallite generating new crystalline material on which crystal growth may continue. The second scenario envisages that a molecular cluster from the solution attaches to the impurity-encumbered surface and condenses into a crystalline surface nucleus without perfect lattice matching.
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| 6. |
- Heffernan, C., et al.
(författare)
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Influence of Structurally Related Impurities on the Crystal Nucleation of Curcumin
- 2018
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Ingår i: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 18:8, s. 4715-4723
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Tidskriftsartikel (refereegranskat)abstract
- In this work, the influence of the structurally related impurities, demethoxycurcumin (DMC) and bisde-methoxycurcumin (BDMC) on the primary nucleation of curcumin (CUR) has been investigated in propan-2-ol. The induction time for nucleation was measured at different CUR driving forces and impurity concentrations 0.10 mmol.dm(-3), 0.30 mmol.dm(-3), and 0.60 mmol.dm(-3) and the results are analyzed by the classical nucleation theory (CNT). The nucleation rate for the impure systems was noticeably lower than the nucleation rate of the pure system, and the times of growth to visibility were much longer for the impure systems. The pre-exponential factors are clearly lower for the impure system compared to the pure CUR system, while the increase in the solid-liquid interfacial energy is small. Density functional theory and metadynamic molecular modeling reveal that the 1:1 bonding between CUR and an impurity molecule is stronger than to another CUR molecule, thus suggesting that the developing CUR nucleus has to overcome a certain energy barrier in order to remove the impurity molecules from their surface, which may explain why nucleation of CUR is more difficult in the presence of the structurally related impurities, DMC and BDMC.
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| 7. |
- Maher, A., et al.
(författare)
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Solubility of the metastable polymorph of piracetam (Form II) in a range of solvents
- 2012
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Ingår i: Journal of Chemical and Engineering Data. - : American Chemical Society (ACS). - 0021-9568 .- 1520-5134. ; 57:12, s. 3525-3531
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Munroe, A., et al.
(författare)
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Relative stabilities of the five polymorphs of sulfathiazole
- 2012
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Ingår i: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 12:6, s. 2825-2835
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Tidskriftsartikel (refereegranskat)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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| 9. |
- Munroe, A., et al.
(författare)
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Solution-mediated polymorphic transformation of FV sulphathiazole
- 2014
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Ingår i: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 14:7, s. 3466-3471
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Tidskriftsartikel (refereegranskat)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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| 10. |
- O'Mahony, M. A., et al.
(författare)
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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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Ingår i: Crystal Growth and Design. - : American Chemical Society (ACS). - 1528-7505 .- 1528-7483. ; 13:5, s. 1861-1871
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Tidskriftsartikel (refereegranskat)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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| 11. |
- O'Mahony, M. A., et al.
(författare)
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Measuring the solubility of a quickly transforming metastable polymorph of carbamazepine
- 2013
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Ingår i: Organic Process Research and Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 17:3, s. 512-518
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Tidskriftsartikel (refereegranskat)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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| 12. |
- O'Mahony, M., et al.
(författare)
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Investigating the dissolution of the metastable triclinic polymorph of carbamazepine using in situ microscopy
- 2014
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Ingår i: CrystEngComm. - Royal Society of Chemistry (RSC)) : Royal Society of Chemistry (RSC). - 1466-8033. ; 16:20, s. 4133-4141
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Tidskriftsartikel (refereegranskat)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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| 13. |
- Ukrainczyk, M., et al.
(författare)
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Process Parameters in the Purification of Curcumin by Cooling Crystallization
- 2016
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Ingår i: Organic Process Research & Development. - : American Chemical Society (ACS). - 1083-6160 .- 1520-586X. ; 20:9, s. 1593-1602
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Tidskriftsartikel (refereegranskat)abstract
- Purification of crude curcumin by up to four successive cooling crystallizations has been investigated for a wide variety of process conditions. For each crystallization step the influence of various processing conditions on crystal purity, polymorphic outcome, and crystal size and shape is reported. By an extensive number of experiments according to a statistical experimental design, the influence on cooling rate, seeding, seed polymorph, and agitation conditions has been identified. Slow cooling and seeding, particularly with the metastable Form II seed, significantly improves the purification. A correlation between product crystal size and purity is found. By tuning the crystallization parameters the number of recrystallization steps required to reach a certain purity can be reduced, which significantly increased the overall curcumin yield from 28% to 50%.
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