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Pharmaceutics
Special Issues
Physico Chemical Profiling Pharmaceutics: Solubility and Permeability
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Physico Chemical Profiling Pharmaceutics: Solubility and Permeability

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

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 12074

Special Issue Editors

Prof. Dr. Krisztina Takács-Novák

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, Semmelweis University, H-1092 Hőgyes Endre u. 9. Budapest, Hungary
Interests: physico-chemical profiling; lipophilicity; solubility; permeability; methods develeopment
Dr. Gergely Völgyi

E-Mail Website
Guest Editor
Department of Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary
Interests: pKa; logP determination; solubility; permeability; effect of exicipients
Dr. Enikő Borbás

E-Mail Website
Guest Editor
Research Group on Pharmaceutical, Environmental and Safety Technology, Budapest University of Technology and Economics, Budapest, Hungary
Interests: dissolution; permeation; absorption; flux assays; formulation development; electrospinning

Special Issue Information

Dear Colleagues,

Solubility and membrane permeability are the two key physico-chemical properties which determine the absorption and, thus, the bioavailability of an active pharmaceutical ingredient (API). Knowing the exact solubility and permeability value of a compound in pharmaceutical development is a basic need for prediction of an in vivo performance. However, the precise in vitro experimental determination of these parameters is often very challenging. If a poorly water-soluble API is formulated using solubilizing agents, the solubility might be altered. Recent studies state, that not only solubility, but also effective permeability of the API may change due to the addition of formulation excipients, and also there is a certain mathematical relation between the two parameters.

The Special Issue is devoted to the discussion of new insights into the experimental aspects of solubility, dissolution and permeation assays and the understanding of the interplay between these physico-chemical parameters.

Contributions could address any of the following topics:

  • Recent method development in solubility, dissolution or permeability assays;
  • Solubility-permeability interplay;
  • Factors influencing solubility and permeability (excipients, particle size, etc.);
  • Tissue specific in vitro membranes (PAMPA);
  • Simultaneous monitoring of dissolution and permeation;
  • ‘Amorphous’ solubility;
  • Toward the better IVIV prediction of absorption (biomimetic assays and media).

Prof. Dr. Krisztina Takács-Novák
Dr. Gergely Völgyi
Dr. Enikő Borbás
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. 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
  • permeability
  • physico-chemical profiling
  • solubility–permeability interplay
  • PAMPA

Published Papers (6 papers)

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Research

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14 pages, 1429 KiB  
Article
Thermodynamic Correlation between Liquid–Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules
by Taiga Uekusa, Tomohiro Watanabe, Daiju Watanabe and Kiyohiko Sugano
Pharmaceutics 2022, 14(12), 2560; https://doi.org/10.3390/pharmaceutics14122560 - 22 Nov 2022
Cited by 3 | Viewed by 1490
Abstract
The purpose of the present study was to experimentally confirm the thermodynamic correlation between the intrinsic liquid–liquid phase separation (LLPS) concentration (S0LLPS) and crystalline solubility (S0c) of drug-like molecules. Based on the [...] Read more.
The purpose of the present study was to experimentally confirm the thermodynamic correlation between the intrinsic liquid–liquid phase separation (LLPS) concentration (S0LLPS) and crystalline solubility (S0c) of drug-like molecules. Based on the thermodynamic principles, the crystalline solubility LLPS concentration melting point (Tm) equation (CLME) was derived (log10S0C=log10S0LLPS−0.0095Tm−310 for 310 K). The S0LLPS values of 31 drugs were newly measured by simple bulk phase pH-shift or solvent-shift precipitation tests coupled with laser-assisted visual turbidity detection. To ensure the precipitant was not made crystalline at <10 s, the precipitation tests were also performed under the polarized light microscope. The calculated and observed log10S0C values showed a good correlation (root mean squared error: 0.40 log unit, absolute average error: 0.32 log unit). Full article
(This article belongs to the Special Issue Physico Chemical Profiling Pharmaceutics: Solubility and Permeability)
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19 pages, 3139 KiB  
Article
Virtual Cocrystal Screening of Adefovir Dipivoxyl: Identification of New Solid Forms with Improved Dissolution and Permeation Profiles
by Rafael Barbas, Hanan Fael, Samuel Lee, Rebeca Ruiz, Christopher A. Hunter, Elisabet Fuguet, Clara Ràfols and Rafel Prohens
Pharmaceutics 2022, 14(11), 2310; https://doi.org/10.3390/pharmaceutics14112310 - 27 Oct 2022
Cited by 2 | Viewed by 1705
Abstract
The application of a computational screening methodology based on the calculation of intermolecular interaction energies has guided the discovery of new multicomponent solid forms of the oral antiviral Adefovir Dipivoxyl. Three new cocrystals with resorcinol, orcinol and hydroquinone have been synthesized and thoroughly [...] Read more.
The application of a computational screening methodology based on the calculation of intermolecular interaction energies has guided the discovery of new multicomponent solid forms of the oral antiviral Adefovir Dipivoxyl. Three new cocrystals with resorcinol, orcinol and hydroquinone have been synthesized and thoroughly characterized. They show improved dissolution profiles with respect to the single solid form, particularly the cocrystals of orcinol and resorcinol, which have 3.2- and 2-fold faster dissolution rates at stomach conditions (pH 1.5). Moreover, dynamic dissolution experiments that simultaneously mimic both the pH variation along the gastrointestinal tract and the partition into biological membranes show that, in addition to the faster initial dissolution, Adefovir Dipivoxyl also penetrates faster into the organic membranes in the form of resorcinol and orcinol cocrystals. Full article
(This article belongs to the Special Issue Physico Chemical Profiling Pharmaceutics: Solubility and Permeability)
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14 pages, 3779 KiB  
Article
Understanding the pH Dependence of Supersaturation State—A Case Study of Telmisartan
by Szabina Kádár, Dóra Csicsák, Petra Tőzsér, Attila Farkas, Tamás Pálla, Arash Mirzahosseini, Blanka Tóth, Gergő Tóth, Béla Fiser, Péter Horváth, János Madarász, Alex Avdeef, Krisztina Takács-Novák, Bálint Sinkó, Enikő Borbás and Gergely Völgyi
Pharmaceutics 2022, 14(8), 1635; https://doi.org/10.3390/pharmaceutics14081635 - 05 Aug 2022
Cited by 2 | Viewed by 2084
Abstract
Creating supersaturating drug delivery systems to overcome the poor aqueous solubility of active ingredients became a frequent choice for formulation scientists. Supersaturation as a solution phenomenon is, however, still challenging to understand, and therefore many recent publications focus on this topic. This work [...] Read more.
Creating supersaturating drug delivery systems to overcome the poor aqueous solubility of active ingredients became a frequent choice for formulation scientists. Supersaturation as a solution phenomenon is, however, still challenging to understand, and therefore many recent publications focus on this topic. This work aimed to investigate and better understand the pH dependence of supersaturation of telmisartan (TEL) at a molecular level and find a connection between the physicochemical properties of the active pharmaceutical ingredient (API) and the ability to form supersaturated solutions of the API. Therefore, the main focus of the work was the pH-dependent thermodynamic and kinetic solubility of the model API, TEL. Based on kinetic solubility results, TEL was observed to form a supersaturated solution only in the pH range 3–8. The experimental thermodynamic solubility-pH profile shows a slight deviation from the theoretical Henderson–Hasselbalch curve, which indicates the presence of zwitterionic aggregates in the solution. Based on pKa values and the refined solubility constants and distribution of macrospecies, the pH range where high supersaturation-capacity is observed is the same where the zwitterionic form of TEL is present. The existence of zwitterionic aggregation was confirmed experimentally in the pH range of 3 to 8 by mass spectrometry. Full article
(This article belongs to the Special Issue Physico Chemical Profiling Pharmaceutics: Solubility and Permeability)
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16 pages, 5285 KiB  
Article
Non-Effective Improvement of Absorption for Some Nanoparticle Formulations Explained by Permeability under Non-Sink Conditions
by Kazuya Sugita, Noriyuki Takata and Etsuo Yonemochi
Pharmaceutics 2022, 14(4), 816; https://doi.org/10.3390/pharmaceutics14040816 - 07 Apr 2022
Cited by 1 | Viewed by 2027
Abstract
We evaluated the in vitro permeability of nanoparticle formulations of high and low lipophilic compounds under non-sink conditions, wherein compounds are not completely dissolved. The permeability of the highly lipophilic compound, griseofulvin, was improved by about 30% due to nanonization under non-sink conditions. [...] Read more.
We evaluated the in vitro permeability of nanoparticle formulations of high and low lipophilic compounds under non-sink conditions, wherein compounds are not completely dissolved. The permeability of the highly lipophilic compound, griseofulvin, was improved by about 30% due to nanonization under non-sink conditions. Moreover, this permeability was about 50% higher than that under sink conditions. On the other hand, for the low lipophilic compound, hydrocortisone, there was no difference in permeability between micro-and nano-sized compounds under non-sink conditions. The nanonization of highly lipophilic compounds improves the permeability of the unstirred water layer (UWL), which in turn improves overall permeability. On the other hand, because the rate-limiting step in permeation for the low lipophilic compounds is the diffusion of the compounds in the membrane, the improvement of UWL permeability by nanonization does not improve the overall permeability. Based on this mechanism, nanoparticle formulations are not effective for low lipophilic compounds. To accurately predict the absorption of nanoparticle formulations, it is necessary to consider their permeability under non-sink conditions which reflect in vivo conditions. Full article
(This article belongs to the Special Issue Physico Chemical Profiling Pharmaceutics: Solubility and Permeability)
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19 pages, 2151 KiB  
Article
Physicochemical Profile of Antiandrogen Drug Bicalutamide: Solubility, Distribution, Permeability
by Tatyana V. Volkova, Olga R. Simonova and German L. Perlovich
Pharmaceutics 2022, 14(3), 674; https://doi.org/10.3390/pharmaceutics14030674 - 18 Mar 2022
Cited by 4 | Viewed by 2040
Abstract
The pharmacologically relevant physicochemical properties of the antiandrogen drug bicalutamide (BCL) have been determined for the first time. Solubility in aqueous solution, 1-octanol, n-hexane, and ethanol was measured by the shake flask method in the temperature range of 293.15–313.15 K. The compound was [...] Read more.
The pharmacologically relevant physicochemical properties of the antiandrogen drug bicalutamide (BCL) have been determined for the first time. Solubility in aqueous solution, 1-octanol, n-hexane, and ethanol was measured by the shake flask method in the temperature range of 293.15–313.15 K. The compound was shown to be poorly soluble in aqueous medium and n-hexane; at the same time, an essentially higher solubility in the alcohols was revealed. The following order of molar solubility was determined: ethanol > 1-octanol > water ≈ n-hexane. The solubility was correlated with the Van’t Hoff and Apelblat equations. Evaluation of the Hansen solubility parameters and the atomic group contribution approach of Hoftyzer and Van Krevelen demonstrated consistency with the experimental data and good potential adsorption of bicalutamide. The temperature dependences of the distribution coefficients in the 1-octanol/water and n-hexane/water two-phase systems were measured and discussed in the framework of the thermodynamic approach. The ∆logD parameter determined from the distribution experiment clearly demonstrated the preference of the lipophilic delivery pathways for the compound in the biological media. The overall thermodynamic analysis based on the solubility and distribution results of the present study and the sublimation characteristics published previously has been performed. To this end, the thermodynamic parameters of the dissolution, solvation, and transfer processes were calculated and discussed in view of the solute-solvent interactions. The permeation rate of BCL through the PermeaPad barrier was measured and compared with PAMPA permeability. Full article
(This article belongs to the Special Issue Physico Chemical Profiling Pharmaceutics: Solubility and Permeability)
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Review

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14 pages, 1569 KiB  
Review
Recent Advancements in Drug Delivery of Sinomenine, A Disease-Modifying Anti-Rheumatic Drug
by Xin Chen, Chengcheng Lu, Yanwen Duan and Yong Huang
Pharmaceutics 2022, 14(12), 2820; https://doi.org/10.3390/pharmaceutics14122820 - 16 Dec 2022
Cited by 8 | Viewed by 1855
Abstract
Sinomenine (SIN) is a benzyltetrahydroisoquinoline-type alkaloid isolated from the dried plant root and stem of Sinomenium acutum (Thumb.) Rehd.et Wils, which shows potent anti-inflammatory and analgesic effects. As a transforming disease-modifying anti-rheumatic drug, SIN has been used to treat rheumatoid arthritis over twenty-five [...] Read more.
Sinomenine (SIN) is a benzyltetrahydroisoquinoline-type alkaloid isolated from the dried plant root and stem of Sinomenium acutum (Thumb.) Rehd.et Wils, which shows potent anti-inflammatory and analgesic effects. As a transforming disease-modifying anti-rheumatic drug, SIN has been used to treat rheumatoid arthritis over twenty-five years in China. In recent years, SIN is also in development for use against other disorders, including colitis, pain, traumatic brain injury, and uveitis. However, its commercial hydrochloride (SIN-HCl) shows low oral bioavailability and certain allergic reactions in patients, due to the release of histamine. Therefore, a large number of pharmaceutical strategies have been explored to address these liabilities, such as prolonging release behaviors, enhancing skin permeation and adsorption for transdermal delivery, targeted SIN delivery using new material or conjugates, and co-amorphous technology. This review discusses these different delivery strategies and approaches employed to overcome the limitations of SIN for its efficient delivery, in order to achieve improved bioavailability and reduced side effects. The potential advantages and limitations of SIN delivery strategies are elaborated along with discussions of potential future SIN drug development strategies. Full article
(This article belongs to the Special Issue Physico Chemical Profiling Pharmaceutics: Solubility and Permeability)
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