17 research outputs found
Methods for estimating supersaturation in antisolvent crystallization systems
The mole fraction and activity coefficient-dependent (MFAD) supersaturation expression is the least-assumptive, practical choice for calculating supersaturation in solvent mixtures. This paper reviews the basic thermodynamic derivation of the supersaturation expression, revisits common simplifying assumptions, and discusses the shortcomings of those assumptions for the design of industrial crystallization processes. A step-by-step methodology for estimating the activity-dependent supersaturation is provided with focus on ternary systems. This method requires only solubility data and thermal property data from a single differential scanning calorimetry (DSC) experiment. Two case studies are presented, where common simplifications to the MFAD supersaturation expression are evaluated: (1) for various levels of supersaturation of L-asparagine monohydrate in water–isopropanol mixtures and (2) for the dynamic and steady-state mixed-suspension, mixed-product removal (MSMPR) crystallization of a proprietary API in water–ethanol–tetrahydrofuran solvent mixtures. When compared to the MFAD supersaturation estimation, it becomes clear that errors in excess of 190% may be introduced in the estimation of the crystallization driving force by making unnecessary simplifications to the supersaturation expression. These errors can result in additional parameter regression errors – sometimes by nearly an order of magnitude – for nucleation and growth kinetic parameters, limiting the accurate simulation of dynamic and steady-state crystallization systems
Impurity incorporation in solution crystallization: diagnosis, prevention, and control
Despite their widespread use for purification, our current methods for the development of solution crystallization processes lack a sufficient understanding on how impurities incorporate in growing crystals. This is, in part, due to the large number of mechanisms often encountered for impurity incorporation, and due to limitations in our methods for diagnosis of those mechanisms. These limitations propagate into largely empirical process development strategies, which are still based on trial and error and centered on solvent selection. This manuscript highlights recent developments in the diagnosis, prevention, and control of impurity incorporation during batch and continuous crystallization. The goal is to provide process development scientists with an updated toolkit for understanding how specific impurities are retained in the solid product, and to review recent prevention and control strategies that may be used to improve crystal purity in industrial crystallization processes
Effect of Air Injection on Nucleation Rates: An Approach from Induction Time Statistics
From
disruption of the supersaturated solution to improved mass
transfer in the crystallizing suspension, the introduction of a moving
gas phase in a crystallizer could lead to improved rates of nucleation
and crystal growth. In this work, saturated air has been injected
to batch crystallizers to study the effects on formation of the first
crystal and subsequent turbidity buildup. To account for the typically
large sample-to-sample variation, nucleation rates were evaluated
for a large number of replicates using probability distributions of
induction times. The slope and the intercept of the distributions
were studied independently, allowing the simultaneous determination
of the mean induction time and a certain detection delay related to
the rate of crystal growth after formation of the first nucleus. When
saturated air was injected in aqueous glycine solutions, the average
detection delay was reduced from 69 to 13 min, and the mean induction
time decreased from 128 to 36 min. The effect on aqueous solutions
of l-arginine was less apparent, with a detection delay reduction
from 15 to 3 min, and no significant changes on the rate of primary
nucleation. These results demonstrate the potential of this technique
for reduction in nucleation induction time and improved mass deposition
rates in crystallization operations
Characterization of a Multistage Continuous MSMPR Crystallization Process assisted by Image Analysis of Elongated Crystals
This work demonstrates
how quantitative image analysis can assist
in the characterization of continuous crystallization processes and
in the proper selection of mathematical models for the early assessment
of crystal quality. An active pharmaceutical ingredient presenting
an elongated crystal habit was crystallized using two stirred tank
crystallizers in series. With image analysis of the crystallization
magma, the sources of crystal breakage in the crystallization cascade
were identified, and the impact on crystal habit was evaluated quantitatively.
As it is expected for particles presenting high aspect ratios, crystal
breakage preferentially occurs in the smallest plane, perpendicular
to the largest dimension. This phenomenon is hardly avoidable in downstream
production, but it can be accounted for with a design approach based
on the real crystal dimensions. The kinetic rate equations for nucleation
and crystal growth were determined based on crystal width, from which
a model for the accurate prediction of this dimension was applied.
The predicted crystal size distribution is consistent through a moderate
degree of crystal breakage during downstream processing
Effect of Air Injection on Nucleation Rates: An Approach from Induction Time Statistics
Impurity incorporation in solution crystallization: diagnosis, prevention, and control
This work highlights recent advances in the diagnosis, prevention, and control of impurity incorporation during solution crystallization
Methods for estimating supersaturation in antisolvent crystallization systems
The mole fraction and activity coefficient-dependent (MFAD) supersaturation expression is the least-assumptive, practical choice for calculating supersaturation in solvent mixtures. This paper reviews the basic thermodynamic derivation of the supersaturation expression, revisits common simplifying assumptions, and discusses the shortcomings of those assumptions for the design of industrial crystallization processes. A step-by-step methodology for estimating the activity-dependent supersaturation is provided with focus on ternary systems. This method requires only solubility data and thermal property data from a single differential scanning calorimetry (DSC) experiment. Two case studies are presented, where common simplifications to the MFAD supersaturation expression are evaluated: (1) for various levels of supersaturation of L-asparagine monohydrate in water–isopropanol mixtures and (2) for the dynamic and steady-state mixed-suspension, mixed-product removal (MSMPR) crystallization of a proprietary API in water–ethanol–tetrahydrofuran solvent mixtures. When compared to the MFAD supersaturation estimation, it becomes clear that errors in excess of 190% may be introduced in the estimation of the crystallization driving force by making unnecessary simplifications to the supersaturation expression. These errors can result in additional parameter regression errors – sometimes by nearly an order of magnitude – for nucleation and growth kinetic parameters, limiting the accurate simulation of dynamic and steady-state crystallization systems. ©2019National Science Foundation (grant no. 1122374
Kinetic Optimization of the Batch Crystallization of an Active Pharmaceutical Ingredient in the Presence of a Low-Solubility, Precipitating Impurity
The presence of impurities above regulatory thresholds has been responsible for recent recalls of pharmaceutical drugs. Crystallization is one of the most used separation processes to control impurities in the final drug. A particular issue emerges when impurities are poorly soluble in the crystallization solvent and simultaneously precipitate with the product. This publication reports the development of a population balance model to investigate if the impurity crystallization kinetics can be selectively inhibited in a seeded batch crystallization system containing acetaminophen (ACM), a commonly used small-molecule active pharmaceutical ingredient (API), and curcumin (CUR), a simulated low-solubility/co-precipitating impurity. Raman spectroscopy was used in combination with a partial least squares (PLS) model for in situ monitoring of the crystallization process. The Raman data were integrated to calibrate a population balance model in gPROMS FormulatedProducts, to predict the evolution of the product’s purity throughout the process. Process optimization demonstrated that a high purity close to equilibrium is feasible within the first 2 h of crystallization, with ACM seed purity being the primary factor controlling this phenomenon. The optimal approach for kinetically rejecting impurities requires a low nucleation rate for the impurity, high product seed purities, and an adjustable crystallization time so the process can be stopped before equilibrium without allowing the impurity to nucleate. Overall, an improvement in product purity before equilibrium is attainable if there is enough difference in growth kinetics between the product and impurity, and if one can generate relatively pure seed crystals
Incorporating Solvent-Dependent Kinetics To Design a Multistage, Continuous, Combined Cooling/Antisolvent Crystallization Process
Combined cooling and antisolvent crystallization enables crystallization of many pharmaceutical products, but its process design typically neglects solvent composition influences on crystallization kinetics. This paper evaluates the influence of solvent-dependent nucleation and growth kinetics on the design of optimal, multistage mixed-suspension, mixed-product removal (MSMPR) crystallization cascades. The ability to independently select temperature and solvent compositions in each stage of the cascade serves to greatly expand the attainable region for a two-stage cascade, with diminishing returns for additional stages. Failure to include solvent-dependent kinetics can result in simulating incorrect attainable regions, active pharmaceutical ingredient (API) yields, and crystal size distributions. This work also demonstrates that commonly employed crystallization process design heuristics, such as equal antisolvent addition and decreasing temperature in successive stages, can result in suboptimal process design if kinetics are strongly solvent dependent. Keyword: Crystals; Crystallization; Solvents; Nucleation kineticsNational Institutes of Health (U.S.) (Grant 1122374