Pharmaceutical Polymorphs and Cocrystals and Their In Vitro and In Vivo Evaluation

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

Deadline for manuscript submissions: 20 July 2025 | Viewed by 12884

Special Issue Editors


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Guest Editor
1. Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100050, China
2. Beijing Key Laboratory of Polymorphic Drugs, Center of Pharmaceutical Polymorphs, Beijing 100050, China
Interests: new technologies and methods for pharmaceutical analysis; polymorphic drugs; quality control of drugs; druggability evaluation of innovative drug

E-Mail Website
Guest Editor
1. Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100050, China
2. Beijing Key Laboratory of Polymorphic Drugs, Center of Pharmaceutical Polymorphs, Beijing 100050, China
Interests: solid state pharmaceutical crystal chemistry; application of computational chemistry to pharmaceutical crystallography; evaluation of pharmaceutical cocrystal in vitro and in vivo

Special Issue Information

Dear Colleagues,

Approximately 90% of new chemical entities and 40% of marketed drugs belong to biopharmaceutical classification system (BCS) classes II or IV, which have poor water solubility and/or poor permeability. These defects result in low bioavailability. The formation of different polymorphs and co-crystals has been proven to be an important method to effectively improve the physicochemical properties, in vivo metabolic processes and bioavailability of these insoluble compounds. Through the efforts of many researchers, many new polymorphs or co-crystals of these compounds have been discovered. Some of them, such as Entresto (sacubitril valsartan sodium tablet, the first co-crystal drug approved by the FDA) and Seglentis (tramadol hydrochloride  and celecoxib), after rigorous preclinical research and clinical trials, have been marketed for clinical service. The research on the polymorphs and co-crystals of these compounds provides new approaches and broad prospects for drug development.

The efficient design, screening and preparation of different polymorphs and co-crystals of drugs, and accurate and scientific evaluation of their physical and chemical properties and in vitro and in vivo processes are the key points in drug research and development. We encourage the submission of research studies exploring these topics to this Special Issue. The different solid states of chemicals affect their physicochemical properties (e.g., solubility, permeability and stability) and in vivo processes (e.g., absorption and distribution), thus affecting bioavailability. Through systematic studies, the optimal crystal forms or co-crystals of drugs can be screened to improve their medicinal properties. This Special Issue aims to explore new research ideas for enriching material resources and promoting drug research and development.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  • Drug permeability improvement and in vitro and in vivo evaluation;
  • Solubility improvement of insoluble drugs and in vitro and in vivo evaluation;
  • Study on the mechanisms of improvement of physical and chemical properties of different drug polymorphs or co-crystals;
  • New methods for evaluating the solubility and permeability of different drug polymorphs or co-crystals;
  • Studies on pharmacokinetics of different drug polymorphs or co-crystals in vivo.

We look forward to receiving your contributions.

Prof. Dr. Li Zhang
Prof. Dr. Dezhi Yang
Guest Editors

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Keywords

  • pharmaceutical polymorphs
  • pharmaceutical cocrystals
  • pharmaceutical salts
  • solubility
  • dissolution
  • permeability

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Published Papers (6 papers)

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Research

16 pages, 9032 KiB  
Article
Mechanistic Insight into the Enhanced Anti-Pulmonary Hypertension Efficacy of Wogonin Co-Amorphous
by Zhongshui Xie, Yucai Chen, Jiaqi Xie, Yan Lei, Chunxue Jia, Yulu Liang, Hongjuan Wang and Jianmei Huang
Pharmaceutics 2025, 17(6), 724; https://doi.org/10.3390/pharmaceutics17060724 - 30 May 2025
Viewed by 383
Abstract
Background: Pulmonary hypertension (PH) remains a life-threatening rare disease characterized by inflammation and oxidative stress in pulmonary artery smooth muscle cells (PASMCs). Wogonin (Wog), a plant-derived polyphenolic compound extracted from Scutellaria baicalensis Georgi, exhibits notable antioxidant activity and anti-PH efficacy, whereas its clinical [...] Read more.
Background: Pulmonary hypertension (PH) remains a life-threatening rare disease characterized by inflammation and oxidative stress in pulmonary artery smooth muscle cells (PASMCs). Wogonin (Wog), a plant-derived polyphenolic compound extracted from Scutellaria baicalensis Georgi, exhibits notable antioxidant activity and anti-PH efficacy, whereas its clinical applications are greatly limited by poor aqueous solubility. Methods: Herein, an innovative wogonin-aloperine co-amorphous (Wog-Alop) was developed to improve the aqueous solubility and, thus, anti-PH efficacy of Wog. Results: As expected, the aqueous solubility of Wog-Alop is about 40-fold that of Wog; meanwhile, the Wog-Alop demonstrates better oral bioavailability and anti-PH efficacy than Wog; moreover, the Wog-Alop exhibits significantly enhanced capacity to attenuate oxidative stress in human PASMCs compared to Wog. Conclusions: The results suggested that Wog-Alop could not only improve the solubility of Wog, thereby enhancing its oral bioavailability but also alleviate Wog’s oxidative stress effects. These synergistic effects ultimately culminate in the enhanced anti-PH efficacy of Wog. In summary, the present study developed an innovative co-amorphous strategy for the delivery of Wog and improved its anti-PH efficacy. Full article
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17 pages, 5406 KiB  
Article
Developing the Oxalate, Fumarate and Succinate Salts of Tetrabenazine: Solid-State Characterization and Solubility
by Marieta Muresan-Pop, Viorica Simon, Gheorghe Borodi and Alexandru Turza
Pharmaceutics 2025, 17(5), 670; https://doi.org/10.3390/pharmaceutics17050670 - 20 May 2025
Viewed by 389
Abstract
Background: Tetrabenazine (brand name Nitoman and Xenazine) is a compound used to treat neurological and psychiatric disorders. Due to its low solubility, this drug is administered to patients in high doses, which produces side effects. Methods: To overcome these deficiencies, we [...] Read more.
Background: Tetrabenazine (brand name Nitoman and Xenazine) is a compound used to treat neurological and psychiatric disorders. Due to its low solubility, this drug is administered to patients in high doses, which produces side effects. Methods: To overcome these deficiencies, we prepared, using the mechanochemical method, three salts of tetrabenazine with three coformers: oxalic, fumaric, and succinic acid. The new solid forms were identified by X-ray powder diffraction (XRPD). Results: Full structural characterization was performed by single-crystal X-ray diffraction (SC-XRD), which revealed that the supramolecular interactions in the new solid forms were achieved by proton transfer between the coformer and the nitrogen of the tetrabenazine molecule. The salts formation was also evidenced by thermal analyses (DSC) and infrared spectroscopy (FTIR). Furthermore, the physical stability of the salts was evaluated under extreme temperature and humidity conditions. Conclusions: From a pharmaceutical perspective, UV-VIS tests of the new salts dissolved in water revealed a significant improvement in their solubility, which could improve their bioavailability in therapeutic applications. Full article
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20 pages, 8895 KiB  
Article
Novel Solid Forms of Cardarine/GW501516 and Their Characterization by X-Ray Diffraction, Thermal, Computational, FTIR, and UV Analysis
by Alexandru Turza, Maria Bosca, Marieta Muresan-Pop, Liviu Mare, Gheorghe Borodi and Violeta Popescu
Pharmaceutics 2025, 17(2), 152; https://doi.org/10.3390/pharmaceutics17020152 - 23 Jan 2025
Viewed by 1956
Abstract
Cardarine (C21H18F3NO3S2), better known by the popular name of GW501516, is a peroxisome proliferator-activated receptor delta (PPR-δ) agonist that presents potential use in the approach of cardiovascular diseases and metabolic disorders, dyslipidemia, and [...] Read more.
Cardarine (C21H18F3NO3S2), better known by the popular name of GW501516, is a peroxisome proliferator-activated receptor delta (PPR-δ) agonist that presents potential use in the approach of cardiovascular diseases and metabolic disorders, dyslipidemia, and insulin resistance. The capability of cardarine to exhibit new solid forms by recrystallization from a broad class of solvents was explored. A total of four new solid forms were obtained: a new polymorph of cardarine (C21H18F3NO3S2), the cardarine: 4,4′-bipyridine cocrystal (C21H18F3NO3S2·0.5C10H8N2), the cardarine methanol solvate (C21H18F3NO3S2·CH3OH), and the cardarine dimethylformamide solvate (C21H18F3NO3S2·C3H7NO). Moreover, two derivatives of cardarine were obtained, in the form of the mono-oxidized cardarine structure (C21H18F3NO4S2) and the dioxidized cardarine structure (C21H18F3NO5S2). The formation process was proven by the determination of their crystal structures using single crystal X-ray diffraction and followed by their lattice energies evaluation. Further investigations have been conducted by powder X-ray diffraction, DTA/TGA thermal analysis, and FTIR spectroscopy. The stability and solubility were analyzed as well. Full article
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17 pages, 3262 KiB  
Article
Five Novel Polymorphs of Cardarine/GW501516 and Their Characterization by X-ray Diffraction, Computational Methods, Thermal Analysis and a Pharmaceutical Perspective
by Alexandru Turza, Petru Pascuta, Marieta Muresan-Pop, Liviu Mare, Gheorghe Borodi and Violeta Popescu
Pharmaceutics 2024, 16(5), 623; https://doi.org/10.3390/pharmaceutics16050623 - 7 May 2024
Cited by 3 | Viewed by 3577
Abstract
GW501516, also known by the name of cardarine, is a synthetic peroxisome-proliferator-activated receptor delta (PPR-δ) agonist agent developed for applications in the treatment of metabolic disorders and cardiovascular diseases. A broad polymorph screening in various solvents and mixtures was completed in order to [...] Read more.
GW501516, also known by the name of cardarine, is a synthetic peroxisome-proliferator-activated receptor delta (PPR-δ) agonist agent developed for applications in the treatment of metabolic disorders and cardiovascular diseases. A broad polymorph screening in various solvents and mixtures was completed in order to explore its capabilities to grow polymorphs. The crystal structures of four polymorphs were elucidated using single-crystal X-ray diffraction, while one structure was solved via a powder X-ray diffraction method. The solid state features (nature of intermolecular interactions) were investigated by computational methods. The polymorphs were further investigated by thermal DSC analysis and X-ray diffraction on powders. From a pharmaceutical perspective, the stability and solubility of the polymorphs were analyzed as well. Full article
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16 pages, 5787 KiB  
Article
Metformin-Mediated Improvement in Solubility, Stability, and Permeability of Nonsteroidal Anti-Inflammatory Drugs
by Qi An, Cheng Xing, Zhipeng Wang, Shuang Li, Wenwen Wang, Shiying Yang, Linglei Kong, Dezhi Yang, Li Zhang, Guanhua Du and Yang Lu
Pharmaceutics 2024, 16(3), 382; https://doi.org/10.3390/pharmaceutics16030382 - 11 Mar 2024
Cited by 6 | Viewed by 2969
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are class II biopharmaceutics classification system drugs. The poor aqueous solubility of NSAIDs can lead to limited bioavailability after oral administration. Metformin (MET), a small-molecule compound, can be used in crystal engineering to modulate the physicochemical properties of drugs [...] Read more.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are class II biopharmaceutics classification system drugs. The poor aqueous solubility of NSAIDs can lead to limited bioavailability after oral administration. Metformin (MET), a small-molecule compound, can be used in crystal engineering to modulate the physicochemical properties of drugs and to improve the bioavailability of orally administered drugs, according to the literature research and preliminary studies. We synthesized two drug–drug molecular salts (ketoprofen–metformin and phenylbutazone–metformin) with NSAIDs and thoroughly characterized them using SCXRD, PXRD, DSC, and IR analysis to improve the poor solubility of NSAIDs. In vitro evaluation studies revealed that the thermal stability and solubility of NSAIDs-MET were substantially enhanced compared with those of NSAIDs alone. Unexpectedly, an additional increase in permeability was observed. Since the structure determines the properties, the structure was analyzed using theoretical calculations to reveal the intermolecular interactions and to explain the reason for the change in properties. The salt formation of NSAIDs with MET could substantially increase the bio-absorption rate of NSAIDs, according to the in vivo pharmacokinetic findings, which provides an experimental basis for developing new antipyretic and analgesic drugs with rapid onset of action. Full article
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22 pages, 9081 KiB  
Article
One Step In Situ Co-Crystallization of Dapsone and Polyethylene Glycols during Fluidized Bed Granulation
by Shizhe Shao, David Bonner, Brendan Twamley, Abhishek Singh and Anne Marie Healy
Pharmaceutics 2023, 15(9), 2330; https://doi.org/10.3390/pharmaceutics15092330 - 16 Sep 2023
Viewed by 2477
Abstract
Several studies have demonstrated the feasibility of in situ co-crystallization in different pharmaceutical processes such as spray drying, hot melt extrusion, and fluidized bed granulation (FBG) to produce co-crystal-in-excipient formulations. However, no previous studies have examined such a one step in situ co-crystallization [...] Read more.
Several studies have demonstrated the feasibility of in situ co-crystallization in different pharmaceutical processes such as spray drying, hot melt extrusion, and fluidized bed granulation (FBG) to produce co-crystal-in-excipient formulations. However, no previous studies have examined such a one step in situ co-crystallization process for co-crystal formulations where the coformer is a polymer. In the current study, we explored the use of FBG to produce co-crystal granules of dapsone (DAP) and different molecular weight polyethylene glycols (PEGs). Solvent evaporation (SE) was proven to generate DAP-PEGs co-crystals at a particular weight ratio of 55:45 w/w between DAP and PEG, which was subsequently used in FBG, using microcrystalline cellulose and hydroxypropyl methyl cellulose as filler excipient and binder, respectively. FBG could generate co-crystals with higher purity than SE. Granules containing DAP-PEG 400 co-crystal could be prepared without any additional binder. DAP-PEG co-crystal granules produced by FBG demonstrated superior pharmaceutical properties, including flow properties and tableting properties, compared to DAP and DAP-PEG co-crystals prepared by SE. Overall, in situ co-crystallization via FBG can effectively produce API-polymer co-crystals and enhance the pharmaceutical properties. Full article
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