Solution In Vial Research Articles

АНАЛИЗ АССОРТИМЕНТА РАСТВОРИТЕЛЕЙ И РАЗБАВИТЕЛЕЙ ИНЪЕКЦИОННЫХ РАСТВОРОВ ДЛЯ ПЕДИАТРИЧЕСКОЙ ПРАКТИКИ

Introduction. Solvents and diluents for parenteral medicines are widely used in pediatric hospitals and occupy leading positions in terms of the number of packages in purchases. Injectables are prescribed to children in reduced volumes, as compared to adults. In this regard, it is relevant to study the solvents and diluents available for parenteral administration of drugs in terms of packaging types and reduced volumes for use in pediatrics in the domestic pharmaceutical market. Aim of the study is to analyze the available solvents and diluents for parenteral medicines, such as water for injection, isotonic solutions of sodium chloride, Ringer, and Ringer lactate, on the Russian pharmaceutical market and in a multidisciplinary children’s hospital. Material and Methods. Objects of the study were data from the State Register of Medicines of Russia, the requisition slips of Medical Devices and Pharmacy of Tatarstan for medicines shipped from a warehouse to the Republic Clinical Children’s Hospital of the Ministry of Health of the Republic of Tatarstan in 2022, the price lists for medicines of pharmaceutical wholesalers (September 2023), and the data from scientific publications. Results and Discussion. The data obtained indicate that the regional pharmaceutical market has about twice as many options for the supply of medicinal solvents and diluents than in a children’s multidisciplinary hospital, and this allows expanding the range of this group of medicines. It can be assumed that pharmaceutical industrial enterprises do not produce a full range of options for the volume of primary packaging of solvents and diluents registered in the State Register of Medicines. Conclusions. In Russia, reduced volumes (20-30 ml) of 0.9% sodium chloride, 5% glucose, Ringer, and Ringer lactate solutions in vials for intravenous drip administration in pediatric practice are neither registered nor produced. The depth coefficient of the assortment of the studied solvents and diluents for parenteral medicines in relation to the volume of primary packaging in a children’s multidisciplinary hospital is 0.102. This indicates the need for medical organizations to consider the possibilities of the pharmaceutical market when drawing up applications for the supply of medicines.

Modeling the freezing process of aqueous solutions considering thermal gradients and stochastic ice nucleation

Despite its importance to multiple scientific fields and industries, the freezing process of aqueous solutions is not yet completely understood. In particular, the relationship between temperature gradients within a solution and the occurrence of stochastic ice nucleation remains elusive. To address this knowledge gap, we have derived a novel stochastic spatial freezing model from first principles. The model predicts with quantitative accuracy how temperature gradients affect the stochastic ice nucleation of sucrose solutions in vials. This motivated a detailed study of the freezing-stage in freeze-drying, revealing that a broad range of temperatures are present at the time of nucleation at different positions within the vial. This must be considered when interpreting experimental studies that measure the temperature only at a single point with a thermocouple. To ensure that both researchers and practitioners benefit from this modeling work, we provide open source access to it within our python package ethz-snow.

Characterizing and measuring the ice nucleation kinetics of aqueous solutions in vials

Characterizing and measuring the ice nucleation kinetics of aqueous solutions in vials

Physicochemical stability of Cabazitaxel Zentiva® solution in vials after opening and diluted solutions in three infusion bags

Abstract Objectives To the best of our knowledge, few studies have been published on the stability of cabazitaxel in infusion bags. Stabilis® database has selected a study demonstrating the stability of this molecule at 0.15 mg/mL for 28 days at 4 °C and 25 °C in polyolefin bags. The aim of this work was to study the physicochemical stability of Cabazitaxel Zentiva® solutions in vials after “opening” with a vented ChemoClave® Spike, at 25 °C, protected from light and in solutions diluted at 0.1 and 0.26 mg/mL in 0.9 % sodium chloride (0.9 % NaCl) or dextrose 5 % (D5W) in 3 types of infusion bags (Easyflex® and Viaflo® at 25 °C, Freeflex® between 2 and 8 °C, protected from light). Methods The chemical stability was analyzed after preparation and then after 14 and 28 days of storage by high performance liquid chromatography (HPLC), coupled to a diode array detector, at the analysis wavelength of 232 nm. The method has been validated according to ICH Q2 (R1) standards. For the study in infusion bags, three preparations were realised for each condition. At each time of analysis, for each bag, a sample was prepared and analyzed by HPLC. Two vials after “openings” were kept at 25 °C and three samples per vial were prepared and analyzed at the three analysis times (D0, D14 and D28). Physical stability was assessed by visual examination (change in colour, appearance of precipitate, gas formation). The pH of the solutions prepared in infusion bags was evaluated at each analysis time. Results Cabazitaxel solutions at 0.1 and 0.26 mg/mL diluted in 0.9 % NaCl or D5W in Easyflex® (polyolefin), Viaflo® (multilayer high density polyethylene, polyamide, polypropylene) bags retained more than 95 % of the concentration after 28 days at 25 °C. In the Freeflex® bag (polypropylene multilayers), cabazitaxel solutions at 0.1 and 0.26 mg/mL diluted in 0.9 % NaCl or D5W retained more than 95 % of the initial concentration between 2 and 8 °C for 28 days. In vials with a Spike, cabazitaxel solutions at 20 mg/mL retained more than 95 % of the initial concentration for 28 days at 25 °C. For all the conditions studied, no visual modification was observed. The pH of solutions in bags were constant during the stability study. Conclusions Cabazitaxel Zentiva® diluted at 0.1 and 0.26 mg/mL in 0.9 % NaCl or D5W was stable for 28 days at 25 °C and between 2 and 8 °C. These stability data allow preparations to be made in advance. The remainder of the cabazitaxel vial fitted with a Spike was stable for 28 days at 25 °C, allowing the remainder of the vial to be used over several days.

An investigative study into an oscillatory reaction in acoustically levitated droplets.

For the first time we have studied an oscillatory chemical reaction (the well-known Belousov-Zhabotinsky (BZ) reaction) in acoustically levitated droplets. Acoustically levitated droplets allow wall-less reaction studies, reduce consumption of sample/reagents, offer high throughput measurements, and enable environmentally friendly chemistry by significantly reducing plastic waste. In this work, microdroplets of the BZ reactants were mixed at the central axis of a low-cost acoustic levitator. The chemical reaction observed in acoustically levitated droplets proceeded in the same way as that in both stirred and unstirred vials where the volume of droplets was 750-fold lower than the solutions in vials. The observed oscillation frequency in droplets was lower than that observed in vials, possibly as a result of evaporative cooling of the droplets. This work has shown that oscillatory reactions can be successfully carried out in acoustically levitated droplets, which allows the application of this technique to areas such as analysis, synthesis and actuation of smart materials and studies of the origins of life.

Relationship between aggregation of therapeutic proteins and agitation parameters: Acceleration and frequency

An increase in protein aggregates during transportation should be suppressed in therapeutic protein products because the aggregates have a potential risk of immunogenicity. In this study, three protein solutions in vials were exposed to tri-axial vibration with various combinations of frequency and acceleration using a transportation test system to investigate the relationship between low g-force stresses and protein aggregate generation. The number concentration of micron aggregates detected by flow imaging analysis increased markedly when the acceleration and frequency of agitation were within a specific range, in other words, above a threshold. This threshold was common among the three protein solutions. The suppression of micron aggregate formation by adding a surfactant suggested that agitation above the threshold increased micron aggregates mainly via interface-mediated routes. Notably, agitation, including agitation below the threshold, accelerated spontaneous oligomerization (nanometer aggregate generation) of proteins in bulk solution even in the presence of the surfactant. Studies of stability against mechanical stresses (e.g., a random vibration test to simulate actual shipment, with a time-compressed setting by increasing acceleration) need to be performed and discussed with careful consideration of the threshold for generating micron aggregates.

Investigation of the Freezing Phenomenon in Vials Using an Infrared Camera.

The freezing phenomenon has a dramatic impact on the quality of freeze-dried products. Several freezing models applied to solutions in vials have been proposed to predict the resulting product morphology and describe heat transfer mechanisms. However, there is a lack of detailed experimental observations of the freezing phenomenon in vials in the literature. Thus, the present work offers new experimental observations of the freezing phenomenon in vials by infrared (IR) thermography. IR imaging allowed each vial’s whole axial temperature profile to be collected during freezing, providing significant insights into the process. Spontaneous nucleation and vacuum-induced surface freezing (VISF), as a controlled nucleation technique, are investigated. Batches having vials in direct contact with the shelf (exchanging heat mainly through conduction) as well as suspended (exchanging heat mainly through natural convection and radiation) were tested. The study used three solutions: sucrose 5%, mannitol 5%, and dextran 10%. SEM images coupled with an automated image segmentation technique were also performed to examine possible correlations between the freezing observations and the resulting pore size distributions. IR thermography was found to be a promising tool for experimentally predicting the resulting product morphology in-line.

Evaluation of physicochemical and biological properties of nonreconstituted MYL-1401O vials, reconstituted MYL-1401O suspension in vial, and diluted MYL-1401O suspension in infusion bags (0.9% saline) for extended duration

ABSTRACT Background MYL-1401O; trastuzumab-dkst (Ogivri™; Mylan Inc.) is a biosimilar to the trastuzumab reference product (Herceptin®; Genentech, USA). Assessment of physicochemical stability and biological activity for the non-reconstituted, reconstituted, and infused solution over an extended, clinically relevant duration is critical for ensuring optimal patient outcomes and health resource utilization. Methods The physicochemical and biological stability of MYL-1401O was assessed in non-reconstituted vials stored at 25 °C ± 2 °C/60% ± 5% relative humidity (RH) for 6 months, reconstituted 21 mg/mL solution in vials stored at 2 °C to 8 °C for 10 days, and diluted in 0.9% saline-containing infusion bags at 0.3 mg/mL and 4.0 mg/mL stored for 77 days at 2 °C to 8 °C, plus an additional 2 days at 25 °C ± 2 °C/60% ± 5% RH. Results At all storage conditions tested, MYL-1401O was physicochemically and biologically stable for extended duration and under various temperature and humidity conditions. Conclusions MYL-1401O retained its physicochemical and biological stability under different storage conditions, which supports advanced preparation of MYL-1401O, better efficiency, less wastage, and cost-savings for better patient management.

Stability of pemetrexed diarginine concentrates for solution in vials and diluted in 0.9% sodium chloride and dextrose 5% polyolefin infusion bags

ObjectivesTo determine the physicochemical stability of pemetrexed diarginine in original vials, and after dilution in two commonly used infusion fluids (0.9% sodium chloride, 5% dextrose) in polyolefin bags, stored under...

Quantifying and Reducing Retained Botulinum Toxin Postinjection.

Retained botulinum toxin solution may be visible in vials and syringe tips after mixing and presumed complete injections, leaving patients without the full prescribed dose. To quantify the mean amount of retained toxin within vials, syringes, and needles following spasticity injections (phase 1) and to design/test a targeted intervention for reduced retained toxin (phase 2). Prospective cohort quality assurance study. Outpatient spasticity program in a rehabilitation facility. Nine physicians specializing in physical medicine and rehabilitation, performing successive mixing and injections for spasticity with onabotulinumtoxinA or incobotulinumtoxinA. After initial review (phase 1), recommendations were made (phase 2) including not inverting the vial to withdraw medication unless needed, favoring 2-mL dilutions when possible, and decapping of vials for more complete medication withdrawal. Retained volume of toxin solution that was not injected and estimated retained units oftoxin. A total of 157 vials of botulinum toxin A were tested. Of the 82 initial, phase 1, preintervention vials (8200 units), 5.5% (∼452 units) of toxin solution was retained following mixing and injections. One and 3-mL syringe tips contained a mean of 3.32 and 1.44 units of toxin respectively. Within vials, saline dilutions with 2 mL contained less mean retained toxin (1.89 vs 3.31 units) relative to 1-mL dilution. Awareness of monitoring significantly decreased retained solution in vials (0.035 mL vs 0.069 mL for naïve group, P = .002). Phase 2, postintervention testing of 75 vials demonstrated that withdrawing toxin from the inferior edge from a non-inverted vial reduced the retained toxin by 32.8% (P < .001). Decapping the vial further reduced the mean retained toxin to 0.42 units per vial (81.9% reduction, P < .001). A potentially clinically significant amount of botulinum toxin solution is retained following mixing and injections. Implementation of guidelines significantly decreased wasted botulinum toxin. III.

A Newly Identified Impurity in Polysorbate 80, the Long-Chain Ketone 12-Tricosanone, Forms Visible Particles in a Biopharmaceutical Drug Product

Visible particles linked to polysorbates (PSs) used in biopharmaceutical drug products (DPs) have been observed repeatedly in recent years as an industry-wide issue, with PS degradation and insoluble degradation products, especially fatty acids and fatty acid esters, being suspected as root cause. We have shown that the visible particles observed in a monoclonal antibody DP solution in vials after 18 months of long-term storage at 5 ± 3°C were neither linked to reduction in PS (PS80) concentration nor to any known PS degradation product, but consist of 12-tricosanone, an impurity present in the raw material PS80, not a degradation product. The occurrence of visible 12-tricosanone particles in DP correlated with the usage of specific PS80 raw material lots, where 12-tricosanone was found as impurity at elevated levels. The quantities detected in these PS80 lots directly translate into the amount found in the respective monoclonal antibody DP batches. This is the first time that a clear correlation between the occurrence of the impurity 12-tricosanone in PS80 and the occurrence of visible particles in DP batches is reported. The observation and techniques described enable the control of this ketone in PS raw materials, providing means to prevent respective visible particle formation in DP.

Measuring and predicting pore size distribution of freeze-dried solutions

ABSTRACTIn this work, a novel procedure is presented for the measurement and prediction of pore size distribution of freeze-dried solutions in vials. A method based on segmentation is proposed for determining the size of the pores left by ice crystals, using images obtained by scanning electron microscopy. The original ice crystal size distribution is also predicted using a mathematical model based on balance equations. The model predictions and the results of the segmentation technique show a fairly good agreement. The proposed procedure could be used to efficiently estimate the resistance to mass transfer during drying and hence optimize the freeze-drying process.

Stability Indicating Rp-HPLC Method for Simultaneous Estimation of Ceftazidime Pentahydrate and its Impurity Product Pyridine in Powder Used for Making Solution in Vial for 1M &amp; IV Injections

Stability Indicating Rp-HPLC Method for Simultaneous Estimation of Ceftazidime Pentahydrate and its Impurity Product Pyridine in Powder Used for Making Solution in Vial for 1M &amp; IV Injections

Solution stability of Captisol-stabilized melphalan (Evomela) versus Propylene glycol-based melphalan hydrochloride injection

Purpose: The objective of this study was to compare the stability of recently approved Captisol-stabilized propylene glycol-free melphalan injection (Evomela™) against currently marketed propylene glycol-based melphalan injection. The products were compared as reconstituted solutions in vials as well as admixture solutions prepared from normal saline in infusion bags.Methods: Evomela and propylene glycol-based melphalan injection were reconstituted in normal saline and organic custom diluent, respectively, according to their package insert instructions. The reconstituted solutions were diluted in normal saline to obtain drug admixture solutions at specific drug concentrations. Stability of the solutions was studied at room temperature by assay of melphalan and determination of melphalan-related impurities.Results: Results show that based on the increase in total impurities in propylene glycol-based melphalan injection at 0.45 mg/mL, Evomela admixture solutions are about 5, 9, 15 and 29 times more stable at concentrations of 0.45, 1.0, 2.0 and 5.0 mg/mL, respectively. Results confirmed that reconstituted Evomela solution can be stored in the vial for up to 1 h at RT or for up to 24 h at refrigerated temperature (2–8 °C) with no significant degradation. After storage in the vial, it remains stable for an additional 3–29 h after preparation of admixture solution in infusion bags at concentrations of 0.25–5.0 mg/mL, respectively. In addition, Evomela solution in saline, at concentration of 5.0 mg/mL melphalan was bacteriostatic through 72 h storage at 2–8 °C.Conclusion: Formulation of melphalan with Captisol technology significantly improved stability compared to melphalan hydrochloride reconstituted with propylene-glycol based diluents.

Epidemiology of cervical cancer development- a hospital based study

Introduction: The present study is an attempt to detect Human papilloma virus infection and immunomodulation status in the development of carcinoma cervix. Methods: Cervical cancer cases were enrolled in between Jan’ 2010 to Dec’ 2012. Cervical tissue biopsies from the both the cancerous region as well as the non cancerous control area of the cervix, and whole blood (3ml) were collected from all the study subjects. The tissue samples were collected either in PBS or RNA later solution in vials and stored in -80°C or liquid nitrogen till further use. Whole blood (2ml) was also collected from age matched voluntary female community controls (n=50), the plasma was separated, and stored at -20°C for cytokine analysis. Extracted DNA was then checked for presence of HPV DNA by PCR amplification method using MY09/11 primer. Th1 (IL-12) and Th2 (IL-10) were analysed both at protein as well as cervical tissue level. Results: The study showed 83.33% cases found to be HPV positive in cancerous area as well as in non cancerous area. There were other significant risk factor association of cervical cancer with early marriage in 70.36% and high parity 87% of cases. There is alteration of Th1 and Th2 ratio indicating immunomodulation plays an important role in the development of cervical cancer. Conclusion: The human papilloma virus infections are the major contributing factor as well as immunomodulation plays a major role in the development of cervical cancer in our region.

Toward 10 000‐fold sensitivity improvement of oligosaccharides in capillary electrophoresis using large‐volume sample stacking with an electroosmotic flow pump combined with field‐amplified sample injection

A combination of two online sample concentration techniques, large-volume sample stacking with an electroosmotic flow pump (LVSEP) and field-amplified sample injection (FASI), was investigated in CE to achieve highly sensitive oligosaccharide analysis. In CE with LVSEP-FASI, analytes injected throughout the capillary were concentrated on the basis of LVSEP, followed by an electrokinetic introduction of concentrated analytes from the inlet vial by the FASI mechanism. After switching the inlet vial solution from the sample to running buffer, the concentrated analytes were then separated by CZE. In the present LVSEP-FASI-CZE, pressure was applied to the capillary inlet until the inlet vial solution was exchanged. The applied pressure generated a counterflow against the EOF. It kept the stacked sample zone within the capillary, minimizing loss of concentrated analytes. Fluorescein was first analyzed by LVSEP-FASI-CZE to optimize preconcentration condition. Up to 110 000-fold sensitivity increase was obtained with 200 μL of sample, compared to normal CZE with sample injection of 0.3psi for 3 s (ca. 1.7 nL). From the results, the pressure application improved the efficiency of the FASI-mode concentration significantly at total concentration time longer than 10 min. In the analysis of maltoheptaose, a 10 000-fold sensitivity increase was achieved, which is the highest concentration efficiency ever reported in CE of oligosaccharides. The relative standard deviations of the detection time and peak height were 2.4 and 11%, respectively. In the analysis of glucose oligomer, up to 8600-fold sensitivity increases were achieved without reducing the separation performance of conventional CZE.

Stability of the ready-to-use solutions of eribulin for intravenous infusion

A simple HPLC-UV method was developed to determine the stability of ready-to-use eribulin solutions under different storage conditions. The developed method was validated with respect to linearity, accuracy, precision and ruggedness. The following admixtures were prepared: 3-mL polypropylene syringes at concentration of 440 μg/mL and multilayer laminate polyolefin containers containing 0.9% sodium chloride (50 mL) at concentrations of 15.4 and 43.3 μg/mL. The open-vial stability of eribulin was also evaluated. The following storage conditions were tested: 4 °C in the refrigerator; 20 °C under room light exposure; and 20 °C with light-protection. The drug was also subjected to stress conditions of hydrolysis, oxidation, photolysis and thermal degradation. The retention time of eribulin was 4.9 min. Admixtures of eribulin solutions in vials, syringes or polyolefin bags at clinically relevant concentrations were physically compatible and chemically stable for at least 14 days at 4 °C in the refrigerator and at 20 °C with or without any protection against light. Degradation was only found to occur under oxidation conditions.

Particulate contamination in solutions of antibiotics packed as dry powders in vials

The particulate contamination in 12 formulations of antibiotic solutions in vials packed as dry powders from five South African sources has been analysed quantitatively using a HIAC PC 320 light blockage particle analyser linked to a CMB 60 sensor. Results showed that the level of particulate contamination fell well within the limits set by the USP XXIst Edition for Small Volume Parenterals although four formulations contained some particles greater than or equal to 50 micron. There was no apparent difference between the quality of the same antibiotics from different sources or between vials of the same antibiotics packed in different strengths.

Baskets for In Situ Hybridization and Immunohistochemistry: Figure 1.

INTRODUCTIONFor large in situ hybridization and immunohistochemistry experiments, changing solutions in vials becomes tedious, and baskets should be used. Commercially available baskets, such as 15-mm Netwell baskets (Corning), fit into 12-well tissue culture plates. Although they are expensive, they can, with extensive washing, be reused. However, these baskets are not readily adaptable to large-scale use, and their relatively shallow wells make cross-contamination between wells a real danger. This protocol describes a procedure for making homemade baskets with plastic microcentrifuge tubes and nylon mesh that are more adaptable to large-scale experiments. The baskets are narrow and deep and thus can be placed in a rack at high density. To change solutions, individual tubes or whole racks of tubes can be moved from one bath of solution to another. Because many tubes can be manipulated simultaneously, there is an enormous saving in work. It is also quite difficult to lose embryos in baskets; embryos in vials stand a good chance of being sucked into the aspirator during solution changes and lost.

Optimal Control of the Secondary Drying Stage of Freeze Drying of Solutions in Vials Using Variational Calculus

: The problem of operating freeze drying of pharmaceutical products in vials loaded on trays of freeze dryer to obtain a desired final bound water content in minimum time is formulated as an optimal control problem. Two different types of freeze dryer designs were considered. In the type I freeze dryer design, upper and lower plate temperatures were controlled together, while in the type II freeze dryer design, upper and lower plate temperatures were controlled independently. The heat input to the material being dried and the drying chamber pressure were considered as control variables. Only the scorch temperature was considered as a constraint on the system state variables during the secondary drying stage, because all the free water content (frozen water) is removed from the solid matrix during the primary drying stage of freeze drying. Necessary conditions of optimality for the secondary drying stage of freeze drying process in vials were derived and presented by using rigorous multidimensional unsteady-state mathematical models. The theoretical approach presented in this work was applied in the freeze drying of skim milk. Significant reductions in drying times of the secondary drying stage of the freeze drying process in vials were observed and more uniform bound water and temperature distributions in the material being dried were obtained compared to the conventional operational policies.