Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
6.9
5.4
Journals
Pharmaceutics
Special Issues
Drug Stability and Stabilization Techniques
share announcement

Drug Stability and Stabilization Techniques

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

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 73087

Special Issue Editor

Prof. Dr. Beverley D. Glass

E-Mail Website
Guest Editor
PHARMACY, College of Medicine and Dentistry, James Cook University, Douglas, Townsville, QLD 4811, Australia
Interests: photo-stability; in-use drug stability; drug regulation and quality; falsified medicines, formulation and excipients
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Stability is a term widely used to designate the chemical and physical integrity of a drug dosage form and its ability to protect the dosage form against exposure to environmental conditions, such as light, air (oxygen) and heat throughout its shelf-life. However, this field of research has expanded over recent years to include the effects on stability of storage and transport, repackaging and importantly the potential clinical outcomes, including photosensitivity reactions for patients, who may be exposed to toxic effects of drug degradants.  Drug stability has also become an important area of research for analytical chemists in the development of stability-indicating methods of analysis, and is critical in drug regulation and quality as regulators especially in developing countries focus their attention on falsified and substandard medicines. The aim of compiling this Special Issue of Pharmaceutics on the topic of “Drug Stability and Stabilization Techniques” is to draw together experts with knowledge in the field across this widely diverse area including chemists, pharmaceutical scientists and clinicians, who are engaged in contemporary pure and applied research to solve the challenges of delivering stable and quality drug dosage forms to all populations. Submissions (original papers and reviews) that contribute to understanding and applications of relevance for Drug Stability and Stabilization Techniques are welcomed for this Special Issue.

Prof. Dr. Beverley D. Glass
Guest Editor

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 stability
  • photo stability
  • drug degradation
  • in-use stability
  • drug stabilization
  • drug quality

Related Special Issue

Published Papers (15 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

19 pages, 4038 KiB  
Article
On the Stability and Degradation Pathways of Venetoclax under Stress Conditions
by Nina Žigart, Martin Črnugelj, Janez Ilaš and Zdenko Časar
Pharmaceutics 2020, 12(7), 639; https://doi.org/10.3390/pharmaceutics12070639 - 07 Jul 2020
Cited by 7 | Viewed by 3330
Abstract
Venetoclax is an orally bioavailable, B-cell lymphoma-2 (BCL-2) selective inhibitor, used for the treatment of various types of blood cancers, such as chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). In this study we investigated the degradation of venetoclax under various stress [...] Read more.
Venetoclax is an orally bioavailable, B-cell lymphoma-2 (BCL-2) selective inhibitor, used for the treatment of various types of blood cancers, such as chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). In this study we investigated the degradation of venetoclax under various stress conditions including acidic, basic, oxidative, photolytic and thermolytic conditions. We isolated and identified six of its main degradation products produced in forced degradation studies. The structures of the isolated degradation products were determined by using nuclear magnetic resonance (NMR) spectroscopy, high resolution mass spectrometry (HRMS) and infrared (IR) spectroscopy. Additionally, one oxidation degradation product was identified with comparison to a commercially obtained venetoclax impurity. We proposed the key degradation pathways of venetoclax in solution. To the best of our knowledge, no structures of degradation products of venetoclax have been previously published. The study provides novel and primary knowledge of the stability characteristics of venetoclax under stress conditions. Venetoclax is currently the only BCL-2 protein inhibitor on the market. In addition to single agent treatment, it is effective in combinational therapy, so future drug development involving venetoclax can be expected. A better insight into the stability properties of the therapeutic can facilitate future studies involving venetoclax and aid in the search of new similar therapeutics. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Graphical abstract

15 pages, 3373 KiB  
Article
Spatially Resolved Effects of Protein Freeze-Thawing in a Small-Scale Model Using Monoclonal Antibodies
by Oliver Spadiut, Thomas Gundinger, Birgit Pittermann and Christoph Slouka
Pharmaceutics 2020, 12(4), 382; https://doi.org/10.3390/pharmaceutics12040382 - 21 Apr 2020
Cited by 3 | Viewed by 2707
Abstract
Protein freeze-thawing is frequently used to stabilize and store recombinantly produced proteins after different unit operations in upstream and downstream processing. However, freeze-thawing is often accompanied by product damage and, hence, loss of product. Different effects are responsible, including cold denaturation, aggregation effects, [...] Read more.
Protein freeze-thawing is frequently used to stabilize and store recombinantly produced proteins after different unit operations in upstream and downstream processing. However, freeze-thawing is often accompanied by product damage and, hence, loss of product. Different effects are responsible, including cold denaturation, aggregation effects, which are caused by inhomogeneities in protein concentration, as well as pH and buffer ingredients, especially during the freeze cycle. In this study, we tested a commercially available small-scale protein freezing unit using immunoglobin G (IgG) as monoclonal antibody in a typical formulation buffer containing sodium phosphate, sodium chloride, and Tween 80. Different freezing rates were used respectively, and the product quality was tested in the frozen sample. Spatially resolved tests for protein concentration, pH, conductivity, and aggregation revealed high spatial differences in the frozen sample. Usage of slow freezing rates revealed high inhomogeneities in terms of buffer salt and protein distribution, while fast rates led to far lower spatial differences. These protein and buffer salt inhomogeneities can be reliably monitored using straight forward analytics, like conductivity and photometric total protein concentration measurements, reducing the need for HPLC analytics in screening experiments. Summarizing, fast freezing using steep rates shows promising results concerning homogeneity of the final frozen product and inhibits increased product aggregation. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Graphical abstract

12 pages, 3829 KiB  
Article
The Stability Maintenance of Protein Drugs in Organic Coatings Based on Nanogels
by Hongzhao Qi, Lijun Yang, Peipei Shan, Sujie Zhu, Han Ding, Sheng Xue, Yin Wang, Xubo Yuan and Peifeng Li
Pharmaceutics 2020, 12(2), 115; https://doi.org/10.3390/pharmaceutics12020115 - 01 Feb 2020
Cited by 16 | Viewed by 2480
Abstract
Protein drugs are often loaded on scaffolds with organic coatings to realize a spatiotemporal controlled release. The stability or activity of protein drugs, however, is largely affected by the organic coating, particularly with organic solvents, which can dramatically reduce their delivery efficiency and [...] Read more.
Protein drugs are often loaded on scaffolds with organic coatings to realize a spatiotemporal controlled release. The stability or activity of protein drugs, however, is largely affected by the organic coating, particularly with organic solvents, which can dramatically reduce their delivery efficiency and limit their application scope. In spite of this, little attention has been paid to maintaining the stability of protein drugs in organic coatings, to date. Here, we used catalase as a model protein drug to exploit a kind of chemically cross-linked nanogel that can efficiently encapsulate protein drugs. The polymeric shells of nanogels can maintain the surface hydration shell to endow them with a protein protection ability against organic solvents. Furthermore, the protection efficiency of nanogels is higher when the polymeric shell is more hydrophilic. In addition, nanogels can be dispersed in polylactic acid (PLA) solution and subsequently coated on scaffolds to load catalase with high activity. To the best of our knowledge, this is the first use of hydrophilic nanogels as a protection niche to load protein drugs on scaffolds through an organic coating, potentially inspiring researchers to exploit new methods for protein drug loading. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Figure 1

17 pages, 5906 KiB  
Article
Solid State Stability and Kinetics of Degradation for Candesartan—Pure Compound and Pharmaceutical Formulation
by Valentina Buda, Bianca Baul, Minodora Andor, Dana Emilia Man, Adriana Ledeţi, Gabriela Vlase, Titus Vlase, Corina Danciu, Petru Matusz, Francisc Peter and Ionuţ Ledeţi
Pharmaceutics 2020, 12(2), 86; https://doi.org/10.3390/pharmaceutics12020086 - 21 Jan 2020
Cited by 5 | Viewed by 3737
Abstract
The aim of this work was to assess the impact of an excipient in a pharmaceutical formulation containing candesartan cilexetil over the decomposition of the active pharmaceutical ingredient and to comparatively investigate the kinetics of degradation during thermolysis in an oxidative atmosphere under [...] Read more.
The aim of this work was to assess the impact of an excipient in a pharmaceutical formulation containing candesartan cilexetil over the decomposition of the active pharmaceutical ingredient and to comparatively investigate the kinetics of degradation during thermolysis in an oxidative atmosphere under controlled thermal stress. To achieve this, the samples were chosen as follows: pure candesartan cilexetil and a commercial tablet of 32 mg strength. As a first investigational tool, Universal attenuated total reflection Fourier transform infrared (UATR-FTIR) spectroscopy was chosen in order to confirm the purity and identity of the samples, as well as to check if any interactions took place in the tablet between candesartan cilexetil and excipients under ambient conditions. Later on, samples were investigated by thermal analysis, and the elucidation of the decomposition mechanism was achieved solely after performing an in-depth kinetic study, namely the use of the modified non-parametric kinetics (NPK) method, since other kinetic methods (American Society for Testing and Materials—ASTM E698, Friedman and Flynn–Wall–Ozawa) led to inadvertencies. The NPK method suggested that candesartan cilexetil and the tablet were degraded by the contribution of two steps, the main being represented by chemical degradation and the secondary being a physical transformation. The excipients chosen in the formulation seemed to have a stabilizing effect on the decomposition of the candesartan cilexetil that was incorporated into the tablet, relative to pure active pharmaceutical ingredient (API), since the apparent activation energy for the decomposition of the tablet was 192.5 kJ/mol, in comparison to 154.5 kJ/mol for the pure API. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Graphical abstract

14 pages, 1583 KiB  
Article
Stability and Compatibility Studies of Levothyroxine Sodium in Solid Binary Systems—Instrumental Screening
by Ionuț Ledeți, Mirabela Romanescu, Denisa Cîrcioban, Adriana Ledeți, Gabriela Vlase, Titus Vlase, Oana Suciu, Marius Murariu, Sorin Olariu, Petru Matusz, Valentina Buda and Doina Piciu
Pharmaceutics 2020, 12(1), 58; https://doi.org/10.3390/pharmaceutics12010058 - 10 Jan 2020
Cited by 15 | Viewed by 4604
Abstract
The influence of excipients on the stability of sodium levothyroxine pentahydrate (LTSS) under ambient conditions and thermal stress was evaluated. Since LTSS is a synthetic hormone with a narrow therapeutic index, the interactions of LTSS with excipients can lead to a drastic diminution [...] Read more.
The influence of excipients on the stability of sodium levothyroxine pentahydrate (LTSS) under ambient conditions and thermal stress was evaluated. Since LTSS is a synthetic hormone with a narrow therapeutic index, the interactions of LTSS with excipients can lead to a drastic diminution of therapeutic activity. Ten commonly used pharmaceutical excipients with different roles in solid formulations were chosen as components for binary mixtures containing LTSS, namely, starch, anhydrous lactose, D-mannitol, D-sorbitol, gelatin, calcium lactate pentahydrate, magnesium stearate, methyl 2-hydroxyethyl cellulose (Tylose), colloidal SiO2 (Aerosil) and talc. As investigational tools, universal attenuated total reflectance- Fourier transform infrared spectroscopy UATR-FTIR spectroscopy and thermal analysis were chosen and used as follows: UATR-FTIR spectra were drawn up for samples kept under ambient conditions, while thermoanalytical tools (TG/DTG/HF data) were chosen to evaluate the inducing of interactions during thermal stress. The corroboration of instrumental results led to the conclusion that LTSS is incompatible with lactose, mannitol and sorbitol, and these excipients should not be considered in the development of new generic solid formulations. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Figure 1

17 pages, 8532 KiB  
Article
Effect of Formulation Factors and Oxygen Levels on the Stability of Aqueous Injectable Solution Containing Pemetrexed
by Dong Han Won, Heejun Park, Eun-Sol Ha, Yong Min Kim, Hyung Don Hwang, Sun Woo Jang and Min-Soo Kim
Pharmaceutics 2020, 12(1), 46; https://doi.org/10.3390/pharmaceutics12010046 - 06 Jan 2020
Cited by 9 | Viewed by 4632
Abstract
The aim of this study was to investigate the effects of various parameters at each control strategy in drug product degradation on the stability of pemetrexed in injectable aqueous solution. A forced degradation study confirmed that oxidation is the main mechanism responsible for [...] Read more.
The aim of this study was to investigate the effects of various parameters at each control strategy in drug product degradation on the stability of pemetrexed in injectable aqueous solution. A forced degradation study confirmed that oxidation is the main mechanism responsible for the degradation of pemetrexed in aqueous solutions. As control strategies, the antioxidant levels, drug concentration, pH of the control formulation, dissolved oxygen (DO) levels in the control process, and headspace oxygen levels in the control packaging were varied, and their effects on the stability of pemetrexed were evaluated. Sodium sulfite was found to be particularly effective in preventing the color change, and N-acetylcysteine (NAC) had a significant effect in preventing chemical degradation. The sulfite and NAC were found to stabilize pemetrexed in the aqueous solution by acting as sacrificial reductants. A pH below 6 caused significant degradation. The stability of pemetrexed in the solution increased as the concentration of the drug increased from 12.5 to 50 mg/mL. In addition, the DO levels in the solution were controlled by nitrogen purging, and the oxygen levels in headspace were controlled by nitrogen headspace, which also had significant positive effects in improving the stability of the pemetrexed solution; thus, it was confirmed that molecular oxygen is involved in the rate-limiting oxidation step. Based on these results obtained by observing the effects of various control strategies, the optimal formulation of an injectable solution of pemetrexed is suggested as follows: sodium sulfite at 0.06 mg/mL, as an antioxidant for prevention of color change; NAC at 1.63 mg/mL, as an antioxidant for prevention of chemical degradation; pH range 7–8; DO levels below 1 ppm; and headspace oxygen levels below 1%. In conclusion, it can be suggested that this study, which includes well-designed control strategies, can lead to a better understanding of the complex degradation mechanism of pemetrexed; thus, it can lead to the development of an injectable solution formulation of pemetrexed, with improved stability. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Graphical abstract

21 pages, 3997 KiB  
Article
A Novel Testing Approach for Oxidative Degradation Dependent Incompatibility of Amine Moiety Containing Drugs with PEGs in Solid-State
by Blaž Robnik, Katerina Naumoska and Zdenko Časar
Pharmaceutics 2020, 12(1), 37; https://doi.org/10.3390/pharmaceutics12010037 - 02 Jan 2020
Cited by 6 | Viewed by 6152
Abstract
Reactive impurities originating from excipients can cause drug stability issues, even at trace amounts. When produced during final dosage form storage, they are especially hard to control, and often, factors inducing their formation remain unidentified. Oxidative degradation dependent formation of formaldehyde and formic [...] Read more.
Reactive impurities originating from excipients can cause drug stability issues, even at trace amounts. When produced during final dosage form storage, they are especially hard to control, and often, factors inducing their formation remain unidentified. Oxidative degradation dependent formation of formaldehyde and formic acid is responsible for N-methylation and N-formylation of amine-moiety-containing drug substances. A very popular combination of polyethylene glycols and iron oxides, used in more than two-thirds of FDA-approved tablet formulation drugs in 2018, was found to be responsible for increased concentrations of N-methyl impurity in the case of paroxetine hydrochloride. We propose a novel testing approach for early identification of potentially problematic combinations of excipients and drug substances. The polyethylene glycol 6000 degradation mechanism and kinetics in the presence of iron oxides is studied. The generality of the proposed stress test setup in view of the susceptibility of amine-moiety-containing drug substances to N-methylation and N-formylation is evaluated. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Graphical abstract

16 pages, 1943 KiB  
Article
Montelukast Nanocrystals for Transdermal Delivery with Improved Chemical Stability
by Sung Hyun Im, Hoe Taek Jung, Myoung Jin Ho, Jeong Eun Lee, Hyung Tae Kim, Dong Yoon Kim, Hyo Chun Lee, Yong Seok Choi and Myung Joo Kang
Pharmaceutics 2020, 12(1), 18; https://doi.org/10.3390/pharmaceutics12010018 - 23 Dec 2019
Cited by 22 | Viewed by 3826
Abstract
A novel nanocrystal system of montelukast (MTK) was designed to improve the transdermal delivery, while ensuring chemical stability of the labile compound. MTK nanocrystal suspension was fabricated using acid-base neutralization and ultra-sonication technique and was characterized as follows: approximately 100 nm in size, [...] Read more.
A novel nanocrystal system of montelukast (MTK) was designed to improve the transdermal delivery, while ensuring chemical stability of the labile compound. MTK nanocrystal suspension was fabricated using acid-base neutralization and ultra-sonication technique and was characterized as follows: approximately 100 nm in size, globular shape, and amorphous state. The embedding of MTK nanocrystals into xanthan gum-based hydrogel caused little changes in the size, shape, and crystalline state of the nanocrystal. The in vitro drug release profile from the nanocrystal hydrogel was comparable to that of the conventional hydrogel because of the rapid dissolution pattern of the drug nanocrystals. The drug degradation under visible exposure (400–800 nm, 600,000 lux·h) was markedly reduced in case of nanocrystal hydrogel, yielding only 30% and 50% amount of cis-isomer and sulfoxide as the major degradation products, as compared to those of drug alkaline solution. Moreover, there was no marked pharmacokinetic difference between the nanocrystal and the conventional hydrogels, exhibiting equivalent extent and rate of drug absorption after topical administration in rats. Therefore, this novel nanocrystal system can be a potent tool for transdermal delivery of MTK in the treatment of chronic asthma or seasonal allergies, with better patient compliance, especially in children and elderly. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Graphical abstract

23 pages, 6646 KiB  
Article
Effect of Stabilizers on Encapsulation Efficiency and Release Behavior of Exenatide-Loaded PLGA Microsphere Prepared by the W/O/W Solvent Evaporation Method
by Heejun Park, Dong-Hyun Ha, Eun-Sol Ha, Jeong-Soo Kim, Min-Soo Kim and Sung-Joo Hwang
Pharmaceutics 2019, 11(12), 627; https://doi.org/10.3390/pharmaceutics11120627 - 24 Nov 2019
Cited by 34 | Viewed by 5922
Abstract
The aim of this study was to investigate the effects of various stabilizers on the encapsulation efficiency and release of exenatide-loaded PLGA (poly(lactic-co-glycolic acid)) microspheres prepared by the water-in-oil-in-water (W/O/W) solvent evaporation (SE) method. It was shown that the stabilizers affected [...] Read more.
The aim of this study was to investigate the effects of various stabilizers on the encapsulation efficiency and release of exenatide-loaded PLGA (poly(lactic-co-glycolic acid)) microspheres prepared by the water-in-oil-in-water (W/O/W) solvent evaporation (SE) method. It was shown that the stabilizers affected exenatide stability in aqueous solutions, at water/dichloromethane interfaces, on PLGA surfaces, or during freeze-thawing and freeze-drying procedures. Sucrose predominantly reduces instability generated during freeze-thawing and freeze-drying. Phenylalanine prevents the destabilization at the water–dichloromethane (DCM) interface through decreased adsorption. Poloxamer 188 enhances stability in aqueous solutions and prevents adsorption to PLGA. Proline and lysine decrease adsorption on PLGA surfaces. Fourier transform infra-red spectroscopy (FT-IR) was used to find the molecular interaction of additives with exenatide or PLGA. Additives used in stability assessments were then added stepwise into the inner or outer water phase of the W/O/W double emulsion, and exenatide-loaded microspheres were prepared using the solvent evaporation method. The effect of each stabilizer on the encapsulation efficiency and release behavior of microspheres correlated well with the stability assessment results, except for the negative effect of poloxamer 188. Particle size analysis using laser diffractometry, scanning electron microscopy (SEM), water vapor sorption analysis, differential scanning calorimetry (DSC), and circular dichroism (CD) spectroscopy were also employed to characterize the prepared exenatide-loaded PLGA microsphere. This study demonstrated that an adequate formulation can be obtained by the study about the effect of stabilizers on peptide stability at the preformulation step. In addition, it can help to overcome various problems that can cause the destabilization of a peptide during the microsphere-manufacturing process and sustained drug release. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Graphical abstract

10 pages, 1682 KiB  
Article
PVP-H2O2 Complex as a New Stressor for the Accelerated Oxidation Study of Pharmaceutical Solids
by Dattatray Modhave, Brenda Barrios and Amrit Paudel
Pharmaceutics 2019, 11(9), 457; https://doi.org/10.3390/pharmaceutics11090457 - 03 Sep 2019
Cited by 16 | Viewed by 4869
Abstract
Reactive impurities, such as hydrogen peroxide in excipients, raise a great concern over the chemical stability of pharmaceutical products. Traditional screening methods of spiking impurities into solid drug-excipient mixtures oversimplify the micro-environment and the physical state of such impurities in real dosage form. [...] Read more.
Reactive impurities, such as hydrogen peroxide in excipients, raise a great concern over the chemical stability of pharmaceutical products. Traditional screening methods of spiking impurities into solid drug-excipient mixtures oversimplify the micro-environment and the physical state of such impurities in real dosage form. This can lead to an inaccurate prediction of the long-term product stability. This study presents the feasibility of using a polyvinylpyrrolidone-hydrogen peroxide complex (PVP-H2O2) as an oxidative agent for the solid state forced degradation of a selected drug, vortioxetine HBr. The PVP-H2O2 complex was prepared and characterized using FT-IR spectroscopy. The tablet compacts were made using a mixture of solid PVP-H2O2 complex and crystalline vortioxetine HBr powder. The compacts were exposed to 40 °C/75% RH condition in open and closed states for different time intervals. The extent and the type of drug degradation were analysed using LC and LC-MS. The extent of degradation was higher in the samples stored at the open state as compared to the close state. The solution state forced oxidation was conducted to verify the peroxide induced degradation reactions. The results evidence the utility of the proposed solid-state stressor and the method for screening the sensitivity of drugs to the excipient reactive impurities involving peroxides in solid-state. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Graphical abstract

21 pages, 4885 KiB  
Article
Understanding and Kinetic Modeling of Complex Degradation Pathways in the Solid Dosage Form: The Case of Saxagliptin
by Blaž Robnik, Blaž Likozar, Baifan Wang, Tijana Stanić Ljubin and Zdenko Časar
Pharmaceutics 2019, 11(9), 452; https://doi.org/10.3390/pharmaceutics11090452 - 02 Sep 2019
Cited by 10 | Viewed by 4483
Abstract
Drug substance degradation kinetics in solid dosage forms is rarely mechanistically modeled due to several potential micro-environmental and manufacturing related effects that need to be integrated into rate laws. The aim of our work was to construct a model capable of predicting individual [...] Read more.
Drug substance degradation kinetics in solid dosage forms is rarely mechanistically modeled due to several potential micro-environmental and manufacturing related effects that need to be integrated into rate laws. The aim of our work was to construct a model capable of predicting individual degradation product concentrations, taking into account also formulation composition parameters. A comprehensive study was done on active film-coated tablets, manufactured by layering of the drug substance, a primary amine compound saxagliptin, onto inert tablet cores. Formulation variables like polyethylene glycol (PEG) 6000 amount and film-coat polymer composition are incorporated into the model, and are connected to saxagliptin degradation, via formation of reactive impurities. Derived reaction equations are based on mechanisms supported by ab initio calculations of individual reaction activation energies. Alongside temperature, relative humidity, and reactant concentration, the drug substance impurity profile is dependent on micro-environmental pH, altered by formation of acidic PEG degradation products. A consequence of pH lowering, due to formation of formic acid, is lower formation of main saxagliptin degradation product epi-cyclic amidine, a better resistance of formulation to high relative humidity conditions, and satisfactory tablet appearance. Discovered insights enhance the understanding of degradational behavior of similarly composed solid dosage forms on overall drug product quality and may be adopted by pharmaceutical scientists for the design of a stable formulation. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Graphical abstract

13 pages, 2126 KiB  
Article
Multilayer-Coated Tablet of Clopidogrel and Rosuvastatin: Preparation and In Vitro/In vivo Characterization
by Ki-Soo Seo and Hyo-Kyung Han
Pharmaceutics 2019, 11(7), 313; https://doi.org/10.3390/pharmaceutics11070313 - 04 Jul 2019
Cited by 10 | Viewed by 5350
Abstract
The acid lability of rosuvastatin hinders the preparation of mixed combination formulations of rosuvastatin with acidic drugs such as clopidogrel. Therefore, the purpose of this study was to develop a multilayer-coated tablet that avoids physicochemical interactions between rosuvastatin and clopidogrel. Among the tested [...] Read more.
The acid lability of rosuvastatin hinders the preparation of mixed combination formulations of rosuvastatin with acidic drugs such as clopidogrel. Therefore, the purpose of this study was to develop a multilayer-coated tablet that avoids physicochemical interactions between rosuvastatin and clopidogrel. Among the tested hydrophobic materials, glyceryl behenate was most effective at inhibiting the production of lactone, the acid degradation product of rosuvastatin. Therefore, the multilayer-coated tablet included a hydrophobic separation layer consisting of glyceryl behenate between the clopidogrel core tablet and the rosuvastatin coating layer. In order to prevent delayed dissolution by the stable hydrophobic separation layer, crospovidone was added into the clopidogrel core tablet as an effective disintegrant. Copovidone was also added to the coating layer of rosuvastatin, achieving a dissolution profile comparable to that of the reference drug, Crestor®. The resulting multilayer-coated tablet exhibited similar pharmacokinetic profiles to those of reference drugs (Plavix® and Crestor®) in beagle dogs, and there was no statistically significant difference in the maximum plasma concentration (Cmax), the time to reach the maximum plasma concentration (Tmax), or the area under the plasma-concentration time curve (AUC) between the test and reference formulations. The storage stability tests showed that the amounts of acid degradation products and total impurities were comparable to that of the reference drug. In conclusion, the present study successfully developed a stable multilayer-coated tablet containing both clopidogrel and rosuvastatin that may improve the patient compliance in combination therapy for cardiovascular diseases. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Graphical abstract

14 pages, 3403 KiB  
Article
Molecular Mobility and Stability Studies of Amorphous Imatinib Mesylate
by Bożena Karolewicz, Agata Górniak, Dominik M. Marciniak and Igor Mucha
Pharmaceutics 2019, 11(7), 304; https://doi.org/10.3390/pharmaceutics11070304 - 01 Jul 2019
Cited by 10 | Viewed by 3489
Abstract
The proposed study examined the characterization and stability of solid-state amorphous imatinib mesylate (IM) after 15 months under controlled relative humidity (60 ± 5%) and temperature (25 ± 2 °C) conditions. After 2 weeks, and 1, 3, 6, and 15 months, the samples [...] Read more.
The proposed study examined the characterization and stability of solid-state amorphous imatinib mesylate (IM) after 15 months under controlled relative humidity (60 ± 5%) and temperature (25 ± 2 °C) conditions. After 2 weeks, and 1, 3, 6, and 15 months, the samples were characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffractometry (XRPD), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and scanning electron microscopy (SEM). Additionally, the amorphous form of imatinib mesylate was obtained via supercooling of the melt in a DSC apparatus, and aged at various temperatures (3, 15, 25 and 30 °C) and time periods (1–16 h). Glass transition and enthalpy relaxation were used to calculate molecular-relaxation-time parameters. The Kohlrausch–Williams–Watts (KWW) equation was applied to fit the experimental enthalpy-relaxation data. The mean molecular-relaxation-time constant (τ) increased with decreasing ageing temperature. The results showed a high stability of amorphous imatinib mesylate adequate to enable its use in solid dosage form. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Figure 1

Review

Jump to: Research

14 pages, 246 KiB  
Review
Fibroblast Growth Factor 2—A Review of Stabilisation Approaches for Clinical Applications
by Leah Benington, Gunesh Rajan, Cornelia Locher and Lee Yong Lim
Pharmaceutics 2020, 12(6), 508; https://doi.org/10.3390/pharmaceutics12060508 - 02 Jun 2020
Cited by 54 | Viewed by 5323
Abstract
Basic fibroblast growth factor (FGF)-2 has been shown to regulate many cellular functions including cell proliferation, migration, and differentiation, as well as angiogenesis in a variety of tissues, including skin, blood vessel, muscle, adipose, tendon/ligament, cartilage, bone, tooth, and nerve. These multiple functions [...] Read more.
Basic fibroblast growth factor (FGF)-2 has been shown to regulate many cellular functions including cell proliferation, migration, and differentiation, as well as angiogenesis in a variety of tissues, including skin, blood vessel, muscle, adipose, tendon/ligament, cartilage, bone, tooth, and nerve. These multiple functions make FGF-2 an attractive component for wound healing and tissue engineering constructs; however, the stability of FGF-2 is widely accepted to be a major concern for the development of useful medicinal products. Many approaches have been reported in the literature for preserving the biological activity of FGF-2 in aqueous solutions. Most of these efforts were directed at sustaining FGF-2 activity for cell culture research, with a smaller number of studies seeking to develop sustained release formulations of FGF-2 for tissue engineering applications. The stabilisation approaches may be classified into the broad classes of ionic interaction modification with excipients, chemical modification, and physical adsorption and encapsulation with carrier materials. This review discusses the underlying causes of FGF-2 instability and provides an overview of the approaches reported in the literature for stabilising FGF-2 that may be relevant for clinical applications. Although efforts have been made to stabilise FGF-2 for both in vitro and in vivo applications with varying degrees of success, the lack of comprehensive published stability data for the final FGF-2 products represents a substantial gap in the current knowledge, which has to be addressed before viable products for wider tissue engineering applications can be developed to meet regulatory authorisation. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Graphical abstract

27 pages, 704 KiB  
Review
Photostability of Topical Agents Applied to the Skin: A Review
by Agata Kryczyk-Poprawa, Anna Kwiecień and Włodzimierz Opoka
Pharmaceutics 2020, 12(1), 10; https://doi.org/10.3390/pharmaceutics12010010 - 20 Dec 2019
Cited by 27 | Viewed by 8598
Abstract
Topical treatment modalities have multiple advantages starting with the convenient application and non-invasive treatment and ending with the reduction of the risk of the systemic side effects. Active pharmaceutical substances must reach the desired concentration at the target site in order to produce [...] Read more.
Topical treatment modalities have multiple advantages starting with the convenient application and non-invasive treatment and ending with the reduction of the risk of the systemic side effects. Active pharmaceutical substances must reach the desired concentration at the target site in order to produce a particular therapeutic effect. In contrast to other dosage forms topical agents applied to the skin may also be susceptible to photodegradation after application. That is why the knowledge of the susceptibility of these topical drugs to UV irradiation, which may contribute to their degradation or changes in chemical structure, is very important. Active pharmaceutical substances used in dermatology may differ both in chemical structure and photostability. Furthermore, various factors—such as light intensity and wavelength, pH, temperature, concentration—can influence the photodegradation process, which is reflected in particular in kinetics of photodegradation of active pharmaceutical substances as well as both the quantitative and qualitative composition of by-products. The aim of this study was to conduct a systematic review of the photostability of dermatological drugs, as well as of other substances commonly applied topically. The photostability of glucocorticosteroids, retinoids, and antifungal drugs as well as non-steroidal anti-inflammatory drugs applied topically and selected UV-filters have been discussed. Furthermore, the impact of photoinstability on the effectiveness of pharmacotherapy and some photostabilization strategies have been also included. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
►▼ Show Figures

Graphical abstract

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-15
Back to TopTop