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.

Measurement of hydrogen peroxide vapor in powders with potassium titanium oxide oxalate loaded cellulose pellets as probes.

An image-based method for determining H2O2 vapor pressures in powder systems was developed based on cellulose pellets loaded with potassium titanium oxide oxalate (PTO Pellets) as probe particles. Solid titanyl salts change color after exposure to hydrogen peroxide vapor and the quantitative response of PTO pellets to H2O2 has been established by comparing reactions with H2O2 in liquid and solid states. Analysis of pictures of the color changes of PTO Pellets mixed into powders can be used to monitor the presence of ppm levels of H2O2 vapor inside powder systems such as bleach containing dry detergent powders.•H2O2 vapor quantification in dry systems with titanyl loaded cellulose particles.•Simple fabrication of H2O2 probe particles.•High sensitivity with LOD 0.190 ppm H2O2 .

Physical Stability of Freeze-Dried Isomalt Diastereomer Mixtures.

PURPOSE: Isomalt is a sugar alcohol used as an excipient in commercially available solid oral dosage forms. The potential of isomalt as a novel freeze-drying excipient was studied in order to increase knowledge of the behavior of isomalt when it is freeze-dried. METHODS: Isomalt was freeze-dried in four different diastereomer compositions and its physical stability was investigated with differential scanning calorimetry, Fourier-transform infrared and Raman spectroscopy, X-ray powder diffraction, Karl-Fischer titration and thermogravimetric analysis in order to verify the solid state form of isomalt after freeze-drying and observe any changes occurring during storage in three different relative humidity conditions. RESULTS: Isomalt was successfully transformed into the amorphous form with freeze-drying and three diastereomer combinations remained stable as amorphous during storage; one of the diastereomer compositions showed signs of physical instability when stored in the highest relative humidity condition. The four different crystalline diastereomer mixtures showed specific identifiable solid state properties. CONCLUSIONS: Isomalt was shown to be a suitable excipient for freeze-drying. Preferably a mixture of the diastereomers should be used, as the mixture containing only one of the isomers showed physical instability. A mixture containing a 1:1 ratio of the two diastereomers showed the best physical stability in the amorphous form.

Influence of temperature on solvent-mediated anhydrate-to-hydrate transformation kinetics.

PURPOSE: To achieve an in-depth understanding of the underlying mechanism of the acceleration or deceleration effect of temperature on solvent-mediated anhydrate-to-hydrate phase transformation. METHODS: The effect of temperature on the phase transformation rate and onset time of two model compounds was investigated using in situ Raman spectroscopy. The thermodynamic driving force of the phase transformation (e.g. supersaturation) at different temperatures was determined by measuring the solubility of the anhydrate and the hydrate. RESULTS: Both acceleration and deceleration effects of temperature on the phase transformation were observed. The mechanism of these temperature effects was studied by exploring the influence of temperature on supersaturation level and crystallization kinetics. Increasing temperature usually leads to accelerated phase transformation kinetics, but it simultaneously decreases supersaturation, which has the opposite effect on the kinetics of the phase transformation. The overall effect of temperature on the phase transformation is therefore determined by the combined effects of supersaturation and temperature on the nucleation and crystal growth kinetics of the hydrate. CONCLUSIONS: By differentiating and comparing the effects of temperature and supersaturation on the anhydrate-to-hydrate phase transformation, a deeper understanding of the underlying principle of the acceleration and deceleration effects of temperature on the phase transformation has been achieved.

Assessment of crystalline disorder in cryo-milled samples of indomethacin using atomic pair-wise distribution functions.

The aim of this study was to investigate the usefulness of the atomic pair-wise distribution function (PDF) to detect the extension of disorder/amorphousness induced into a crystalline drug using a cryo-milling technique, and to determine the optimal milling times to achieve amorphisation. The PDF analysis was performed on samples of indomethacin obtained by cryogenic ball milling (cryo-milling) for different periods of time. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), polarised light microscopy (PLM) and solid state nuclear magnetic resonances (ss-NMR) were also used to analyse the cryo-milled samples. The high similarity between the γ-indomethacin cryogenic ball milled samples and the crude γ-indomethacin indicated that milled samples retained residual order of the γ-form. The PDF analysis encompassed the capability of achieving a correlation with the physical properties determined from DSC, ss-NMR and stability experiments. Multivariate data analysis (MVDA) was used to visualize the differences in the PDF and XRPD data. The MVDA approach revealed that PDF is more efficient in assessing the introduced degree of disorder in γ-indomethacin after cryo-milling than MVDA of the corresponding XRPD diffractograms. The PDF analysis was able to determine the optimal cryo-milling time that facilitated the highest degree of disorder in the samples. Therefore, it is concluded that the PDF technique may be used as a complementary tool to other solid state methods and that further investigations are warranted to elucidate the capabilities of this technique.