Polymorphic Control and Scale-Up Strategy for Antisolvent Crystallization Using Direct Nucleation Control

Østergaard, Iben; Szilágyi, Botond; Diego, Heidi Lopez de; Qu, Haiyan

doi:10.1021/acs.cgd.0c00101

Cited by 21 publications

(33 citation statements)

References 41 publications

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“…Consequently, the former equilibrium bonding between DL ‐methionine and water molecules gets disrupted owing to the interaction between the solute and solvent molecules. Hence, the DL ‐methionine molecules are liberated into the solution and excess concentration is made available than that of the equilibrium state which leads to the generation of supersaturation within the mother solution 2, 7. Thereby, a further rise in the antisolvent concentration increases the supersaturation to a critical level which creates the nucleation of DL ‐methionine crystals within the solution.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, varying the initial supersaturation ratio and antisolvent fraction alters the nucleation rate significantly 4–6. More specifically, the addition of precise substances, i.e., drowning‐out antisolvent/salting‐out agents/precipitants, to the initial solution leads to the decrease of solubility, which consequently creates supersaturation 7, 8. Instead of cooling and evaporative crystallization process, salting‐out is a commonly used technique for the separation and isolation of pharmaceuticals owing to its energy efficiency and cost‐effectiveness.…”

Section: Introductionmentioning

confidence: 99%

“…In particular, the metastable and stable polymorphs will have high and low solubilities, respectively. Recently, several reports described the formation of different polymorphs in the antisolvent crystallization process as a function of supersaturation 5–7.…”

Section: Introductionmentioning

confidence: 99%

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Concomitant Polymorphism and Nucleation Control of DL‐Methionine Through Antisolvent Crystallization

Suresh

Srinivasan

2021

Chem Eng & Technol

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The concomitant polymorphism of the sulfur‐containing essential amino acid DL‐methionine was revealed, and α‐ and β‐polymorphic forms were separated from aqueous solution through antisolvent crystallization with ethanol as antisolvent. The addition of different volume fractions of ethanol into the mother solution reduces the solubility of DL‐methionine in double‐distilled water and in turn proportionately generates a range of supersaturation levels. This induces the nucleation of a stable β‐polymorph at low supersaturation levels, a mixture of α‐ and β‐ polymorphs at intermediate supersaturation levels, and a metastable α‐form at high supersaturation levels. Needle‐shaped α‐polymorphs and platy‐shaped β‐polymorphs were well distinguished through in‐situ optical microscopic analysis and their structural confirmation was done by X‐ray diffraction analysis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Concomitant Polymorphism and Nucleation Control of DL‐Methionine Through Antisolvent Crystallization

Suresh

Srinivasan

2021

Chem Eng & Technol

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“…In addition, DNC has a good application in controlling the particle size and size distribution in the process of antisolvent crystallization. Ostergaard et al used the DNC strategy to obtain the desired solid morphology in a ternary solvent and antisolvent system [70].…”

Section: Direct Nucleation Controlmentioning

confidence: 99%

Application of PAT-Based Feedback Control Approaches in Pharmaceutical Crystallization

Gao

Zhang

et al. 2021

Crystals

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Crystallization is one of the important unit operations for the separation and purification of solid products in the chemical, pharmaceutical, and pesticide industries, especially for realizing high-end, high-value solid products. The precise control of the solution crystallization process determines the polymorph, crystal shape, size, and size distribution of the crystal product, which is of great significance to improve product quality and production efficiency. In order to develop the crystallization process in a scientific method that is based on process parameters and data, process analysis technology (PAT) has become an important enabling platform. In this paper, we review the development of PAT in the field of crystallization in recent years. Based on the current research status of drug crystallization process control, the monitoring methods and control strategies of feedback control in the crystallization process were systematically summarized. The focus is on the application of model-free feedback control strategies based on the solution and solid information collected by various online monitoring equipment in product engineering, including improving particle size distribution, achieving polymorphic control, and improving purity. In this paper, the challenges of feedback control strategy in the crystallization process are also discussed, and the development trend of the feedback control strategy has been prospected.

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“…In addition, a product with bimodal PSD (measured by a laser diffraction particle size analyzer) was obtained and the presence of the undesired polymorph was also detected, which was partly caused by the uncontrolled injection-type antisolvent addition. In subsequent work, [28][29][30] the injection-type addition was substituted by continuous antisolvent feeding, and two different feedback control strategies, i.e., antisolvent based SSC (AS-SSC) and DNC (AS-DNC), were implemented to the design of the crystallization process at 500 mL scale, and the process was subsequently scaled up 10 times, to a 5 L crystallizer. There were two aims of the implementation of the SSC and DNC: (i) the first aim was to ensure that only the desired polymorph was observed throughout the entire process; and (ii) secondly to improve the PSD by eliminating/decreasing the bimodality in the distribution.…”

Section: Introductionmentioning

confidence: 99%

Polymorphic Control and Scale-Up Strategy for Antisolvent Crystallization Using a Sequential Supersaturation and Direct Nucleation Control Approach

Østergaard

Szilágyi

Diego

et al. 2020

Crystal Growth & Design

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In this work, a rapid direct design approach for crystallization processes was implemented using the novel Quality-by-Control (QbC) framework by sequentially applying antisolvent based supersaturation control (AS-SSC) and temperature driven direct nucleation control (T-DNC) strategies. This novel strategy was used to optimize and scale-up the batch crystallization of indomethacin (IMC) from a ternary solvents/antisolvent system, which enables the production of the desired polymorphic γ form with significantly increased process yield. Sequentially applying the supersaturation control (SSC) and direct nucleation control (DNC) led to a combination of the advantages of the two feedback control strategies. SSC-based direct design and scale-up strategy showed high efficiency in providing high productivity (high process yield and shorter batch time), whereas DNC is advantageous in ensuring reproducible particle size distribution from processes at different scales. The combined AS-SSC and T-DNC strategy presented in this work showed a promising synergy, which enabled a good balance between the high productivity of the crystallization process and reproducible crystal properties from the processes at different scales.The results provide a proof-of-concept showing that the proposed QbC approach based on the sequential SSC-DNC implementation can be applied for rapid and successful scale-up, leading to similar particulate properties across scales.

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Polymorphic Control and Scale-Up Strategy for Antisolvent Crystallization Using Direct Nucleation Control

Cited by 21 publications

References 41 publications

Concomitant Polymorphism and Nucleation Control of DL‐Methionine Through Antisolvent Crystallization

Concomitant Polymorphism and Nucleation Control of DL‐Methionine Through Antisolvent Crystallization

Application of PAT-Based Feedback Control Approaches in Pharmaceutical Crystallization

Polymorphic Control and Scale-Up Strategy for Antisolvent Crystallization Using a Sequential Supersaturation and Direct Nucleation Control Approach

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