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Pharmaceutics
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Drug Stability: Factors and New Approaches to Overcome Drug Instability
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Drug Stability: Factors and New Approaches to Overcome Drug Instability

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (30 May 2023) | Viewed by 19614

Special Issue Editors

Prof. Dr. Krassimira Yoncheva

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Guest Editor
Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Medical University of Sofia, Dunav Str. 2, 1000 Sofia, Bulgaria
Interests: nanoparticulate drug delivery systems; polymeric micelles; bioadhesive polymers; pegylated nanoparticles
Dr. Maya Zaharieva

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Guest Editor
The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
Interests: cytotoxicity of drugs and drug-delivery systems; experimental chemotherapy; signal transduction; pharmacodynamics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The stability of drugs and drug formulations is of great importance for both the efficacy and safety of therapy. Various factors can influence drug stability, either during production and storage (temperature, light etc.) or in physiological conditions (pH, enzymes etc.). The estimation of these factors and the processes that they induce (polymorphism, photolysis, oxidation, hydrolysis etc.) is essential for their avoidance. At present, with the advancement of analytical methods, it is possible to accurately determine the degradation products of biologically active substances. It should be emphasized that the evaluation of drug stability and the search for new approaches to improve it is an important stage in the development of drug products. Specifically, the development of new drug delivery systems that are able to stabilize the incorporated drug in body fluids is one of the challenges faced by modern pharmaceutical research.

This Special Issue aims to present new data on the stability of both well-known active pharmaceutical ingredients and new substances, including those from natural sources. Furthermore, this Issue will collect research articles reporting different methods for improvement of drug stability like complexation, coating and development of new drug delivery systems. Special focus will be given to nanosized drug delivery systems, particularly nanoparticles, liposomes, amphiphilic micelles, nanogels, nanoemulsions etc. We will also appreciate additional investigations on drug stability in two- and three-dimensional cell systems, as well as in vivo models.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: in vitro (production, storage, tests with cell systems) and in vivo (in physiological fluids) drug stability; physical, chemical or microbial instability of drug/drug products; drug formulations with improved stability (complexes, coated forms, micro- and nanosized drug delivery systems).

I look forward to receiving your contributions.

Prof. Dr. Krassimira Yoncheva
Dr. Maya Zaharieva
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

  • drug/drug product stability
  • drug degradation
  • evaluation of stability
  • innovative formulations with improved drug stability
  • micro- and nanoparticles
  • complexes

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Published Papers (7 papers)

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Research

20 pages, 1462 KiB  
Article
Intranasal Microemulsion as an Innovative and Promising Alternative to the Oral Route in Improving Stiripentol Brain Targeting
by Sara Meirinho, Márcio Rodrigues, Adriana O. Santos, Amílcar Falcão and Gilberto Alves
Pharmaceutics 2023, 15(6), 1641; https://doi.org/10.3390/pharmaceutics15061641 - 1 Jun 2023
Cited by 5 | Viewed by 2137
Abstract
Stiripentol (STP) is a new-generation antiepileptic only available for oral administration. However, it is extremely unstable in acidic environments and undergoes gastrointestinal slow and incomplete dissolution. Thus, STP intranasal (IN) administration might overcome the high oral doses required to achieve therapeutic concentrations. An [...] Read more.
Stiripentol (STP) is a new-generation antiepileptic only available for oral administration. However, it is extremely unstable in acidic environments and undergoes gastrointestinal slow and incomplete dissolution. Thus, STP intranasal (IN) administration might overcome the high oral doses required to achieve therapeutic concentrations. An IN microemulsion and two variations were herein developed: the first contained a simpler external phase (FS6); the second one 0.25% of chitosan (FS6 + 0.25%CH); and the last 0.25% chitosan plus 1% albumin (FS6 + 0.25%CH + 1%BSA). STP pharmacokinetic profiles in mice were compared after IN (12.5 mg/kg), intravenous (12.5 mg/kg), and oral (100 mg/kg) administrations. All microemulsions homogeneously formed droplets with mean sizes ≤16 nm and pH between 5.5 and 6.2. Compared with oral route, IN FS6 resulted in a 37.4-fold and 110.6-fold increase of STP plasmatic and brain maximum concentrations, respectively. Eight hours after FS6 + 0.25%CH + 1%BSA administration, a second STP brain concentration peak was observed with STP targeting efficiency being 116.9% and direct-transport percentage 14.5%, suggesting that albumin may potentiate a direct STP brain transport. The relative systemic bioavailability was 947% (FS6), 893% (FS6 + 0.25%CH), and 1054% (FS6 + 0.25%CH + 1%BSA). Overall, STP IN administration using the developed microemulsions and significantly lower doses than those orally administrated might be a promising alternative to be clinically tested. Full article
(This article belongs to the Special Issue Drug Stability: Factors and New Approaches to Overcome Drug Instability)
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13 pages, 1761 KiB  
Article
Drug Shelf Life and Release Limits Estimation Based on Manufacturing Process Capability
by Alexis Oliva and Matías Llabrés
Pharmaceutics 2023, 15(4), 1070; https://doi.org/10.3390/pharmaceutics15041070 - 26 Mar 2023
Cited by 2 | Viewed by 3875
Abstract
Specification limits are the competence regulatory agencies, whereas the release limit is a manufacturer’s internal specification to be applied at the time of batch release to assure that quality attributes will remain within the specification limits until the expiry time. The aim of [...] Read more.
Specification limits are the competence regulatory agencies, whereas the release limit is a manufacturer’s internal specification to be applied at the time of batch release to assure that quality attributes will remain within the specification limits until the expiry time. The aim of this work is to propose a method to set the shelf life from drug manufacture process capacity and degradation rate, using a modified version of the proposed method by Allen et al. (1991) Two different data sets were used to do this. The first data set corresponds to analytical method validation to measure the insulin concentration in order to estimate the specification limits, whereas the latter set gathered information on stability data of six batches of human insulin pharmaceutical preparation. In this context, the six batches were divided into two groups: Group 1 (batches 1, 2, and 4) was used to estimate shelf life; Group 2 (batches 3, 5, and 6) was used to test the estimated lower release limit (LRL). The ASTM E2709-12 approach was applied to verify that the future batches fulfill the release criterium. The procedure has been implemented in R-code. Full article
(This article belongs to the Special Issue Drug Stability: Factors and New Approaches to Overcome Drug Instability)
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15 pages, 2224 KiB  
Article
Screening Autoxidation Propensities of Drugs in the Solid-State Using PVP and in the Solution State Using N-Methyl Pyrrolidone
by Jayant Iyer, Anjali Karn, Michael Brunsteiner, Andrew Ray, Adrian Davis, Isha Saraf and Amrit Paudel
Pharmaceutics 2023, 15(3), 848; https://doi.org/10.3390/pharmaceutics15030848 - 5 Mar 2023
Cited by 3 | Viewed by 2487
Abstract
Oxidative degradation of drugs is one of the major routes of drug substance and drug product instability. Among the diverse routes of oxidation, autoxidation is considered to be challenging to predict and control, potentially due to the multi-step mechanism involving free radicals. C–H [...] Read more.
Oxidative degradation of drugs is one of the major routes of drug substance and drug product instability. Among the diverse routes of oxidation, autoxidation is considered to be challenging to predict and control, potentially due to the multi-step mechanism involving free radicals. C–H bond dissociation energy (C–H BDE) is evidenced to be a calculated descriptor shown to predict drug autoxidation. While computational predictions for the autoxidation propensity of drugs are both swift and possible, no literature to date has highlighted the relationship between the computed C–H BDE and the experimentally-derived autoxidation propensities of solid drugs. The objective of this study is to investigate this missing relationship. The present work is an extension to the previously reported novel autoxidation approach that involves subjecting a physical mixture of pre-milled polyvinyl pyrrolidone (PVP) K-60 and a crystalline drug under high temperature and pressurized oxygen setup. The drug degradation was measured using chromatographic methods. An improved trend between the extent of solid autoxidation and C–H BDE could be observed after normalizing the effective surface area of drugs in the crystalline state, pointing to a positive relationship. Additional studies were conducted by dissolving the drug in N-methyl pyrrolidone (NMP) and exposing the solution under a pressurized oxygen setup at diverse elevated temperatures. Chromatographic results of these samples indicated a similarity in the formed degradation products to the solid-state experiments pointing to the utility of NMP, a PVP monomer surrogate, as a stressing agent for faster and relevant autoxidation screening of drugs in formulations. Full article
(This article belongs to the Special Issue Drug Stability: Factors and New Approaches to Overcome Drug Instability)
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12 pages, 2373 KiB  
Article
Pharmaceutical Systems as a Strategy to Enhance the Stability of Oxytetracycline Hydrochloride Polymorphs in Solution
by Maria S. Bueno, Marcela R. Longhi and Claudia Garnero
Pharmaceutics 2023, 15(1), 192; https://doi.org/10.3390/pharmaceutics15010192 - 5 Jan 2023
Cited by 4 | Viewed by 1952
Abstract
In order to improve the stability of oxytetracycline hydrochloride, a polymorphic antibiotic set of novel binary systems were developed using β-cyclodextrin and amino acids with different acid-basic characteristics as ligands. The formation constants for each system containing β-cyclodextrin, L-aspartic acid, histidine and N-acetylcysteine [...] Read more.
In order to improve the stability of oxytetracycline hydrochloride, a polymorphic antibiotic set of novel binary systems were developed using β-cyclodextrin and amino acids with different acid-basic characteristics as ligands. The formation constants for each system containing β-cyclodextrin, L-aspartic acid, histidine and N-acetylcysteine were determined by Scott’s method and statistical studies. The structure of the binary systems with β-cyclodextrin and N-acetylcysteine was elucidated by NMR experiments. The effect β-cyclodextrin and N-acetylcysteine on the polymorph’s chemical stability in aqueous and phosphate buffered saline solutions at 25 °C was monitored by an optimized and validated high-performance liquid chromatography method. The combination of N-acetylcysteine with the three polymorphs and the β-cyclodextrin system obtained with the form III demonstrated a reduction in the degradation rate of oxytetracycline hydrochloride in the aqueous solution when compared to each free form, with an increase of 20 h in the half time. It evidences that the use of amino acids as ligands constitutes an interesting alternative for pharmaceutical areas. In conclusion, based on the results obtained, these pharmaceutical systems could be candidates for the development of a pharmaceutical formulation for the administration of the drug through reconstituted solutions using the binary system as a promising tool for improving the stability of oxytetracycline hydrochloride polymorphs in solution. Full article
(This article belongs to the Special Issue Drug Stability: Factors and New Approaches to Overcome Drug Instability)
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22 pages, 7452 KiB  
Article
Stability and Antibiotic Potency Improvement of Levofloxacin by Producing New Salts with 2,6- and 3,5-Dihydroxybenzoic Acid and Their Comprehensive Structural Study
by Ilma Nugrahani, Muhammad Ramadhan Sulaiman, Chiaki Eda, Hidehiro Uekusa and Slamet Ibrahim
Pharmaceutics 2023, 15(1), 124; https://doi.org/10.3390/pharmaceutics15010124 - 29 Dec 2022
Cited by 6 | Viewed by 3192
Abstract
Recently, solid-state engineering has become a promising approach to improving the stability and potency of antibiotics. Levofloxacin (LF) is a broad-spectrum fluoroquinolone antibiotic marketed in solid and solution dosage forms. However, this substance forms solid hydrates under ambient conditions and degrades due to [...] Read more.
Recently, solid-state engineering has become a promising approach to improving the stability and potency of antibiotics. Levofloxacin (LF) is a broad-spectrum fluoroquinolone antibiotic marketed in solid and solution dosage forms. However, this substance forms solid hydrates under ambient conditions and degrades due to lighting, which may change its solid properties and dose. In addition, resistance cases have been reported due to long-time antibiotic usage. This research aims to allow LF to react with antioxidant dihydroxybenzoic acid (DHBA), which has low antimicrobial activity, to produce a more stable compound under water and lighting conditions and improve LF’s potency. The experiment begins with a screening to select potential DHBA isomers that can react with LF and predict the stoichiometric ratio using phase diagrams, which show that 2,6-DHBA and 3,5-DHBA are prospective antioxidants that can react with LF in a (1:1) molar ratio. Multicomponent systems are prepared by dissolving the LF–DHBA mixture in (1:1) ethanol–methanol (95% grade) and evaporating it. Then, the new solid phase formation is confirmed by thermal analysis and powder X-ray diffractometry. Next, infrared spectrophotometry and neutron magnetic resonance analyses are used to identify the LF–DHBA’s interactions. Finally, single-crystal X-ray diffractometry is used to solve the three-dimensional structure of the multicomponent system. We then conduct a hygroscopicity and stability test followed by a lighting and potency test using the microdilution method. Our data reveal that both reactions produce salts, which are named LF-26 and LF-35, respectively. Structurally, LF-26 is found in an anhydrous form with a triclinic crystal packing, while LF-35 is a hemihydrate in a monoclinic system. Afterward, both salts are proven more stable regarding water adsorption and UV lighting than LF. Finally, both multicomponent systems have an approximately two-fold higher antibiotic potency than LF. LF-26 and LF-35 are suitable for further development in solid and liquid dosage formulations, especially LF-35, which has superior stability compared with LF-26. Full article
(This article belongs to the Special Issue Drug Stability: Factors and New Approaches to Overcome Drug Instability)
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11 pages, 2521 KiB  
Article
Identification of the Major Degradation Pathways of Selumetinib
by Tahar Sif eddine Bouchema, Maxime Annereau, Victoire Vieillard, Raphael Boquet, Gisele Abreu Coelho, Florence Castelli, Audrey Solgadi, Muriel Paul, Najet Yagoubi, Philippe-Henri Secretan and Bernard Do
Pharmaceutics 2022, 14(12), 2651; https://doi.org/10.3390/pharmaceutics14122651 - 30 Nov 2022
Cited by 2 | Viewed by 2188
Abstract
Selumetinib is administered orally in capsule form and is indicated for the treatment of neurofibromatosis. To facilitate dosage adjustments, liquid preparations, such as solutions or suspensions, are to be developed. This led, first, to determine the stability profile of soluble or dispersed selumetinib [...] Read more.
Selumetinib is administered orally in capsule form and is indicated for the treatment of neurofibromatosis. To facilitate dosage adjustments, liquid preparations, such as solutions or suspensions, are to be developed. This led, first, to determine the stability profile of soluble or dispersed selumetinib and, secondly, to look for ways to stabilize the active substance. The degradation kinetics of selumetinib as a function of stress conditions were determined and compared. The degradation products were detected and identified by LC-HRMSn. In solution, selumetinib is sensitive to oxidation and degrades by photooxidation. In both cases, the side chain represented by the oxoamide group is concerned, leading to the formation of an amide derivative for the first case and an ester derivative for the second. The identification of such degradation mechanisms allowed us to study, in a targeted way, processes aiming at stabilizing the active molecule. Full article
(This article belongs to the Special Issue Drug Stability: Factors and New Approaches to Overcome Drug Instability)
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20 pages, 5112 KiB  
Article
Degradation of Losartan Potassium Highlighted by Correlated Studies of Photoluminescence, Infrared Absorption Spectroscopy and Dielectric Spectroscopy
by Mirela Paraschiv, Ion Smaranda, Irina Zgura, Paul Ganea, Madalina Chivu, Bogdan Chiricuta and Mihaela Baibarac
Pharmaceutics 2022, 14(11), 2419; https://doi.org/10.3390/pharmaceutics14112419 - 9 Nov 2022
Cited by 1 | Viewed by 2026
Abstract
In this paper, new results on the degradation of losartan potassium (LP, (1)), in the absence and presence of excipients, which was induced by UV light, the acid character of phosphate buffer solution (PBS) and alkaline medium, respectively, are reported through [...] Read more.
In this paper, new results on the degradation of losartan potassium (LP, (1)), in the absence and presence of excipients, which was induced by UV light, the acid character of phosphate buffer solution (PBS) and alkaline medium, respectively, are reported through correlated studies of FTIR spectroscopy, photoluminescence and dielectric spectroscopy. The photoluminescence (PL) spectra of LP and the drug marked under the name Lorista (LO) are characterized by intense emission bands, peaking at 378 nm and 380 nm, respectively, accompanied by low intensity bands with a maximum at ~450–460 nm. Photodegradation of LO in a solid state is evidenced by a decrease in the intensity of the PL band at 380 nm, a variation that originates both in the adsorption of water vapors from the air and in the interaction of LP with excipients such as cornstarch, silicon dioxide and cellulose. The LP-water interaction is described, taking into account the main electrical parameters, i.e., complex dielectric permittivity and electrical conductivity. Photodegradation of LP and LO also induces an increase in the intensity of the emission band, at ~450–460 nm. The influence of acid and alkaline medium on the LO degradation is analyzed using phosphate buffer (PBS) and NaOH solutions, respectively. In both cases, a decrease in the intensity of the PL band, at 380 nm, is reported. The intensity diminution of the PL spectra of NaOH-reacted LP and LO is the result of the formation of the photodegradation product N-methanolamide-{[2′-(1H-tetrazol-5-yl)(1,1′-biphenyl)-4-yl]methyl} (2). This compound was proven by the studies of FTIR spectroscopy achieved on LP and NaOH-reacted LP. The appearance of the IR band at 1740 cm−1 and the increase in the absorbance in the IR band at 1423 cm−1 indicate that the photodegradation product (2) contains the C=O and C-OH functional groups. Full article
(This article belongs to the Special Issue Drug Stability: Factors and New Approaches to Overcome Drug Instability)
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