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Pharmaceutics
Special Issues
Controlled Crystallization of Active Pharmaceutical Ingredients, 2nd Edition
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Controlled Crystallization of Active Pharmaceutical Ingredients, 2nd Edition

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (31 December 2024) | Viewed by 7832

Special Issue Editors

Prof. Dr. Il Won Kim

E-Mail Website
Guest Editor
Department of Chemical Engineering, Soongsil University, Seoul 06978, Republic of Korea
Interests: biomineralization; pharmaceutical crystallization; interfacial phenomena
Special Issues, Collections and Topics in MDPI journals
Dr. Varin Titapiwatanakun

E-Mail Website
Guest Editor
Pharmaceutical Sciences and Technology Program, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
Interests: crystal engineering; 3D-printing; drug delivery; pharmaceutical process development

Special Issue Information

Dear Colleagues,

Crystallization is an important separation process that generates crystalline materials with high purity and yield. In the area of pharmaceutical research, the crystallization of active pharmaceutical ingredients (APIs) has been vigorously studied because of its great influence on the physicochemical properties of APIs. The size, shape, and phase of the crystals are some of the features frequently controlled during crystallization and they are closely related to the solubility, dissolution rate, and stability of the resulting API solid forms.

The aim of this Special Issue is to provide a forum for researchers in the broad field of pharmaceutical crystallization. While the focus is specifically on the crystallization of APIs, this Special Issue is open to original research and review articles on all aspects of pharmaceutical crystallization.

Prof. Dr. Il Won Kim
Dr. Varin Titapiwatanakun
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. Pharmaceutics 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 2900 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

  • active pharmaceutical ingredients
  • crystal shape and size (e.g., nanodrug)
  • crystal phases (e.g., polymorph, salt, cocrystal)
  • separation processes (e.g., purity, chirality)
  • industrial process development

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Published Papers (4 papers)

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Research

20 pages, 5589 KiB  
Article
Quantification of Amlodipine Maleate Content in Amorphous Solid Dispersions Produced by Fluidized Bed Granulation Using Process Analytical Technology Tools
by Sandi Svetič, Laura Medved, Klemen Korasa and Franc Vrečer
Pharmaceutics 2024, 16(12), 1538; https://doi.org/10.3390/pharmaceutics16121538 - 1 Dec 2024
Viewed by 1007
Abstract
Background: Active pharmaceutical ingredient (API) content is a critical quality attribute (CQA) of amorphous solid dispersions (ASDs) prepared by spraying a solution of APIs and polymers onto the excipients in fluid bed granulator. This study presents four methods for quantifying API content during [...] Read more.
Background: Active pharmaceutical ingredient (API) content is a critical quality attribute (CQA) of amorphous solid dispersions (ASDs) prepared by spraying a solution of APIs and polymers onto the excipients in fluid bed granulator. This study presents four methods for quantifying API content during ASD preparation. Methods: Raman and three near-infrared (NIR) process analysers were utilized to develop methods for API quantification. Four partial least squares (PLS) models were developed using measurements from three granulation batches, with an additional batch used to evaluate model predictability. Models performance was assessed using metrics such as root mean square error of prediction (RMSEP), root mean square error of cross-validation (RMSECV), residual prediction deviation (RPD), and others. Results: Off-line and at-line NIR models were identified as suitable for process control applications. Additionally, at-line Raman measurements effectively predicted the endpoint of the spraying phase. Conclusions: To the best of authors’ knowledge, this is the first study focused on monitoring API content during fluidized bed granulation (FBG) used for ASD preparation. The findings provide novel insights into the application of Raman and NIR process analysers with PLS modelling for monitoring and controlling ASD preparation processes. Full article
(This article belongs to the Special Issue Controlled Crystallization of Active Pharmaceutical Ingredients, 2nd Edition)
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17 pages, 4243 KiB  
Article
The Continuous and Reversible Transformation of the Polymorphs of an MGAT2 Inhibitor (S-309309) from the Anhydrate to the Hydrate in Response to Relative Humidity
by Tetsuya Miyano, Katsuji Sugita and Hiroshi Ueda
Pharmaceutics 2024, 16(7), 949; https://doi.org/10.3390/pharmaceutics16070949 - 17 Jul 2024
Cited by 3 | Viewed by 1317
Abstract
Polymorphic control is vital for the quality control of pharmaceutical crystals. Here, we investigated the relationship between the hydrate and anhydrate polymorphs of a monoacylglycerol acyltransferase 2 inhibitor (S-309309). Solvent evaporation and slurry conversion revealed two polymorphs, the hydrate and the solvate. The [...] Read more.
Polymorphic control is vital for the quality control of pharmaceutical crystals. Here, we investigated the relationship between the hydrate and anhydrate polymorphs of a monoacylglycerol acyltransferase 2 inhibitor (S-309309). Solvent evaporation and slurry conversion revealed two polymorphs, the hydrate and the solvate. The solvate was transformed into the hydrate by heating. X-ray powder diffraction demonstrated that the hydrate was transformed into an anhydrate via an intermediate state when heated. These crystal forms were confirmed under controlled humidity conditions; the presence of the anhydrate, the intermediate hydrate, or the hydrate depended on the relative humidity at 25 °C. The stoichiometry of S-309309 in water in the hydrate form was 4:1. The hydrates and anhydrates exhibited similar crystal structures and stability. The water of hydration in the intermediate hydrate was 0.1–0.15 mol according to the dynamic vapor sorption profile. The stability and dissolution profile of the anhydrate and hydrate showed no significant change due to similar crystal lattices and quick rehydration of the anhydrate. A mechanism for the reversible crystal transformation between the anhydrate and pseudo-polymorphs of the hydrate was discovered. We concluded that S-309309 causes a pseudo-polymorphic transformation; however, this is not a critical issue for pharmaceutical use. Full article
(This article belongs to the Special Issue Controlled Crystallization of Active Pharmaceutical Ingredients, 2nd Edition)
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20 pages, 6068 KiB  
Article
Polymorphism and Multi-Component Crystal Formation of GABA and Gabapentin
by Daniel Komisarek, Fulya Demirbas, Takin Haj Hassani Sohi, Klaus Merz, Carsten Schauerte and Vera Vasylyeva
Pharmaceutics 2023, 15(9), 2299; https://doi.org/10.3390/pharmaceutics15092299 - 10 Sep 2023
Cited by 1 | Viewed by 1838
Abstract
This study exploits the polymorphism and multi-component crystal formation of γ-amino butanoic acid (GABA) and its pharmaceutically active derivative, gabapentin. Two polymorphs of GABA and both polymorphs of gabapentin are structurally revisited, together with gabapentin monohydrate. Hereby, GABA form II is only accessible [...] Read more.
This study exploits the polymorphism and multi-component crystal formation of γ-amino butanoic acid (GABA) and its pharmaceutically active derivative, gabapentin. Two polymorphs of GABA and both polymorphs of gabapentin are structurally revisited, together with gabapentin monohydrate. Hereby, GABA form II is only accessible under special conditions using additives, whereas gabapentin converts to the monohydrate even in the presence of trace amounts of water. Different accessibilities and phase stabilities of these phases are still not fully clarified. Thus, indicators of phase stability are discussed involving intermolecular interactions, molecular conformations, and crystallization environment. Calculated lattice energy differences for polymorphs reveal their similar stability. Quantification of the hydrogen bond strengths with the atoms-in-molecules (AIM) model in conjunction with non-covalent interaction (NCI) plots also shows similar hydrogen bond binding energy values for all polymorphs. We demonstrate that differences in the interacting modes, in an interplay with the intermolecular repulsion, allow the formation of the desired phase under different crystallization environments. Salts and co-crystals of GABA and gabapentin with fumaric as well as succinic acid further serve as models to highlight how strongly HBs act as the motif-directing force in the solid-phase GABA-analogs. Six novel multi-component entities were synthesized, and structural and computational analysis was performed: GABA fumarate (2:1); two gabapentin fumarates (2:1) and (1:1); two GABA succinates (2:1) and (1:1); and a gabapentin:succinic acid co-crystal. Energetically highly attractive carboxyl/carboxylate interaction overcomes other factors and dominates the multi-component phase formation. Decisive commonalities in the crystallization behavior of zwitterionic GABA-derivatives are discussed, which show how they can and should be understood as a whole for possible related future products. Full article
(This article belongs to the Special Issue Controlled Crystallization of Active Pharmaceutical Ingredients, 2nd Edition)
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16 pages, 10935 KiB  
Article
Polymeric Microspheres Designed to Carry Crystalline Drugs at Their Surface or Inside Cavities and Dimples
by Meitong Shen, Ling Zheng and Leo H. Koole
Pharmaceutics 2023, 15(8), 2146; https://doi.org/10.3390/pharmaceutics15082146 - 15 Aug 2023
Viewed by 1876
Abstract
Injectable polymer microparticles with the ability to carry and release pharmacologically active agents are attracting more and more interest. This study is focused on the chemical synthesis, characterization, and preliminary exploration of the utility of a new type of injectable drug-releasing polymer microparticle. [...] Read more.
Injectable polymer microparticles with the ability to carry and release pharmacologically active agents are attracting more and more interest. This study is focused on the chemical synthesis, characterization, and preliminary exploration of the utility of a new type of injectable drug-releasing polymer microparticle. The particles feature a new combination of structural and physico-chemical properties: (i) their geometry deviates from the spherical in the sense that the particles have a cavity; (ii) the particles are porous and can therefore be loaded with crystalline drug formulations; drug crystals can reside at both the particle’s surfaces and inside cavities; (iii) the particles are relatively dense since the polymer network contains covalently bound iodine (approximately 10% by mass); this renders the drug-loaded particles traceable (localizable) by X-ray fluoroscopy. This study presents several examples. First, the particles were loaded with crystalline voriconazole, which is a potent antifungal drug used in ophthalmology to treat fungal keratitis (infection/inflammation of the cornea caused by penetrating fungus). Drug loading as high as 10% by mass (=mass of immobilized drug/(mass of the microparticle + mass of immobilized drug) × 100%) could be achieved. Slow local release of voriconazole from these particles was observed in vitro. These findings hold promise regarding new approaches to treat fungal keratitis. Moreover, this study can help to expand the scope of the transarterial chemoembolization (TACE) technique since it enables the use of higher drug loadings (thus enabling higher local drug concentration or extended therapy duration), as well as application of hydrophobic drugs that cannot be used in combination with existing TACE embolic particles. Full article
(This article belongs to the Special Issue Controlled Crystallization of Active Pharmaceutical Ingredients, 2nd Edition)
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