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Crystals
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Pharmaceutical Crystallization
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Pharmaceutical Crystallization

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

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 30260

Special Issue Editors

Prof. Hiroshi Ooshima

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Guest Editor
1. Professor Emeritus Osaka City University, Osaka, Japan
2. Kansai Chemical Engineering Co., Ltd., Hyogo, Japan
Interests: structure of supersaturated solution; crystal nucleation; industrial crystallization
Prof. Dr. Joop H. ter Horst

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Guest Editor
UFR des Sciences et Techniques, Laboratoire SMS-EA3233, Universite de Rouen Normandie, Place Emile Blondel, 76821 Mont-Saint-Aignan, France
Interests: industrial crystallization fundamentals; crystal nucleation; chiral separation and deracemization; continuous crystallization; separation technology
Special Issues, Collections and Topics in MDPI journals
Prof. Koichi Igarashi

E-Mail Website
Guest Editor
Osaka City University, Department of Applied Chemistry and Bioengineering, Osaka, Japan
Interests: industrial crystallization; continuous crystallization; crystal polymorphs; bio-assisted crystallization

Special Issue Information

Dear Colleagues,

Currently, about 80% of approved pharmaceuticals are small organic compounds with a molecular weight of less than roughly 500 g/mol. These compounds are used in the treatments of many types of diseases that plague humanity. Crystallization plays a major role in the manufacture of these compounds as it is a highly selective separation and purification technology resulting in a particulate product. The characteristics of a particulate pharmaceutical product, namely the kind of solid state, size, shape, and purity, are strongly related to pharmaceutical activity through important properties such as bioavailability.

The chemical structure of newly proposed small pharmaceutical molecules shows increasing complexity and, with this, an increasingly complex crystallization behavior. Therefore, the community continues to put strong efforts into obtaining fundamental crystallization knowledge. As an example, the association behavior of solute molecules in supersaturated solutions strongly influences the nucleation process but is not yet completely understood.

Industrial crystallization is a molecular-level process where molecules are incorporated into kinks of steps at growing crystal surfaces. Controlling the incorporation of molecules in such a macroscopic process is a challenge. While research on continuous pharmaceutical crystallization continues to be fruitful, progress must be made in modeling, monitoring, and control.

We would like this Special Issue of Crystals to provide a forum on the current state of pharmaceutical crystallization research by collecting contributions to the crystallization of pharmaceuticals on subjects including, but not limited to, the following:

  • Particulate pharmaceutical product characteristics: polymorphism, co-crystals, solvates, salts, chiral compounds, crystal size distribution, crystal morphology, purity.
  • Crystallization fundamentals: crystal nucleation, crystal growth, secondary nucleation, agglomeration, solution structure, chiral separation and deracemization.
  • Industrial crystallization: batch-wise and continuous crystallization; crystallization process monitoring, modeling, and control; crystallization process design; hybrid crystallization processes. 

Prof. Hiroshi Ooshima
Prof. Joop H. ter Horst
Prof. Koichi Igarashi
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Crystals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2100 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Polymorphism
  • Crystal size distribution control
  • Crystal morphology control
  • Co-crystals
  • Chiral separation
  • Structure of supersaturated solution
  • Crystal nucleation
  • Crystal growth
  • Continuous crystallization
  • Crystallization process monitoring
  • Others

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Published Papers (8 papers)

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Research

19 pages, 5467 KiB  
Article
Impact of Impurities on Crystallization and Product Quality: A Case Study with Paracetamol
by Stephanie J. Urwin, Stephanie Yerdelen, Ian Houson and Joop H. ter Horst
Crystals 2021, 11(11), 1344; https://doi.org/10.3390/cryst11111344 - 3 Nov 2021
Cited by 13 | Viewed by 8246
Abstract
A thorough, systematic study into the effect that structurally related impurities have on both the process and product quality during the crystallization of an active pharmaceutical ingredient is presented. The presence of acetanilide and metacetamol influences the crystallization and product quality of paracetamol. [...] Read more.
A thorough, systematic study into the effect that structurally related impurities have on both the process and product quality during the crystallization of an active pharmaceutical ingredient is presented. The presence of acetanilide and metacetamol influences the crystallization and product quality of paracetamol. Where high concentrations of either impurity were present in the crystallization feed, product recovery decreased by up to 15%. Acetanilide is included in the final product through adsorption onto the particle surface in concentrations up to 0.79 mol%, which can be reduced to acceptable levels through product reslurrying. The presence of metacetamol results in much higher concentrations—up to 6.78 mol% in the final product, of which approximately 1 mol% is incorporated into the crystal lattice, resulting in the perturbation of the unit-cell dimensions. The incidental crystallization and subsequent isolation of metastable Form II paracetamol increased product purity in the presence of a low metacetamol concentration. This metastable product converts to stable paracetamol Form I through reslurrying, offering an efficient metacetamol impurity rejection route. The morphology of the product is modified consistently by both impurities. An elongation of the normal prismatic shape is observed, which in the extreme case of high metacetamol contamination results in the isolation of fine, fragile needles. This problematic morphology is also improved by a reslurrying of the crystallization product to give a more equilateral shape. This systematic study of the influence of acetanilide and metacetamol on the crystallization of paracetamol builds a well-rounded picture of the concomitant impact of impurities on the principal quality attributes of a crystallization product. Full article
(This article belongs to the Special Issue Pharmaceutical Crystallization)
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11 pages, 2622 KiB  
Article
The Crystallization of Active Pharmaceutical Ingredients with Low Melting Points in the Presence of Liquid–Liquid Phase Separation
by Wei Han Lin, Zai-Qun Yu, Pui Shan Chow and Reginald Beng Hee Tan
Crystals 2021, 11(11), 1326; https://doi.org/10.3390/cryst11111326 - 30 Oct 2021
Cited by 5 | Viewed by 3604
Abstract
Liquid–liquid phase separation (LLPS) during the crystallization of active pharmaceutical ingredients (APIs) often causes agglomeration and other quality issues in crystal products; thus, it should be avoided if possible. However, LLPS in the crystallization of APIs with low melting points cannot be circumvented [...] Read more.
Liquid–liquid phase separation (LLPS) during the crystallization of active pharmaceutical ingredients (APIs) often causes agglomeration and other quality issues in crystal products; thus, it should be avoided if possible. However, LLPS in the crystallization of APIs with low melting points cannot be circumvented in some cases due to yield considerations. The crystallization of ibuprofen in an ethanol/water mixture was studied to explore methods to reduce agglomeration in the presence of LLPS. It was found that unseeded crystallization produced agglomerates when LLPS took place. The two liquid phases resulting from LLPS underwent LLPS again when they were cooled separately, indicating the dynamic nature of LLPS. Seeding and seed ageing at a low supersaturation were very effective in mitigating agglomeration. The effects of two widely used surfactants, i.e., Tween 80 and hydroxypropyl methylcellulose (HPMC), on LLPS and crystallization were confirmed preliminarily. More work needs to be conducted to explore their usefulness in LLPS handling. The findings and techniques presented in this study may be applicable to the crystallization of other APIs with low melting points. Full article
(This article belongs to the Special Issue Pharmaceutical Crystallization)
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16 pages, 4138 KiB  
Article
Ultrasound in Continuous Tubular Crystallizers: Parameters Affecting the Nucleation Rate
by Arne Vancleef, Tom Van Gerven, Leen C. J. Thomassen and Leen Braeken
Crystals 2021, 11(9), 1054; https://doi.org/10.3390/cryst11091054 - 1 Sep 2021
Cited by 5 | Viewed by 2331
Abstract
Ultrasound has proven to be an important tool for controlling nucleation in continuous tubular crystallizers. However, insufficient information is available about the parameters controlling the nucleation rate in a continuous ultrasonic process. Previous research has studied parameters related to the nucleation rate, but [...] Read more.
Ultrasound has proven to be an important tool for controlling nucleation in continuous tubular crystallizers. However, insufficient information is available about the parameters controlling the nucleation rate in a continuous ultrasonic process. Previous research has studied parameters related to the nucleation rate, but has not measured the nucleation rate directly or continuously. In this work, the nucleation rate is measured continuously and inline to solve this problem and achieve a better process understanding. The results indicate that the ultrasound-assisted nucleation process is presumably dominated by secondary nucleation. Additionally, the supersaturation, residence time and flow rate have a strong influence on the nucleation rate. On the other hand, the influence of the ultrasonic power is crucial but levels off once a certain amount of power is reached. The static pressure in the system determines the effective ultrasonic power and is therefore also important for the nucleation rate. Finally, maintaining an equal power per unit of volume and an equal residence time by increasing the tubing diameter seems to be a good scale-up method. These results will improve understanding of ultrasonic tubular crystallizers and how to control them. Full article
(This article belongs to the Special Issue Pharmaceutical Crystallization)
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8 pages, 2400 KiB  
Article
The Fluidization Effect of a Bilayer Membrane on a Fatty Acid Vesicle by a Detergent
by Shogo Taguchi, Yuta Kimura, Yasuaki Tachibana, Takuji Yamamoto and Kouji Maeda
Crystals 2021, 11(9), 1023; https://doi.org/10.3390/cryst11091023 - 25 Aug 2021
Cited by 4 | Viewed by 2223
Abstract
A bicelle, which is a bilayer molecular assembly, can be prepared by fluidizing a vesicle in the presence of a detergent. We investigated the effect of two different detergents, 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxypropane sulfonate (CHAPSO) and Triton X-100 (TX), on the formation of a bicelle from [...] Read more.
A bicelle, which is a bilayer molecular assembly, can be prepared by fluidizing a vesicle in the presence of a detergent. We investigated the effect of two different detergents, 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxypropane sulfonate (CHAPSO) and Triton X-100 (TX), on the formation of a bicelle from a vesicle containing oleic acid (OA) and the detergent molecules. The fluidization effect of the detergent was evaluated using the membrane packing density, which we measured using the fluorescent probe method with Laurdan, in conjunction with transmission electron microscopy to examine the morphology of the prepared bilayer molecular assemblies. As a result, it was discovered that the OA/CHAPSO system could form a heterogeneous phase with the highest packing density, implying that CHAPSO was the better detergent for a bicelle preparation, whereas the OA/TX system formed a disordered phase with the lowest packing density. Full article
(This article belongs to the Special Issue Pharmaceutical Crystallization)
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13 pages, 6026 KiB  
Article
Polymorphic Crystallization Design to Prevent the Degradation of the β-Lactam Structure of a Carbapenem
by Shinji Matsuura, Koichi Igarashi, Masayuki Azuma and Hiroshi Ooshima
Crystals 2021, 11(8), 931; https://doi.org/10.3390/cryst11080931 - 11 Aug 2021
Cited by 3 | Viewed by 2288
Abstract
The cooling crystallization of carbapenem CS-023 was performed at 25 °C in an aqueous solution. Tetrahydrate crystals (form H) were obtained. Hydrate crystals are promising drugs, but there has been problems in manufacturing such crystals. During cooling crystallization, a dissolution process at a [...] Read more.
The cooling crystallization of carbapenem CS-023 was performed at 25 °C in an aqueous solution. Tetrahydrate crystals (form H) were obtained. Hydrate crystals are promising drugs, but there has been problems in manufacturing such crystals. During cooling crystallization, a dissolution process at a high temperature of 70 °C was utilized. The main problem in manufacturing was that the degradation rate of CS-023 at 70 °C was high, as expressed in the half-life period of 2.97 h. Poor solvent crystallization using ethanol was observed at 25 °C. Thus, a different polymorph (Form A) was obtained. Form A comprised CS-023, 5/2 ethanol, and 1/2 H2O. Form A, containing ethanol, is not suitable as a drug. Form A was then transformed to another polymorph of hydrate crystals or tetrahydrate Form H. Another hydrate polymorph, Form B, was obtained through the solid phase transformation of Form A and further transformed to the tetrahydrate Form H, at high humidity over 80% RH. This process, which proceeded at the low temperature of 25 °C, helped to prevent the degradation of CS-023, thereby avoiding wastage. Furthermore, the solid-phase transition could be controlled with vapor composition. Full article
(This article belongs to the Special Issue Pharmaceutical Crystallization)
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11 pages, 4570 KiB  
Article
Operation Design of Reaction Crystallization Using Homogeneity Evaluation for the Quality Improvement of Agglomerated Crystalline Particles
by Mitsuki Ohyama, Shuntaro Amari and Hiroshi Takiyama
Crystals 2021, 11(8), 844; https://doi.org/10.3390/cryst11080844 - 21 Jul 2021
Cited by 5 | Viewed by 2438
Abstract
In the quality control of crystalline particles, the uniformity of the distribution of each characteristic, such as size and shape, is important. In particular, the problem in reaction crystallization is that the comprehensive uniformity of characteristic distributions is frequently reduced by the agglomeration [...] Read more.
In the quality control of crystalline particles, the uniformity of the distribution of each characteristic, such as size and shape, is important. In particular, the problem in reaction crystallization is that the comprehensive uniformity of characteristic distributions is frequently reduced by the agglomeration phenomena. In this study, we designed an operation method to improve the comprehensive uniformity in a liquid–liquid reaction crystallization by evaluating the dynamic variation in the uniformity of particle size and crystal shape using homogeneity. The homogeneity of final particles increased when the supersaturation was lowered by intermittent operation with inner seed production. Since the ratios of the uniformities of particle sizes and crystal shapes constituting homogeneity varied dynamically, the intermittent operation was designed by focusing on individual uniformities. The uniformity of particle size for the final particles was increased via modulation operation using reverse addition for the dissolution of the microparticles. In the growth stage after the reverse addition, the uniformity of the shape of the final particles was increased by raising the number of times of adding solution for decreasing the supersaturation. In addition, we proposed suitable addition methods to improve comprehensive uniformity by controlling uniformity constituting homogeneity at each stage of intermittent operation. Full article
(This article belongs to the Special Issue Pharmaceutical Crystallization)
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18 pages, 4002 KiB  
Article
Co-Crystallization Kinetics of 2:1 Benzoic Acid–Sodium Benzoate Co-Crystal: The Effect of Templating Molecules in a Solution
by Freshsya Zata Lini, Dhanang Edy Pratama and Tu Lee
Crystals 2021, 11(7), 812; https://doi.org/10.3390/cryst11070812 - 12 Jul 2021
Cited by 3 | Viewed by 4334
Abstract
The addition of dissolved templating molecules in crystallization will create “supramolecular assemblies” within the solution, serving as “anchor points” for the solute molecules to nucleate and grow. In this work, nucleation and crystal growth kinetics of 2:1 benzoic acid (HBz)–sodium benzoate (NaBz) co-crystallization [...] Read more.
The addition of dissolved templating molecules in crystallization will create “supramolecular assemblies” within the solution, serving as “anchor points” for the solute molecules to nucleate and grow. In this work, nucleation and crystal growth kinetics of 2:1 benzoic acid (HBz)–sodium benzoate (NaBz) co-crystallization with or without templates in a solution were analyzed by monitoring the concentration of the mother liquor during cooling crystallization. The results showed that the addition of the dissolved 2:1 or 1:1 HBz–NaBz co-crystals as templating molecules could reduce the critical free energy barrier of 2:1 HBz–NaBz co-crystal during its nucleation, but did not significantly affect the order of crystal growth rate. On the other hand, the critical free energy barrier of the nucleation process was increased if dissolved NaBz was used as a templating molecule, while a significant rise in the order of crystal growth rate occurred. The crystal habit obtained from the NaBz-templated system was needle-like, suggesting that sodium–sodium coordination chains of NaBz supramolecular assemblies in the solution phase were responsible for creating elongated crystals. Conversely, a large prismatic crystal habit found in non-templated and 2:1 and 1:1 HBz–NaBz co-crystal-templated systems implied that those templating molecules formed sparsely interconnected supramolecular assemblies in the solution phase. Full article
(This article belongs to the Special Issue Pharmaceutical Crystallization)
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11 pages, 4616 KiB  
Article
Effect of Batchelor Flow on Polymorphic Crystallization in a Rotating Disk Crystallizer
by Zun-Hua Li, Jinsoo Kim and Woo-Sik Kim
Crystals 2021, 11(6), 701; https://doi.org/10.3390/cryst11060701 - 18 Jun 2021
Cited by 2 | Viewed by 2640
Abstract
In this work, the influence of Batchelor flow on the polymorphic crystallization in a rotating disk (RD) crystallizer was investigated. By regulating crystallization parameters, i.e., the rotation speed, cooling rate, and ethanol fraction, we found that a higher fraction of L-histidine stable Form-A [...] Read more.
In this work, the influence of Batchelor flow on the polymorphic crystallization in a rotating disk (RD) crystallizer was investigated. By regulating crystallization parameters, i.e., the rotation speed, cooling rate, and ethanol fraction, we found that a higher fraction of L-histidine stable Form-A at the induction time and a faster rate of phase transformation could be obtained in the RD crystallizer as compared to previous results in a mixing tank crystallizer. Based on these results, we concluded that the polymorphic crystallization in the RD crystallizer was more effective due to Batchelor flow fluid motion. Full article
(This article belongs to the Special Issue Pharmaceutical Crystallization)
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