Pyridine-based lanthanide complexes combining MRI and NIR luminescence activities.

A series of novel triazole derivative pyridine-based polyamino-polycarboxylate ligands has been synthesized for lanthanide complexation. This versatile platform of chelating agents combines advantageous properties for both magnetic resonance (MR) and optical imaging applications of the corresponding Gd(3+) and near-infrared luminescent lanthanide complexes. The thermodynamic stability constants of the Ln(3+) complexes, as assessed by pH potentiometric measurements, are in the range log K(LnL)=17-19, with a high selectivity for lanthanides over Ca(2+), Cu(2+), and Zn(2+). The complexes are bishydrated, an important advantage to obtain high relaxivities for the Gd(3+) chelates. The water exchange of the Gd(3+) complexes (k(ex)(298)=7.7-9.3×10(6) s(-1)) is faster than that of clinically used magnetic resonance imaging (MRI) contrast agents and proceeds through a dissociatively activated mechanism, as evidenced by the positive activation volumes (ΔV(≠)=7.2-8.8 cm(3) mol(-1)). The new triazole ligands allow a considerable shift towards lower excitation energies of the luminescent lanthanide complexes as compared to the parent pyridinic complex, which is a significant advantage in the perspective of biological applications. In addition, they provide increased epsilon values resulting in a larger number of emitted photons and better detection sensitivity. The most conjugated system PheTPy, bearing a phenyl-triazole pendant on the pyridine ring, is particularly promising as it displays the lowest excitation and triplet-state energies associated with good quantum yields for both Nd(3+) and Yb(3+) complexes. Cellular and in vivo toxicity studies in mice evidenced the non-toxicity and the safe use of such bishydrated complexes in animal experiments. Overall, these pyridinic ligands constitute a highly versatile platform for the simultaneous optimization of both MRI and optical properties of the Gd(3+) and the luminescent lanthanide complexes, respectively.

Towards real-time release of pharmaceutical tablets: 100% in-line control via near-infrared spatially resolved spectroscopy and 3D microwave resonance technology.

In the scope of 100% in-line quality control and real-time release of pharmaceutical tablets, the authors present a flexible inspection module for in-line tablet analysis with integrated multipoint near-infrared (NIR) spectroscopy and 3D microwave resonance technology (3D MRT). Via an industrial case study on Diclofenac Sodium tablets, the abilities of this versatile process analytical technology (PAT) tool are presented. It is demonstrated that the combination of Diclofenac concentration prediction via NIR spectroscopy and mass prediction via 3D MRT allow to estimate the dosage of each individual tablet. Single sample repetition tests were performed on 5 tablets, measured 10 times on three different days. A high accuracy and precision of prediction was shown, with an average standard deviation below 0.5 mg. The inspection run demonstrated the added value of such inspection and sorting strategies based on the calculated dosage of individual tablets.

Efficient pallado-catalyzed C6-(het)arylation of Imidazo[1,2-b][1,2,4,5]tetrazines under microwave irradiations.

A versatile protocol for the preparation of a library of 5,6-(het)bisarylated imidazo[1,2-b][1,2,4,5]tetrazines is described. Target compounds were obtained in fairly good yields, starting from ethoxy-7-(4-methoxyphenyl)imidazo[1,2-b][1,2,4,5]tetrazine and a large panel of bromoaryl derivatives, using palladium catalysis under microwave irradiation. Compatibility with various chemical groups and heterocycles was proven. Steric and electronic effects do not have any effect on the efficiency of the reaction. Purifications were performed without any difficulties, and the structure of a final compound was proven by crystal X-ray diffraction studies.

Continuous manufacturing process monitoring of pharmaceutical solid dosage form: A case study.

Continuous Manufacturing (CM) of pharmaceutical drug products is a rather new approach within the pharmaceutical industry. In the presented paper, a GMP continuous wet granulation line used for clinical production of solid dosage forms was investigated with a thorough monitoring strategy regarding process performance and robustness. The line was composed of the subsequent continuous unit operations feeding - twin-screw wet-granulation - fluid-bed drying - sieving and tableting; the formulation of a new pharmaceutical entity in development was selected for this study. In detail, a Design of Experiments (DoE) was used to evaluate the impact of the three main factors (amount of water, filling rate, and shear force in twin-screw granulator) on the tablet quality. The process was monitored via in-process control (IPC) tests (e.g. weight, hardness, disintegration, and loss-on-drying), Process Analytical Technologies (PAT), and through the analysis of the process parameters (multivariate process control). The tested formulation was very robust to the large process variation of the DoE: all IPC results were in specification, the PAT probes provided stable results for the content uniformity and no critical variations can be detected in the process parameters. An adequate monitoring strategy was presented and the robustness of the process with one formulation has been demonstrated. In summary, this continuous process in combination with smart formulation development allows the robust production of constant quality tablets. The synergy between PAT, process data science and IPC creates an adequate monitoring framework of the continuous manufacturing line.

Process analytical technology for continuous manufacturing tableting processing: A case study.

The use of Near Infrared Spectroscopy (NIRS) as a fast and non-destructive technique was employed for the control and monitoring of the tableting step during a continuous manufacturing process. Two NIRS methods were optimized in order to in-line control the blend uniformity in the tablet feed frame and the API concentration of freshly pressed tablets prior the ejection. The novelty of this work first lies in the acquisition speed of NIR spectra reaching up to 70,000 tablets/h. Partial Least Square (PLS) regression was used as chemometric tool for the computation that resulted in excellent predictive calibration results. A coefficient of correlation (r) value of 0.99 was obtained for both probes. The root mean square error of calibration (RMSEC) and the root mean square error of prediction (RMSEP) were respectively 1.8% and 1.8% for active content in the tablet feeder and 2.2% and 2.3% for the tablet content. In addition, calibration performance and robustness of the methods were evaluated. Moreover several qualitative methods were proposed to monitor the tableting process in different stages of development (single wavelength, Principal Component Analysis, and Independent Component Analysis). In early phase development, the requirement/quality of the input material is not established yet; hence the use of a qualitative approach allows to confirm the suitability of the PAT methodology for in-process material monitoring & control. Later, the qualitative approach constitutes the foundation for the quantitative approach when input materials are fixed and larger production size occurs. The proposed strategy is a performant PAT tool for continuous manufacturing and a step forward to real time release.

Pyridine-based lanthanide complexes: towards bimodal agents operating as near infrared luminescent and MRI reporters.

We report two prototype Ln(3+) complexes that address requirements for both MRI and luminescence imaging and we demonstrate that the presence of two H(2)O molecules bound to the Ln(3+), beneficial for MRI applications of the Gd(3+) analogue, is not a major limitation for the development of NIR luminescent agents.

Hydrophobic chromophore cargo in micellar structures: a different strategy to sensitize lanthanide cations.

We propose a new approach for the versatile sensitization of luminescent lanthanide cations. A hydrophobic chromophore is incorporated into a micellar assembly formed by the amphiphilic lanthanide chelate. The sensitizer to lanthanide energy transfer occurs between the two moieties without covalent linkage.