Long-term Physicochemical Stability Research Articles

Long-term stability of esketamine in polypropylene syringes at 5 ± 3°C

ObjectiveEsketamine (Vesierra) is a molecule, used alone or in combination, to induce and maintain general anaesthesia and to relieve pain in emergency medicine. The aim of this study is to...

Synthesis of Highly Luminescent Silica-Coated Upconversion Nanoparticles from Lanthanide Oxides or Nitrates Using Co-Precipitation and Sol-Gel Methods.

Upconversion nanoparticles (UCNPs) are under consideration for their use as bioimaging probes with enhanced optical performance for real time follow-up under non-invasive conditions. Photostable and core-shell NaYF4:Yb3+, Er3+-SiO2 UCNPs obtained by a novel and simple co-precipitation method from lanthanide nitrates or oxides were herein synthesized for the first time. The sol-gel Stöber method followed by oven or supercritical gel drying was used to confer biocompatible surface properties to UCNPs by the formation of an ultrathin silica coating. Upconversion (UC) spectra were studied to evaluate the fluorescence of UCNPs upon red/near infrared (NIR) irradiation. ζ-potential measurements, TEM analyses, XRD patterns and long-term physicochemical stability were also assessed and confirmed that the UCNPs co-precipitation synthesis is a shape- and phase-controlling approach. The bio- and hemocompatibility of the UCNPs formulation with the highest fluorescence intensity was evaluated with murine fibroblasts and human blood, respectively, and provided excellent results that endorse the efficacy of the silica gel coating. The herein synthesized UCNPs can be regarded as efficient fluorescent probes for bioimaging purposes with the high luminescence, physicochemical stability and biocompatibility required for biomedical applications.

Highly stable pulsed fiber laser generation modulated by chromium iodide film

Abstract Highly stable pulsed fiber lasers are key optical components in optical communication, optical sensing, and precision micromachining systems due to the high beam quality, high peak power, and compact configurations. However, the available optical modulators in the fiber laser suffer from the operation bandwidth limitations and poor long-term physicochemical stability. Here, we have investigated the broadband nonlinear optical absorption behavior of the chromium iodide (CrI3) film, which exhibits broadband saturable absorption towards the mid-infrared regime and excellent long-term stability. The conventional soliton fiber laser operating at telecom wavelength has been obtained from an Er3+-doped fiber laser (EDFL) utilizing CrI3 film with a signal-to-noise ratio (SNR) of 92.4 dB and a pulse width of 492 fs. In addition, a passively Q-switched operation around 2.8 μm has also been obtained from an Er3+-doped ZBLAN fiber laser (EDZFL) modulated by the CrI3 film with a SNR of 46.8 dB and a pulse width of 766 ns. The demonstration shows that the CrI3 film exhibits robust broadband optical modulation, and may make inroads for developing highly stable ultrafast optoelectronic devices.

The Development of Super-Saturated Rebamipide Eye Drops for Enhanced Solubility, Stability, Patient Compliance, and Bioavailability

The present study aimed to develop clear aqueous rebamipide (REB) eye drops to enhance solubility, stability, patient compliance, and bioavailability. For the preparation of a super-saturated 1.5% REB solution, the pH-modification method using NaOH and a hydrophilic polymer was employed. Low-viscosity hydroxypropyl methylcellulose (HPMC 4.5cp) was selected and worked efficiently to suppress REB precipitation at 40 °C for 16 days. The additionally optimized eye drops formulation (F18 and F19) using aminocaproic acid and D-sorbitol as a buffering agent and an osmotic agent, respectively, demonstrated long-term physicochemical stability at 25 °C and 40 °C for 6 months. The hypotonicity (<230 mOsm) for F18 and F19 noticeably extended the stable period, since the pressure causing the REB precipitation was relieved compared to the isotonic. In the rat study, the optimized REB eye drops showed significantly long-lasting pharmacokinetic results, suggesting the possibility of reducing daily administration times and increasing patient compliance (0.50- and 0.83-times lower Cmax and 2.60- and 3.64-times higher exposure in the cornea and aqueous humor). In conclusion, the formulations suggested in the present study are promising candidates and offer enhanced solubility, stability, patient compliance, and bioavailability.

Long-term physicochemical stability of 5-fluorouracil at selected standardised rounded doses in polyolefin bags.

Chemotherapy doses are usually prescribed on the basis of body surface area but dose banding is emerging as an efficient alternative. Dose banding presents the possibility of in-advance preparation in a Centralized Intravenous Admixture Service. To evaluate the long-term stability of 5-fluorouracil at banded doses (700 mg and 800 mg) in polyolefin bags. Ten polyolefin bags were prepared under aseptic conditions and stored at 23 ± 2°C for 24 days. Five of them were composed of 14 mL 5-fluorocuracil (700 g) in 100 mL 0.9% sodium chloride solution and the five other of 16 mL 5-fluorouracil (800 mg) in 100 mL 0.9% sodium chloride solution. At defined times, physical stability parameters were assessed: optical densities, pH measurements, visual and microscopical inspections. Solutions concentrations were measured using high-performance liquid chromatography coupled with a photodiode array detector. No change was observed on pH and optical density measurements during the study period. Visual and microscopical inspections remained free of colour change, precipitate, microagregate or crystal. The concentrations of 5-Fluorouracil in 800 mg bags remained stable for 24 days while the concentration in 700 mg bags showed a stability of at least 17 days. Five-fluorouracil at banded doses of 700 and 800 mg in polyolefin bags is physicochemically stable for at least 17 days at 23 ± 2°C. These results support the possibility of in advance centralised preparation.

Elaboration and Properties of an Oil-in-Water Nanoemulsion Loaded with a Terpene-Enriched Oil Mixture Obtained Biotechnologically

Biotechnological production is an economical and sustainable pathway to produce some natural terpenes of major industrial importance such as limonene (LIM) and α-terpineol (α-TOH). Thus, in this article, the raw and nonpurified product obtained from the LIM biotransformation (mixture of soybean oil, LIM, and α-TOH), namely as a biotransformation product (BP), was encapsulated into nanoemulsion (NEs) using Quillaja saponins as a natural small-molecule surfactant. Since the long-term physicochemical stability of the NEs is questionable, the emulsion was kept at different storage temperatures (5, 25, 50 °C) up to 280 days, turbidity and mean droplet diameter being selected as destabilization criteria. Furthermore, gas chromatography was applied to track and monitor the concentration of LIM and α-TOH that could be retained in NEs over time. The NEs that were kept at both 5 and 25 °C were considered stable up to the 280th day, although these monoterpenes were more retained in an emulsion stored at 5 °C. The results also showed that the NEs displayed substantial physicochemical stability at room temperature, indicating that the encapsulation of the BP may work as an alternative natural-friendly nanocolloidal system to deliver these monoterpenes in foodstuff.

Biosurfactants: Properties and Applications in Drug Delivery, Biotechnology and Ecotoxicology.

Surfactants are amphiphilic compounds having hydrophilic and hydrophobic moieties in their structure. They can be of synthetic or of microbial origin, obtained respectively from chemical synthesis or from microorganisms’ activity. A new generation of ecofriendly surfactant molecules or biobased surfactants is increasingly growing, attributed to their versatility of applications. Surfactants can be used as drug delivery systems for a range of molecules given their capacity to create micelles which can promote the encapsulation of bioactives of pharmaceutical interest; besides, these assemblies can also show antimicrobial properties. The advantages of biosurfactants include their high biodegradability profile, low risk of toxicity, production from renewable sources, functionality under extreme pH and temperature conditions, and long-term physicochemical stability. The application potential of these types of polymers is related to their properties enabling them to be processed by emulsification, separation, solubilization, surface (interfacial) tension, and adsorption for the production of a range of drug delivery systems. Biosurfactants have been employed as a drug delivery system to improve the bioavailability of a good number of drugs that exhibit low aqueous solubility. The great potential of these molecules is related to their auto assembly and emulsification capacity. Biosurfactants produced from bacteria are of particular interest due to their antibacterial, antifungal, and antiviral properties with therapeutic and biomedical potential. In this review, we discuss recent advances and perspectives of biosurfactants with antimicrobial properties and how they can be used as structures to develop semisolid hydrogels for drug delivery, in environmental bioremediation, in biotechnology for the reduction of production costs and also their ecotoxicological impact as pesticide alternative.

Long-term physico-chemical stability of 5-fluorouracile at standardised rounded doses (SRD) in MyFuser® portable infusion pump

Management of chemotherapies is a strategic issue for european healthcare. Dose-banding enables to reduce waiting time of patients in day care units and drug wastage. The aim of this study was to assess the stability of 5-Fluorouracile (5-FU) at standardised rounded doses of 4 and 5 g in MyFuser® portable infusion pump for in-advance preparation. Ten MyFuser® (4 and 5 gr 5-FU added to NaCl 0.9%) were prepared under aseptic conditions and stored at room temperature (23 ± 2 °C) for 28 days then at 30 °C for three days. Physical stability tests were periodically performed: visual and microscopic inspection, pH measurements and optical densities. The concentration of solutions was measured by High Performance Liquid Chromatography/UV detector. Results confirm the stability of 5-FU at selected SRD of 4 g and 5 g with NaCl 0.9% in MyFuser® for at least 28 days at room temperature and three days at 30 °C, allowing in-advance preparation.

Long-term physicochemical stability of acyclovir 5 mg/mL solution stored in polypropylene bags as a simulated hospital stock preparation.

To investigate the long-term chemical and physical stability of 5-mg/mL acyclovir solution in polypropylene bags stored at 5°C ± 3°C for 2 months in order to determine the feasibility of batch production by a centralized intravenous additive service. Eight empty 100-mL polypropylene bags (bags A) and 8 empty 250-mL bags (bags B) were respectively filled with 60 mL and 200 mL of 5-mg/mL acyclovir and 0.9% sodium chloride injection (NaCl) under aseptic conditions through a semiautomated manufacturing process and vacuum packed before storage at 5°C ± 3°C. Four bags A and 4 bags B were tested for chemical stability via a stability-indicating high-performance liquid chromatography (HPLC) method immediately after preparation (time 0) and after 7, 14, 21, 28, 35, 42, and 63 days. Samples for microbiological assay were collected on days 0 and 63 from 4 bags A and 4 bags B immediately after breaking the vacuum. Osmolality, pH, and physical stability were assessed by visual examination, Subvisible particle counting was performed on 6 additional bags (3 each of bags A and B). Mean percentage loss of acyclovir relative to the mean experimental concentration at time 0 was below 5% over the 63-day study period.. No significant differences of pH, no change in color and no precipitate were observed during the study. Subvisible particle counts were compliant with European Pharmacopoeia requirements. Acyclovir solutions remained sterile over the 63 days of the study. Extemporaneously prepared acyclovir 5 mg/mL solutions in 0.9% NaCl stored in polypropylene bags were chemically and physically stable over 63 days when stored at 5°C ± 3°C.

Hierarchically porous nanoarchitecture constructed by ultrathin CoSe2 embedded Fe-CoO nanosheets as robust electrocatalyst for water oxidation

The sluggish kinetics and high cost of the noble-metal based electrocatalyst for oxygen evolution reaction (OER) still seriously limits the efficiencies of water splitting. Herein, for the first time, we rationally design a porous hierarchical nanoarchitecture, constructed by ultrathin CoSe2 embedded Fe-CoO nanosheets (CoSe2@Fe-CoO), which is synthesized via self-assembly hydrolysis driven in-situ synergetic selenization of Fe/Co/O/Se precursor followed by Ostwald ripening. As an OER catalyst, the porous CoSe2@Fe-CoO hybrid with abundant CoOOH electroactive sites delivers a small Tafel of 56.2 mV/dec with very low onset overpotential of 280 mV@10 mA/cm2 and excellent long-term physicochemical stability till 62 h without obvious decay, which outperforms well-established benchmark electrocatalysts (RuO2). The boosted OER performance of CoSe2@Fe-CoO nanosheets is mainly attributed to its iron-doping effect, porous nanoarchitecture, and multicomponent synergetic/interfacial effect between ultrathin cobalt (II) oxide and conductive cobalt selenide (CoSe2) nanoframework. This work presents a facile construction strategy to find a nonprecious hybrid OER electrocatalyst with excellent performance and long-term stability.

Food-grade emulsions stabilized by marine Antarctic krill (Euphausia superba) proteins with long-term physico-chemical stability

The amino acids composition, secondary structure and aggregation profiles of Antarctic krill proteins were characterized. Ability of the proteins to stabilize sunflower oil-based emulsions was firstly evaluated, and further the effects of NaCl concentration, pH values and storage temperatures on their stabilization were investigated. Results showed that the krill proteins contained much balanced essential amino acids compared to some plant proteins, and hydrophobic interactions and disulfide bonds greatly contributed to the development and stabilization of the protein aggregates. Antarctic krill proteins formed emulsions with their particle size less than 20 μm under 3%–4% protein and oil/water ratios of 3:7–5:5. Moreover, higher krill proteins content (≥3%), lower NaCl concentration (≤100 mM) or higher temperatures (≥40 °C) greatly favored the formation of gel-like networks of emulsions. Notably, the emulsions stabilized by 3% Antarctic krill proteins and oil/water ratio of 3:7 could resist the fluctuation of pH (3–9), salt concentration (50–400 mM) and temperatures (4–60 °C). Meanwhile, the emulsions exhibited a comparable long-term stability after 30 days storage compared to the existing proteins or biopolymers-stabilized emulsions. This study expends the knowledges of constructing novel Antarctic krill proteins-stabilized emulsions to unlock the high value-added utilization of marine protein resources in food industry.

A Facile Strategy to Generate High Drug Payload Celecoxib Micelles for Enhanced Corneal Permeability.

Topical ocular drug administration aimed at providing a high drug concentration at the precorneal site accompanied with enhanced corneal permeability to avoid systemic side effects is a very important therapeutic goal in ocular disorder therapy. In the present study, the solubility of the poorly soluble drug celecoxib (CXB) was significantly improved using a facile strategy to generate a high drug payload micellar formulation. By varying the drug/polymer feed ratios, the mean diameter of the formed CXB micelles ranged from 21.34 ± 0.23 to 28.53 ± 0.11 nm, and the drug loading capacity ranged from 4.31 to 15.87%. Transmission electron microscopy (TEM) showed that the formed CXB micelles had a uniform spherical morphology. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) were used to characterize the physicochemical properties of lyophilized CXB micelles. The obtained CXB micelles retained their properties through freeze-drying and rehydration, thereby providing long-term physicochemical stability over 3 months of storage at -20 °C. An in vitro release study showed that the CXB micelles released CXB in a sustained release manner without any apparent burst release over 72 h by the Higuchi non-Fickian diffusion mechanism. Notably, using corneas excised from rabbits, the in vitro corneal permeability of CXB from the micellar formulation was observed to be significantly greater than that of the microparticle formulation. Overall, the proposed micelles might be a promising vehicle for ophthalmic delivery of CXB with the significant enhancement of water solubility and corneal permeability.

Physicochemical stable standard all-in-one parenteral nutrition admixtures for infants and children in accordance with the ESPGHAN/ESPEN guidelines.

Because there are almost no standard all-in-one parenteral nutrition admixtures available for infants and children, the aim was to develop standard two-compartment parenteral nutrition bags for different weight categories based on the ESPGHAN/ESPEN (European Society of Paediatric Gastroenterology, Hepatology and Nutrition/European Society for Clinical Nutrition and Metabolism) guidelines. The 1 g/kg/d lipid version for the 3 to 10 kg weight category (PED1) was assessed for short- and long-term physicochemical stability with the ability to add additional electrolytes (PED1+E). The lipid compartment A and the all-in-one admixture of A + B + vitamins + trace elements were assessed physically by visual inspection, Sudan red test, pH measurement, and lipid droplet size distribution. Chemical stability for compartment A was evaluated by quantitative analyses of non-esterified fatty acids and peroxide content. The glucose-amino acid-electrolyte compartment B was evaluated physically by visual inspection, measuring particle contamination and pH. Chemical stability was assessed by discoloration, quantitative analyses of glucose, and the amino acids L-cysteine, L-tyrosine, and L-tryptophan. No phase separation or coalescence occurred, and the mean droplet size diameter did not exceed 0.5 µm. Peroxide content and non-esterified fatty acids concentration of compartment A remained well below the limit of acceptation. No precipitation was detected for compartment B; only a slight yellow discoloration was noted at 80 d. Concentrations of glucose, L-tyrosine, and L-tryptophan remained stable; only L-cysteine decreased significantly from its initial concentration. The two-compartment PED1 and PED1+E admixtures are stable up to 80 d 2° to 8°C + 24 h room temperature (RT) with an additional 7 d 2° to 8°C + 48 h RT after mixing and addition of vitamins and trace elements.

Physical Characterization of Tobramycin Inhalation Powder: II. State Diagram of an Amorphous Engineered Particle Formulation.

Tobramycin Inhalation Powder (TIP) is a spray-dried engineered particle formulation used in TOBI Podhaler, a drug-device combination for treatment of cystic fibrosis (CF). A TIP particle consists of two phases: amorphous, glassy tobramycin sulfate and a gel-phase phospholipid (DSPC). The objective of this work was to characterize both the amorphous and gel phases following exposure of TIP to a broad range of RH and temperature. Because, in principle, changes in either particle morphology or the solid-state form of the drug could affect drug delivery or biopharmaceutical properties, understanding physical stability was critical to development and registration of this product. Studies included morphological assessments of particles, thermal analysis to measure the gel-to-liquid crystalline phase transition (Tm) of the phospholipid and the glass transition temperature (Tg) of tobramycin sulfate, enthalpy relaxation measurements to estimate structural relaxation times, and gravimetric vapor sorption to measure moisture sorption isotherms of TIP and its components. Collectively, these data enabled development of a state diagram for TIP-a map of the environmental conditions under which physical stability can be expected. This diagram shows that, at long-term storage conditions, TIP is at least 50 °C below the Tg of the amorphous phase and at least 40 °C below the Tm of the gel phase. Enthalpy relaxation measurements demonstrate that the characteristic structural relaxation times under these storage conditions are many orders of magnitude greater than that at Tg. These data, along with long-term physicochemical stability studies conducted during product development, demonstrate that TIP is physically stable, remaining as a mechanical solid over time scales and conditions relevant to a pharmaceutical product. This met a key design goal in the development of TIP: a room-temperature-stable formulation (3-year shelf life) that obviates the need for refrigeration for long-term storage. This has enabled development of TOBI Podhaler-an approved inhaled drug product that meaningfully reduces the treatment burden of CF patients worldwide.

Mucoadhesive tetrahydrocannabinol-loaded NLC – Formulation optimization and long-term physicochemical stability

Tetrahydrocannabinol (THC) is used to treat pain in cancer patients. On the market there are mainly oral formulations. Especially to treat the problematic breakthrough pain in cancer, an easy applicable formulation with fast onset is desired. This formulation was developed as an aqueous nasal spray using nanostructured lipid carriers (NLC). The NLC were prepared with cetyl palmitate, having good miscibility with the oily THC and yielding particles with 1year physical long-term stability. To make the particles mucoadhesive, small particles with diameters of about 200nm were produced and additionally their surface positively charged using a cationic stabilizer. Optimal NLC suspensions contained 1% particles (lipid:THC ratio 7:1) stabilized with 0.05% cetylpyridinium chloride (CPC), and 2% particles with a mixture of 0.05% CPC, and 0.05% Tween® 80. The particle size remained unchanged during spraying using commercial spray bottle, and PARI BOY. A strong interaction with negatively charged mucin was shown by a sharp decrease of the positive NLC zeta potential and fast charge reversal in the mucin solution test. The solid matrix of the NLC had a stabilizing effect on THC. 91% THC remained after 6months storage at 4°C, and 79% under stress conditions at 40°C. By adding additional chemical stabilizers, and producing under protective conditions, a commercial formulation for patient seems feasible.

Chemical Insights into Antibacterial N-Halamines.

Microbial contamination arising from pathogens poses serious threats to human health and in recent decades has presented an unprecedented challenge to antibacterial research. Of the various antibacterial agents that effectively kill pathogens, halogen-based antibacterial compounds have been successful in eliminating harmful pathogen-associated diseases and are becoming the most popular disinfectants. As a significant subcategory of halogen antibacterial agents, N-halamines have drawn increasing research interest into their chemistry and practical applications. N-Halamines have many advantages over other antibacterial agents, including effectiveness against a broad spectrum of microorganisms, long-term physicochemical stability, high structural durability, and the regenerability of their functional groups, with corresponding renewal of their antibacterial properties. This review examines recent progress and research trends in both theoretical and experimental studies of N-halamines, with the aim of providing a systematic and comprehensive survey and assessment of the significant advances in our understanding of antibacterial N-halamines. This review serves as a practical guide to developing N-halamines through both broad and in-depth basic research and offers suggestions for their potential future applications.

Physical and antimicrobial properties of anise oil loaded nanoemulsions on the survival of foodborne pathogens

The purpose of this research was to investigate antimicrobial effects of nano emulsions of anise oil (AO) on the survival of common food borne pathogens, Listeria monocytogenes and Escherichia coli O157:H7. Series of emulsions containing different level of anise oil as potential antimicrobial delivery systems were prepared. Antimicrobial activities of bulk anise oil and its emulsions (coarse and nano) was tested by the minimum inhibitory concentration and time kill assay. Our results showed that bulk anise oil reduced the population of E. coli O157:H7 and L. monocytogenes by 1.48 and 0.47logcfu/ml respectively after 6h of contact time. However, under the same condition anise oil nanoemulsion (AO75) reduced E. coli O157:H7 and L. monocytogenes count by 2.51 and 1.64logcfu/ml, respectively. Physicochemical and microbial analyses indicated that both nano and coarse emulsions of anise oil showed better and long-term physicochemical stability and antimicrobial activity compared to bulk anise oil.

PP-014 Preliminary study to implement dose banding in a teaching hospital

Background“Dose-banding” is a concept of standardising cytotoxic drugs that enables standardised rounded doses (SRD) to be prepared in advance, covering the most frequently prescribed doses rounded to ± 5%. Standard...

Long-term physico-chemical stability of diluted trastuzumab

Using several complementary analytical methods, we demonstrated that the monoclonal antibody Trastuzumab (Tz), diluted in 0.9% sodium chloride can be stored in polyolefin infusion bags at 4°C or room temperature up to 6 months with no evidence of chemical or physical instability. No aggregation of Tz was observed and its three dimensional structure remains unaltered. Thus, the practical use of diluted Tz can be safely extended to optimize the workload of centralized preparation units and to minimize costs.

Long-term physico-chemical stability of standard parenteral nutritions for neonates

Two ready-to-use parenteral nutritions (PN) have been developed, for the first days of life of the premature newborn, along with syringes of lipid emulsion with or without vitamins. Long-term physico-chemical stability for storage in wards was assessed. Physico-chemical stability of PN: visual inspection, particle size, pH, osmolarity measurement, amino acids, glucose, and electrolytes dosages. Physico-chemical stability of lipid emulsion: visual inspection, globule size, peroxide level and vitamins A, E, and C dosages. Stability was studied for 12 weeks on refrigerated (2-8 °C) and room temperature (30 ± 2 °C) samples. No precipitation was detected in any PN. A brown coloration was observed in PN stored for four weeks at room temperature but not in the refrigerator. Concentrations of all the nutrients remained constant over the 12 week-study period. Phase separation of the lipid emulsion occurred after three weeks, but particle size complied with the USP limits for 12 weeks. Peroxide content increased only in the samples without vitamins at room temperature. Vitamins remained stable for one week under refrigeration. The PN did not present a detectable change of the tested properties when refrigerated for 12 weeks. The lipid emulsion with vitamins is stable for one week when refrigerated.