1,721,774 research outputs found
A link between the ATR-UV/Vis and Raman spectra of zwitterionic solutions and the polymorphic outcome in cooling crystallization
No full textMany substances can exist in different crystalline forms called polymorphs that have the same chemical formula but different properties such as solubility, density, melting point, stability or bioavailability. In order to guarantee the purity and quality of the final product it is very important to monitor and control the polymorphic form of the crystals during batch or continuous crystallization. Additionally, understanding the solvent effect and how the equilibrium of the different chemical species in solution influences the nucleation and transformation of different polymorphs is fundamental for better design and control of polymorphic crystallization processes. Zwitterionic compounds represent an important class of active pharmaceutical ingredients; in this study ATR-UV/Vis and Raman spectroscopy are used to investigate the relationship between the amount of zwitterions in the clear solution and the polymorphic outcome of cooling crystallizations, using anthranilic acid (OABA) as the model compound. It is shown that the shift in the UV absorbance and in the Raman signal in clear solution caused by changing the equilibrium of different species of OABA (by modifying the composition of the solvent) can be correlated with the polymorphic outcome of the crystallization. The results provide new insight on the effect of equilibrium of the ionic, zwitterionic and neutral species in solution on the polymorphic outcome of crystallization and demonstrate how UV and Raman spectroscopy can be used to control the polymorphic crystallization of zwitterionic compounds by manipulating the solvent composition
Application of process analytical technology-based feedback control strategies to improve purity and size distribution in biopharmaceutical crystallization
No full textPurity is a critical quality attribute for both pharmaceutical and biopharmaceutical products. The presence of impurities (solvents, salts, or byproducts of the synthetic path) in drugs can cause a reduction of their effectiveness or can even be toxic for the patients. Biopharmaceuticals are produced by biological processes which are difficult to control. Therefore, the amount of impurities that has to be removed can be significantly higher than in the case of synthetic pharmaceuticals. The aim of this work is to exploit process analytical technology tools and different feedback control strategies (T-control, direct nucleation control, and supersaturation control) for the crystallization of a biopharmaceutical product. UV/vis spectroscopy and focused beam reflectance measurement combined with a Crystallization Process Informatics System (CryPRINS) were used to improve the crystal size distribution and purity of crystallized vitamin B12. The different feedback control strategies were compared to classical crystallization techniques in terms of purity of the final crystal and quality of the crystal size distribution, and it is shown that using suitable crystallization feedback control strategies, the purity and quality of crystals can be improved
Improving purity and size distribution in biopharmaceutical crystallization using pat-based feedback control strategies
No full textSystematic model identification and optimization-based active polymorphic control of crystallization processes
No full textPolymorphism is an important issue in industrial crystallization, since polymorphs of the same compound can present very different properties, such as solubility, melting point or density, influencing considerably the manufacturability and bioavailability of the final product. This work proposes a model-based active polymorphic control strategy that allows obtaining large crystals of the stable polymorph at the end of a batch crystallization process, even in the case of erroneous seeding or in situ nucleation of a mixture of both the stable and metastable forms. A novel systematic experimental design was applied to estimate the kinetic parameters of dissolution, growth and secondary nucleation of the stable and metastable polymorphs of the model compound (ortho-aminobenzoic acid, OABA). Such experimental approach allows the determination of the studied kinetics without any correlation between parameters during the estimation, and without the need of off-line measurements of the crystal size distribution during the experiments. The estimated kinetic parameters were used to build a population balance model for the calculation of the optimal temperature profile needed, during a batch cooling crystallization process, for the (i) elimination of the metastable form crystals nucleated in situ or erroneously seeded and the (ii) maximisation of the size of the crystals of the stable polymorph obtained at the end of the batch process
Application of raman and ATR-UV/Vis spectroscopy for a model-free and model-based active polymorphic feedback control of crystallization processes
No full textTailoring crystal shape and polymorphism using combinations of solvents and a structurally related additive
No full textControlling polymorphism is one of the most difficult challenges for the pharmaceutical industry. Polymorphs of the same compound can have very different properties that might affect the quality of the final drug. Many studies have focused on trying to determine robust methods to produce specific polymorphs that exhibit the desired characteristics of the drug (solubility and rate of dissolution in particular). The choice of solvent, pH, kinetic conditions and the presence of impurities can all have very strong effects on the polymorphic outcome of cooling crystallization. In this work, the crystallization of ortho-aminobenzoic acid (OABA) in the presence of a structurally related additive (benzoic acid) will be studied using both in situ PAT tools and offline techniques. The effect on morphology, polymorphic outcome, polymorphic transformation kinetics and tendency towards agglomeration in different solvents will be studied using a large variety of instrumentation. The incorporation of benzoic acid in solid solution in the three different polymorphs of OABA will also be quantified and discussed. The results of the crystallization experiments and offline analysis will be compared and interpreted using the information on the crystal structures of the three OABA polymorphs from the Cambridge Crystallographic database
Model-based monitoring of an intensified unit for continuous pharmaceutical filtration-drying
No full textActive pharmaceutical ingredient (API) separation from synthesis and crystallization
mother liquors is typically carried out in pharmaceutical manufacturing through filtration
and drying. These steps are of utmost importance, as impurities herein retained will
inevitably end up in the drug product. Recently, a novel carousel has been developed for
carrying out filtration and drying in a continuous intensified fashion. The unit represents
a step forward with respect to traditional batch filtration and drying, as continuous
operation can reduce the variability of the product quality. However, the occurrence of
faults compromising product compliance can be assessed only upon discharge of the final
cake of API crystals, when its purity can be measured. In this work, we develop a modelbased
monitoring system for the unit, based on state and parameter estimation. The
implemented monitoring system succeeds in tracking the product critical quality
attributes (CQAs), and in detecting common faults for the carousel, such as sudden
variations of the feed attributes
Tailoring polymorphism of ortho-aminobenzoic acid(OABA) using combinations of several solvents and a structurally related additive
No full textAnalysis of the crystallization process of a biopharmaceutical compound in the presence of impurities using process analytical technology (PAT) tools
No full textBACKGROUND: The crystallization of biopharmaceuticals can be problematic since, because the biosynthesis of these compounds is very difficult to control, they can contain a significant amount of impurities that have to be eliminated. In fact, impurities can lead to changes in the properties of the drug that can significantly reduce its effectiveness or even put the user in danger. The aim of this work is to exploit process analytical technology (PAT) tools to study the crystallization step of vitamin B12 crude product extracted via fermentation. RESULTS: Linear cooling crystallization experiments were performed using different conditions. The effects of solvent, cooling rate, seeding and purity of the initial material on the final size distribution and purity of the crystals were investigated through the use of UV/Vis spectroscopy, focused beam reflectance measurement (FBRM) and the CryPRINS software (Crystallization Process Informatics System). It was found that impurities strongly inhibit the growth of vitamin B12 crystals, promoting nucleation and leading to poor final crystal size distribution. CONCLUSION: Slow cooling can help to increase the purity of the final product but also generates a broad crystal size distribution because of secondary nucleation. Preparing the solution with material already crystallized once and using purified seeds helped to obtain a narrower crystal size distribution and also to reduce breakage
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