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Pharmaceutics
Special Issues
Controlled Crystallization of Active Pharmaceutical Ingredients
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Controlled Crystallization of Active Pharmaceutical Ingredients

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

Deadline for manuscript submissions: closed (15 April 2021) | Viewed by 16766

Special Issue Editor

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

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, crystallization of active pharmaceutical ingredients (APIs) has been vigorously studied because of its great influence on the physicochemical properties of APIs. 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. Il Won Kim
Guest Editor

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. 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 (6 papers)

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Research

23 pages, 5332 KiB  
Article
Combined Use of Structure Analysis, Studies of Molecular Association in Solution, and Molecular Modelling to Understand the Different Propensities of Dihydroxybenzoic Acids to Form Solid Phases
by Aija Trimdale, Anatoly Mishnev and Agris Bērziņš
Pharmaceutics 2021, 13(5), 734; https://doi.org/10.3390/pharmaceutics13050734 - 16 May 2021
Cited by 6 | Viewed by 2528
Abstract
The arrangement of hydroxyl groups in the benzene ring has a significant effect on the propensity of dihydroxybenzoic acids (diOHBAs) to form different solid phases when crystallized from solution. All six diOHBAs were categorized into distinctive groups according to the solid phases obtained [...] Read more.
The arrangement of hydroxyl groups in the benzene ring has a significant effect on the propensity of dihydroxybenzoic acids (diOHBAs) to form different solid phases when crystallized from solution. All six diOHBAs were categorized into distinctive groups according to the solid phases obtained when crystallized from selected solvents. A combined study using crystal structure and molecule electrostatic potential surface analysis, as well as an exploration of molecular association in solution using spectroscopic methods and molecular dynamics simulations were used to determine the possible mechanism of how the location of the phenolic hydroxyl groups affect the diversity of solid phases formed by the diOHBAs. The crystal structure analysis showed that classical carboxylic acid homodimers and ring-like hydrogen bond motifs consisting of six diOHBA molecules are prominently present in almost all analyzed crystal structures. Both experimental spectroscopic investigations and molecular dynamics simulations indicated that the extent of intramolecular bonding between carboxyl and hydroxyl groups in solution has the most significant impact on the solid phases formed by the diOHBAs. Additionally, the extent of hydrogen bonding with solvent molecules and the mean lifetime of solute–solvent associates formed by diOHBAs and 2-propanol were also investigated. Full article
(This article belongs to the Special Issue Controlled Crystallization of Active Pharmaceutical Ingredients)
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12 pages, 2955 KiB  
Article
Enhanced Dissolution of Naproxen by Combining Cocrystallization and Eutectic Formation
by Hakyeong Kim, Soeun Jang and Il Won Kim
Pharmaceutics 2021, 13(5), 618; https://doi.org/10.3390/pharmaceutics13050618 - 25 Apr 2021
Cited by 9 | Viewed by 2818
Abstract
Improving dissolution properties of active pharmaceutical ingredients (APIs) is a critical step in drug development with the increasing occurrence of sparingly soluble APIs. Cocrystal formation is one of the methods to alter the physicochemical properties of APIs, but its dissolution behavior in biorelevant [...] Read more.
Improving dissolution properties of active pharmaceutical ingredients (APIs) is a critical step in drug development with the increasing occurrence of sparingly soluble APIs. Cocrystal formation is one of the methods to alter the physicochemical properties of APIs, but its dissolution behavior in biorelevant media has been scrutinized only in recent years. We investigated the combined strategy of cocrystallization and eutectic formation in this regard and utilized the cocrystal model system of naproxen and three pyridinecarboxamide isomers. Binary melting diagrams were constructed to discover the eutectic compositions of the three cocrystals with excess amounts of pyridinecarboxamides. The melt–crystallized eutectics and cocrystals were compared in their dissolution behaviors with respect to neat naproxen. The eutectics enhanced the early dissolution rates of the cocrystals in both the absence and presence of biologically relevant bile salt and phospholipid components, whereas the cocrystal dissolution was expedited and delayed, respectively. The combined strategy in the present study will be advantageous in maximizing the utility of the pharmaceutical cocrystals. Full article
(This article belongs to the Special Issue Controlled Crystallization of Active Pharmaceutical Ingredients)
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Graphical abstract

14 pages, 3328 KiB  
Article
Stabilization of Metastable Indomethacin α in Cellulose Nanocrystal Aerogel Scaffolds
by Manali Banerjee and Blair Brettmann
Pharmaceutics 2021, 13(4), 441; https://doi.org/10.3390/pharmaceutics13040441 - 24 Mar 2021
Cited by 2 | Viewed by 2926
Abstract
Indomethacin (IM) is a small molecule active pharmaceutical ingredient (API) that exhibits polymorphism with the γ-form being the most thermodynamically stable form of the drug. The α-form is metastable, but it exhibits higher solubility, making it a more attractive form for drug delivery. [...] Read more.
Indomethacin (IM) is a small molecule active pharmaceutical ingredient (API) that exhibits polymorphism with the γ-form being the most thermodynamically stable form of the drug. The α-form is metastable, but it exhibits higher solubility, making it a more attractive form for drug delivery. As with other metastable polymorphs, α-IM undergoes interconversion to the stable form when subjected to certain stimuli, such as solvent, heat, pH, or exposure to seed crystals of the stable form. In this study, IM was crystallized into cellulose nanocrystal aerogel scaffolds as a mixture of the two polymorphic forms, α-IM and γ-IM. Differential scanning calorimetry (DSC) and Raman spectroscopy were used to quantitatively determine the amount of each form. Our investigation found that the metastable α-IM could be stabilized within the aerogel without phase transformation, even in the presence of external stimuli, including heat and γ-IM seed crystals. Because interconversion is often a concern during production of metastable forms of APIs, this approach has important implications in being able to produce and stabilize metastable drug forms. While IM was used as a model drug in this study, this approach could be expanded to additional drugs and provide access to other metastable API forms. Full article
(This article belongs to the Special Issue Controlled Crystallization of Active Pharmaceutical Ingredients)
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Graphical abstract

16 pages, 1409 KiB  
Article
Understanding the Salt-Dependent Outcome of Glycine Polymorphic Nucleation
by Guangjun Han, Pui Shan Chow and Reginald B. H. Tan
Pharmaceutics 2021, 13(2), 262; https://doi.org/10.3390/pharmaceutics13020262 - 15 Feb 2021
Cited by 13 | Viewed by 2328
Abstract
The salt-dependent polymorphs of glycine crystals formed from bulk solutions have been a longstanding riddle. In this study, in order to shed fresh light, we studied the effects of seven common salts on primary nucleation of the metastable α-glycine and the stable γ-glycine. [...] Read more.
The salt-dependent polymorphs of glycine crystals formed from bulk solutions have been a longstanding riddle. In this study, in order to shed fresh light, we studied the effects of seven common salts on primary nucleation of the metastable α-glycine and the stable γ-glycine. Our nucleation experiments and in-depth data analyses enabled us to reveal that (NH4)2SO4, NaCl and KNO3, in general, promote γ-glycine primary nucleation very significantly while simultaneously inhibiting α-glycine primary nucleation, thereby explaining why these three salts induce γ-glycine readily. In comparison, Ca(NO3)2 and MgSO4 also promote γ-glycine and inhibit α-glycine primary nucleation but not sufficiently to induce γ-glycine. More interestingly, Na2SO4 and K2SO4 promote not only γ-glycine but also α-glycine primary nucleation, which is unexpected and presents a rare case where a single additive promotes the nucleation of both polymorphs. As a result, the promoting effects of Na2SO4 and K2SO4 on γ-glycine do not enable γ-glycine nucleation to be more competitive than α-glycine nucleation, with γ-glycine failing to appear. These observations help us to better understand salt-governed glycine polymorphic selectivity. Full article
(This article belongs to the Special Issue Controlled Crystallization of Active Pharmaceutical Ingredients)
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Figure 1

10 pages, 1826 KiB  
Article
Binary Mixtures of Some Active Pharmaceutical Ingredients with Fatty Alcohols—The Criteria of Successful Eutectic Formation and Dissolution Improvement
by Songhee Jin, Jisun Jang, Soyeon Lee and Il Won Kim
Pharmaceutics 2020, 12(11), 1098; https://doi.org/10.3390/pharmaceutics12111098 - 16 Nov 2020
Cited by 8 | Viewed by 2994
Abstract
Pharmaceutical eutectics are solid mixtures, where the crystals of active pharmaceutical ingredients (APIs) are finely divided in the phase-separated microstructures. The size reduction makes the eutectic formation a viable option to improve the dissolution rate of the poorly soluble APIs. In the present [...] Read more.
Pharmaceutical eutectics are solid mixtures, where the crystals of active pharmaceutical ingredients (APIs) are finely divided in the phase-separated microstructures. The size reduction makes the eutectic formation a viable option to improve the dissolution rate of the poorly soluble APIs. In the present study, ibuprofen, naproxen, and sorafenib were investigated in terms of their phase behaviors with fatty alcohols, such as tetradecanol, octadecanol, and docosanol. Among the studied APIs, only ibuprofen was able to form eutectics with the fatty alcohols, and this was in agreement with the feasibility prediction based on the van ’t Hoff equation and solubility parameters. In vitro release behavior was significantly improved for the ibuprofen/octadecanol eutectic mixture, although the practical insolubility of octadecanol in water was the opposite of the outstanding hydrophilicity of usual eutectic formers. The feasibility prediction and the choice of eutectic formers in the present study will be useful in advancing the utility of the pharmaceutical eutectics. Full article
(This article belongs to the Special Issue Controlled Crystallization of Active Pharmaceutical Ingredients)
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Graphical abstract

16 pages, 4593 KiB  
Article
Mechanochemical Synthesis and Structure of the Tetrahydrate and Mesoporous Anhydrous Metforminium(2+)-N,N′-1,4-Phenylenedioxalamic Acid (1:2) Salt: The Role of Hydrogen Bonding and n→π * Charge Assisted Interactions
by Sayuri Chong-Canto, Efrén V. García-Báez, Francisco J. Martínez-Martínez, Angel A. Ramos-Organillo and Itzia I. Padilla-Martínez
Pharmaceutics 2020, 12(10), 998; https://doi.org/10.3390/pharmaceutics12100998 - 21 Oct 2020
Cited by 5 | Viewed by 2242
Abstract
A new organic salt of metformin, an antidiabetic drug, and N,N′-(1,4-phenylene)dioxalamic acid, was mechanochemically synthesized, purified by crystallization from solution and characterized by single X-ray crystallography. The structure revealed a salt-type crystal hydrate composed of one dicationic metformin unit, two [...] Read more.
A new organic salt of metformin, an antidiabetic drug, and N,N′-(1,4-phenylene)dioxalamic acid, was mechanochemically synthesized, purified by crystallization from solution and characterized by single X-ray crystallography. The structure revealed a salt-type crystal hydrate composed of one dicationic metformin unit, two monoanionic units of the acid and four water molecules, namely H2Mf(HpOXA)2∙4H2O. X-ray powder, IR, 13C-CPMAS, thermal and BET adsorption–desorption analyses were performed to elucidate the structure of the molecular and supramolecular structure of the anhydrous microcrystalline mesoporous solid H2Mf(HpOXA)2. The results suggest that their structures, conformation and hydrogen bonding schemes are very similar. To the best of our knowledge, the selective formation of the monoanion HpOXA−, as well as its structure in the solid, is herein reported for the first time. Regular O(δ−)∙∙∙C(δ), O(δ−)∙∙∙N+ and bifacial O(δ−)∙∙∙C(δ)∙∙∙O(δ−) of n→π * charge-assisted interactions are herein described in H2MfA organic salts which could be responsible of the interactions of metformin in biologic systems. The results support the participation of n→π * charge-assisted interactions independently, and not just as a short contact imposed by the geometric constraint due to the hydrogen bonding patterns. Full article
(This article belongs to the Special Issue Controlled Crystallization of Active Pharmaceutical Ingredients)
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