In-line particle size measurement based on image analysis in a fully continuous granule manufacturing line for rapid process understanding and development.

The present paper serves as a demonstration how an in-line PAT tool can be used for rapid and efficient process development in a fully continuous powder to granule line consisting of an interconnected twin-screw wet granulator, vibrational fluid bed dryer, and a regranulating mill. A new method was investigated for the periodic in-line particle size measurement of high mass flow materials to obtain real-time particle size data of the regranulated product. The system utilises a vibratory feeder with periodically altered feeding intensity in order to temporarily reduce the mass flow of the material passing in front of the camera. This results in the drastic reduction of particle overlapping in the images, making image analysis a viable tool for the in-line particle size measurement of high mass-flow materials. To evaluate the performance of the imaging system, the effect of several milling settings and the liquid-to-solid ratio was investigated on the product's particle size in the span of a few hours. The particle sizes measured with the in-line system were in accordance with the expected trends as well as with the results of the off-line reference particle size measurements. Based on the results, the in-line imaging system can serve as a PAT tool to obtain valuable real-time information for rapid process development or quality assurance.

Stepwise aromatic nucleophilic substitution in continuous flow. Synthesis of an unsymmetrically substituted 3,5-diamino-benzonitrile library.

Aromatic or heteroaromatic ring precursors with 2-3 identical functionalities are often used in sequential derivatization depending on the reactivity difference or the selective execution of the reaction such as nucleophilic aromatic substitution. Continuous flow chemistry offers an enhanced parameter space (pressure and temperature) with rapid parameter optimization that ensures selectivity in many cases. We developed a flow chemistry procedure to carry out a stepwise aromatic nucleophilic substitution of difluoro-benzenes having an activating group in meta position to the fluorines. The mono-aminated products were obtained in high yield and selectivity in an extremely short reaction time, while applying higher temperature, longer reaction zone (or time), and employing higher excess of another amine reactant, the subsequent introduction of the second amino group was also successfully achieved leading to an unsymmetrically substituted 3,5-diamino-benzonitrile library.

Videometric mass flow control: A new method for real-time measurement and feedback control of powder micro-feeding based on image analysis.

The present paper reports the first monitoring and control of ultra-low dose powder feeding using a camera image-based mass flow measurement system. Caffeine was fed via a single-screw microfeeder as a model active pharmaceutical ingredient (API). The mass, mass flow and sizes of the particles were successfully monitored in real-time by the developed videometric system consisting of a high-speed process camera coupled with an image analysis software. The system was also tested in feedback control mode to automatically reach the desired mass flow values by adjusting the feeder speed based on the mass flow measured by the image analysis system. Based on these features, the developed videometric system can serve as a multi-purpose PAT-tool and can provide valuable real-time information about the process which is indispensable for modern continuous pharmaceutical manufacturing.

[Results in 42 non-resectable NSCLC IIA-B patients with initial concurrent Taxotere-Cisplatin chemoradiotherapy]. / IIIA-B stádiumú NSCLC elsovonalbeli Taxotere-Cisplatin konkuráló kemo-radioterápiájának eredményei 42 irreszekábilis daganatos beteg vizsgálata alapján.

GOALS: A prospective multicenter study to treat non-small cell lung cancer (NSCLC) with inductive chemoradiotherapy for improving chances of operability. If used as first-line therapy, combined treatment improves survival and it is well tolerated with a low rate of side effects. PATIENTS: 42 patients with stage IIIA-B NSCLC from which 36 could be followed. METHODS: A full dose Taxotere-Cisplatin chemotherapy was given to patients with concurrent radiotherapy in 2 Gy fractions up to 60 Gy via conformal irradiation. RESULTS: Local response was very high and 40.47% of patients became operable while in inoperable cases consolidation chemotherapy showed similar results as other protocols. We also found a low rate of side effects. The high rate of brain metastasis suggests that prophylactic cranial irradiation (PCI) should be considered.

[Therapy of brain metastasis based on the RPA classification]. / Agyi metasztázisok kezelése RPA klasszifikáció alapján.

RPA classification of patients suffering from brain metastases is not widely used in Hungary. The authors reviewed the RPA disposition-based therapeutic recommendations in the literature. Retrospective analysis of their 123 brain metastatic cases showed 3.8 months median, 34.1% 1-year and 7.9% 2-year overall survival. Patient number and median survival in subgroups: RPA 1: 42/14 months, RPA 2: 38/6,2 months, RPA 3a: 6/3.1 months, 3b: 13/2 months, 3c: 10/0.7 months. Median survival of patients with brain metastases from cancer of unknown primary (CUP) was 3 months. In RPA class 1 and 2, 10% undertreatment has been found for solid brain metastases, and all of the 3c patients were over-treated according to literature recommendations. The authors strongly recommend the use of RPA classification in the management of brain metastases and in contemplation of the capacity of radiotherapy/neurosurgery and oncology.

Effect of beta-carotene supplementation on plasma and yolk IgY levels induced by NDV vaccination in Japanese quail.

Newly hatched Japanese quail (Coturnix coturnix japonica) chicks were fed diets containing different levels of retinoids (vitamin A) or beta-carotene. Group A received a commercial diet containing 10,000 IU vitamin A per kilogram. The diets of Groups B, C, and D contained no vitamin A but were supplemented with 1-, 2.5-, and 5-fold retinol equivalents of beta-carotene. Each group contained 16 quails in a 1:1 sex ratio. At 8 weeks of age the quails were immunized orally with Newcastle disease virus (NDV) vaccine according to the manufacturer's recommendations. Boosters were given three times at two-week intervals. Blood samples were taken at two-week intervals until 14 weeks of age. The anti-NDV IgY titre was determined by a locally developed direct enzyme-linked immunosorbent assay (ELISA). Groups A and B showed nearly the same antibody response. This indicates that the preformed vitamin A and the equivalent beta-carotene have the same immunomodulatory effect. Groups receiving higher doses of beta-carotene (Groups C and D) exhibited significantly higher plasma IgY levels compared to Groups A and B. The results indicate that elevated doses of beta-carotene have a slight effect on the adaptive immune response in Japanese quail.