Identification and quantification of glucose degradation products in heat-sterilized glucose solutions for parenteral use by thin-layer chromatography.

During heat sterilization of glucose solutions, a variety of glucose degradation products (GDPs) may be formed. GDPs can cause cytotoxic effects after parenteral administration of these solutions. The aim of the current study therefore was to develop a simple and quick high-performance thin-layer chromatography (HPTLC) method by which the major GDPs can be identified and (summarily) quantified in glucose solutions for parenteral administration. All GDPs were derivatized with o-phenylenediamine (OPD). The resulting GDP derivatives (quinoxalines) were applied to an HPTLC plate. After 20 minutes of chamber saturation with the solvent, the HPTLC plate was developed in a mixture of 1,4-dioxane-toluene-glacial acetic acid (49:49:2, v/v/v), treated with thymol-sulfuric acid spray reagent, and heated at 130°C for 10 minutes. Finally, the GDPs were quantified by using a TLC scanner. For validation, the identities of the quinoxaline derivatives were confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Glyoxal (GO)/methylglyoxal (MGO) and 3-deoxyglucosone (3-DG)/3-deoxygalactosone (3-DGal) could be identified and quantified in pairs, glucosone (2-KDG), 5-hydroxymethylfurfural (5-HMF), and 3,4-dideoxyglucosone-3-ene (3,4-DGE) each individually. For 2-KDG, the linearity of the method was demonstrated in the range of 1-50 µg/mL, for 5-HMF and 3,4-DGE 1-75 µg/mL, for GO/MGO 2-150 µg/mL, and for 3-DG/3-DGal 10-150 µg/mL. All GDPs achieved a limit of detection (LOD) of 2 µg/mL or less and a limit of quantification (LOQ) of 10 µg/mL or less. R2 was 0.982 for 3.4-DGE, 0.997 for 5-HMF, and 0.999 for 2-KDG, 3-DG/3-DGal, and GO/MGO. The intraday precision was between 0.4 and 14.2% and the accuracy, reported as % recovery, between 86.4 and 112.7%. The proposed HPTLC method appears to be an inexpensive, fast, and sufficiently sensitive approach for routine quantitative analysis of GDPs in heat-sterilized glucose solutions.

A facile and rapid approach to synthesize uric acid-capped Ti3C2 MXene quantum dots for the sensitive determination of 2,4,6-trinitrophenol both on surfaces and in solution.

Herein, uric acid@Ti3C2 quantum dots (UA@Ti3C2 QDs) were synthesized via a microwave-assisted strategy on the basis of acid etching and stripping. The UA@Ti3C2 QDs have bright blue emission. Intriguingly, the fluorescence emission of the UA@Ti3C2 QDs was significantly quenched after the addition of 2,4,6-trinitrophenol (TNP), due to inner-filter effect (IFE). Based on these findings, a novel environmentally friendly and water-soluble fluorescence probe based on UA@Ti3C2 QDs was demonstrated for the sensitive and selective detection of TNP. The method presented a wide linear range for TNP detection in the 0.01-40 µM range, with a low detection limit of 9.58 nM. Furthermore, the probe was successfully used for the sensitive detection of TNP in real water and smartphone-based colorimetric (SPBC) detection of TNP on surfaces with the linear range from 10.0 to 100.0 ng. On the whole, this work provides an effective strategy for the synthesis of UA@Ti3C2 QDs and an alternative fluorescence probe for detecting TNP both on surface and in solution.

Prefilled Cyclic Olefin Sterilized Syringes of Norepinephrine Injection Solution Do Not Need to Be Stabilized by Antioxidants.

Norepinephrine is a potent α-sympathomimetic drug which plays an important role in the acute treatment of hypotension and shock. Commercially available norepinephrine solutions contain sodium metabisulfite (Na2S2O5) as an antioxidant. However, prefilled cyclic olefin polymer syringes are not compatible with sodium metabisulfite. The aim of this study was to develop a new formulation of 0.1-mg/mL norepinephrine solution without sodium metabisulfite which is chemically stable and sterile and can be stored in prefilled polymer syringes. Formulation studies were performed with 0.1-mg/mL norepinephrine solution with 0, 0.05, or 0.1% ascorbic acid added as antioxidant. The syringes were filled under nitrogen gassing, stored at 20 ± 5°C, and protected from daylight. Based on the formulation test results, the final formulation was defined and stability testing at 20 ± 5°C was performed measuring norepinephrine concentration, pH, clarity, color of the solution, subvisible particles, and sterility at time intervals up to 12 months. The norepinephrine concentrations at t = 22 weeks were 100.4%, 95.4%, and 92.2% for the formulations with no ascorbic acid and with 0.05% and 0.10% ascorbic acid, respectively. Three batches for the stability study were produced containing norepinephrine, sodium edetate, sodium chloride, and water for injections filled under nitrogen gassing and stored at 20 ± 5°C. Norepinephrine concentrations were respectively 98.8%, 98.6%, and 99.3% for batches 1, 2, and 3 at t = 12 months. It can be concluded that norepinephrine (0.1 mg/mL) solution without metabisulfite is stable for at least 12 months at room temperature when protected from daylight.

Physicochemical stability of nefopam and nefopam/droperidol solutions in polypropylene syringes for intensive care units.

Introduction: Nefopam has been reported to be effective in postoperative pain control with an opioid-sparing effect, but the use of nefopam can lead to nausea and vomiting. To prevent these side effects, droperidol can be mixed with nefopam. In intensive care units, high concentrations of nefopam and droperidol in syringes can be used with a continuous flow. Objectives: The first objective of this work was to study the physicochemical stability of a nefopam solution 2.5 mg/mL diluted in NaCl 0.9% in polypropylene syringes immediately after preparation and after 6, 24 and 48 hours at room temperature. The second objective was to study the physicochemical stability of mixtures of nefopam 2.5 mg/mL and droperidol 52 µg/mL diluted in NaCl 0.9% in polypropylene syringes at room temperature over 48 hours. Materials and methods: Three syringes for each condition were prepared. For each time of analysis, three samples for each syringe were prepared and analysed by high performance liquid chromatography coupled to photodiode array detection. The method was validated according to the International Conference on Harmonisation Q2(R1). Physical stability was evaluated by visual and subvisual inspection (turbidimetry by UV spectrophotometry). pH values were measured at each time of analysis. Results: Solutions of nefopam at 2.5 mg/mL and the mixture of nefopam 2.5 mg/mL with droperidol 52 µg/mL, diluted in NaCl 0.9%, without protection from light, retained more than 90% of the initial concentration after 48 hours storage at 20-25°C. No modification in visual or subvisual evaluation and pH values were observed. Conclusion: Nefopam solutions at 2.5 mg/mL and the mixture of nefopam 2.5 mg/mL with droperidol 52 µg/mL diluted in NaCl 0.9% were stable over a period of 48 hours at room temperature. These stability data provide additional knowledge to assist intensive care services in daily practice.

Long-term stability of an infusion containing paracetamol, alizapride, ketorolac and tramadol in glass bottles at 5±3°C.

Background and objective: Infusion containing paracetamol, alizapride, ketorolac and tramadol is used after a general anaesthesia in order to limit pain, fever and nausea. Currently, these infusions are prepared according to demand in the anaesthesia unit, but the preparation in advance could improve quality of preparation and time management. The aim of this study was to investigate the long-term stability of this infusion in glass bottles at 5°C ± 3 °C. Method: Five bottles of infusion were stored at 5°C ± 3 °C for 60 days. A visual and microscope inspection were performed periodically to observe any particle appearance or colour change. pH and absorbance at three wavelengths were measured. The concentrations were measured by ultra-high performance liquid chromatography - diode array detection. Results: Multiple verifications were performed during the first 35 days and no crystal, impurity or colour change were observed. At the next time point (42nd day), crystals were visible to the naked eye. pH and absorbance at 350 nm and 550 nm were stable. A slight increase in the absorbance at 410 nm was observed during the study, suggesting that a degradation product could be formed and absorb at this wavelength. The infusion was considered chemically stable while the lower one-sided prediction limit at 95% remains superior to 90% of the initial concentration. Concentration measurements demonstrated that ketorolac and alizapride remained stable in the infusion for 35 days. The stability of tramadol was 28 days. However, degradation of paracetamol was much faster given that concentration has fallen below 90% of the initial concentration after 7 days. Conclusion: Infusion of paracetamol, alizapride, ketorolac and tramadol remains stable for 7 days in glass bottles at 5°C ± 3 °C and could be prepared in advance with these storage conditions.

Development and validation of a capillary electrophoresis method applied to the analysis of l-citrulline in an oral formulation for pediatric use.

A simple and highly sensitive CE-UV method was applied in the determination of l-ctrulline, which was developed from an oral formulation for pediatric use. The novel method was based on the analysis of l-citrulline for direct ultraviolet detection at 198 nm. The BGE consisted of 10 mM sodium tetraborate and 50 mM SDS at pH 9, and the electrophoretic parameters were optimized. The method was validated in terms of specificity, linearity, LOD, LOQ, precision, accuracy, and robustness. The LOD and LOQ obtained were 1.36 and 4.54 µg/mL, respectively. In addition, the method offers higher sensitivity and specificity compared with the results obtained from HPLC method using UV-detectors, in which l-citrulline needs to be derivatizated. Furthermore, low cost and simplicity of the system allowed the rapid and simple quantitation of l-citrulline in the oral formulation for quality control and stability indicated method.

Development of a new liquid chromatographic method for the simultaneous separation of ciprofloxacin degradation products with 5-hydroxymethyl-furfural, impurity of D-glucose, in an intravenous solution for perfusion.

The place occupied by fluoroquinolones is very important clinically. Ciprofloxacin has been the most widely prescribed one which exhibits good activity against Pseudomonas aeruginosa and Acinetobacter. D-glucose is frequently used as an excipient in most formulations for perfusion solutions. Since there is much interest in pharmaceutical quality control of such formulations, separation of impurities from the main drug substances and accurate assay quantification, and since there is no reference or monograph until nowadays that has been reported for the simultaneous separation of ciprofloxacin degradation products along with 5-hydroxymethyl-furfural (5-HMF), impurity of D-glucose, classified as a high toxic substance, thus our aim of this work is to develop a new simple, sensitive and stability indicating method allowing this separation by high-performance liquid chromatography. We have started from the chromatographic conditions recommended by the British Pharmacopoeia, and by optimizing the nature of the stationary phase, the composition of the mobile phase and the injection volume. After optimisation, the retained chromatographic conditions have enabled the separation of all impurities with good resolution factor greater than 1.5 for each pair of peaks and with good symmetry peak shape. The developed method was validated according to the International Conference of Harmonisation (ICH) guidelines for specificity, detection and quantification limits, and then it was applied to stability study of the formulation subjected to different ICH prescribed stress conditions. The 5-HMF was checked to be the impurity issued from D-glucose hydrolysis by high temperature mainly after autoclaving of pharmaceuticals. The developed method was proved to be simple, specific with very low limit of quantification. Hence, it can be considered as a method for stability indicating and routine quality control analysis in pharmaceutical industries.

Research on the relationship between cephalosporin structure, solution clarity, and rubber closure compatibility using volatile components profile of butyl rubber closures.

OBJECTIVE: Establish an effective experimental strategy to determine the compatibility of rubber closures for drugs. SIGNIFICANCE: Various types of rubber closures with different compositions are available for drug packaging. Many additives of rubber closures can be released from rubber closures and may affect the quality of drugs and pose a risk to human health. In this study, we aimed to determine the relationship between cephalosporin structure, solution clarity, and rubber closure compatibility using volatile components profile of butyl rubber closures. METHODS: Two opposite polarity gas chromatography (GC) systems and GC-mass spectrometry (MS) were used to achieve rapid qualitative determination of the main volatile components in rubber closures. Simulated adsorption experiment was performed to investigate the adsorption of main volatile components in rubber closures by cephalosporins with different side chain structures, and to determine the effects of adsorption on solution clarity. RESULTS: A volatile components screening library of rubber closures was established and the structures of some volatile component were confirmed. The specific adsorption of the structure of cephalosporins on volatile components from rubber closures was studied. CONCLUSION: Based on the results of this study, rubber closures with good compatibility for cephalosporins with different side chain structures can be selected rapidly. This experimental strategy not only facilitates the screening of suitable rubber closures more effectively, but also enables the quick determination of volatile components adsorbed by drugs.

Influence of the solvent system on the stability of doxycycline solutions.

Concentrated solutions of doxycycline are often added to drinking water of animals for oral antibiotic therapy. However, stability concerns of doxycycline in solution involve an accurate selection of the solvent system to ensure that the active substance will remain within the acceptance range during the product shelf-life and to avoid sub-therapeutic dosage. Different solvent systems have been evaluated in order to determine their influence on the stability of concentrated doxycycline solutions. The results showed differences in the degradation kinetics of doxycycline depending on the co-solvent used and they permitted to select a solvent system for liquid doxycycline hyclate formulations with low rate of degradation even after several months of storage. So, the inclusion of ethanol together with propylene glycol as main excipient was found to be beneficial, while no benefit was observed concerning the addition of citric acid. Once administered to drinking water, the solutions were stable for 24 h with no influence of the solvent system.

Improving Viscosity and Stability of a Highly Concentrated Monoclonal Antibody Solution with Concentrated Proline.

PURPOSE: To explain the effects of the osmolyte proline on the protein-protein interactions (PPI), viscosity and stability of highly concentrated antibody solutions in contrast to other neutral osmolytes. METHODS: The viscosity of ~225 mg/mL mAb solutions was measured with proline, glycine and trehalose as a function of pH and co-solute concentration up to 1.3 M. The stability was assessed via turbidity as well as size exclusion chromatography after 4 weeks storage at 40°C. The PPI strength was assessed qualitatively via the high concentration diffusion rate by dynamic light scattering. RESULTS: Increasing proline significantly reduced the mAb viscosity and increased the colloidal stability at pH 6, but not at pH 5 further from the mAb pI. In contrast, glycine and trehalose did not improve the viscosity nor stability. The normalized diffusion coefficient at high concentration, which is inversely proportional to the attractive PPI strength, increased with proline concentration but decreased with increasing glycine. CONCLUSIONS: Proline demonstrated greater efficacy for improving mAb viscosity and stability in contrast to glycine and trehalose due to its amphipathic structure and partial charge on the pyrrolidine side chain. These properties likely allow proline to screen the attractive electrostatic and hydrophobic interactions that promote self-association and high viscosities. Binary proline-histidine formulations also demonstrated greater viscosity reduction effects than histidine alone at the same total co-solute concentration, while maintaining a lower total solution osmolarity.

Migration of plasticizers from poly(vinyl chloride) and multilayer infusion bags using selective extraction and GC-MS.

Flexible poly(vinyl chloride) (PVC) is widely used in the pharmaceutical industry for the manufacture of medical devices (tubes, probes, bags, primary packaging, etc.). The objective of the present study was to develop a procedure to evaluate the migration potential of nine plastic additives in aqueous infusion bags (NaCl 0.9% and glucose 5%): five phthalates, one adipate, two alkylphenols, and benzophenone. Two types of materials were analyzed: (i) new and outdated plasticized PVC (containing 40% of diethylhexyl phthalate DEHP); and (ii) tri-laminate polyethylene-polyamide-polypropylene, a multilayer material presumably exempt from DEHP. In addition, we evaluated the migration of plasticizers from PVC raw materials (film and grain) under controlled conditions to compare the migration levels according to Regulation 2011/10. Solid phase extraction and liquid-liquid extraction with gas-chromatography coupled to mass spectrometry were used in all tests. The migration of DEHP in PVC grain exceeded the maximum regulated level of 5000 µg/kg, whereas the levels were much lower in films. In new PVC bags, DEHP was the only compound detected at 4.31 ±â€¯0.5 µg/L in NaCl 0.9% and 4.29 ±â€¯0.25 µg/L in glucose 5% serums, whereas the levels increased 10 times in three-year shelf-life bags. In multilayer bags, DEHP was not found but instead, two plasticizers were detected namely dibuthylphthalate (DBP) and diethylphthalate (DEP) at 0.7 ±â€¯0.1 µg/L and 4.14 ±â€¯0.6 µg/L, respectively. These plasticizers are not mentioned as additives allowed in materials intended for parenteral use (European Pharmacopoeia 8.0, 3.1.5. and 3.1.6.). Caprolactam was tentatively identified and could have stemmed from the polyamide of the multilayer composite. The levels of phthalates remained low but not negligible and might constitute a risk to public health in the case of reiterative infusions.

An NMR strategy to detect conformational differences in a protein complexed with highly analogous inhibitors in solution.

This manuscript presents an NMR strategy to investigate conformational differences in protein-inhibitor complexes, when the inhibitors tightly bind to a protein at sub-nanomolar dissociation constants and are highly analogous to each other. Using HIV-1 protease (PR), we previously evaluated amide chemical shift differences, ΔCSPs, of PR bound to darunavir (DRV) compared to PR bound to several DRV analogue inhibitors, to investigate subtle but significant long-distance conformation changes caused by the inhibitor's chemical moiety variation [Khan, S. N., Persons, J. D. Paulsen, J. L., Guerrero, M., Schiffer, C. A., Kurt-Yilmaz, N., and Ishima, R., Biochemistry, (2018), 57, 1652-1662]. However, ΔCSPs are not ideal for investigating subtle PR-inhibitor interface differences because intrinsic differences in the electron shielding of the inhibitors affect protein ΔCSPs. NMR relaxation is also not suitable as it is not sensitive enough to detect small conformational differences in rigid regions among similar PR-inhibitor complexes. Thus, to gain insight into conformational differences at the inhibitor-protein interface, we recorded 15N-half filtered NOESY spectra of PR bound to two highly analogous inhibitors and assessed NOEs between PR amide protons and inhibitor protons, between PR amide protons and hydroxyl side chains, and between PR amide protons and water protons. We also verified the PR amide-water NOEs using 2D water-NOE/ROE experiments. Differences in water-amide proton NOE peaks, possibly due to amide-protein hydrogen bonds, were observed between subunit A and subunit B, and between the DRV-bound form and an analogous inhibitor-bound form, which may contribute to remote conformational changes.

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.

Simultaneous Estimation of Ofloxacin, Clotrimazole, and Lignocaine Hydrochloride in Their Combined Ear-Drop Formulation by Two Spectrophotometric Methods.

Two sensitive, accurate, and precise spectrophotometric methods have been developed and validated for the simultaneous estimation of ofloxacin (OFX), clotrimazole (CLZ), and lignocaine hydrochloride (LGN) in their combined dosage form (ear drops) without prior separation. The derivative ratio spectra method (method 1) includes the measurement of OFX and CLZ at zero-crossing points (ZCPs) of each other obtained from the ratio derivative spectra using standard LGN as a divisor, whereas the measurement of LGN at the ZCP of CLZ is obtained from the ratio derivative spectra using standard OFX as a divisor. The double divisor-ratio derivative method (method 2) includes the measurement of each drug at its amplitude in the double divisor-ratio spectra obtained using a standard mixture of the other two drugs as the divisor. Both methods were found to be linear (correlation coefficients of >0.996) over the ranges of 3-15, 10-50, and 20-100 µg/mL for OFX, CLZ, and LGN, respectively; precise (RSD of <2%); and accurate (recovery of >98%) for the estimation of each drug. The developed methods were successfully applied for the estimation of these drugs in a marketed ear-drop formulation. Excipients and other ingredients did not interfere with the estimation of these drugs. Both methods were statistically compared using the t-test.

Determination of calcium and zinc in gluconates oral solution and blood samples by liquid cathode glow discharge-atomic emission spectrometry.

A novel flowing liquid cathode glow discharge (LCGD) was developed as an excitation source of the atomic emission spectrometry (AES) for the determination of Ca and Zn in digested calcium and zinc gluconates oral solution and blood samples, in which the glow discharge is produced between the electrolyte (as cathode) overflowing from a quartz capillary and the needle-like Pt anode. The electron temperature and electron density of LCGD were calculated at different discharge voltages. The discharge stability and parameters affecting the LCGD were investigated in detail. In addition, the measured results of real samples using LCGD-AES were verified by ICP-AES. The results showed that the optimized analytical conditions are pH = 1 HNO3 as supporting electrolyte, 4.5mLmin-1 solution flow rate. The power consumption of LCGD is 43.5-66.0W. The R2 and the RSD ranged from 630 to 680V are 0.9942-0.9995 and 0.49%-2.43%, respectively. The limits of detections (LODs) for Zn and Ca are 0.014-0.033 and 0.011-0.097mgL-1, respectively, which are in good agreement with the closed-type electrolyte cathode atmospheric glow discharge (ELCAD). The obtained results of Ca and Zn in real samples by LCGD-AES are basically consistent with the ICP-AES and reference value. The results suggested that LCGD-AES can provide an alternative analytical method for the detection of metal elements in biological and medical samples.

Electrospraying of polymer solutions: Study of formulation and process parameters.

Over the past decade, electrospraying has proven to be a promising method for the preparation of amorphous solid dispersions, an established formulation strategy to improve the oral bioavailability of poorly soluble drug compounds. Due to the lack of fundamental knowledge concerning adequate single nozzle electrospraying conditions, a trial-and-error approach is currently the only option. The objective of this paper is to study/investigate the influence of the different formulation and process parameters, as well as their interplay, on the formation of a stable cone-jet mode as a prerequisite for a reproducible production of monodisperse micro- and nanoparticles. To this purpose, different polymers commonly used in the formulation of solid dispersions were electrosprayed to map out the workable parameter ranges of the process. The experiments evaluate the importance of the experimental parameters as flow rate, electric potential difference and the distance between the tip of the nozzle and collector. Based on this, the type of solvent and the concentration of the polymer solutions, along with their viscosity and conductivity, were identified as determinative formulation parameters. This information is of utmost importance to rationally design further electrospraying methods for the preparation of amorphous solid dispersions.

Stability of tacrolimus ophthalmic solution.

PURPOSE: The stability of 0.3-mg/mL tacrolimus ophthalmic solution at different storage temperatures was studied. METHODS: A sterile ophthalmic solution of 0.3 mg/mL tacrolimus was prepared in triplicate under aseptic conditions by diluting tacrolimus in eye drops. Three aliquots of this solution were transferred into polypropylene bottles and stored at 25, 2-8, or -15 to -25 °C. Samples were collected immediately after preparation and at selected time points and assayed in triplicate using high-performance liquid chromatography (HPLC). Samples were also visually examined for macroscopic changes. The 0.3-mg/mL tacrolimus solution was also exposed to acidic treatment and heat to force its degradation and to evaluate the selectivity of the analytic method. The tacrolimus ophthalmic solution was considered stable if at least 90% of the mean initial concentration remained when analyzed by HPLC. RESULTS: When stored at 2-8 °C and between -15 and -25 °C, at least 90% of the initial tacrolimus concentration remained throughout the 85-day study period. There were no significant differences in tacrolimus concentrations between the starting and ending points (p > 0.05). However, when tacrolimus solution was stored at 25 °C, the percentage of the initial tacrolimus concentration remaining had decreased to less than 90% on day 28. CONCLUSION: Tacrolimus diluted to 0.3 mg/mL in eye drop solution was stable for 20 days when stored at 25 °C and for at least 85 days when stored at 2-8 °C or between -15 and -25 °C in polypropylene bottles and protected from light.

Physical stability of highly concentrated injectable drugs solutions used in intensive care units.

BACKGROUND: The intensive care department of the institution use drug solutions within higher concentration to avoid fluid overload. The purpose of the study is to prove the physical stability of different injectable drugs within high concentration (amiodarone 25mg/mL, isosorbide 0.60mg/mL, lorazepam 0.16mg/mL, noradrenalin 0.120 and 0.240mg/mL, salbutamol 0.06mg/mL and sodium valproate 12mg/mL) to ensure the patients safety. METHODS: Five of 30 or 50mL polypropylene syringes were prepared for each solution under aseptic conditions and stored at room temperature. Immediately after the preparation (hour 0) and after 1, 4, 8, 24 and 48hours, 2mL of each solution were withdrawn from each syringe and placed in glass tubes to proceed to the stability test. All specimens were visually inspected in front of a black and of a white background and aliquots of each solution were centrifuged to proceed to microscopic inspection with a ten-fold magnification. The pH of each solution was measured with glass electrode pH-meter (Inolab level 1, WTW Weilhem, Germany with biotrode electrode, Hamilton, Bonaduz, Switzerland) and spectrophotometric measurements (Genesys 10 series, New-York, USA) were performed at three wavelengths (350, 410 and 550nm) to avoid the apparition of turbidity. RESULTS: For all the drugs included in the study, there was no significant change in pH, no color change, no turbidity or opacity and no precipitation observed in the solutions during the storage at room temperature for 48hours. No microaggregates were detected by microscope neither revealed by a change of absorbance. CONCLUSION: Within these limits, the preparations of amiodarone in 5% glucose polypropylene syringes and isosorbide, lorazepam, noradrenalin, salbutamol, valproate in 0.9% sodium chloride polypropylene syringes are physically stable at room temperature for 48hours. These results allow us to consider a study of chemical stability by high-performance liquid chromatography (HPLC).

Silicone Migration From Baked-on Silicone Layers. Particle Characterization in Placebo and Protein Solutions.

A significant number of therapeutic proteins are marketed as pre-filled syringes or other drug/device combination products and have been safely used in these formats for years. Silicone oil, which is used as lubricant, can migrate into the drug product and may interact with therapeutic proteins. In this study, particles in the size range of 0.2-5 µm and ≥1 µm as determined by resonant mass measurement and micro-flow imaging/light obscuration, respectively, resulted from silicone sloughing off the container barrel after agitation. The degree of droplet formation correlated well with the applied baked-on silicone levels of 13 µg and 94 µg per cartridge. Silicone migration was comparable in placebo, 2 mg/mL and 33 mg/mL IgG1 formulations containing 0.04% (w/v) polysorbate 20. Headspace substantially increased the formation of silicone droplets during agitation. The highest particle concentrations reached, however, were still very low compared to numbers described for spray-on siliconized containers. When applying adequate baked-on silicone levels below 100 µg, bake-on siliconization efficiently limits silicone migration into the drug product without compromising device functionality.