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Novel Pharmaceutical Cocrystals and Their Applications

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Keywords
Published Papers

A special issue of Crystals (ISSN 2073-4352).

Deadline for manuscript submissions: closed (30 June 2017) | Viewed by 51715

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Special Issue Editors

Dr. Srinivasulu Aitipamula

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Guest Editor

Crystallization and Particle Sciences, Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research Singapore), Singapore, Singapore
Interests: pharmaceuticals; encapsulation; structure-property relationships; crystal engineering; polymorphism; drug formulations
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Reginald Tan

E-Mail Website
Guest Editor

https://www.a-star.edu.sg/ices/Research-Development/Researcher-Portfolio/Reginald-Tan-Prof.aspx
Interests: crystallisation; modelling; process development; cocrystallization; formulation

Special Issue Information

Dear Colleagues,

Pharmaceutical cocrystals are molecular complexes that consist of an active pharmaceutical ingredient (API) and a pharmaceutically acceptable coformer that is a solid under ambient conditions. Crystal engineering strategies that rely on intermolecular interactions between the API and coformers have proved effective in the design and synthesis of cocrystals. Recent case studies in literature have demonstrated diverse applications of cocrystals in modifying physicochemical properties of APIs. By judicious selection of coformers, one can fine tune the properties such as solubility, dissolution rate, stability, bioavailability, mechanical strength, permeability, etc. Recent endorsement by the Food and Drug Administration of the USA and the European Medicines Agency further validated the use of cocrystals as potential alternative solid forms for drug development.

This Special Issue on "Novel Pharmaceutical Cocrystals and Their Applications" is expected to provide an international platform to report results that highlight the design and synthesis of cocrystals and their potential applications in the fields of pharmaceuticals and material science. We invite contributions from scientists working in all disciplines related to the development of pharmaceutical cocrystals.

The following keywords provide a glimpse of sub-topics covered in the proposed Special Issue. In addition, this Special Issue is open to any topic that advances the current understanding of cocrystal design and applications of pharmaceutical cocrystals.

Dr. Srinivasulu Aitipamula
Prof. Dr. Reginald Tan
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

pharmaceutical cocrystal
crystal engineering
cocrystal design,
crystal growth
physicochemical properties
structure-property relationship,
cocrystal processing and formulation

Published Papers (5 papers)

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Research

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12 pages, 8325 KiB

Open AccessArticle

Febuxostat-Minoxidil Salt Solvates: Crystal Structures, Characterization, Interconversion and Solubility Performance

by Li-Yang Li, Rong-Kai Du, You-Li Du, Chun-Jing Zhang, Su Guan, Chang-Zhi Dong and Lei Zhang

Crystals 2018, 8(2), 85; https://doi.org/10.3390/cryst8020085 - 05 Feb 2018

Cited by 11 | Viewed by 5593

Abstract

Three febuxostat-minoxidil salt solvates with acetone (ACE), tetrahydrofuran (THF) and isopropanol (IPA) are synthesized by solvent-assisted grinding and characterized by infrared (IR), nuclear magnetic resonance (¹H-NMR), single crystal and powder X-ray diffraction (PXRD), thermogravimetry (TG) and differential scanning calorimetry (DSC). These febuxostat-minoxidil salt solvates feature isostructural with the same stoichiometries (1:1:1 molecule ratio). The proton transfers from the carboxylic group of febuxostat (FEB) to imino N atom of minoxidil (MIN), which forms the motif with combined

R_{2}^{2}

(9)

R_{4}^{2}

(8)

R_{2}^{2}

(9) graph set in the three solvates. The solvents occupy the different positions related to the motif, which results in the apparent differences in PXRD patterns before/after desolvation although they are isostructures. The FEB-MIN·THF was more thermostable than FEB-MIN·ACE and FEB-MIN·IPA relative to solvent removal from DSC patterns, which is different from the results from the solvent-exchange experiments in chemical kinetics. All three salt solvates exhibit increased equilibrium solubility compared to FEB in aqueous medium. Full article

(This article belongs to the Special Issue Novel Pharmaceutical Cocrystals and Their Applications)

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1837 KiB

Open AccessArticle

Structural Characterization of Febuxostat/l-Pyroglutamic Acid Cocrystal Using Solid-State ¹³C-NMR and Investigational Study of Its Water Solubility

by Ji-Hun An, Changjin Lim, Hyung Chul Ryu, Jae Sun Kim, Hyuk Min Kim, Alice Nguvoko Kiyonga, Minho Park, Young-Ger Suh, Gyu Hwan Park and Kiwon Jung

Crystals 2017, 7(12), 365; https://doi.org/10.3390/cryst7120365 - 08 Dec 2017

Cited by 15 | Viewed by 7981

Abstract

Febuxostat (FB) is a poorly water-soluble drug that belongs to BCS class II. The drug is employed for the treatment of inflammatory disease arthritis urica (gout), and the free base, FB form-A, is most preferred for drug formulation. In order to achieve a goal of improving the water solubility of FB form-A, this study was carried out using the cocrystallization technique called the liquid-assisted grinding method to produce FB cocrystals. Here, five amino acids containing amine (NH), oxygen (O), and hydroxyl (OH) functional groups, and possessing difference of pKa less than 3 with FB, were selected as coformers. Then, solvents including methanol, ethanol, isopropyl alcohol, n-hexane, dichloromethane, and acetone were used for the cocrystal screening. As a result, a cocrystal was obtained when acetone and l-pyroglutamic acid (PG) of 0.5 eq. were employed as solvent and coformer, respectively. The ratio of 2:1, which is the ratio of FB to PG within FB-PG cocrystal, was predicted by means of solid-state CP/MAS ¹³C-NMR, solution-state NMR (¹H, ¹³C, and 2D) and FT-IR. Moreover, Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), and Thermogravimetric Analysis (TGA) were used to investigate the characteristics of FB-PG cocrystal. In addition, comparative solubility tests between FB-PG cocrystal and FB form-A were conducted in deionized water and under simulated gastrointestinal pH (1.2, 4, and 6.8) conditions. The result revealed that FB-PG cocrystal has a solubility of four-fold higher than FB form-A in deionized water and two-fold and five-fold greater than FB form-A at simulated gastrointestinal pH 1.2 and pH 4, respectively. Besides, solubilities of FB-PG cocrystal and FB form-A at pH 6.8 were similar to the results measured in deionized water. Therefore, it is postulated that FB-PG cocrystal has a potential overcoming the limitations related to the low aqueous solubility of FB form-A. Accordingly, FB-PG cocrystal is suggested as an alternative active pharmaceutical ingredient of the currently used FB form-A. Full article

(This article belongs to the Special Issue Novel Pharmaceutical Cocrystals and Their Applications)

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1701 KiB

Open AccessArticle

Ivabradine Hydrochloride (S)-Mandelic Acid Co-Crystal: In Situ Preparation during Formulation

by Veronika Sládková, Ondřej Dammer, Gregor Sedmak, Eliška Skořepová and Bohumil Kratochvíl

Crystals 2017, 7(1), 13; https://doi.org/10.3390/cryst7010013 - 06 Jan 2017

Cited by 21 | Viewed by 7972

Abstract

The pharmaceutical salt ivabradine hydrochloride is indicated for the symptomatic treatment of chronic stable angina pectoris and chronic heart failure. It exhibits extensive polymorphism and co-crystallization, which could be a way to provide an alternative solid form. We conducted a co-crystal screen, from which two hits were identified: with (S)-mandelic and (R)-mandelic acid. Both structures were determined from single-crystal X-ray diffraction data as co-crystals. The co-crystals were further characterized by common solid-state techniques, such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), solid-state NMR, IR and Raman spectroscopy, and dynamic vapor sorption (DVS). The co-crystal with (S)-mandelic acid was selected for further development; its physical and chemical stability was compared with two different polymorphs of the hydrochloride salt. The co-crystal exhibited a similar stability with the polymorph used in the original drug product and was, therefore, selected for formulation into the drug product. During the pre-formulation experiments, the in situ formation of the co-crystal was achieved during the wet granulation process. The following formulation experiments showed no influence of in situ prepared co-crystal on the overall stability of the bulk, when compared with pre-prepared co-crystal formulation. Full article

(This article belongs to the Special Issue Novel Pharmaceutical Cocrystals and Their Applications)

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Graphical abstract

1740 KiB

Open AccessArticle

Raman and Terahertz Spectroscopic Investigation of Cocrystal Formation Involving Antibiotic Nitrofurantoin Drug and Coformer 4-aminobenzoic Acid

by Yong Du, Qiang Cai, Jiadan Xue and Qi Zhang

Crystals 2016, 6(12), 164; https://doi.org/10.3390/cryst6120164 - 16 Dec 2016

Cited by 14 | Viewed by 6510

Abstract

Cocrystallization could improve most physicochemical properties of specific active pharmaceutical ingredients, which has great potential in pharmaceutical development. In this study, the cocrystal of nitrofurantoin and 4-aminobenzoic acid was prepared with solid-state (solvent-free or green-chemistry) grinding approach, and the above cocrystal has been characterized by Raman and terahertz vibrational spectroscopic techniques. Spectral results show that the vibrational modes of the cocrystal within the whole spectral region are different from those of the corresponding parent materials. The dynamic process of such pharmaceutical cocrystal formation has also been monitored directly with Raman spectra. These results offer us unique means for characterizing the cocrystal conformation from the molecule-level, and provides us with rich information about the reaction dynamic of cocrystal formation within pharmaceutical fields. Full article

(This article belongs to the Special Issue Novel Pharmaceutical Cocrystals and Their Applications)

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Review

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39 pages, 23020 KiB

Open AccessReview

Drug‑Drug and Drug‑Nutraceutical Cocrystal/Salt as Alternative Medicine for Combination Therapy: A Crystal Engineering Approach

by Ranjit Thakuria and Bipul Sarma

Crystals 2018, 8(2), 101; https://doi.org/10.3390/cryst8020101 - 18 Feb 2018

Cited by 113 | Viewed by 22016

Abstract

The pre-formulation of pharmaceutical cocrystals and salts is a concept of crystal engineering that has emerged as a promising technique for drug development in pharmaceutical industry. Recent introduction of pharmaceutical cocrystals in regulatory guidelines of US Food and Drug Administration (FDA) made them one of the potential alternatives when salt preparation is not feasible. Apart from generally regarded as safe (GRAS) coformers, drug‑drug and drug‑nutraceutical cocrystals are recent additions to pharmaceutical cocrystal family that have additional health benefits. Indeed, preparation of salt forms is a routine practice to deal with inadequacies associated with the active pharmaceutical ingredient (API) and happens to be a potentially reliable method. Amongst them, drug-drug and drug-nutraceutical cocrystals have drawn significant importance in the recent past as they reduce drug load and cost effects during multiple disease diagnosis. However, one has to be prudent in the selection of drug molecules, the presence of complementary hydrogen bond synthon, disease management during multiple disease therapy, etc. that play important roles in their preparation. That is the reason why drug–drug cocrystals are scarce in the literature compared to pharmaceutical cocrystals containing GRAS coformers and salt forms. Herein, we discuss case studies preferably the reported drug‑drug, drug‑nutraceutical cocrystals, and a few salts with an emphasis on their role in physicochemical property modulation. Full article

(This article belongs to the Special Issue Novel Pharmaceutical Cocrystals and Their Applications)

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