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24 pages, 10586 KiB

Open AccessArticle

Development and Characterization of Pharmaceutical Systems Containing Rifampicin

by Antonella V. Dan Córdoba, Virginia Aiassa, Jesica A. Dimmer, Camila N. Barrionuevo, Mario A. Quevedo, Marcela R. Longhi and Ariana Zoppi

Pharmaceutics 2023, 15(1), 198; https://doi.org/10.3390/pharmaceutics15010198 - 05 Jan 2023

Cited by 5 | Viewed by 1312

Abstract

Rifampicin is a potent antimicrobial drug with some suboptimal properties, such as poor stability, low solubility, and variable bioavailability. Therefore, in the current study, a multicomponent complex between rifampicin, γ-cyclodextrin, and arginine was prepared with the aim of improving drug properties. Solubility was [...] Read more.

Rifampicin is a potent antimicrobial drug with some suboptimal properties, such as poor stability, low solubility, and variable bioavailability. Therefore, in the current study, a multicomponent complex between rifampicin, γ-cyclodextrin, and arginine was prepared with the aim of improving drug properties. Solubility was evaluated by phase-solubility studies. The mechanism of interaction was established through proton nuclear magnetic resonance spectroscopy and molecular modeling. Physicochemical characterization was investigated using Fourier transform-infrared spectroscopy, powder X-ray diffraction, and scanning electron microscopy. The dissolution properties, antimicrobial activity (antibacterial, antibiofilm, and antileishmanial), and stability of the different samples were studied. The results obtained in this investigation demonstrate that multicomponent complexes can improve the water solubility and dissolution rate of rifampicin, as well as its antibacterial and antileishmanial action, and present suitable stability. In conclusion, rifampicin complexed with γ-cyclodextrin and arginine is an attractive approach for developing pharmaceutical dosage forms of rifampicin with increased antimicrobial activities. Full article

(This article belongs to the Special Issue Drug Stability and Stabilization Techniques Volume II)

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16 pages, 2181 KiB

Open AccessArticle

Formation Thermodynamics of Carbamazepine with Benzamide, Para-Hydroxybenzamide and Isonicotinamide Cocrystals: Experimental and Theoretical Study

by Alex N. Manin, Denis E. Boycov, Olga R. Simonova, Tatyana V. Volkova, Andrei V. Churakov and German L. Perlovich

Pharmaceutics 2022, 14(9), 1881; https://doi.org/10.3390/pharmaceutics14091881 - 06 Sep 2022

Cited by 6 | Viewed by 1776

Abstract

Formation thermodynamic parameters for three cocrystals of carbamazepine (CBZ) with structurally related coformers (benzamide (BZA), para-hydroxybenzamide (4-OH-BZA) and isonicotinamide (INAM)) were determined by experimental (cocrystal solubility and competitive reaction methods) and computational techniques. The experimental solubility values of cocrystal components at eutectic points [...] Read more.

Formation thermodynamic parameters for three cocrystals of carbamazepine (CBZ) with structurally related coformers (benzamide (BZA), para-hydroxybenzamide (4-OH-BZA) and isonicotinamide (INAM)) were determined by experimental (cocrystal solubility and competitive reaction methods) and computational techniques. The experimental solubility values of cocrystal components at eutectic points and solubility product of cocrystals [CBZ + BZA], [CBZ + 4-OH-BZA], and [CBZ + INAM] in acetonitrile at 293.15 K, 298.15 K, 303.15 K, 308.15 K, and 313.15 K were measured. All the thermodynamic functions (Gibbs free energy, enthalpy, and entropy) of cocrystals formation were evaluated from the experimental data. The crystal structure of [CBZ + BZA] (1:1) cocrystal was solved and analyzed by the single crystal X-ray diffractometry. A correlation between the solubility products and pure coformers solubility values has been found for CBZ cocrystals. The relationship between the entropy term and the molecular volume of the cocrystal formation has been revealed. The effectiveness of the estimation of the cocrystal formation thermodynamic parameters, based on the knowledge of the melting temperatures of active pharmaceutical ingredients, coformers, cocrystals, as well as the sublimation Gibbs energies and enthalpies of the individual components, was proven. A new method for the comparative assessment of the cocrystal stability based on the H-bond propensity analysis was proposed. The experimental and theoretical results on the thermodynamic parameters of the cocrystal formation were shown to be in good agreement. According to the thermodynamic stability, the studied cocrystals can be arranged in the following order: [CBZ + 4-OH-BZA] > [CBZ + BZA] > [CBZ + INAM]. Full article

(This article belongs to the Special Issue Drug Stability and Stabilization Techniques Volume II)

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11 pages, 649 KiB

Open AccessArticle

Telmisartan Tablets Repackaged into Dose Administration Aids: Physicochemical Stability under Tropical Conditions

by Anthony P. Ma, Sherryl G. Robertson and Beverley D. Glass

Pharmaceutics 2022, 14(8), 1667; https://doi.org/10.3390/pharmaceutics14081667 - 11 Aug 2022

Viewed by 2067

Abstract

Dose administration aids (DAAs) are commonly used to assist patients with chronic disease to manage multiple medications and thus improve adherence. Several brands of telmisartan, commonly prescribed for hypertension, are available in Australia. Manufacturer’s storage advice is to leave tablets in the blister [...] Read more.

Dose administration aids (DAAs) are commonly used to assist patients with chronic disease to manage multiple medications and thus improve adherence. Several brands of telmisartan, commonly prescribed for hypertension, are available in Australia. Manufacturer’s storage advice is to leave tablets in the blister strip until administered to patients. This study aimed to investigate the stability of telmisartan tablets when repackaged and stored in DAAs, to identify a brand, which is sufficiently stable to be repackaged. All available brands of telmisartan tablets in Australia, which contain different excipients, were repackaged into DAAs and stored at 30 °C, 75% RH for 28 days before screening, using visual inspection and physical testing. A candidate brand was then selected for physicochemical and photostability testing using pharmacopoeial methods. Repackaged Mizart^® tablets were shown to be sufficiently stable, when repackaged and stored under tropical conditions (30 °C, 75% RH) for 28 days. Several of the other brands were deemed inappropriate for repackaging, due to physical instability, highlighting the importance of considering not only the drug, but also excipients to ensure the stability of repackaged medicines. Although the repackaging of telmisartan tablets is not advised, this study provides evidence to support the Mizart^® brand as an option for pharmacists to recommend for repackaging. Full article

(This article belongs to the Special Issue Drug Stability and Stabilization Techniques Volume II)

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24 pages, 4061 KiB

Open AccessArticle

Stability-Indicating Analytical Approach for Stability Evaluation of Lactoferrin

by Nika Osel, Timeja Planinšek Parfant, Albin Kristl and Robert Roškar

Pharmaceutics 2021, 13(7), 1065; https://doi.org/10.3390/pharmaceutics13071065 - 11 Jul 2021

Cited by 8 | Viewed by 2799

Abstract

Lactoferrin is a multifunctional iron-binding glycoprotein in milk. Due to its potential for the treatment of various diseases, interest in products containing lactoferrin is increasing. However, as a protein, it is prone to degradation, which critically affects the quality of products. Therefore, the [...] Read more.

Lactoferrin is a multifunctional iron-binding glycoprotein in milk. Due to its potential for the treatment of various diseases, interest in products containing lactoferrin is increasing. However, as a protein, it is prone to degradation, which critically affects the quality of products. Therefore, the main purpose of our work was to develop a stability-indicating analytical approach for stability evaluation of lactoferrin. We were focused on two complementary methods: reversed-phase and size-exclusion chromatography. The stability-indicating nature of the selected methods was confirmed. They were successfully validated by following the ICH guidelines and applied to preliminary lactoferrin stability studies. Up to three degradation products, as well as aggregates and fragments of lactoferrin, were detected in various samples using complementary reversed-phase and size-exclusion chromatographic methods. The analytical approach was additionally extended with three spectroscopic techniques (absorbance, intrinsic fluorescence, and bicinchoninic acid method), which may provide valuable complementary information in some cases. The presented analytical approach allows the stability evaluation of lactoferrin in various samples, including the ability to detect differences in its degradation mechanisms. Furthermore, it has the potential to be used for the quality control of products containing lactoferrin. Full article

(This article belongs to the Special Issue Drug Stability and Stabilization Techniques Volume II)

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21 pages, 12481 KiB

Open AccessArticle

Prediction of Drug Stability Using Deep Learning Approach: Case Study of Esomeprazole 40 mg Freeze-Dried Powder for Solution

by Jovana Ajdarić, Svetlana Ibrić, Aleksandar Pavlović, Ljubiša Ignjatović and Branka Ivković

Pharmaceutics 2021, 13(6), 829; https://doi.org/10.3390/pharmaceutics13060829 - 03 Jun 2021

Cited by 3 | Viewed by 3514

Abstract

A critical step in the production of Esomeprazole powder for solution is a period between the filling process and lyophilization, where all vials, partially closed, are completely exposed to environmental influences. Excessive instability reflects in pH value variations caused by oxygen’s impact. In [...] Read more.

A critical step in the production of Esomeprazole powder for solution is a period between the filling process and lyophilization, where all vials, partially closed, are completely exposed to environmental influences. Excessive instability reflects in pH value variations caused by oxygen’s impact. In order to provide pH control, which consequently affects drug stability, Esomeprazole batches, produced in the same way, were kept in partially closed vials for 3 h at temperatures of 20 °C and −30 °C, after which they were lyophilized and stored for long-term stability for 36 months. The aim of the presented study was to apply a deep-learning algorithm for the prediction of the Esomeprazole stability profile and to determine the pH limit for the reconstituted solution of the final freeze-dried product that would assure a quality product profile over a storage period of 36 months. Multilayer perceptron (MLP) as a deep learning tool, with four layers, was used. The pH value of Esomeprazole solution and time of storage (months) were inputs for the network, while Esomeprazole assay and four main impurities were outputs of the network. In order to keep all related substances and Esomeprazole assay in accordance with specifications for the whole shelf life, the pH value for the reconstituted finish product should be set in the range of 10.4–10.6. Full article

(This article belongs to the Special Issue Drug Stability and Stabilization Techniques Volume II)

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20 pages, 2733 KiB

Open AccessArticle

Comprehensive Stability Study of Vitamin D3 in Aqueous Solutions and Liquid Commercial Products

by Žane Temova Rakuša, Mitja Pišlar, Albin Kristl and Robert Roškar

Pharmaceutics 2021, 13(5), 617; https://doi.org/10.3390/pharmaceutics13050617 - 25 Apr 2021

Cited by 17 | Viewed by 5422

Abstract

Vitamin D3 has numerous beneficial effects, such as musculoskeletal, immunomodulatory, and neuroprotective. However, its instability is the main obstacle to formulating quality products. Despite increased attention and growing use, data on vitamin D3 stability is scarce because data from individual studies is inconclusive [...] Read more.

Vitamin D3 has numerous beneficial effects, such as musculoskeletal, immunomodulatory, and neuroprotective. However, its instability is the main obstacle to formulating quality products. Despite increased attention and growing use, data on vitamin D3 stability is scarce because data from individual studies is inconclusive and mostly qualitative. Therefore, we have systematically investigated the influence of various factors (temperature, light, oxygen, pH, concentration, and metal ions) on its stability in aqueous media using a stability-indicating HPLC-UV method. First-order kinetics fitted its degradation under all tested conditions except light and oxygen. In both cases, the established models in chemical kinetics were inappropriate and upgraded with the Weibull model. Metal ions and acidic conditions had the main destabilizing effect on vitamin D3 in aqueous media, but these solutions were successfully stabilized after the addition of ethylenediaminetetraacetic acid (EDTA), ascorbic acid, and citric acid, individually and in combination. EDTA showed the most significant stabilizing effect. Synergism among antioxidants was not observed. Our findings on vitamin D3 instability in aqueous media also correlated with its instability in commercial products. Vitamin D3 aqueous products require proper stabilization, thereby signifying the importance and contribution of the obtained results to the formulation of stable and quality products. Full article

(This article belongs to the Special Issue Drug Stability and Stabilization Techniques Volume II)

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12 pages, 2156 KiB

Open AccessArticle

Use of Pluronic Surfactants in Gel Formulations of Photosensitive 1,4-Dihydropyridine Derivatives: A Potential Approach in the Treatment of Neuropathic Pain

by Giuseppina Ioele, Rita Muzzalupo, Miyase Gözde Gündüz, Michele De Luca, Elisabetta Mazzotta, Fedora Grande, Maria Antonietta Occhiuzzi, Antonio Garofalo and Gaetano Ragno

Pharmaceutics 2021, 13(4), 527; https://doi.org/10.3390/pharmaceutics13040527 - 10 Apr 2021

Cited by 4 | Viewed by 1737

Abstract

1,4-Dihydropyridines (DHPs) are the most important class of L-type calcium channel blockers that are employed for the treatment of cardiovascular diseases, particularly hypertension. Various modifications on this scaffold lead to the discovery of new DHPs blocking different types of calcium channels. Among them, [...] Read more.

1,4-Dihydropyridines (DHPs) are the most important class of L-type calcium channel blockers that are employed for the treatment of cardiovascular diseases, particularly hypertension. Various modifications on this scaffold lead to the discovery of new DHPs blocking different types of calcium channels. Among them, the T-type calcium channel has recently attracted great interest due to its role in chronic pain conditions. In this study, we selected three newly synthesized DHPs (HM8, HM10 and MD20) with different selectivity profiles to the T-type calcium channel and formulated them in micellar solutions and micellar-in-gel matrices to be tested for potential topical use in the treatment of neuropathic pain. To prevent the well-known sensitivity to light of the DHPs, the studied compounds were entrapped in colloidal aggregates obtained by using edible Pluronic^® surfactants and adding α-tocopherol as an antioxidant. All the prepared formulations were exposed to stressing light, according to international rules. Along with the degradation experiments, the concentrations of the parent compounds and by-products were calculated by multivariate curve resolution—alternating least squares (MCR-ALS) applied to the spectral data. The defined formulations proved suitable as light-stable matrices for the DHP compounds, showing an increase in stability for HM8 and MD20 and an almost complete photoprotection for HM10, compared to ethanol solutions and standard gel formulations. Full article

(This article belongs to the Special Issue Drug Stability and Stabilization Techniques Volume II)

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15 pages, 1763 KiB

Open AccessArticle

Drug–Drug Compatibility Evaluation of Sulfasalazine and Folic Acid for Fixed-Dose Combination Development Using Various Analytical Tools

by Mario-Livio Jeličić, Edvin Brusač, Stanislav Kurajica, Matija Cvetnić, Daniela Amidžić Klarić, Biljana Nigović and Ana Mornar

Pharmaceutics 2021, 13(3), 400; https://doi.org/10.3390/pharmaceutics13030400 - 17 Mar 2021

Cited by 3 | Viewed by 2734

Abstract

The simultaneous administration of sulfasalazine and folic acid is regular practice in the therapy of inflammatory bowel diseases in order to maintain sufficient folate concentration in patients. Having multiple drugs in the therapy increases the possibility of patients failing adherence, thus unintentionally endangering [...] Read more.

The simultaneous administration of sulfasalazine and folic acid is regular practice in the therapy of inflammatory bowel diseases in order to maintain sufficient folate concentration in patients. Having multiple drugs in the therapy increases the possibility of patients failing adherence, thus unintentionally endangering their health. A fixed-dose combination of sulfasalazine and folic would simplify the classical polytherapeutic approach; however, the physicochemical compatibility investigation of two active pharmaceutical ingredients plays an important role in the development of such a product. In this work, various analytical tools were used to determine the physicochemical compatibility of sulfasalazine and folic acid. For the evaluation of chemical compatibility, infrared spectroscopy in combination with advanced statistical methods, such as the principal component analysis and cluster analysis, were used, whilst a simultaneous thermogravimetry/differential thermal analysis gave us an insight into the physical compatibility of two drugs. Isothermal stress testing, forced degradation and dissolution studies, followed by the analysis with a developed chromatographic method for the monitoring of folic acid, sulfasalazine and two of its related impurities, sulfapyridine and salicylic acid, gave us an insight into its chemical compatibility. The combination of the results obtained from the used techniques implies a satisfactory physicochemical compatibility between sulfasalazine and folic acid, which opens the path to the development of the proposed fixed-dose combination. Full article

(This article belongs to the Special Issue Drug Stability and Stabilization Techniques Volume II)

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Review

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53 pages, 2059 KiB

Open AccessReview

Antimicrobial Preservatives for Protein and Peptide Formulations: An Overview

by Luisa Stroppel, Torsten Schultz-Fademrecht, Martin Cebulla, Michaela Blech, Richard J. Marhöfer, Paul M. Selzer and Patrick Garidel

Pharmaceutics 2023, 15(2), 563; https://doi.org/10.3390/pharmaceutics15020563 - 07 Feb 2023

Cited by 9 | Viewed by 3944

Abstract

Biological drugs intended for multi-dose application require the presence of antimicrobial preservatives to avoid microbial growth. As the presence of certain preservatives has been reported to increase protein and peptide particle formation, it is essential to choose a preservative compatible with the active [...] Read more.

Biological drugs intended for multi-dose application require the presence of antimicrobial preservatives to avoid microbial growth. As the presence of certain preservatives has been reported to increase protein and peptide particle formation, it is essential to choose a preservative compatible with the active pharmaceutical ingredient in addition to its preservation function. Thus, this review describes the current status of the use of antimicrobial preservatives in biologic formulations considering (i) appropriate preservatives for protein and peptide formulations, (ii) their physico-chemical properties, (iii) their in-/compatibilities with other excipients or packaging material, and (iv) their interactions with the biological compound. Further, (v) we present an overview of licensed protein and peptide formulations. Full article

(This article belongs to the Special Issue Drug Stability and Stabilization Techniques Volume II)

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