Monitoring and optimization of industrial batch crystallization processes using NIR and ATR UV-vis spectroscopy

In the pharmaceutical industry, batch crystallization processes at production scale are not always well understood. Several factors have a significant impact on the process of crystallization, such as the physicochemical properties (solubility curve and super-saturation level), the crystal seeding (amount, purity and specific area), the engineering design (crystallizer and propeller), and the control (heating, cooling and stirring rates) [1]. When these factors are poorly understood or insufficiently controlled, they may produce batch-to-batch inconsistencies in terms of size distribution or polymorphic structure of crystals, and lead to pharmaceutical products that may be out of specifications. Online spectroscopic techniques are widely used in industry as they allow to acquire data in real-time, without any sampling, quenching or dilution procedure. Near-infrared (NIR) and attenuated total reflectance (ATR) ultraviolet visible (UV-vis) spectroscopy are two of these online spectroscopic techniques that are routinely used in industry to test, validate and monitor batch crystallization processes [2,3]. [1] Billot et al, "A Review of the use of process analytical technology for the understanding and optimization of production batch crystallization processes" Org. Process Res. Dev., 2010, 14, 511-523 [2] Fevotte et al, "Applications of NIR spectroscopy to monitoring and analyzing the solid state during industrial crystallization processes" Int. J. Pharm., 2004, 273, 159-169 [3] Barrett et al, "Application of ATR-UV spectroscopy for monitoring the crystallization of UV absorbing and non-absorbing molecules" Org. Process Res. Dev., 2005, 9, 348-35

Unraveling the Effect of Rh Isolation on Shallow d States of Gallium–Rhodium Alloys

In this study, we report the electronic and chemical structure of supported GaRh alloys as model systems for the active phase in supported catalytically active liquid metal solutions (SCALMS). We prepared a series of gallium–rhodium samples with different Rh contents and tracked the evolution of the sample topography and surface electronic structure via photoemission spectroscopy in combination with ab initio calculations and electron microscopy. Our results reveal a characteristic shift of the Rh 3d core levels and narrowing and shifting of the Rh 4d derived band with decreasing Rh content. Calculations show that these spectroscopic observations can be explained by the coexistence of isolated Rh atoms in random GaRh alloys and GaRh intermetallic compounds (IMCs). These results contribute to an enhancement of the fundamental understanding of the electronic surface structure of GaRh alloys, which is crucially required for apprehending and thus further exploiting the improved catalytic activity of GaRh SCALMS

Multivariate Modeling and Chemometric Resolution of Mixture Spectra in Dynamic Reaction Systems

In chemometrics, two very different classes of mathematical tools, self-modeling curve resolution and hard-modeling (first-principles) methods, have been developed to resolve pure component concentration profiles and spectra from mixture spectra recorded over time during dynamic processes in application areas from overlapped chromatographic peaks to industrial batch processes. This paper presents advantages and disadvantages of each approach via examples, and two novel applications for modeling dissolution, reaction and crystallization process in one comprehensive first-principles model. In self-modeling curve resolution (SMCR) methods, realistic constraints such as non-negativity of concentration profiles or equality constraints for known pure component spectra are imposed to produce solutions that obey the constraints and Beer’s law. In many cases, SMCR may be the only method available for resolving the pure component profiles; however, it is widely appreciated that in most circumstances, SMCR techniques do not produce unique mathematical solutions, rather a family of feasible solutions that obey boundaries imposed by the constraints. In this presentation, SMCR with a method for computing the range of feasible solutions is illustrated. An algorithm for SMCR that yields improved results by use of soft constraints with penalty functions is also described. Methods of fitting first-principles multivariate kinetic models are powerful alternatives to SMCR. Such modeling methods do not suffer from ambiguities in the resulting solutions. In process monitoring and control applications, numerical fitting of comprehensive kinetic models use dynamic information to estimate reaction rates, chemical equilibria, process states, end-points, deviations from optimal performance and can provide mechanistic information for process adjustment and optimization

Kinetic modelling of dissolution and crystallization of slurries with attenuated total reflectance UV-visible absorbance and near-infrared reflectance measurements

Slurries are often used in chemical and pharmaceutical manufacturing processes but present challenging on-line measurement and monitoring problems. In this paper, a novel multivariate kinetic modeling application is described that provides calibration-free estimates of time-resolved profiles of the solid and dissolved fractions of a substance in a model slurry system. The kinetic model of this system achieved data fusion of time-resolved spectroscopic measurements from two different kinds of fiber-optic probes. Attenuated total reflectance UV-Visible (ATR UV-Vis) and diffuse reflectance near infrared (NIR) spectra were measured simultaneously in a small-scale semi-batch reactor. A simplified comprehensive kinetic model was then fitted to the time-resolved spectroscopic data to determine the kinetics of crystallization and the kinetics of dissolution for online monitoring and quality control purposes. The parameters estimated in the model included dissolution and crystal growth rate constants, as well as the dissolution rate order. The model accurately estimated the degree of supersaturation as a function of time during conditions when crystallization took place and accurately estimated the degree of undersaturation during conditions when dissolution took place

Kinetic modeling of dissolution of salicylic acid with in situ ATR UV-vis spectroscopy

Process Analytical Technologies (PAT) recommended by the Food and Drug Administration (FDA) have significantly increased during the past years in the design, control and monitoring of pharmaceutical manufacturing processes [1]. Nowadays PAT is also commonly used in Good Manufacturing Practices (GMP). Some PAT techniques employ on-line fiber-optic sensors to acquire non-destructive measurements of physical properties, kinetic information about dissolved molecule and solid fraction of particles in slurries, in real time [2]. This study uses attenuated total reflectance ultra-violet visible (ATR UV-vis) spectroscopy for kinetic modeling of the dissolution of salicylic acid in ethanol-water within a small-scale semi-batch reactor. The dissolution model, which relies on a power-law equation, can be obtained by adding aliquots of an ethanol-water mixture into a salicylic acid slurry. Near-infrared (NIR) diffuse reflectance spectroscopy is used to detect the degree of saturation and quantify the solid fraction using a classical Kubelka-Munk transformation followed by a calibration. A temperature probe is also used to monitor heat changes involved in this dissolution. [1] Fevotte G., International Journal of Pharmaceutics 241 (2002) 263-278 [2] Gemperline et al, Analytical Chemistry 76 (2004) 2575-258

Kinetic modeling of dissolution and crystallization of batch reactions with in situ spectroscopic measurements

The use of Process Analytical Technologies (PATs) recommended by the Food and Drug Administration (FDA) has significantly increased during the past years in the design, control and monitoring of pharmaceutical or chemical manufacturing processes [1]. Nowadays PAT is also commonly used in Good Manufacturing Practices (GMPs). Some PAT techniques employ on-line fiber-optic sensors to acquire non-destructive measurements of physical properties and kinetic information of dissolved and solid fraction of molecular substances in slurries in real time [2]. The main objective of this project is to develop a global model for DuPont’s sulfonylurea coupling reaction for monitoring purposes (e.g. detect process upset, detect endpoint, and forecast changes). The global model will allow us to estimate the kinetics of the reaction, the kinetics of nucleation, the kinetics of dissolution, and the kinetics of crystallization. Before such complex model can be developed, it is necessary to conduct experiments in a simpler system (e.g. salicylic acid in water-ethanol mixture). These experiments allow us to control critical parameters and establish precisely known conditions. In addition, they are designed so the process of dissolution and the process of crystallization can be observed independently one another, and independently of chemical reactions. Consequently, we will be able to develop an appropriate model for each process in our small-scale semi-batch reactor. For the simpler system, this study uses attenuated total reflectance ultra-violet visible (ATR UV-vis) spectroscopy for kinetic modeling of the dissolution and crystallization of salicylic acid in ethanol-water. The dissolution model, which relies on a power-law equation, can be obtained by adding aliquots of an ethanol-water mixture into a salicylic acid slurry. Near-infrared (NIR) diffuse reflectance spectroscopy is used to detect the degree of saturation, quantify the solid fraction present in a slurry using a calibration, and for verification and validation purposes. A temperature probe is also used to monitor heat changes involved in this dissolution. [1] Fevotte G., International Journal of Pharmaceutics 241 (2002) 263-278 [2] Gemperline et al, Analytical Chemistry 76 (2004) 2575-258

Kinetic modelling of batch slurry reactions

Slurries are widely used in important chemical and pharmaceutical manufacturing processes. In this presentation we report chemical monitoring and modeling of batch slurry reactions using optical and calorimetric measurement where key analytes are present in both the solid and liquid phases. Experimental studies were performed to: (1) Generate supersaturated solutions for the development of kinetic models of seeded crystallization, crystal growth, and dissolution; (2) Generate unseeded crystallization from homogeneous reaction mixtures for the development of kinetic models of reacting systems, including crystal growth as well as measurement of crystallization driven by cooling of reaction mixtures including the necessary corresponding solubility curves as a function of temperature; (3) Reproduce at laboratory scale, a commercially relevant slurry reaction starting with heterogeneous reaction mixture, producing a product slurry. Simultaneous UV/visible attenuated total reflectance (ATR) and NIR reflectance measurements enabled reliable characterization of reaction mixtures and detection of the onset of crystallization. Kinetic models for dissolution, seeded crystallization, unseeded crystallization, homogeneous reaction and crystallization driven by cooling were successfully developed relating the mass of substance in the solution phase and solid phase to UV/Vis ATR and NIR reflectance measurements. Reactive crystallization experiments with kinetic modeling demonstrated that simultaneous measurements of slurries with UV/Vis ATR and NIR reflectance is an effective means of characterizing the dissolved fraction and the onset of nucleation and crystallization. Work with research partner DuPont Crop Protection Science included development of a 4 L glass reactor with a recirculation loop and sampling system for off-line HPLC analysis. Several different sampling strategies were tested to develop a robust, reproducible method for off-line HPLC analysis. NIR reflectance measurements of slurry reactions at DuPont were demonstrated to be relevant to the property of interest. Kinetic models were obtained for product and reactant from NIR reflectance measurements. Reaction progression was followed by depletion of triazine heterocycle, as indicated by N-H overtone band dissipation. Spectroscopic evidence of a precipitation event was also observed and confirmed by focused beam reflectance measurements (FBRM). Kinetic models of reaction measurements provided clear resolution of two components, the solid phase reactant and solid phase product. Initial product appearance in the kinetic model concentration profile estimates corresponded temporally with the spectroscopic evidence of precipitation. Estimation of spectral profiles from kinetic models include an N-H overtone band observed around 2010nm

Pseudogap-less high Tc_{c} superconductivity in BaCox_{x}Fe2−x_{2-x}As2_{2}

The pseudogap state is one of the peculiarities of the cuprate high temperature superconductors. Here we investigate its presence in BaCo$_{x}$Fe$_{2-x}$As$_{2}$, a member of the pnictide family, with temperature dependent scanning tunneling spectroscopy. We observe that for under, optimally and overdoped systems the gap in the tunneling spectra always closes at the bulk T$_{c}$, ruling out the presence of a pseudogap state. For the underdoped case we observe superconducting gaps over large fields of view, setting a lower limit of tens of nanometers on the length scale of possible phase separated regions.Comment: 5 pages, 3 figure

Informed consent for MRI and fMRI research: Analysis of a sample of Canadian consent documents

<p>Abstract</p> <p>Background</p> <p>Research ethics and the measures deployed to ensure ethical oversight of research (e.g., informed consent forms, ethics review) are vested with extremely important ethical and practical goals. Accordingly, these measures need to function effectively in real-world research and to follow high level standards.</p> <p>Methods</p> <p>We examined approved consent forms for Magnetic Resonance Imaging (MRI) and functional Magnetic Resonance Imaging (fMRI) studies approved by Canadian research ethics boards (REBs).</p> <p>Results</p> <p>We found evidence of variability in consent forms in matters of physical and psychological risk reporting. Approaches used to tackle the emerging issue of incidental findings exposed extensive variability between and within research sites.</p> <p>Conclusion</p> <p>The causes of variability in approved consent forms and studies need to be better understood. However, mounting evidence of administrative and practical hurdles within current ethics governance systems combined with potential sub-optimal provision of information to and protection of research subjects support other calls for more scrutiny of research ethics practices and applicable revisions.</p