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Crystals
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Anti-Solvent Crystallization
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Anti-Solvent Crystallization

A special issue of Crystals (ISSN 2073-4352). This special issue belongs to the section "Crystal Engineering".

Deadline for manuscript submissions: closed (31 May 2019) | Viewed by 40567

Special Issue Editors

Prof. Dr. Reginald Beng Hee Tan

E-Mail Website
Guest Editor
National University of Singapore, Department of Chemical and Biomolecular Engineering, Singapore City, Singapore
Interests: hydrodynamics and mixing in gas–liquid systems; fluid–particle mechanics; process safety; health and environmental protection
Dr. Zaiqun Yu

E-Mail Website
Guest Editor
Institute of Chemical and Engineering Sciences, Agency for Science, Technology and Research, Singapore (A*STAR), Singapore City, Singapore
Interests: process development; process simulation and control; separation process; crystallization of pharmaceuticals and fine chemicals; solid form screening

Special Issue Information

Dear Colleagues,

Anti-solvent crystallization is employed extensively in pharmaceutical and fine chemical industries for separation and purification purposes. It involves the mixing of two liquids, which adds to the complex interactions between thermodynamics and kinetics of crystallization. It is well known that the instantaneous local supersaturation at feeding points can reach an extremely high level if the solubility of solute changes fast with solvent composition. On the one hand, high supersaturation can cause deleterious effects on crystal products, i.e., generation of undesired solid forms, inadequate rejection of impurities, etc. On the other hand, it can be leveraged on to generate small particles with narrow size distribution that can be directly used in formulations without further size reduction.

Much work has been done in an effort to understand the mixing process and its effects on crystallization. Apart from experimental work, process modelling has been used to quantify the temporal and spatial influence of supersaturation on nucleation and growth. Microfluidic devices have been attempted to have more precise control over these temporal and spatial effects. With these progresses, the following topics are of industrial interest:

  1. Trouble shooting of anti-solvent crystallization. Various quality issues may arise during anti-solvent crystallization, e.g., oiling out, appearance of undesired solid forms, unacceptable solvent residual or crystal habit, failure to pass clarity test or dissolution test, etc. It is rare that the results in a case study are directly applicable to other cases. However, the analysis and rationale in a case study can go a long way.
  2. Solvent effects on crystallization. The choice of solvents/anti-solvents seems to be the most important decision in anti-solvent crystallization development. The mechanism of solvent effects is yet to be understood to speed up solvent screening.
  3. Seeding has proved effective in mitigation of oiling out, polymorph and size control. However, arbitrary elements still exist in seeding protocol determination. Industrial experiences and understanding with seed preparation, assessment of seed qality and seed application will help with rational design of seeding protocols.
  4. It has been demonstrated that aditives can effectively modify crystal habit, mitigate agglomeration and affect the generation of polymorphs. Notwithstanding, the addition of exogenous additives to crystallizers of pharmaceuticals is a regulatory concern. Discussions on the uses of additives in industrial context and exchange of views are warmly welcome.
  5. Size reduction by anti-solvent crystallization. Micron-sized particles, usually prepared by milling, are needed for various delivery vehicles, including injectable suspension, inhaling powders, gel, etc. Anti-solvent crystallization is a promising alternaitve to milling. However, measures must be taken to address pratical problems in anti-solvent crystallization such as agglomeration during drying, Ostwald ripening, solvent residual, etc. Sharing of effective measures are especially encouraged.
  6. Continuous anti-solvent crystallization. Crystallization step is a discontinuous point in continuous prcoessing of pharmaceuticals. Currently, continuous crystallization is afflicted by a few issues, such as blockage of piping, lower yield than batch crystallization, accumulation of impurities, etc. More work needs to be done to tackle these problems.

The list is not exhaustive. Any case studies or reviews on anti-solvent crystallization with practical values will be considered.

Prof. Dr. Reginald Beng Hee Tan
Dr. Zaiqun Yu
Guest Editors

Manuscript Submission Information

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Keywords

  • anti-solvent crystallization
  • solvent effects
  • additive
  • seeding
  • size reduction
  • agglomeration
  • quality attributes
  • polymorph
  • solvent residual
  • dissolution
  • oiling out
  • continuous crystallization

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Published Papers (7 papers)

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Editorial

Jump to: Research

2 pages, 157 KiB  
Editorial
Anti-Solvent Crystallization
by Zai-Qun Yu and Reginald Beng Hee Tan
Crystals 2020, 10(9), 748; https://doi.org/10.3390/cryst10090748 - 26 Aug 2020
Cited by 2 | Viewed by 2462
Abstract
n/a Full article
(This article belongs to the Special Issue Anti-Solvent Crystallization)

Research

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16 pages, 3154 KiB  
Article
Continuous Generation of Millimeter-Sized Glycine Crystals in Non-Seeded Millifluidic Slug Flow
by Mingyao Mou, Huayu Li, Bing-Shiou Yang and Mo Jiang
Crystals 2019, 9(8), 412; https://doi.org/10.3390/cryst9080412 - 9 Aug 2019
Cited by 21 | Viewed by 5108
Abstract
Millimeter-sized α-glycine crystals were generated from continuous non-seeded cooling crystallization in slug flow. The crystallization process is composed of three steps in sequence: slug formation, crash-cooling nucleation, and growth. Stable uniform slugs of three different aspect ratios (slug length/tubing inner diameter) were formed, [...] Read more.
Millimeter-sized α-glycine crystals were generated from continuous non-seeded cooling crystallization in slug flow. The crystallization process is composed of three steps in sequence: slug formation, crash-cooling nucleation, and growth. Stable uniform slugs of three different aspect ratios (slug length/tubing inner diameter) were formed, by adjusting the flow rates of both the solution and air streams. Besides supersaturation, the slug aspect ratio can also affect primary nucleation outcome. Stable slug flow can accommodate a relative supersaturation (C/C*) of up to 1.5 without secondary nucleation. Large glycine crystals can grow to millimeter size within 10 min, inside millimeter-sized slugs without reducing the slug quality. Full article
(This article belongs to the Special Issue Anti-Solvent Crystallization)
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11 pages, 1752 KiB  
Article
Tuning the Crystal Habits of Organic Explosives by Antisolvent Crystallization: The Case Study of 2,6-dimaino-3,5-dinitropyrazine-1-oxid (LLM-105)
by Xiaoqing Zhou, Junhui Shan, Dong Chen and Hongzhen Li
Crystals 2019, 9(8), 392; https://doi.org/10.3390/cryst9080392 - 30 Jul 2019
Cited by 22 | Viewed by 4682
Abstract
Crystallization is one of the most important methods in the crystal habit control of explosive products. For this study, the antisolvent crystallization experiments were carried out to tune the crystal habits of 2,6-dimaino-3,5-dinitropyrazine-1-oxid (LLM-105). Dimethyl sulphoxide (DMSO) was used as an organic solvent. [...] Read more.
Crystallization is one of the most important methods in the crystal habit control of explosive products. For this study, the antisolvent crystallization experiments were carried out to tune the crystal habits of 2,6-dimaino-3,5-dinitropyrazine-1-oxid (LLM-105). Dimethyl sulphoxide (DMSO) was used as an organic solvent. Water, methanol, acetic acid, nitromethane, acetone, ethanol, methylene chloride, o-dichlorobenzene, and toluene were selected as antisolvents. The X-shaped, spherical cluster-like, rod-like, needle-like, and dendritic crystals were successfully produced by varying the kind of the antisolvent. These results manifested that the polarity and functional groups of antisolvent molecules played important roles in the crystal habits of LLM-105 explosive. The powder X-ray diffraction (PXRD) and Fourier transform infrared (FT-IR) measurements indicated that these antisolvents just tuned the crystal habit of LLM-105 but did not change the crystal structure. The differential scanning calorimetry (DSC) and thermogravimetry (TG) results of the obtained crystals showed that the crystal habits significantly affected the thermal properties. This study can contribute to the investigation of the mechanism of antisolvent-induced crystal habit modification and screen out the efficient antisolvents. Full article
(This article belongs to the Special Issue Anti-Solvent Crystallization)
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14 pages, 6608 KiB  
Article
Crystal Structure, Stability and Desolvation of the Solvates of Sorafenib Tosylate
by Peng Yang, Chunlei Qin, Shichao Du, Lina Jia, Yujia Qin, Junbo Gong and Songgu Wu
Crystals 2019, 9(7), 367; https://doi.org/10.3390/cryst9070367 - 17 Jul 2019
Cited by 21 | Viewed by 6115
Abstract
In this study, three solvates of sorafenib tosylate were obtained from methanol, ethanol and n-methyl-2-pyrrolidone (NMP) after solvate screening and the effect of solvent on the formation of solvate was analyzed. The solvents with high value of polarity/dipolarity and appropriate hydrogen bond donor/acceptor [...] Read more.
In this study, three solvates of sorafenib tosylate were obtained from methanol, ethanol and n-methyl-2-pyrrolidone (NMP) after solvate screening and the effect of solvent on the formation of solvate was analyzed. The solvents with high value of polarity/dipolarity and appropriate hydrogen bond donor/acceptor propensity are more likely to form corresponding solvates. The crystal structures of the solvates were elucidated for the first time by using single crystal X-ray diffraction data. The analysis results indicate that methanol solvate and ethanol solvate are isostructural and hydrogen bonds could be formed between solvent molecules and sorafenib tosylate molecules. Hirshfeld surface analysis was used to research the interactions in the solvates, and the results reveal that the H···H, C···H/H···C and O···H/ H···O contacts play the vital role in molecular packing. In addition, three solvates were characterized by polarized light microscope, powder X-ray diffraction, thermogravimetric analysis and differential scanning calorimetry. The solvates show different thermodynamic stability in methanol +NMP and ethanol +NMP mixtures. Furthermore, the desolvation of solvates was studied by hot stage microscope and discussed. Full article
(This article belongs to the Special Issue Anti-Solvent Crystallization)
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15 pages, 4449 KiB  
Article
Comparative Study of Different Crystallization Methods in the Case of Cilostazol Crystal Habit Optimization
by Tímea Tari, Piroska Szabó-Révész and Zoltán Aigner
Crystals 2019, 9(6), 295; https://doi.org/10.3390/cryst9060295 - 5 Jun 2019
Cited by 14 | Viewed by 6128
Abstract
The therapeutic usage of cilostazol is limited owing to its poor aqueous solubility and oral bioavailability. Our aim was to produce cilostazol crystals with small average particle size; besides suitable roundness, narrow particle size distribution and stable polymorphic form to increase its dissolution [...] Read more.
The therapeutic usage of cilostazol is limited owing to its poor aqueous solubility and oral bioavailability. Our aim was to produce cilostazol crystals with small average particle size; besides suitable roundness, narrow particle size distribution and stable polymorphic form to increase its dissolution rate and improve processability. Different conventional crystallization methods with or without sonication were compared with impinging jet crystallization combined with cooling, and the optimization of the various parameters was also implemented. The effects of post-mixing time and temperature difference were studied by means of a full factorial design. The physical properties of powder particles were characterized by, i.a., XRPD, DSC and SEM. The dissolution rate and the contact angle of solid surfaces were also determined to elucidate the relationship between wettability and dissolution. It was observed that impinging jet crystallization combined with cooling is a very effective and reproducible method for reducing the particle size of cilostazol. This method resulted in significantly smaller particle size (d(0.5) = 3–5 μm) and more uniform crystals compared to the original ground material (d(0.5) = 24 μm) or the conventional methods (d(0.5) = 8–14 μm), and it also resulted in a stable polymorphic form and enhanced the dissolution rate. Full article
(This article belongs to the Special Issue Anti-Solvent Crystallization)
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14 pages, 5548 KiB  
Article
Theoretical Model and Experimental Investigations on Solution-Mediated Polymorphic Transformation of Theophylline: From Polymorph I to Polymorph II
by Manli Zhu, Yongli Wang, Fei Li, Ying Bao, Xin Huang, Huanhuan Shi and Hongxun Hao
Crystals 2019, 9(5), 260; https://doi.org/10.3390/cryst9050260 - 19 May 2019
Cited by 13 | Viewed by 4679
Abstract
In this work, theophylline was selected as the model compound to study and simulate the solution-mediated polymorphic transformation. The polymorph I and polymorph II of theophylline were prepared and fully characterized. Raman and UV spectra methods were carried out to observe the phase [...] Read more.
In this work, theophylline was selected as the model compound to study and simulate the solution-mediated polymorphic transformation. The polymorph I and polymorph II of theophylline were prepared and fully characterized. Raman and UV spectra methods were carried out to observe the phase transformation of theophylline from polymorph I to polymorph II at different temperatures. The theoretical models, including dissolution model, nucleation model, and growth model, were established to describe and simulate the transformation processes. By combination of experiments and simulations, the controlling steps of the transformation processes were discussed. The effects of temperature and/or solvent on the transformation processes were evaluated. This work can shed light on the polymorphic transformation processes. Full article
(This article belongs to the Special Issue Anti-Solvent Crystallization)
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13 pages, 3797 KiB  
Article
Simple and Efficient Spherical Crystallization of Clopidogrel Bisulfate Form-I via Anti-Solvent Crystallization Method
by Ji-Hun An, Alice Nguvoko Kiyonga, Eun Hee Lee and Kiwon Jung
Crystals 2019, 9(1), 53; https://doi.org/10.3390/cryst9010053 - 17 Jan 2019
Cited by 8 | Viewed by 6754
Abstract
Clopidogrel bisulfate (CLP) form-I crystals are irregular, rectangular-shaped crystals. Because of their poor compressibility, flowability and their strong surface tension, manufacturers apply spherical crystallization methods to produce CLP form-I spherical agglomerates with a uniform particle size distribution. Consequently, manufacturers primarily synthesize CLP form-I [...] Read more.
Clopidogrel bisulfate (CLP) form-I crystals are irregular, rectangular-shaped crystals. Because of their poor compressibility, flowability and their strong surface tension, manufacturers apply spherical crystallization methods to produce CLP form-I spherical agglomerates with a uniform particle size distribution. Consequently, manufacturers primarily synthesize CLP form-I crystal salts utilizing very complex methods, which produces form-I spherical agglomerates by means of spherical crystallization. In this study, spherical crystals of CLP Form-I were directly prepared from CLP Form-II, the most stable polymorph at room temperature, by using ethanol as solvent and a mixture of isopropyl alcohol (IPA)/n-Hexane (Hex) as an anti-solvent. To provide systematic inputs for the development of spherical agglomerates of optimal morphology, size, particle size distribution (PSD), and polymorphic form, processing parameters such as anti-solvent type, a mixture of IPA/Hex, pure Hex, or pure acetone; stirring speeds of 500, 600, 700, or 800 rpm; and temperatures ranging from 25 to 40 °C were explored. The effects of these parameters on spherical crystallization and polymorphic form were studied in terms of supersaturation, a driving force for polymorphic transformation, and the crystallization solution. Notably, our method does not require a large volume of anti-solvent which is the main complication of conventional anti-solvent crystallization methods. Full article
(This article belongs to the Special Issue Anti-Solvent Crystallization)
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