Advances in Pharmaceutical Crystals: Control over Nucleation and Polymorphism

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

Deadline for manuscript submissions: closed (25 June 2023) | Viewed by 13262

Special Issue Editors


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Guest Editor
Laboratorio de Estudios Cristalográficos, IACT, (CSIC-UGR), Av. de las Palmeras, 4, Armilla, 18100 Granada, Spain
Interests: protein crystallization: nucleation, growth and crystals quality; protein crystallography; protein crystals biocompostites and properties; enzymatic crystals (CLEC)
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Guest Editor
Department of Applied Science and Technology, Politecnico di Torino, 10129 Turin, Italy
Interests: protein crystallization; pharmaceutical crystallization
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
Interests: protein crystallisation; drug crystallisation; supramolecular gels; soft matter; composite materials; cancer therapy

Special Issue Information

Dear Colleagues,

Controlling the crystallisation process is of utmost importance in the pharmaceutical field. The Finished Pharmaceutical Products (FPPs), which include crystal forms of the Active Pharmaceutical Ingredient (API) in their formulation, must meet strict constraints in order to be commercialised. Crystallographic parameters such as numerical density, crystal size, habit and, especially, polymorphism have a direct influence over crucial pharmaceutical properties such as the dissolution rate, the drug stability, bioavailability or tabletability. Having control over the crystal ensures the reliability of the drug. In this scenario, the nucleation step is proven to be pivotal in determining the final properties of the crystals, and thus, it has been widely studied. This rationale can be applied to melt or solution crystallisation and supports studies on crystal engineering, co-crystallisation, drug polymorphism, protein structural determination, etc.

This Special Issue entitled “Advances in Pharmaceutical Crystals: Control over Nucleation and Polymorphism” welcomes original papers and reviews focusing on advances in the preparation and formulation of pharmaceutical crystals, with a particular emphasis on the control over the nucleation step and polymorphism. Experimental and theoretical studies are equally welcome.

Dr. José Gavira
Dr. Fiora Artusio
Dr. Rafael Contreras-Montoya
Guest Editors

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Keywords

  • nucleation
  • protein crystallisation
  • drug polymorphism
  • crystal engineering
  • pharmaceutical co-crystals
  • melt crystallisation
  • solution crystallisation
  • process control
  • nucleation models

Published Papers (8 papers)

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Research

28 pages, 8523 KiB  
Article
End-to-End Continuous Small-Scale Drug Substance Manufacturing: From a Continuous In Situ Nucleator to Free-Flowing Crystalline Particles
by Anne Cathrine Kufner, Marc Meier and Kerstin Wohlgemuth
Crystals 2023, 13(12), 1675; https://doi.org/10.3390/cryst13121675 - 11 Dec 2023
Viewed by 752
Abstract
In the evolving landscape of pharmaceutical manufacturing, a comprehensive continuous production process is being crafted for the small-scale production of active pharmaceutical ingredients. This study focuses on continuous crystallization with separate nucleation and crystal growth units, as well as continuous downstream processing, encompassing [...] Read more.
In the evolving landscape of pharmaceutical manufacturing, a comprehensive continuous production process is being crafted for the small-scale production of active pharmaceutical ingredients. This study focuses on continuous crystallization with separate nucleation and crystal growth units, as well as continuous downstream processing, encompassing filtration, washing, and drying until the formation of free-flowing particles. We introduce a novel continuous nucleator designed based on solubility data and produced via 3D printing, enabling the fast and precise small-scale manufacturing of a nucleator meeting the requirements for nucleation and further growth processes. The nucleator is evaluated with regard to its suitability for continuous long-term operation across various coupled crystallizers. As a practical application example, it is connected to a slug flow crystallizer to enable high-quality continuous crystallization. Additionally, the full integration of downstream processes using a continuous vacuum screw filter to achieve free-flowing product particles is realized. Even under non-optimized process conditions, with the help of the in situ generation of nuclei, free-flowing product particles are successfully obtained. This is particularly useful during drug development when no material is available for seed addition and to quickly obtain products for further characterization. Full article
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18 pages, 4708 KiB  
Article
Kinetic Optimization of the Batch Crystallization of an Active Pharmaceutical Ingredient in the Presence of a Low-Solubility, Precipitating Impurity
by Mitchell Paolello, Ilyes Bichari, Davinia Brouckaert, Mirvatte Francis, Dawn Yang and Gerard Capellades
Crystals 2023, 13(11), 1569; https://doi.org/10.3390/cryst13111569 - 03 Nov 2023
Cited by 1 | Viewed by 1437
Abstract
The presence of impurities above regulatory thresholds has been responsible for recent recalls of pharmaceutical drugs. Crystallization is one of the most used separation processes to control impurities in the final drug. A particular issue emerges when impurities are poorly soluble in the [...] Read more.
The presence of impurities above regulatory thresholds has been responsible for recent recalls of pharmaceutical drugs. Crystallization is one of the most used separation processes to control impurities in the final drug. A particular issue emerges when impurities are poorly soluble in the crystallization solvent and simultaneously precipitate with the product. This publication reports the development of a population balance model to investigate if the impurity crystallization kinetics can be selectively inhibited in a seeded batch crystallization system containing acetaminophen (ACM), a commonly used small-molecule active pharmaceutical ingredient (API), and curcumin (CUR), a simulated low-solubility/co-precipitating impurity. Raman spectroscopy was used in combination with a partial least squares (PLS) model for in situ monitoring of the crystallization process. The Raman data were integrated to calibrate a population balance model in gPROMS FormulatedProducts, to predict the evolution of the product’s purity throughout the process. Process optimization demonstrated that a high purity close to equilibrium is feasible within the first 2 h of crystallization, with ACM seed purity being the primary factor controlling this phenomenon. The optimal approach for kinetically rejecting impurities requires a low nucleation rate for the impurity, high product seed purities, and an adjustable crystallization time so the process can be stopped before equilibrium without allowing the impurity to nucleate. Overall, an improvement in product purity before equilibrium is attainable if there is enough difference in growth kinetics between the product and impurity, and if one can generate relatively pure seed crystals. Full article
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10 pages, 6456 KiB  
Article
Synthesis and Structure Characterization of Three Pharmaceutical Compounds Based on Tinidazole
by Na Li, Yuting Chen, Ruixin Chen, Mingjuan Zhang, Tingting Wu and Kang Liu
Crystals 2023, 13(6), 947; https://doi.org/10.3390/cryst13060947 - 12 Jun 2023
Viewed by 1052
Abstract
Tinidazole (TNZ), a 5-nitroimidazole derivative, has received increasing attention due to its pharmacological activities in treatment for amebic and parasitic infections. In this paper, we synthesized three novel drug supramolecular compounds successfully based on TNZ. The three compounds discussed were formed by TNZ [...] Read more.
Tinidazole (TNZ), a 5-nitroimidazole derivative, has received increasing attention due to its pharmacological activities in treatment for amebic and parasitic infections. In this paper, we synthesized three novel drug supramolecular compounds successfully based on TNZ. The three compounds discussed were formed by TNZ and 2,6-dihydroxybenzoic acid (2,6-DHBA), 4-methylsalicylic acid (4-MAC), and 5-chloro-2-hydroxybenzoic acid (5-C-2-HBA). The N-H···O and O-H···O hydrogen bonds and weak C-H···O hydrogen bonds are the primary intermolecular forces in the construction of the three compounds. Crystal structure analysis revealed that all the compounds exhibit three-dimensional frameworks consisting of non-covalent interactions. Furthermore, six primary synthons, Ⅰ R22 (8), Ⅱ R21(6), Ⅲ R22(12), Ⅳ R33(9), Ⅴ R22(12), Ⅵ R33(9), formed through various hydrogen bonds are found in the three compounds. Moreover, the resulting pharmaceutical supramolecular compounds show improved stability. Single-crystal X-ray diffraction analysis, infrared spectroscopy (IR), element analysis, and thermogravimetric analysis (TGA) are reported. Full article
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16 pages, 5082 KiB  
Article
Drug Release from Carrier Systems Comprising Meloxicam Crystals Formed by Impregnation-Evaporation
by Petr Zámostný, Michal Drahozal, Ondřej Švehla, Simona Römerová and Nikita Marinko
Crystals 2023, 13(3), 527; https://doi.org/10.3390/cryst13030527 - 19 Mar 2023
Cited by 1 | Viewed by 1524
Abstract
The impregnation of poorly water-soluble drug onto the surface of a suitable pharmaceutical excipient, used as a hydrophilic carrier, can lead to the preparation of systems with improved dissolution properties due to the separation of drug crystal particles on the carrier surface. For [...] Read more.
The impregnation of poorly water-soluble drug onto the surface of a suitable pharmaceutical excipient, used as a hydrophilic carrier, can lead to the preparation of systems with improved dissolution properties due to the separation of drug crystal particles on the carrier surface. For this purpose, a method based on impregnation of hydrophilic matrix by the hydrophobic poorly water-soluble drug Meloxicam (MX) solution in volatile organic solvent was used. After the evaporation of the solvent, the method resulted in coverage of the carrier surface by drug crystals. The influence of the amount and concentration of the impregnating solution on the formed MX crystal size and the dissolution rate was evaluated. Firstly, the impregnation forming crystals on the planar surface was studied and the MX maximum dissolution flux from that surface was determined. The optimum preparation method was further used to produce a volume of impregnated granules. The dissolution performance of the granules was evaluated, and the dissolution kinetics was described by mathematical models. The polymorphic modification of impregnated API and influence of impregnated drug amount on the hydrophilic carrier surface coverage were considered. From the results of this work, it is clear that the impregnated drug amount and the number of impregnations cycles can be optimized to achieve maximum drug release rate. Full article
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16 pages, 3492 KiB  
Article
pH-Driven Polymorphic Behaviour of the Third PDZ Domain of PSD95: The Role of Electrostatic Interactions
by Mª Carmen Salinas-García, Marina Plaza-Garrido, Jose A. Gavira, Javier Murciano-Calles, Montserrat Andújar-Sánchez, Emilia Ortiz-Salmerón, Jose C. Martinez and Ana Cámara-Artigas
Crystals 2023, 13(2), 218; https://doi.org/10.3390/cryst13020218 - 24 Jan 2023
Viewed by 1250
Abstract
The PDZ domains are modular domains that recognise short linear C-terminal sequences in proteins that organise the formation of complex multi-component assemblies. We have crystallised the third PDZ domain of the neuronal postsynaptic density-95 protein (PSD95-PDZ3) at mildly acidic pH conditions and obtained [...] Read more.
The PDZ domains are modular domains that recognise short linear C-terminal sequences in proteins that organise the formation of complex multi-component assemblies. We have crystallised the third PDZ domain of the neuronal postsynaptic density-95 protein (PSD95-PDZ3) at mildly acidic pH conditions and obtained up to four polymorphs. Thus, below pH 4.0, the protein crystallised into prism-shaped crystals that belonged to the trigonal space group P3112. In contrast, above this pH value, the crystals’ shape changes to long needles belonging to the monoclinic P21 and two different orthorhombic packings of the P212121 space group. In addition, all the polymorphs share the main crystallographic interface, where the sidechain of the Asp332 imitates the binding of the C-terminal moiety to the canonical binding motif. Furthermore, we have analysed how changes in the ionisation state of some specific residues might be critical for crystallising the different polymorphs. The analysis of these polymorphs provides clues on the relevance of specific protein-protein interactions in protein crystallisation. However, these structures allow dissecting those electrostatic interactions that play a role in the conformation adopted by some residues and the extra-domain components upon binding C-terminal sequences. Full article
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11 pages, 2494 KiB  
Article
Crystal Structure of a New 1:1 Acridine-Diclofenac Salt, Obtained with High Yield by a Mechanochemical Approach
by Artur Mirocki, Eleonora Conterosito, Luca Palin, Artur Sikorski, Marco Milanesio and Mattia Lopresti
Crystals 2022, 12(11), 1573; https://doi.org/10.3390/cryst12111573 - 04 Nov 2022
Cited by 2 | Viewed by 2430
Abstract
The liquid-assisted grinding (LAG) approach was exploited to efficiently produce a new salt cocrystal with a minimum expenditure of reagents and energy, with possible application in the pharmaceutical field. LAG was applied to the acridine/diclofenac couple, and a new cocrystal was obtained with [...] Read more.
The liquid-assisted grinding (LAG) approach was exploited to efficiently produce a new salt cocrystal with a minimum expenditure of reagents and energy, with possible application in the pharmaceutical field. LAG was applied to the acridine/diclofenac couple, and a new cocrystal was obtained with a 1:1 ratio of reagents and its structure resolved by X-ray powder diffraction (XRPD). The XRPD analysis confirmed that the yield is higher than 90% and the limited use of solvents and the absence of waste generally makes the synthesis very efficient and with the minimum possible environmental impact. The crystal structure of the title compound was compared to a previously solved 1:2 cocrystal, also with the aid of Hirshfeld’s surface analysis and calculations of the energy framework. The packing of the 1:1 structure is stabilized by a strong H-bond and partial ππ-stacking interactions. It differs considerably from that of the previously identified cocrystal, in which two strong hydrogen bonds and a perfect interlocking of the molecules thanks to the the ππ stacking induce a much higher stability, as confirmed by energy framework calculations. DSC analysis confirmed its purity and a melting point at 140 °C, which is different from those of the two reactants. Full article
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26 pages, 7177 KiB  
Article
A Lection in Humbleness: Crystallization of Chiral and Zwitterionic APIs Baclofen and Phenibut
by Marco Herbst, Daniel Komisarek, Till Strothmann and Vera Vasylyeva
Crystals 2022, 12(10), 1393; https://doi.org/10.3390/cryst12101393 - 01 Oct 2022
Cited by 5 | Viewed by 2022
Abstract
Crystallization and multicomponent crystal formation of active pharmaceutical ingredients Baclofen and Phenibut with dicarboxylic acid co-formers are discussed. The crystallization process of several crystalline entities is elucidated via single crystal—as well as powder X-ray—diffraction, followed by thermal analysis and phase stability studies over [...] Read more.
Crystallization and multicomponent crystal formation of active pharmaceutical ingredients Baclofen and Phenibut with dicarboxylic acid co-formers are discussed. The crystallization process of several crystalline entities is elucidated via single crystal—as well as powder X-ray—diffraction, followed by thermal analysis and phase stability studies over time. Both APIs form increasingly complex crystalline phases with co-formers malic and tartaric acid, where phase purity of a desired compound is not necessarily a given. Therefore, the influence of different solution and milling environments during crystallization on the outcome is studied. Emphasis is laid on how molecular influences such as the chirality, propensity to form hydrates as well as low solubility of Baclofen and Phenibut impede attempts to gather high-quality single crystals. The results highlight that targeted crystallization of these compounds with dicarboxylic acids can be difficult and unreliable. Full article
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10 pages, 1622 KiB  
Article
Investigation of Glycine Polymorphic Transformation by In Situ ATR-FTIR and FT-Raman Spectroscopy
by Zunhua Li and Bowen Zhang
Crystals 2022, 12(8), 1141; https://doi.org/10.3390/cryst12081141 - 13 Aug 2022
Cited by 2 | Viewed by 1902
Abstract
The solution-mediated phase transformation of α-form to γ-form glycine, including dissolution of metastable α-form, nucleation, and growth of stable γ-form during polymorphic transformation, was investigated using in situ attenuated total-reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and Fourier transform Raman spectroscopy (FT-Raman). The mechanistic [...] Read more.
The solution-mediated phase transformation of α-form to γ-form glycine, including dissolution of metastable α-form, nucleation, and growth of stable γ-form during polymorphic transformation, was investigated using in situ attenuated total-reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and Fourier transform Raman spectroscopy (FT-Raman). The mechanistic influence of operating parameters such as agitation speed, crystallization temperature, α-form seed concentration, and NaCl concentration on polymorphic phase transformation was examined. When the agitation speed, crystallization temperature, and NaCl concentration were increased, the polymorphic transformation process was improved due to the promotion of nucleation and growth of stable γ-form, in addition to the promotion of dissolution of metastable α-form. Moreover, the time to induce γ-form nucleation and complete conversion of α-form to γ-form was also reduced with increasing α-form seed concentration. Full article
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