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Pharmaceutics
Special Issues
Formulation of Poorly Water-Soluble Drugs
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Formulation of Poorly Water-Soluble Drugs

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

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 8738

Special Issue Editors

Prof. Dr. Qiang Fu

E-Mail Website
Guest Editor
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
Interests: poorly water-soluble drugs; crystalline/amorphous drugs; amorphous solid dispersions; nanocrystals; novel drug-delivery systems
Dr. Xiangfei Han

E-Mail Website
Guest Editor
Center for Nanomedicine and Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Interests: lipid nanoparticles; zwitterionic micelles; drug conjugates; nanosuspensions
Dr. Longfa Kou

E-Mail Website
Guest Editor
Department of Pharmacy, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, China
Interests: targeted drug delivery; metabolsim modulation; membrane transporters; novel drug-delivery systems

Special Issue Information

Dear Colleagues,

In recent years, the emergence of poorly water-soluble drug candidates in the drug development pipeline has been a challenging issue for the pharmaceutical industry. Increasing the bioavailability of these drugs via the improvement of solubility/dissolution has become a major concern in the efforts to develop a reasonable dosing regimen for patients. Many delivery systems, such as cocrystals, nanocrystals, nanoparticles, inclusion complex, amorphous solid dispersions, and lipid-based formulations have been developed to overcome these problems. The use of novel methods not only increases the solubility and permeability of the poorly bioavailable drugs but also improves their stability and targeting efficacy. Moreover, in order to select the best approach some critical considerations must be taken into account, for example the physicochemical properties of the drug, the possibility to scale-up the production process, the toxicological considerations of the use of adjuvant, and the development of a more patient-friendly dosage form.

This Special Issue aims to collect groundbreaking studies and valuable reviews on the formulation of poorly water-soluble drugs. 

Prof. Dr. Qiang Fu
Dr. Xiangfei Han
Dr. Longfa Kou
Guest Editors

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

  • poorly water-soluble drugs
  • solubility
  • dissolution enhancement
  • oral bioavailability
  • physico-chemical properties
  • drug delivery
  • formulation design
  • cocrystals
  • nanocrystals
  • inclusion complex
  • amorphous solid dispersions
  • nanoparticles
  • liposome
  • lipid-based formulations

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Published Papers (5 papers)

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Research

11 pages, 5736 KiB  
Article
Co-Amorphization of Acemetacin with Basic Amino Acids as Co-Formers for Solubility Improvement and Gastric Ulcer Mitigation
by Jiayue Hou, Peixu Zhao, Yanfei Wang, Xiwei Jiang and Qiang Fu
Pharmaceutics 2024, 16(6), 745; https://doi.org/10.3390/pharmaceutics16060745 - 31 May 2024
Viewed by 949
Abstract
Acemetacin (ACM) is a new non-steroidal anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. However, the poor water solubility and gastrointestinal side effects limit its use. Recently, the co-amorphous (CAM) strategy has attracted great interest to improve solubility for poorly water-soluble drugs, and [...] Read more.
Acemetacin (ACM) is a new non-steroidal anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. However, the poor water solubility and gastrointestinal side effects limit its use. Recently, the co-amorphous (CAM) strategy has attracted great interest to improve solubility for poorly water-soluble drugs, and basic amino acids have the potential to protect the gastrointestinal tract. In order to develop a highly efficient and low-toxic ACM formulation, we prepared ACM CAM systems, with basic amino acids (lysine, arginine, and histidine) as co-formers, using a cryo-milling method. The solid-state behaviors of the ACM CAM systems were characterized by polarizing light microscopy, differential scanning calorimetry, and powder X-ray diffraction. Fourier transform infrared spectroscopy and molecular docking were carried out to understand the formation mechanism. Moreover, the gastro-protective effects of ACM CAM systems were evaluated in a rat gastric ulcer model. The results demonstrated that the CAM systems improved the dissolution rates of ACM compared with the neat amorphous counterpart. Furthermore, ACM CAM systems are significantly effective in mitigating the ACM-induced gastric ulcer in rats, and the ulcer inhibition rates were almost 90%. More importantly, this study provided a useful method for mitigating drug-induced gastrointestinal damage and broadened the applications of drug–amino acid CAM systems. Full article
(This article belongs to the Special Issue Formulation of Poorly Water-Soluble Drugs)
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17 pages, 17237 KiB  
Article
Using Polymers as Crystal Inhibitors to Prevent the Crystallization of the Rotigotine Patch
by Qiantong Liu, Xing Li, Bo Liu, Jiahao Kong, Qing Wang and Zhigang Gao
Pharmaceutics 2024, 16(5), 630; https://doi.org/10.3390/pharmaceutics16050630 - 8 May 2024
Cited by 1 | Viewed by 1117
Abstract
This study aimed to enhance the stability of the Rotigotine (ROT) patch using polymers as crystal inhibitors. Three polymers (Poloxamer 188, Soluplus, TPGS) were selected as crystal inhibitors to formulate ROT patches with varying drug loadings (20%, 40%, 60%, and 80%, w/ [...] Read more.
This study aimed to enhance the stability of the Rotigotine (ROT) patch using polymers as crystal inhibitors. Three polymers (Poloxamer 188, Soluplus, TPGS) were selected as crystal inhibitors to formulate ROT patches with varying drug loadings (20%, 40%, 60%, and 80%, w/w). SEM and XRD analysis revealed that the Soluplus and Soluplus-TPGS groups with a high concentration (80%, w/w) of ROT could be stored at room temperature for at least 90 days without crystallization. Moreover, the crystallization nucleation time and growth rate were utilized to assess the ability of Poloxamer 188, Soluplus, and TPGS to hinder the formation of ROT crystals and slow down its crystallization rate. Molecular docking results elucidated the intermolecular forces between ROT and different polymers, revealing their mechanisms for crystal inhibition. The ROT-Soluplus-TPGS combination exhibited the lowest binding free energy (−5.3 kcal/mol), indicating the highest binding stability, thereby effectively reducing crystal precipitation. In vitro skin permeation studies demonstrated that ROT patches containing crystal inhibitors exhibited promising transdermal effects. With increasing ROT concentration, the cumulative drug permeation substantially increased, while the lag time was notably reduced. This study offers novel insights for the development of ROT patches. Full article
(This article belongs to the Special Issue Formulation of Poorly Water-Soluble Drugs)
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20 pages, 9412 KiB  
Article
Tri-Layer Core–Shell Fibers from Coaxial Electrospinning for a Modified Release of Metronidazole
by Ying Wang, Lin Liu, Yuanjie Zhu, Liangzhe Wang, Deng-Guang Yu and Li-ying Liu
Pharmaceutics 2023, 15(11), 2561; https://doi.org/10.3390/pharmaceutics15112561 - 31 Oct 2023
Cited by 45 | Viewed by 2283
Abstract
Polymers are the backbone of drug delivery. Electrospinning has greatly enriched the strategies that have been explored for developing novel drug delivery systems using polymers during the past two decades. In this study, four different kinds of polymers, i.e., the water-soluble polymer poly [...] Read more.
Polymers are the backbone of drug delivery. Electrospinning has greatly enriched the strategies that have been explored for developing novel drug delivery systems using polymers during the past two decades. In this study, four different kinds of polymers, i.e., the water-soluble polymer poly (vinyl alcohol) (PVA), the insoluble polymer poly(ε-caprolactone) (PCL), the insoluble polymer Eudragit RL100 (ERL100) and the pH-sensitive polymer Eudragit S100 (ES100) were successfully converted into types of tri-layer tri-polymer core–shell fibers through bi-fluid coaxial electrospinning. During the coaxial process, the model drug metronidazole (MTD) was loaded into the shell working fluid, which was an emulsion. The micro-formation mechanism of the tri-layer core–shell fibers from the coaxial emulsion electrospinning was proposed. Scanning electron microscope and transmission electron microscope evaluations verified the linear morphology of the resultant fibers and their obvious tri-layer multiple-chamber structures. X-ray diffraction and Fourier transform infrared spectroscopy measurements demonstrated that the drug MTD presented in the fibers in an amorphous state and was compatible with the three polymeric matrices. In vitro dissolution tests verified that the three kinds of polymer could act in a synergistic manner for a prolonged sustained-release profile of MTD in the gut. The drug controlled-release mechanisms were suggested in detail. The protocols reported here pioneer a new route for creating a tri-layer core–shell structure from both aqueous and organic solvents, and a new strategy for developing advanced drug delivery systems with sophisticated drug controlled-release profiles. Full article
(This article belongs to the Special Issue Formulation of Poorly Water-Soluble Drugs)
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15 pages, 5202 KiB  
Article
Saquinavir-Piperine Eutectic Mixture: Preparation, Characterization, and Dissolution Profile
by Cinira Fandaruff, María Isabel Quirós-Fallas, José Roberto Vega-Baudrit, Mirtha Navarro-Hoyos, Diego German Lamas and Andrea Mariela Araya-Sibaja
Pharmaceutics 2023, 15(10), 2446; https://doi.org/10.3390/pharmaceutics15102446 - 11 Oct 2023
Cited by 4 | Viewed by 1753
Abstract
The dissolution rate of the anti-HIV drug saquinavir base (SQV), a poorly water-soluble and extremely low absolute bioavailability drug, was improved through a eutectic mixture formation approach. A screening based on a liquid-assisted grinding technique was performed using a 1:1 molar ratio of [...] Read more.
The dissolution rate of the anti-HIV drug saquinavir base (SQV), a poorly water-soluble and extremely low absolute bioavailability drug, was improved through a eutectic mixture formation approach. A screening based on a liquid-assisted grinding technique was performed using a 1:1 molar ratio of the drug and the coformers sodium saccharinate, theobromine, nicotinic acid, nicotinamide, vanillin, vanillic acid, and piperine (PIP), followed by differential scanning calorimetry (DSC). Given that SQV-PIP was the only resulting eutectic system from the screening, both the binary phase and the Tammann diagrams were adapted to this system using DSC data of mixtures prepared from 0.1 to 1.0 molar ratios in order to determine the exact eutectic composition. The SQV-PIP system formed a eutectic at a composition of 0.6 and 0.40, respectively. Then, a solid-state characterization through DSC, powder X-ray diffraction (PXRD), including small-angle X-ray scattering (SAXS) measurements to explore the small-angle region in detail, Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and a powder dissolution test were performed. The conventional PXRD analyses suggested that the eutectic mixture did not exhibit structural changes; however, the small-angle region explored through the SAXS instrument revealed a change in the crystal structure of one of their components. FT-IR spectra showed no molecular interaction in the solid state. Finally, the dissolution profile of SQV in the eutectic mixture was different from the dissolution of pure SQV. After 45 min, approximately 55% of the drug in the eutectic mixture was dissolved, while, for pure SQV, 42% dissolved within this time. Hence, this study concludes that the dissolution rate of SQV can be effectively improved through the approach of using PIP as a coformer. Full article
(This article belongs to the Special Issue Formulation of Poorly Water-Soluble Drugs)
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16 pages, 1870 KiB  
Article
Cocrystals Enhance Biopharmaceutical and Antimicrobial Properties of Norfloxacin
by Samantha Nascimento Gomes, Isabela Fanelli Barreto Biscaia, Diana Schon Lopes, Mariana Mengarda, Fábio Seigi Murakami, Paulo Renato Oliveira and Larissa Sakis Bernardi
Pharmaceutics 2023, 15(9), 2211; https://doi.org/10.3390/pharmaceutics15092211 - 26 Aug 2023
Cited by 3 | Viewed by 1653
Abstract
A solvate cocrystal of the antimicrobial norfloxacin (NFX) was formed by using isonicotinamide (INA) as a coformer with the solvent evaporation technique. The cocrystal formation was confirmed by performing solid-state characterization techniques. We evaluated the dissolution under supersaturated conditions and also the solubility [...] Read more.
A solvate cocrystal of the antimicrobial norfloxacin (NFX) was formed by using isonicotinamide (INA) as a coformer with the solvent evaporation technique. The cocrystal formation was confirmed by performing solid-state characterization techniques. We evaluated the dissolution under supersaturated conditions and also the solubility at the vertex of triphasic domain of cocrystal and NFX in both water and Fasted-State Simulated Intestinal Fluid (FaSSIF). The antimicrobial activity was evaluated using the microdilution technique. The cocrystal showed 1.8 times higher dissolution than NFX in water at 60 min and 1.3 times higher in FaSSIF at 180 min in the kinetic study. The cocrystal also had an increase in solubility of 8.38 times in water and 6.41 times in FaSSIF. The biopharmaceutical properties of NFX with cocrystallization improved antimicrobial action, as shown in the results of minimum inhibitory concentration (MIC) and inhibitory concentrations of 50% (IC50%) and 90% (IC90%). This paper presents, for the first time, a more in-depth analysis of the cocrystal of NFX–INA concerning its dissolution, solubility, and antimicrobial activity. In all these criteria, the cocrystal obtained better results compared to the pure drug. Full article
(This article belongs to the Special Issue Formulation of Poorly Water-Soluble Drugs)
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