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Pharmaceutics
Special Issues
Emerging Technologies to Improve the Solubility of Poorly Soluble Drugs
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Emerging Technologies to Improve the Solubility of Poorly Soluble Drugs

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (20 April 2025) | Viewed by 8397

Special Issue Editors

Prof. Dr. Elisabet Fuguet

E-Mail Website
Guest Editor
Department of Chemical Engineering and Analytical Chemistry, Institute of Biomedicine (IBUB), University of Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain
Interests: solubility; dissolution; lipophilicity; acidity; permeability; biomimetic chromatography; high-throughput methodology
Prof. Dr. Clara Ràfols

E-Mail Website
Guest Editor
Department of Chemical Engineering and Analytical Chemistry, University of Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain
Interests: solubility; dissolution; lipophilicity; acidity; permeability; drug-protein/excipients interactions

Special Issue Information

Dear Colleagues,

Advances in drug development technologies have led to complex chemical entities that, in most cases, have poor aqueous solubility and, consequently, poor bioavailability and efficacy. Solubility is, therefore, one of the main challenges that scientists face in the drug discovery process. This is why the development of strategies aimed at enhancing the solubility and dissolution of poor-soluble compounds has increased in recent years. Some of these approaches are focused on the chemical modification of drugs, others on physical changes, and strategies based on the use of excipients and carriers have also been explored.

This Special Issue aims to provide an overview of the recent advances in drug solubility enhancement strategies. Research areas may include (but are not limited to) the following: solid dispersions; micellization; particle size modification; the stabilization of supersaturated solutions; complexation; salt formation; and crystallization strategies. In this Special Issue, original research articles and reviews are welcome.

We look forward to receiving your contributions.

Prof. Dr. Elisabet Fuguet
Prof. Dr. Clara Ràfols
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

  • solubility
  • solid dispersions
  • particle size
  • complexation
  • micellization
  • salt formation
  • crystallization
  • supersaturation

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Published Papers (6 papers)

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Research

14 pages, 2415 KiB  
Article
Influence of Ionization and the Addition of Cyclodextrins and Hydrophilic Excipients on the Solubility of Benzthiazide, Isoxicam, and Piroxicam
by Diego Lucero-Borja, Rebeca Ruiz, Elisabet Fuguet and Clara Ràfols
Pharmaceutics 2025, 17(5), 571; https://doi.org/10.3390/pharmaceutics17050571 - 25 Apr 2025
Viewed by 238
Abstract
Background: The bioavailability of a drug depends, among other parameters, on solubility. One of the strategies used to enhance the solubility of sparingly soluble drugs is the use of excipients. Excipients can interact with the drug by increasing its solubility and/or stabilizing [...] Read more.
Background: The bioavailability of a drug depends, among other parameters, on solubility. One of the strategies used to enhance the solubility of sparingly soluble drugs is the use of excipients. Excipients can interact with the drug by increasing its solubility and/or stabilizing supersaturated solutions. Some of the most common excipients are cyclodextrins and hydrophilic polymers. Objectives: The effect of two cyclodextrins (captisol and cavasol) and three hydrophilic polymers (klucel, kollidon and plasdone S630) on the solubility of three ionizable drugs (benzthiazide, isoxicam, and piroxicam) is evaluated at biorelevant pH values, using two complementary techniques. Methods: The solubility enhancement was evaluated by the comparison of the solubility with and without the presence of excipients through the shake-flask and CheqSol methodology. Results: Captisol and cavasol slightly increase the concentration of the neutral species of the drugs in the solution before precipitation begins, although they do not enhance the supersaturation duration nor the thermodynamic solubility of the drugs. The increase in solubility in the presence of cyclodextrins is mainly caused by the ionization state of the drug. Hydrophilic polymers not only improve thermodynamic solubility but also the extent and the duration of the supersaturation. Some metastable forms are observed for benzthiazide and isoxicam in the presence of kollidon and plasdone S630. Conclusions: The shake-flask method enabled the evaluation of thermodynamic solubility both in the absence and presence of excipients. Meanwhile, the CheqSol method provided insights into the presence of supersaturated solutions. Different behavior is observed depending on the nature of the excipient. Full article
(This article belongs to the Special Issue Emerging Technologies to Improve the Solubility of Poorly Soluble Drugs)
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15 pages, 4647 KiB  
Article
Effects of Different Weak Small Organic Acids on Clofazimine Solubility in Aqueous Media
by Igor A. Topalović, Olivera S. Marković, Miloš P. Pešić, Mufaddal H. Kathawala, Martin Kuentz, Alex Avdeef, Abu T. M. Serajuddin and Tatjana Ž. Verbić
Pharmaceutics 2024, 16(12), 1545; https://doi.org/10.3390/pharmaceutics16121545 - 2 Dec 2024
Cited by 1 | Viewed by 1691
Abstract
Background/Objectives: Clofazimine (CFZ) is a Biopharmaceutics Classification System (BCS) II drug introduced in the US market in 1986 for the treatment of leprosy. However, CFZ was later withdrawn from the market due to its extremely low aqueous solubility and low absorption. In the [...] Read more.
Background/Objectives: Clofazimine (CFZ) is a Biopharmaceutics Classification System (BCS) II drug introduced in the US market in 1986 for the treatment of leprosy. However, CFZ was later withdrawn from the market due to its extremely low aqueous solubility and low absorption. In the literature, the intrinsic solubility of CFZ has been estimated to be <0.01 μg/mL, and solubilities of its different salt forms in simulated gastric and intestinal fluids are <10 µg/mL. These are extremely low solubilities for the dissolution of a drug administered orally at 100–200 mg doses. Methods: In the present investigation, seven weak organic acids (adipic, citric, glutaric, maleic, malic, succinic, and tartaric) were tested by determining the aqueous solubility of CFZ as the function of acid concentration to investigate whether any of the acids would lead to the supersolubilization of CFZ. Results: There were only minimal increases in solubilities when concentrations of acids in water were increased up to 2.4 M. The solubilities, however, increased to 0.32, 1.23, and 10.68 mg/mL, respectively, in 5 M solutions of tartaric, malic, and glutaric acids after equilibration for 24 h at 25 °C. Crystalline solids were formed after the equilibration of CFZ with all acids. Apparently, salts or cocrystals were formed with all acids, except for glutaric acid, as their melting endotherms in DSC scans were in the range of 207.6 to 248.5 °C, which were close to that of CFZ itself (224.8 °C). In contrast, the adduct formed with glutaric acid melted at the low temperature of 77 °C, and no other peak was observed at a higher temperature, indicating that the material converted to an amorphous state. Conclusions: The increase in CFZ solubility to >10 mg/mL in the presence of 5 M glutaric acid could be called supersolubilization when compared to the intrinsic solubility of the basic drug. Such an increase in CFZ solubility and the conversion of the glutarate adduct to an amorphous state are being exploited to develop rapidly dissolving dosage forms. Full article
(This article belongs to the Special Issue Emerging Technologies to Improve the Solubility of Poorly Soluble Drugs)
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Graphical abstract

14 pages, 2139 KiB  
Article
Exploring Orodispersible Films Containing the Proteolysis Targeting Chimera ARV-110 in Hot Melt Extrusion and Solvent Casting Using Polyvinyl Alcohol
by Valentina Meloni, Laura Halstenberg, Lena Mareczek, Jankin Lu, Bonnie Liang, Nadine Gottschalk and Lena K. Mueller
Pharmaceutics 2024, 16(12), 1499; https://doi.org/10.3390/pharmaceutics16121499 - 22 Nov 2024
Viewed by 1382
Abstract
Background/Objectives: This project aims to provide valuable insights into the formulation of orodispersible films (ODFs) for the delivery of PROTAC ARV-110. The primary objective of this drug delivery formulation is to enhance the solubility of PROTAC ARV-110, which faces significant challenges due to [...] Read more.
Background/Objectives: This project aims to provide valuable insights into the formulation of orodispersible films (ODFs) for the delivery of PROTAC ARV-110. The primary objective of this drug delivery formulation is to enhance the solubility of PROTAC ARV-110, which faces significant challenges due to the low solubility of this active pharmaceutical ingredient, as it belongs to a molecular class that is considered to exceed the “Rule of Five”. Methods: We employed the concept of developing a rapidly disintegrating ODF to enhance the solubility of PROTAC ARV-110, utilizing polyvinyl alcohol as the polymer of choice. Given the high thermal stability of ARV-110, the PROTAC was subjected to two primary ODF manufacturing techniques: Hot melt extrusion (HME) and solvent casting. To establish the HME method, pre-screening through vacuum compression molding was performed. The films were characterized based on their disintegration in artificial saliva, drug release in a physiological environment, and mechanical strength. Results: All formulations demonstrated enhanced solubility of ARV-110, achieving exceptional results in terms of disintegration times and resistance to applied stress. Conclusions: The findings from the experiments outlined herein establish a solid foundation for the successful production of orodispersible films for the delivery of PROTACs. Full article
(This article belongs to the Special Issue Emerging Technologies to Improve the Solubility of Poorly Soluble Drugs)
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13 pages, 3660 KiB  
Article
A Perspective on the Use of Hydroxyapatites to Improve the Dissolution Behavior of Poorly Water-Soluble Piretanide
by Valeria Friuli, Claudia Loi, Giovanna Bruni, Lauretta Maggi and Marcella Bini
Pharmaceutics 2024, 16(11), 1450; https://doi.org/10.3390/pharmaceutics16111450 - 13 Nov 2024
Viewed by 1048
Abstract
Background/Objectives: Interest in drug delivery systems (DDS) based on inorganic substrates has increased in parallel with the increase in the number of poorly water-soluble drugs. Hydroxyapatite is one of the ideal matrices for DDS due to its biocompatibility, low cost, and ease of [...] Read more.
Background/Objectives: Interest in drug delivery systems (DDS) based on inorganic substrates has increased in parallel with the increase in the number of poorly water-soluble drugs. Hydroxyapatite is one of the ideal matrices for DDS due to its biocompatibility, low cost, and ease of preparation. Methods: We propose two doped hydroxyapatites, one with Ba on Ca sites another with Si on P sites, with the aim of improving the dissolution rate of piretanide, a diuretic, poorly water-soluble drug. The hybrids were characterized by different physical–chemical techniques, and their formation was demonstrated by infrared spectroscopy, thermal analysis, and electron microanalysis, as well as by comparing the results with those obtained on physical mixtures of HAPs and properly prepared piretanide. Results: Both the hybrids improved the piretanide dissolution rate compared with the physical mixtures and the drug alone. The dose was completely solubilized from the Si-doped hybrid in about 5 min in the three fluids considered. This remarkable improvement can be explained by an increase in the wettability and solubility of the drug loaded in the drug-carrier systems. Conclusions: Different experimental techniques, in particular spectroscopy and electronic microanalysis, proved the successful loading of piretanide onto doped HAP. Pharmaceutical measurements demonstrated rapid drug release in different fluids simulating gastrointestinal conditions after oral administration. These hybrid systems could be a very promising platform for drug delivery. Full article
(This article belongs to the Special Issue Emerging Technologies to Improve the Solubility of Poorly Soluble Drugs)
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17 pages, 3859 KiB  
Article
Optimizing Antitumor Effect of Triple-Negative Breast Cancer via Rosmarinic Acid–β-Cyclodextrin Inclusion Complex
by Yuan Li, Muhammad Inam, Muhammad Waqqas Hasan, Kaixin Chen, Zhongqian Zhang, Yongcheng Zhu, Jiayu Huang, Zhuowen Wu, Wenjie Chen and Min Li
Pharmaceutics 2024, 16(11), 1408; https://doi.org/10.3390/pharmaceutics16111408 - 1 Nov 2024
Viewed by 1467
Abstract
Background: Rosmarinic acid (ROS) has gained notable attention for its anticancer potential; however, its limited aqueous solubility hinders its effective delivery and application in pharmaceutical formulations. Methods: To overcome this limitation, an inclusion complex of ROS with β-cyclodextrin (β-CD) was prepared [...] Read more.
Background: Rosmarinic acid (ROS) has gained notable attention for its anticancer potential; however, its limited aqueous solubility hinders its effective delivery and application in pharmaceutical formulations. Methods: To overcome this limitation, an inclusion complex of ROS with β-cyclodextrin (β-CD) was prepared using the recrystallization method. The resultant ROS–β-CD complex was comprehensively characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM). Results: The ROS–β-CD complex showed a significant improvement in the solubility and dissolution profile of ROS, underscoring its potential for enhanced bioavailability and therapeutic efficacy in pharmaceutical applications. In vitro assays were performed to assess the effects on cell viability, proliferation, apoptotic pathways, and 3D spheroid tumor models. Conclusions: The results demonstrated that ROS–β-CD exhibited superior anticancer properties compared to free ROS, effectively reducing the viability and proliferation of the MD-MBA-231 cell line and inducing apoptosis. This research signifies a substantial advancement in developing therapeutic strategies for TNBC, leveraging the distinct properties of the ROS–β-CD inclusion complex. Full article
(This article belongs to the Special Issue Emerging Technologies to Improve the Solubility of Poorly Soluble Drugs)
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23 pages, 10530 KiB  
Article
Formulation and Evaluation of pH-Modulated Amorphous Solid Dispersion-Based Orodispersible Tablets of Cefdinir
by Yahya Alhamhoom, Thanusha Kumaraswamy, Avichal Kumar, Shivakumar Hagalavadi Nanjappa, Sanjana S. Prakash, Mohamed Rahamathulla, Kamal Y. Thajudeen, Mohammed Muqtader Ahmed and Thippeswamy Boreddy Shivanandappa
Pharmaceutics 2024, 16(7), 866; https://doi.org/10.3390/pharmaceutics16070866 - 27 Jun 2024
Cited by 2 | Viewed by 1771
Abstract
Cefdinir (CEF) is a semi-synthetic third-generation broad-spectrum oral cephalosporin that exhibits poor solubility at lower pH values. Considering this, pH-modulated CEF solid dispersions (ASDs) were produced by solvent evaporation method employing various hydrophilic carriers and alkalizers. Among different carriers, ASDs produced using PEG [...] Read more.
Cefdinir (CEF) is a semi-synthetic third-generation broad-spectrum oral cephalosporin that exhibits poor solubility at lower pH values. Considering this, pH-modulated CEF solid dispersions (ASDs) were produced by solvent evaporation method employing various hydrophilic carriers and alkalizers. Among different carriers, ASDs produced using PEG 6000 with meglumine as alkalizer were found to significantly increase (p < 0.005) the drug solubility (4.50 ± 0.32 mg/mL) in pH 1.2. Fourier transform infrared spectrophotometry confirmed chemical integrity of CEF while differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) indicated CEF was reduced to an amorphous state in ASD8. Antimicrobial assay performed by well diffusion method against Staphylococcus aureus (MTCC96) and Escherichia coli (MTCC118) demonstrated significantly superior (p < 0.001) efficacy of CEFSD compared to CEF. The porous orodispersible tablets (ODTs) of ASD8 (batch F5) were developed by incorporating ammonium bicarbonate as a subliming agent by direct compression, followed by vacuum drying displayed quick disintegration (27.11 ± 1.96 s) that met compendial norms and near-complete dissolution (93.85 ± 1.27%) in 30 min. The ODTs of ASD8 appear to be a promising platform to mitigate the pH-dependent solubility and dissolution issues associated with CEF in challenging physiological pH conditions prevalent in stomach. Thus, ODTs of ASD8 are likely to effectively manage various infections and avoid development of drug-resistant strains, thereby improving the curing rates. Full article
(This article belongs to the Special Issue Emerging Technologies to Improve the Solubility of Poorly Soluble Drugs)
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