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Special Issue "Advances in Pharmaceutical Crystals: Control over Nucleation and Polymorphism"

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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 8016

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Special Issue Editors

Dr. José Gavira

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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)
Special Issues, Collections and Topics in MDPI journals

Dr. Fiora Artusio

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Supramolecular Nanomaterials and Interfaces Laboratory, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Interests: pharmaceutical crystallisation; protein crystallisation; nucleation and crystal growth; gels; drug delivery; surface functionalisation; freeze-drying; antiviral drugs

Dr. Rafael Contreras-Montoya

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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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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 2600 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

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

Published Papers (6 papers)

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Research

Open AccessArticle

Synthesis and Structure Characterization of Three Pharmaceutical Compounds Based on Tinidazole

and

Crystals 2023, 13(6), 947; https://doi.org/10.3390/cryst13060947 - 12 Jun 2023

Viewed by 523

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 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

(This article belongs to the Special Issue Advances in Pharmaceutical Crystals: Control over Nucleation and Polymorphism)

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Open AccessArticle

Drug Release from Carrier Systems Comprising Meloxicam Crystals Formed by Impregnation-Evaporation

and

Crystals 2023, 13(3), 527; https://doi.org/10.3390/cryst13030527 - 19 Mar 2023

Viewed by 1049

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 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

(This article belongs to the Special Issue Advances in Pharmaceutical Crystals: Control over Nucleation and Polymorphism)

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Open AccessArticle

pH-Driven Polymorphic Behaviour of the Third PDZ Domain of PSD95: The Role of Electrostatic Interactions

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 903

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 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

(This article belongs to the Special Issue Advances in Pharmaceutical Crystals: Control over Nucleation and Polymorphism)

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Open AccessArticle

Crystal Structure of a New 1:1 Acridine-Diclofenac Salt, Obtained with High Yield by a Mechanochemical Approach

and

Crystals 2022, 12(11), 1573; https://doi.org/10.3390/cryst12111573 - 04 Nov 2022

Cited by 1 | Viewed by 1984

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 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

π \dots π

-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

π \dots π

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

(This article belongs to the Special Issue Advances in Pharmaceutical Crystals: Control over Nucleation and Polymorphism)

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Open AccessEditor’s ChoiceArticle

A Lection in Humbleness: Crystallization of Chiral and Zwitterionic APIs Baclofen and Phenibut

and

Crystals 2022, 12(10), 1393; https://doi.org/10.3390/cryst12101393 - 01 Oct 2022

Cited by 2 | Viewed by 1521

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 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

(This article belongs to the Special Issue Advances in Pharmaceutical Crystals: Control over Nucleation and Polymorphism)

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Open AccessArticle

Investigation of Glycine Polymorphic Transformation by In Situ ATR-FTIR and FT-Raman Spectroscopy

Zunhua Li

and

Bowen Zhang

Crystals 2022, 12(8), 1141; https://doi.org/10.3390/cryst12081141 - 13 Aug 2022

Cited by 1 | Viewed by 1337

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 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

(This article belongs to the Special Issue Advances in Pharmaceutical Crystals: Control over Nucleation and Polymorphism)

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