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Alejandro J. Alvarez

Bio: Alejandro J. Alvarez is an academic researcher from Monterrey Institute of Technology and Higher Education. The author has contributed to research in topics: Crystallization & Self-healing hydrogels. The author has an hindex of 10, co-authored 16 publications receiving 733 citations. Previous affiliations of Alejandro J. Alvarez include Illinois Institute of Technology.

Papers
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TL;DR: In this article, a static mixer was used to promote homogeneous mixing of active pharmaceutical ingredient solution and antisolvent along the crystallizer to control the size of the crystals, and it was found that smaller crystals with a narrower size distribution can be obtained with the static mixers.
Abstract: Crystallization processes in the pharmaceutical industry are usually designed to obtain crystals with controlled size, shape, purity, and polymorphic form. Knowledge of the process conditions required to fabricate crystals with controlled characteristics is critical during process development. In this work, continuous crystallization of ketoconazole, flufenamic acid, and l-glutamic acid in a nonconventional plug flow crystallizer was investigated. Kenics type static mixers were used to promote homogeneous mixing of active pharmaceutical ingredient solution and antisolvent. A strategy of multiple points of addition of antisolvent along the crystallizer was evaluated to control the size of the crystals. Interestingly, it was found that crystal size can be increased or decreased with an increased number of antisolvent addition points, depending on the kinetics of the system. It was also found that smaller crystals with a narrower size distribution can be obtained with the static mixers. A model to describe t...

259 citations

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TL;DR: In this paper, a multistage mixed suspension mixed product removal (MSMPR) crystallizer was employed which allowed simple analysis of kinetic parameters employing the population balance, and the continuous crystallization system was able to operate without any clogging issues for more than four residence times.
Abstract: Crystallization processes can be batch or continuous. Potential advantages such as operating at steady state, small equipment size (relative to batch), and ability to recycle are encouraging the pharmaceutical industry to investigate continuous processes. In this work, a continuous cooling crystallization process for the immunosuppressant drug cyclosporine was developed. A multistage mixed suspension mixed product removal (MSMPR) crystallizer was employed which allowed simple analysis of kinetic parameters employing the population balance. Experimentally, the continuous crystallization system was able to operate without any clogging issues for more than four residence times. The experimental yield and purity of the crystals was determined as 71% and 96%, respectively (without recycle) and 87% and 94%, respectively (with recycle). In a batch cooling crystallization experiment, carried out under conditions similar to those of the continuous experiment without recycle, the experimental yield and purity of th...

139 citations

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TL;DR: In this article, a two-stage mixed suspension mixed product removal (MSMPR) continuous reactive crystallization procedure was developed for Aliskiren hemifumarate, which achieved high purity and high yield.
Abstract: Active ingredients in most pharmaceutical products are complex organic molecules that require crystallization as a purification and isolation step that results in a pure product at a high process yield. Knowledge of the operating conditions required to obtain crystals with the desired crystal shape, polymorph, and morphology is critical during process development. This paper describes a two-stage mixed suspension mixed product removal (MSMPR) continuous reactive crystallization procedure developed for Aliskiren hemifumarate. This process was able to crystallize Aliskiren hemifumarate at both high purity (>99%) and high yield (>92%). A model of the crystallization was developed through the simultaneous solution of a population balance equation, kinetic expression for crystal growth and nucleation, and a mass balance. Experimental data were fit to the model to obtain kinetic parameters for crystal growth and nucleation. After including equilibrium distribution coefficient data, the model was used to optimiz...

126 citations

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TL;DR: In this paper, a two-stage mixed-suspension, mixed-product removal (MSMPR) continuous crystallization was developed for a pharmaceutical intermediate which uses anti-solvent and cooling to generate supersaturation.

111 citations

Journal ArticleDOI
TL;DR: In this article, a semi-automated approach was used to find polymorphic forms of sulfathiazole, mefenamic acid, flufenamic acid and ROY.
Abstract: Polymorph screening studies of sulfathiazole, mefenamic acid, flufenamic acid, and ROY were carried out using a semi-automated apparatus. Cooling crystallization and slurry aging experiments were conducted with varying process conditions and a selection of 16 diverse solvents to find as many polymorphic forms as possible. Results yielded four out of five polymorphs of sulfathiazole, both polymorphs and a solvate of mefenamic acid, four out of the seven stable forms of ROY, as well as the two most commonly encountered polymorphs and a solvate of flufenamic acid. The results obtained in this study were compared with a novel high throughput method based on patterned substrates of self-assembled monolayers.(17, 32, 38) It was shown that in the case of sulfathiazole and mefenamic acid the same number of polymorphs were obtained using the two approaches. In the case of ROY, the semi-automated approach was not able to produce three of the forms found using the patterned self-assembled monolayers (SAMs) method. T...

58 citations


Cited by
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TL;DR: This Review considers several aspects of the most prominent sustainable organicsolvents in use today, ionic liquids, deep eutectic solvents, supercritical fluids, switchable solVents, liquid polymers, and renewable solvent, giving a more complete picture of the current status of sustainable solvent research and development.
Abstract: Sustainable solvents are a topic of growing interest in both the research community and the chemical industry due to a growing awareness of the impact of solvents on pollution, energy usage, and contributions to air quality and climate change. Solvent losses represent a major portion of organic pollution, and solvent removal represents a large proportion of process energy consumption. To counter these issues, a range of greener or more sustainable solvents have been proposed and developed over the past three decades. Much of the focus has been on the environmental credentials of the solvent itself, although how a substance is deployed is as important to sustainability as what it is made from. In this Review, we consider several aspects of the most prominent sustainable organic solvents in use today, ionic liquids, deep eutectic solvents, supercritical fluids, switchable solvents, liquid polymers, and renewable solvents. We examine not only the performance of each class of solvent within the context of the...

1,051 citations

Journal ArticleDOI
TL;DR: The comprehensive study summarizes the latest progress on assorted classes of ILs along with discussing their prospective applications in the first half and the synthesis of homo/heterogeneous ILs is thoroughly elaborated in the second half.

522 citations

Journal ArticleDOI
TL;DR: The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system.
Abstract: A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system.

485 citations

Journal ArticleDOI
TL;DR: This review article aims to illustrate the holistic systems approach and diverse applications of flow chemistry to the preparation of pharmaceutically active molecules, demonstrating the value of this strategy towards every aspect ranging from synthesis, in-line analysis and purification to final formulation and tableting.
Abstract: The implementation of continuous flow processing as a key enabling technology has transformed the way we conduct chemistry and has expanded our synthetic capabilities. As a result many new preparative routes have been designed towards commercially relevant drug compounds achieving more efficient and reproducible manufacture. This review article aims to illustrate the holistic systems approach and diverse applications of flow chemistry to the preparation of pharmaceutically active molecules, demonstrating the value of this strategy towards every aspect ranging from synthesis, in-line analysis and purification to final formulation and tableting. Although this review will primarily concentrate on large scale continuous processing, additional selected syntheses using micro or meso-scaled flow reactors will be exemplified for key transformations and process control. It is hoped that the reader will gain an appreciation of the innovative technology and transformational nature that flow chemistry can leverage to an overall process.

274 citations

Journal ArticleDOI
TL;DR: Research opportunities are described in model-free controller design, new crystallizer designs with enhanced control of crystal size distribution, strategies for the robust control ofcrystal shape, and interconnected crystallization systems for multicomponent crystallization.
Abstract: The academic literature on and industrial practice of control of solution crystallization processes have seen major advances in the past 15 years that have been enabled by progress in in-situ real-time sensor technologies and driven primarily by needs in the pharmaceutical industry for improved and more consistent quality of drug crystals. These advances include the accurate measurement of solution concentrations and crystal characteristics as well as the first-principles modeling and robust model-based and model-free feedback control of crystal size and polymorphic identity. Research opportunities are described in model-free controller design, new crystallizer designs with enhanced control of crystal size distribution, strategies for the robust control of crystal shape, and interconnected crystallization systems for multicomponent crystallization.

271 citations