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Experimental investigations of the batch seeded crystallization of paracetamol in 2-propanol were carried out at 200, 300, and 375 rpm agitation rates, using a large seed size (355-500 μm) and a low level of initial supersaturation (S0 = 1.2) in a laboratory scale reactor. Such experiments are normally conducted for the indirect measurement of crystal growth, contingent on the assumption of negligible nucleation, agglomeration, and breakage. In the present work a copious increase in crystals nuclei was noted shortly following seed addition. The formation of substantial numbers of new nuclei was substantiated through focused beam reflectance measurement, laser diffraction, and scanning electron microscopy. Secondary nucleation was proposed as the origin of the new crystals, and a secondary nucleation threshold was determined, with relative supersaturation between 1.09 and 1.11. Below this limit, crystal growth only was apparent. A study was undertaken to investigate the origin of secondary nucleation. Crystal nuclei breeding, as a mechanism of secondary nucleation, has being theorized for many years; however, it is only very recently that definitive molecular dynamics simulations have provided mechanistic insight as to its action. The mechanically driven attrition and breakage mechanism of secondary nucleation remains prominent in the literature. Stirred vessel experiments were conducted using paracetamol seed crystals suspended in a nonsolvent indicated. Despite 3 h of continuous agitation, no significant change in particle number or size was detected. Only after a threshold of 4 h were significant crystal fatigue and fragmentation evident. Shadowgraphy investigations of crystal jet wall impingement revealed the squeeze film as a key protective element in preventing crystal attrition and breakage. A low temperature (283.15 K) crystallization was conducted which indicated a significant temperature dependency, entirely inconsistent with the attrition and breakage mechanism of secondary nucleation. It was shown through the use of smaller seed crystals (125-250 μm), a high agitation rate, and elevated solution temperature that the rate of secondary nucleation could be enhanced thereby creating the potential for confounding rapid secondary nucleation with growth. The current work elucidates the potential impact of cluster breeding in laboratory scale crystallizations and furthermore provides additional experimental support for the crystal breeding mechanism of secondary nucleation. [ABSTRACT FROM AUTHOR]

The solubility of (S)-3-(aminomethyl)-5-methylhexanoic acid in both 2-propanol and water and methanol and water mixtures, as well as in pure solvents, is reported across the temperature range of 283.15-338.15 K, as determined gravimetrically under atmospheric conditions. The experimental data is correlated using the empirical Apelblat and (CNIBS)/Redlich-Kister equations to describe the influence of temperature and solvent composition on solubility, respectively. A maximum solubility is observed between x2/(x2 + x3) = 0.15 and x2/(x2 + x3) = 0.25 for 2-propanol and water mixtures and between x2/(x2 + x3) = 0.35 and x2/(x2 + x3) = 0.5 for methanol and water mixtures. The solubility data is then used to estimate the binary activity coefficient using the Wilson and NRTL activity coefficient models, as well as the coefficients of the Jouyban-Acree empirical solubility model, as a function of temperature and composition. The goodness of fit is determined using the mean square error as a metric in which the Jouyban-Acree model provides the best fit to the solubility data. The modified Apelblat equation is also used to calculate enthalpies of solution under standard conditions. [ABSTRACT FROM AUTHOR]

A stochastic formulation for the description of cooling-antisolvent mediated crystal growth processes based on the Fokker-Planck equation is discussed. Previous results are further extended to include not only the additional degree of freedom (temperature) in the approach, but also to formulate the model parameters dependencies with the input manipulated variables (antisolvent flow rate and temperature) toward a global model to be used within all possible operating regimes. The obtained global models are used to define, for the first time, an operating map of the crystallization process, where asymptotic isomean and isovariance curves are reported in an antisolvent flow-rate-temperature plane. Input multiplicities are identified and validated both numerically and experimentally for the NaCl-water-ethanol nonisothermal antisolvent crystallization system. © 2013 American Institute of Chemical Engineers AIChE J, 59: 2843-2851, 2013 [ABSTRACT FROM AUTHOR]

A new formulation of the recent stochastic approach for the description of the particle-size distribution (PSD) time evolution in antisolvent crystal-growth processes is presented. In this new approach, the crystals size is modeled as a random variable driven by a Gompertz growth term and the corresponding Fokker-Planck equation is carried out. This proposed formulation, allows an analytical solution to describe the time evolution of the PSD as a function of the model parameters. The analytical solution is obtained by exploiting the typical properties of linear partial differential equations with linear coefficients, and using the analogy with Kalman filter, in terms of the first two stochastic moments: mean and variance of the PSD. Furthermore, an alternative way for the parameters estimation based on the maximum likelihood estimation is also introduced. Validations against experimental data are provided for the NaCl-water-ethanol antisolvent crystallization system. © 2012 American Institute of Chemical Engineers AIChE J, 2012 [ABSTRACT FROM AUTHOR]

[Display omitted] The ongoing transition from batch to continuous manufacturing offers both challenges and opportunities in the field of oral solid dosage form production. In turn, Process Analytical Technology (PAT) offers a path towards the successful deployment of continuous tablet manufacturing in rotary tablet presses. One promising PAT tool for this endeavour is the NIR-derived potency measurement. However, the high degree of noise in the data may hamper the extraction of useful information. For this reason, this work focused on the implementation of an adaptive Kalman filter algorithm that incorporates and reconciles the potency prediction given by one or more NIR probes with those of a semi-mechanistic compartmental model developed for the application at hand. This approach allowed for more robust concentration estimations. Furthermore, it was observed that potency levels in multiple locations in the studied tablet press (including those in the finished tablets) could be appropriately inferred using a single in-line measurement data stream. This methodology thus opens the door to advanced process control applications. [ABSTRACT FROM AUTHOR]

[Display omitted] • A hybrid quantitative method combining a PLS and a Soft Sensor potency estimation. • Implemented and applied on continuous direct compression manufacturing. • Improved overall estimation robustness and facilitates cross-site method transfer. Near Infrared (NIR) spectroscopy is commonly utilized for continuous manufacturing as Process Analytical Technology (PAT) tool. This paper focus on a continuous direct compression manufacturing process, in which an NIR PAT probe is integrated into the tablet press feed frame and into the tablet diversion control system to ensure continuous monitoring of the potency and homogeneity of the blend within the process line. The quantification of NIR spectra is achieved through Partial Least-Squares (PLS) modeling, calibrated with offline analyzed tablet cores at different potency levels. Because the NIR measurements are often sensitive to sample physical properties caused by raw materials or process conditions, etc., adopting a data-driven approach will require a large amount of representative data throughout the method lifecycle. During the early stages of process development, whenever new uncaptured source of variability in the model space are encountered, the chemometric predictions can deviate from the offline reference, requiring frequent model updates. These deviations can be reduced by integrating process and physico-chemical knowledge in the on-line potency estimation. This paper presents a novel hybrid method combining the online NIR PLS and a potency soft sensor estimation, enabling a robust potency prediction whilst minimizing maintenance downtimes and facilitating cross-site method transfer. [ABSTRACT FROM AUTHOR]

[Display omitted] The influence of different tableting process parameters on lead-lag was studied by collecting in-line near-infrared (NIR) spectra in the filling chamber of the tablet press feed frame and off-line NIR tablet data. Lead-lag is defined as the difference in time and API concentration between the measured in-line feed frame NIR response and the off-line NIR tablet data. Lead-lag results from the product formulation blend undergoing additional mixing after passing the NIR probe inside the feed frame, before being filled into the dies of the tablet press. A design of experiments (DoE) was performed to evaluate the effect of the tableting process factors paddle speed, turret speed, overfill level, paddle speed ratio and feed frame type upon lead-lag. Paddle speed and turret speed were identified as the only tableting parameters affecting lead-lag. Lead-lag decreased with increasing paddle speed or turret speed and became negligible at high paddle speed and high turret speed. Overfill level, paddle speed ratio and feed frame type did not affect lead-lag, suggesting that the amount and the trajectory of the recirculating powder in the feed frame did not significantly vary and hence influence the lead-lag within the examined process factor ranges. Finally, a methodology was developed using the in-line feed frame NIR measurements for the continuous monitoring and control of blend potency and tablet content uniformity. Tablet diversion should start when the in-line feed frame monitored blend potency exceeds the predefined control limits and can discontinue when this blend potency is again within the control limits for a duration equal to the lead-lag time. A combination of continuous blend potency monitoring inside the feed frame and in-process tablet weight control allows real-time tablet content uniformity assurance. Although the findings of this study are restricted to the specific equipment, tableting parameter ranges and product formulation used, the suggested approach for lead-lag determination and continuous tablet content uniformity monitoring can be applied to any rotary tablet press and product formulation. [ABSTRACT FROM AUTHOR]

[Display omitted] • A novel hybrid soft sensor for monitoring blend potency along continuous direct compression line. • Capable of estimating tablet potency with R2 = 96% linearity across 85%-115% potency range. • Application in control strategy for product diversion and APC to minimize variability in potency. One of the critical quality attributes of the solid oral dosage forms produced in continuous direct compression operations is the tablet potency. A novel soft sensor comprising of a combination of first principle-based and empirical models has been developed to enable real-time monitoring of blend and tablet potency, and concentrations of other excipients at various stream levels along the direct compression line. The soft sensor model has only three adjustable parameters, primarily associated with the equipment design and operation, so the model is product agnostic which is key to enable flexible manufacturing. The estimation accuracy of the soft sensor is demonstrated through a series of real time experiments which include steady state and dynamic transitions of potency during the runs, compared with offline analytically tested tablet cores. The results indicate that the proposed soft sensor can be utilized as a robust tool for real-time monitoring of potency, suggesting an extension of its utilization to higher levels of control. Two potential applications of the soft sensor are: 1. An element of a control strategy for product diversion; 2. A predictive model for advanced process control strategy to minimize the variability in tablet composition. [ABSTRACT FROM AUTHOR]