Improvement of drug processability in a connected continuous crystallizer system using formulation additive

Tacsi, Kornélia; Stoffán, György; Galata, Dorián László; Pusztai, Éva; Gyürkés, Martin; Nagy, Brigitta; Szilágyi, Botond; Nagy, Zsombor Kristóf; Marosi, György; Pataki, Hajnalka

doi:10.1016/j.ijpharm.2023.122725

Cited by 3 publications

(4 citation statements)

References 41 publications

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“…In antisolvent crystallization, the antisolvent or precipitant provides the driving force of the supersaturation of the solute (drug) by decreasing its solubility [28][29][30][31][32][33][34]. Antisolvent crystallization has numerous advantages compared to the other crystallization methods, such as low cost, ease of scale-up, and superior control on the polymorph and size distribution of drug crystals, which can consequently lead to the enhancement of the final API solubility.…”

Section: Figure 1 (A) Schematic Illustrationmentioning

confidence: 99%

Recent Progress in Antisolvent Crystallization of Pharmaceuticals with a Focus on the Membrane‐Based Technologies

Haghighizadeh,

Mahdavi,

Rajabi

2024

Chem Eng & Technol

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Continuous crystallization of pharmaceuticals has been in the center of attention during the past two decades, with a more focus on the large‐scale production of active pharmaceutical ingredients. The increasing demand for pharmaceuticals requires high‐throughput production of drug crystals with different solubilities, stabilities, shapes, habits, polymorphs, and size distributions. With numerous advantages including low cost, ease of scale‐up, and superior control over polymorph and size distribution of drug crystals, antisolvent crystallization is one of the most promising crystallization methods recently attempted. However, it fails to deliver the required characteristic where the crystal systems tend to grow and for the preparation of metastable polymorphs. This review focuses on the most recent efforts to tackle these drawbacks by coupling antisolvent crystallization with cooling, supercritical‐assisted, microfluidics‐assisted, and membrane‐assisted crystallization. This systematic review aims to provide a concise summary of each coupled antisolvent technique and their positive and negative aspects. This review can be used as a guideline for pharmacist, biologists, and chemists, who are interested in the crystal engineering of pharmaceuticals to pave the way for further developments in this field.

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Section: Figure 1 (A) Schematic Illustrationmentioning

confidence: 99%

Recent Progress in Antisolvent Crystallization of Pharmaceuticals with a Focus on the Membrane‐Based Technologies

Haghighizadeh,

Mahdavi,

Rajabi

2024

Chem Eng & Technol

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“…They can significantly widen the metastable zone, elongate induction time, or completely stabilize the supersaturated solution . Overall, additive-controlled crystallization has already been successfully employed as a technological tool for polymorphic, , size and habit control of APIs, ,,, as well as for process stability enhancement and simplification of downstream formulation procedure. , Most of these additives are well-known formulation additives with low or no toxic effects on humans; therefore, the industrial application of such crystallization technologies should give no rise for regulatory holdbacks. All at the same, there are numerous examples of additive-controlled crystallization which are dominantly performed in batch mode, and only a few publications discuss the adaptation of continuous technologies.…”

Section: Introductionmentioning

confidence: 99%

“…When hydroxypropyl methylcellulose (HPMC) was added to the crystallization media, not only could encrustation and fouling be avoided, but steady-state operation was achieved more rapidly. Tacsi et al investigated the continuous antisolvent crystallization of acetylsalicylic acid in the presence of PVP in an integrated TC-MSMPR system . The small crystals produced in the first sonicated TC aggregated in the second MSMPR stage, resulting in simultaneously fast dissolution characteristics and improved technological properties.…”

Section: Introductionmentioning

confidence: 99%

“…Tacsi et al investigated the continuous antisolvent crystallization of acetylsalicylic acid in the presence of PVP in an integrated TC-MSMPR system. 24 The small crystals produced in the first sonicated TC aggregated in the second MSMPR stage, resulting in simultaneously fast dissolution characteristics and improved technological properties. Testa et al successfully developed an evaporative-cooling-MSMPR system for the continuous heterogeneous crystallization of paracetamol.…”

Section: ■ Introductionmentioning

confidence: 99%

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Development of Continuous Additive-Controlled MSMPR Crystallization by DoE-Based Batch Experiments

Stoffán,

Lőrincz,

Pusztai

et al. 2024

Ind. Eng. Chem. Res.

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Additive-controlled crystallization is a promising method to improve crystal morphology and produce solid drug particles with the desired technological and pharmacological properties. However, its adaptation to continuous operation is a hardly researched area. Accordingly, in this work, we aimed to come up with a methodology that provides the systematic and fast development of a continuous three-stage MSMPR cascade crystallizer. For that, a cooling crystallization of famotidine (FMT) from water, in the presence of a formulation additive, poly(vinylpyrrolidone) (PVP-K12), was developed. Process parameters with a significant impact on product quality and quantity were examined in batch mode through a 2 4−1 fractional factorial design for the implementation of additive-controlled continuous crystallization. These batch experiments represented one residence time of the continuous system. Based on the statistical analysis, the residence time (RT) had the highest effect on yield, while the polymer amount was critical from the product polymorphism, crystal size, and flowability points of view. The values of critical process parameters in continuous operation were fixed according to the batch results. Two continuous cooling crystallization experiments were carried out, one with 1.25 w/w FMT % PVP-K12 and one with no additive. A mixture of FMT polymorphs (Form A and Form B) crystallized without the additive through five residence times (>6.5 h) with 70.8% overall yield. On the other hand, the additive-controlled continuous experiment resulted pure and homogeneous Form A product with excellent flowability. The system could be operated for >6.5 h without clogging with a 71.1% overall yield and a 4-fold improvement in productivity compared to its batch equivalent.

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A Commentary on Co-Processed API as a Promising Approach to Improve Sustainability for the Pharmaceutical Industry

Schenck,

Risteen,

Johnson

et al. 2024

Journal of Pharmaceutical Sciences

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Improvement of drug processability in a connected continuous crystallizer system using formulation additive

Cited by 3 publications

References 41 publications

Recent Progress in Antisolvent Crystallization of Pharmaceuticals with a Focus on the Membrane‐Based Technologies

Recent Progress in Antisolvent Crystallization of Pharmaceuticals with a Focus on the Membrane‐Based Technologies

Development of Continuous Additive-Controlled MSMPR Crystallization by DoE-Based Batch Experiments

A Commentary on Co-Processed API as a Promising Approach to Improve Sustainability for the Pharmaceutical Industry

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