Highly Sensitive Detection of the Antibiotic Ciprofloxacin by Means of Fiber Enhanced Raman Spectroscopy.

Sepsis and septic shock exhibit a rapid course and a high fatality rate. Antibiotic treatment is time-critical and precise knowledge of the antibiotic concentration during the patients' treatment would allow individual dose adaption. Over- and underdosing will increase the antimicrobial efficacy and reduce toxicity. We demonstrated that fiber enhanced Raman spectroscopy (FERS) can be used to detect very low concentrations of ciprofloxacin in clinically relevant doses, down to 1.5 µM. Fiber enhancement was achieved in bandgap shifted photonic crystal fibers. The high linearity between the Raman signals and the drug concentrations allows a robust calibration for drug quantification. The needed sample volume was very low (0.58 µL) and an acquisition time of 30 s allowed the rapid monitoring of ciprofloxacin levels in a less invasive way than conventional techniques. These results demonstrate that FERS has a high potential for clinical in-situ monitoring of ciprofloxacin levels.

Fiber-Array-Based Raman Hyperspectral Imaging for Simultaneous, Chemically-Selective Monitoring of Particle Size and Shape of Active Ingredients in Analgesic Tablets.

The particle shape, size and distribution of active pharmaceutical ingredients (API) are relevant quality indicators of pharmaceutical tablets due to their high impact on the manufacturing process. Furthermore, the bioavailability of the APIs from the dosage form depends largely on these characteristics. Routinely, particle size and shape are only analyzed in the powder form, without regard to the effect of the formulation procedure on the particle characteristics. The monitoring of these parameters improves the understanding of the process; therefore, higher quality and better control over the biopharmaceutical profile can be ensured. A new fiber-array-based Raman hyperspectral imaging technique is presented for direct simultaneous in-situ monitoring of three different active pharmaceutical ingredients- acetylsalicylic acid, acetaminophen and caffeine- in analgesic tablets. This novel method enables a chemically selective, noninvasive assessment of the distribution of the active ingredients down to 1 µm spatial resolution. The occurrence of spherical and needle-like particles, as well as agglomerations and the respective particle size ranges, were rapidly determined for two commercially available analgesic tablet types. Subtle differences were observed in comparison between these two tablets. Higher amounts of acetaminophen were visible, more needle-shaped and bigger acetylsalicylic acid particles, and a higher incidence of bigger agglomerations were found in one of the analgesic tablets.

Counterfeit and Substandard Test of the Antimalarial Tablet Riamet® by Means of Raman Hyperspectral Multicomponent Analysis.

The fight against counterfeit pharmaceuticals is a global issue of utmost importance, as failed medication results in millions of deaths every year. Particularly affected are antimalarial tablets. A very important issue is the identification of substandard tablets that do not contain the nominal amounts of the active pharmaceutical ingredient (API), and the differentiation between genuine products and products without any active ingredient or with a false active ingredient. This work presents a novel approach based on fiber-array based Raman hyperspectral imaging to qualify and quantify the antimalarial APIs lumefantrine and artemether directly and non-invasively in a tablet in a time-efficient way. The investigations were carried out with the antimalarial tablet Riamet® and self-made model tablets, which were used as examples of counterfeits and substandard. Partial least-squares regression modeling and density functional theory calculations were carried out for quantification of lumefantrine and artemether and for spectral band assignment. The most prominent differentiating vibrational signatures of the APIs were presented.

Fiber-Enhanced Raman Sensing of Cefuroxime in Human Urine.

Fiber-enhanced Raman spectroscopy was developed for the chemically selective and sensitive quantification of the important antibiotic cefuroxime in human urine. A novel optical sensor fiber was drawn and precisely prepared. In this fiber structure, light is strongly confined in the selectively filled liquid core, and the Raman scattered signal is collected with unprecedented efficiency over an extended interaction length. The filling, emptying, and robustness are highly improved due to the large core size (>30 µm). Broadband step-index guidance allows the free choice of the most suitable excitation wavelength in complex body fluids. The limit of detection of cefuroxime in human urine was improved by 2 orders of magnitude (to µM level). The quantification of cefuroxime was achieved in urine after oral administration. This method has great potential for the point-of-care monitoring of antibiotics concentrations and is an important step forward to enable clinicians to rapidly adjust doses.

Fiber enhanced Raman spectroscopic analysis as a novel method for diagnosis and monitoring of diseases related to hyperbilirubinemia and hyperbiliverdinemia.

Fiber enhanced resonance Raman spectroscopy (FERS) is introduced for chemically selective and ultrasensitive analysis of the biomolecules hematin, hemoglobin, biliverdin, and bilirubin. The abilities for analyzing whole intact, oxygenated erythrocytes are proven, demonstrating the potential for the diagnosis of red blood cell related diseases, such as different types of anemia and hemolytic disorders. The optical fiber enables an efficient light-guiding within a miniaturized sample volume of only a few micro-liters and provides a tremendously improved analytical sensitivity (LODs of 0.5 µM for bilirubin and 0.13 µM for biliverdin with proposed improvements down to the pico-molar range). FERS is a less invasive method than the standard ones and could be a new analytical method for monitoring neonatal jaundice, allowing a precise control of the unconjugated serum bilirubin levels, and therefore, providing a better prognosis for newborns. The potential for sensing very low concentrations of the bile pigments may also open up new opportunities for cancer research. The abilities of FERS as a diagnostic tool are explored for the elucidation of jaundice with different etiologies including the rare, not yet well understood diseases manifested in green jaundice. This is demonstrated by quantifying clinically relevant concentrations of bilirubin and biliverdin simultaneously in the micro-molar range: for the case of hyperbilirubinemia due to malignancy, infectious hepatitis, cirrhosis or stenosis of the common bile duct (1 µM biliverdin together with 50 µM bilirubin) and for hyperbiliverdinemia (25 µM biliverdin and 75 µM bilirubin). FERS has high potential as an ultrasensitive analytical technique for a wide range of biomolecules and in various life-science applications.