Co-administration of Intravenous Drugs: Rapidly Troubleshooting the Solid Form Composition of a Precipitate in a Multi-drug Mixture Using On-Site Raman Spectroscopy.

Intravenous drugs are often co-administrated in the same intravenous catheter line due to which compatibility issues, such as complex precipitation processes in the catheter line, may occur. A well-known example that led to several neonatal deaths is the precipitation due to co-administration of ceftriaxone- and calcium-containing solutions. The current study is exploring the applicability of Raman spectroscopy for testing intravenous drug compatibility in hospital settings. The precipitation of ceftriaxone calcium was used as a model system and explored in several multi-drug mixtures containing both structurally similar and clinically relevant drugs for co-infusion. Equal molar concentrations of solutions containing ceftriaxone and calcium chloride dihydrate were mixed with solutions of cefotaxime, ampicillin, paracetamol, and metoclopramide. The precipitate formed was collected as an "unknown" material, dried, and analyzed. Several solid-state analytical methods, including X-ray powder diffraction, Raman spectroscopy, and thermogravimetric analysis, were used to characterize the precipitate. Raman microscopy was used to investigate the identity of single sub-visual particles precipitated from a mixture of ceftriaxone, cefotaxime, and calcium chloride. X-ray powder diffraction suggested that the precipitate was partially crystalline; however, the identity of the solid form of the precipitate could not be confirmed with this standard method. Raman spectroscopy combined with multi-variate analyses (principal component analysis and soft independent modelling class analogy) enabled the correct detection and identification of the precipitate as ceftriaxone calcium. Raman microscopy enabled the identification of ceftriaxone calcium single particles of sub-visual size (around 25 µm), which is in the size range that may occlude capillaries. This study indicates that Raman spectroscopy is a promising approach for supporting clinical decisions and especially for compatibility assessments of drug infusions in hospital settings.

Adjusting the dose in paediatric care: dispersing four different aspirin tablets and taking a proportion.

OBJECTIVES: When caring for children in a hospital setting, tablets are often manipulated at the ward to obtain the right dose. One example is manipulation of tablets containing the slightly water-soluble substance aspirin, used in paediatric care as an antiplatelet agent. The evidence base, however, for choosing certain tablet formulations and manipulation methods over others for extraction of proportions is lacking. The aim of this study was to investigate the effect of tablet formulation and manipulation technique on the dose accuracy and precision attained when dispersing different commercially available aspirin tablets and extracting a small proportion suitable for children. METHODS: The manipulation methods investigated simulated those observed in the paediatric clinic. Four tablet formulations-one chewable, one conventional and two dispersible-were dispersed in 10 mL water in a medicine measure. On (1) passive dispersion, (2) mixing by stirring with the syringe, or (3) stirring and pumping the dispersion in and out of the syringe, respectively, proportions (1 mL or 2 mL) were extracted and the doses recovered were determined using a validated UHPLC (ultra high-pressure liquid chromatography) method. RESULTS: Fractions from the four different dispersed aspirin tablet formulations varied from 99% to 3% of that intended with the lowest degree of mixing, and from 96% to 34% of that intended with the highest degree of mixing. Only the dispersible tablets gave average doses within 20% of the intended dose. CONCLUSIONS: Fraction extraction from dispersed aspirin tablets only gave doses within 20% of intended for the dispersible tablets, and then only for some of the manipulation methods: 'passive dispersion' for the 75 mg dispersible tablet and 'stirring and pumping' for the 300 mg dispersible tablet. The tablets not intended for dispersion gave unsatisfactory results, outside 20%, regardless of manipulation method. The findings underline the importance of considering both tablet formulation and dose extraction technique when manipulations are required.

Comparing Two Methods of Tablet Manipulation to Adjust the Warfarin Dose in Paediatric Care.

Tablets containing prescribed doses are not always available, and this is of particular importance in paediatric care where suitable age-appropriate formulations are generally lacking. To obtain a child-adjusted dose, tablets are manipulated in several ways; e.g., they may be dispersed in water before a fraction is extracted, or they may be split before the resulting fragment is dispersed. In this study, the accuracy attained through these manipulation methods was investigated for two generic tablets containing the anticoagulant warfarin. Tablets were dispersed in water (10 mL) before a fraction (10%) was withdrawn, alternatively tablets were split in half or quarter fragments before the fragments were dispersed in water. To investigate the contribution of variability from the different steps in the manipulation processes, the amount of warfarin recovered from the various dispersions was determined, as was the accuracy of the splitting. A validated UHPLC-method was used for quantitative determination of warfarin. Splitting of the tablets could result in deviation >30% from the ideal, theoretical weight. The amount of drug substance extracted as a fraction from the dispersed tablets deviated no more than 10% from the intended amount. To obtain the most accurate child-adjusted fraction dose of warfarin, the tablets investigated in this study should be dispersed and the desired proportion extracted. Practices that involve splitting tablets are likely to increase the variation, and should be avoided.

Adjusting the dose in paediatric care by dispersing fragments of four different aspirin tablets.

AIM: Tablets can be manipulated in several ways to obtain a fraction as the dose-a practice frequently seen in paediatric care due to lack of suitable formulations. Splitting tablets prior to fragment dispersion in a small volume of liquid is one such method. The objective of this study was to investigate the accuracy and precision of this method. METHODS: Four different types of aspirin tablets (two dispersible, one conventional and one chewing) were split with a tablet splitter into half and quarter fragments. The fragments were dispersed in a medicine measure or an oral syringe. The amount recovered was determined by UHPLC analysis. RESULTS: The largest quarter fragments ranged from 26.7% to 31.5% of the full tablet weight. Dispersing the fragment in an oral syringe, the amount recovered was greater than 90.8% of the fragment manipulated for all four tablet types, when rinsing was performed. Dispersing the fragment in a medicine measure, the amounts recovered spanned from 32.9% for the conventional tablets to 98.7% for one of the dispersible tablets. CONCLUSION: Dispersion of half or quarter tablets directly in an oral syringe, but not a medicine measure, could give satisfactory recovery from fragments of all the investigated aspirin tablets.

A new method for pharmaceutical compounding and storage of anti-VEGF biologics for intravitreal use in silicone oil-free prefilled plastic syringes.

Intravitreal injections of antibody-based biologics targeting vascular endothelial growth factor (VEGF) are highly effective and have markedly decreased the risk of visual impairment associated with prevalent retinal diseases, such as neovascular age-related macular degeneration and diabetes macular oedema. The diseases are chronic in their nature, and most patients need long-term therapy to suppress disease activity. We previously reported a compounding method for repackaging and storage of aflibercept (Eylea), a commonly used anti-VEGF biologic, in silicone oil-coated plastic syringes without compromising drug stability or activity. In addition to improving safety and time spent per patient, compounding of anti-VEGF biologics enables single-dose vials to be split into multiple syringes, thereby considerably reducing waste and drug expenses. However, symptomatic silicone oil droplets may deposit in the eye's vitreous body after repetitive injections. To fully avoid this complication, we here report on a novel pharmaceutical compounding method using silicone oil-free syringes and a 33 G × 9 mm Low Dead Space Needle hub injection needle. We evaluate the method for three anti-VEGF biologics commonly used in ophthalmology: aflibercept, ranibizumab (Lucentis) and bevacizumab (Avastin). Our results show that compounding and storage for one week does not compromise the functional activity of the biologics and allows for safe and cost-effective compounding of anti-VEGF biologics for intravitreal injections in prefilled silicone oil-free syringes.

Manipulating tablets and capsules given to hospitalised children in Norway is common practice.

AIM: This study provided an overview of manipulating oral medicines given to hospitalised children and evaluated this practice in two hospitals. It focused on the type of manipulation and the dosage forms that were manipulated. METHOD: This was a cross-sectional, prospective study, carried out on the paediatric wards at two Norwegian hospitals for four weeks in 2013. A medicine was said to have been manipulated if it was not administered as described in the Norwegian summary of product characteristics. RESULTS: This study showed that 17% of the 3070 administrations of oral medicines to the hospitalised children involved manipulation. Tablets, including modified release preparations, were the most frequently manipulated medicines. In approximately half of these cases, only a segment of the unit dose was administered. No manipulation of oral liquids was seen. The bioavailability of as much as 44% of the most frequent given substances may be sensitive to such manipulations due to limited aqueous solubility. Various routines for splitting and handling the unit doses were observed. CONCLUSION: Manipulation of oral medication was regularly performed on paediatric wards. There is an urgent need for age-appropriate medicines, documented and standardised processes for manipulating medicines and staff training on the consequences of manipulation.

Long-term stability of extemporaneously prepared captopril oral liquids in glass bottles.

PURPOSE: The long-term stability of captopril in extemporaneously prepared oral liquids was studied. METHODS: Captopril solutions of 1 and 5 mg/mL were prepared in sterile water for irrigation with sorbitol, disodium edetate, and sodium benzoate. The samples were stored in 100-mL amber glass bottles with a headspace of air at 22 degrees C for 12 months. The captopril concentration was determined by high-performance liquid chromatography at 0, 3, 6, 9, and 12 months. The pH of the solutions was also measured, and the physical appearance was recorded. The stability of the 1-mg/mL captopril preparation during 1 month of simulated use when stored at 2-8 degrees C was tested at the start and the end of the 12-month study period. Chemical stability was defined as retention of at least 90% of the initial captopril concentration. The microbiological quality of the preparations was tested at 0, 6, and 12 months (1 mg/mL) and 0 and 12 months (5 mg/mL). RESULTS: Throughout the 12-month study period, the captopril concentration in the oral liquids exceeded 90% of the initial concentration. The lowest concentration (98.5%) was detected in the 5-mg/mL preparation after 3 months of storage. The 1-mg/mL preparation was stable during 1 month of simulated use, both at the start and the end of the 12-month study period. No microbiological growth was observed in any of the samples tested. CONCLUSION: Extemporaneously prepared oral liquid formulations of captopril 1 and 5 mg/mL were chemically stable when stored in glass bottles at room temperature for 12 months when stabilized with 0.1 mg/ mL disodium edetate at a low pH.

Formation and reactivity of free radicals in 5-hydroxymethyl-2-furaldehyde--the effect on isoprenaline photostability.

Solutions of glucose are used as diluents for drugs in various drug infusions. When sterilized by heat small amounts of the substance 5-hydroxymethyl-2-furaldehyde (5-HMF) is produced from glucose. At a hospital ward such infusions may be exposed to irradiation; including UV-light. The photoreactivity of the furaldehyde is investigated. It is shown to photodestabilize the catecholamine isoprenaline. It is shown to be a producer, but also a consumer, of singlet oxygen. The excited triplet, cation and anion radical have been produced by pulse radiolysis and flash photolysis and their absorbance characteristics have been determined. The triplet absorption spectrum showed absorption bands at 320 and 430 nm with molar absorption coefficients of 4700 and 2600 M-1 cm-1, respectively. The anion radical showed absorption bands at 330 and 420 nm with molar absorption coefficients of 2000 and 300 M-1 cm-1, respectively. The cation radical had an absorption band at 320 nm with a molar absorption coefficient of 5000 M-1 cm-1. The quantum yield for the production of singlet oxygen, sensitized by the 5-HMF triplet, was determined to be 0.6, whilst the quantum yield for the triplet formation was 1.0. Aqueous solutions of 5-HMF were found to photoionize to yield the hydrated electron and the cation radical of 5-HMF in a biphotonic process. The influences of pH, buffer and glucose on the formation of transients were evaluated. The reactions between 5-HMF and the solvated electron, the hydroxyl radical and the superoxide were also studied.