Predictive modeling of die filling of the pharmaceutical granules using the flexible neural tree

In this work, a computational intelligence (CI) technique named flexible neural tree (FNT) was developed to predict die filling performance of pharmaceutical granules and to identify significant die filling process variables. FNT resembles feedforward neural network, which creates a tree-like structure by using genetic programming. To improve accuracy, FNT parameters were optimized by using differential evolution algorithm. The performance of the FNT-based CI model was evaluated and compared with other CI techniques: multilayer perceptron, Gaussian process regression, and reduced error pruning tree. The accuracy of the CI model was evaluated experimentally using die filling as a case study. The die filling experiments were performed using a model shoe system and three different grades of microcrystalline cellulose (MCC) powders (MCC PH 101, MCC PH 102, and MCC DG). The feed powders were roll-compacted and milled into granules. The granules were then sieved into samples of various size classes. The mass of granules deposited into the die at different shoe speeds was measured. From these experiments, a dataset consisting true density, mean diameter (d50), granule size, and shoe speed as the inputs and the deposited mass as the output was generated. Cross-validation (CV) methods such as 10FCV and 5x2FCV were applied to develop and to validate the predictive models. It was found that the FNT-based CI model (for both CV methods) performed much better than other CI models. Additionally, it was observed that process variables such as the granule size and the shoe speed had a higher impact on the predictability than that of the powder property such as d50. Furthermore, validation of model prediction with experimental data showed that the die filling behavior of coarse granules could be better predicted than that of fine granules

An Alkaloid from a Highly Invasive Seaweed Increases the Voracity and Reproductive Output of a Model Fish Species

The invasive macroalga Caulerpa cylindracea has spread widely in the Mediterranean Sea, becoming a favorite food item for native fish for reasons yet unknown. By using a combination of behavioral, morphological, and molecular approaches, herein we provide evidence that the bisindole alkaloid caulerpin, a major secondary metabolite of C. cylindracea, significantly increases food intake in the model fish Danio rerio, influencing the regulation of genes involved in the orexigenic pathway. In addition, we found that the compound improves fish reproductive performance by affecting the hypothalamus-pituitary-gonadal axis. The obtained results pave the way for the possible valorization of C. cylindracea as a sustainable source of a functional feed additive of interest to face critical challenges both in aquaculture and in human nutrition

Dry granulation using roll compaction process : powder characterization and p rocess understanding.

In recent years, dry granulation using roll compaction (DGRC) attracts considerable interest of engineers and researchers, especially in the pharmaceutical industry, due to its distinct feature that no liquid binder is needed. It is generally anticipated that as a size enlarge process, DGRC would improve properties of feed powders (such as flowability and bulk density), but it was also reported that DGRC could cause a reduction in powder compactibility. A wide range of powder properties, such as size, shape, flowability, compactibility and compressibility, were analysed for several pharmaceutical excipients using the state of art techniques. Elastic-plastic properties of single component powders and mixtures were also determined using the Drucker Prager Cap (DPC) model and an example of FEM application was presented. All the properties determined were used to investigate: 1) the prediction of ribbon milling from friability tests and 2) the effect of granule size on die filling and die compaction behaviour of pharmaceutical powders. A new and easy method was developed for predicting fines produced during ribbon milling. An exponential relation between the filling ratio and the shoe speed was found. Furthermore, it is shown that flowability is strongly influenced by the granule size, and there is a decrease in the tensile strength with the increase of the granule size. Additionally, for all the materials analysed a strong correlation between the flow indexes and the critical filling speed was observed and an empirical equation is obtained

The effect of dry granulation on flow behaviour of pharmaceutical powders during die filling

Flowability that quantifies the flow behaviour of powders is an important material attribute for such applications as packing, hopper flow and powder transport. It is also one of the critical material attributes of pharmaceutical formulations for solid dosage forms. It is anticipated that size enlargement via dry/wet granulation will improve the flowability of feed powders, but it is still unclear how significant the flowability can be enhanced. Therefore, in this study, an experimental investigation was performed to explore how dry granulation affects the flowability of pharmaceutical powders, such as microcrystalline cellulose (MCCs), mannitol and lactose. Both as-received powders and binary mixtures were considered. Granules of various sizes were produced using roll compaction followed by ribbon milling, and the flowability of as-received powders and produced granules was characterised using two methods: 1) the critical filling speed measured using a model die filling system and 2) the flow index measured using a Flodex tester. It was shown that the flowability increases as the size of the granules increases for all materials considered. Furthermore, it was found that there is a strong correlation between the critical filling speed and the flow index: the critical filling speed is proportional to the flow index to a power of − 5/2

Predictive Modelling of Die Filling of the Pharmaceutical Granules Using the Flexible Neural Tree

In this work, a computational intelligence (CI) technique named flexible neural tree (FNT) was developed to predict die filling performance of pharmaceutical granules and to identify significant die filling process variables. FNT resembles feedforward neural network, which creates a tree-like structure by using genetic programming. To improve accuracy, FNT parameters were optimized by using differential evolution algorithm. The performance of the FNT-based CI model was evaluated and compared with other CI techniques: multilayer perceptron, Gaussian process regression, and reduced error pruning tree. The accuracy of the CI model was evaluated experimentally using die filling as a case study. The die filling experiments were performed using a model shoe system and three different grades of microcrystalline cellulose (MCC) powders (MCC PH 101, MCC PH 102, and MCC DG). The feed powders were roll-compacted and milled into granules. The granules were then sieved into samples of various size classes. The mass of granules deposited into the die at different shoe speeds was measured. From these experiments, a dataset consisting true density, mean diameter (d50), granule size, and shoe speed as the inputs and the deposited mass as the output was generated. Cross-validation (CV) methods such as 10FCV and 5x2FCV were applied to develop and to validate the predictive models. It was found that the FNT based CI model (in the cases of both CV methods) performed much better than other CI models. Additionally, it was observed that process variables such as the granule size and the shoe speed had a higher impact on the predictability than that of the powder property such as d50. Furthermore, validation of model prediction with experimental data showed that the die filling behavior of coarse granules could be better predicted than that of fine granules

Determination of the flow/no-flow transition from a flat bottom hopper

Hoppers and silos are widely used in storing powders in various industries, such as agricultural, chemical, food and pharmaceutical industries. It is of practical importance to design hoppers and silos to ensure smooth discharge of bulk solids from these devices, and to minimise the occurrence of arching, blockage and build-up of materials around the walls. However, due to the complex nature of bulk solids, arching behaviour of bulk solids in silos and hoppers is still not well understood. In this study, a combined experimental and numerical study was performed to explore the transition from non-flow to flow of bulk solids from a flat bottom hopper. Glass beads of various sizes were considered and the minimal orifice size through which these materials can be discharged was determined experimentally using a FlodexT

Risk of professional accidental exposure to biological agents in health care workers a retrospective analysis carried out in a southern Italian tertiary hospital

Worldwide the needlestick injuries of health care workers (HCWs) still represent a major health problem. The authors aimed to evaluate the risk of HCW needlestick injuries in a tertiary university hospital in southern Italy in relation to some HCW characteristics (age, sex, professional profile, work department) and the source of infection. All HCWs of the University Hospital "Federico II" in Naples, Italy, attending the Infectious Diseases Unit after potential accidental contact to blood-borne viruses through needlestick injuries were enrolled during a 22-year period. HCWs underwent clinical analysis and were administered a specific questionnaire to collect (in anonymous fashion) data about age, sex, professional profile and work department. From 1995 to 2016 1,477 needlestick injuries in the same number of people (one accident per person) were recorded by our service. The HCWs were predominately males (n = 806, 55%) and the mean age was 39.4 years (±10.1 SD). The job categories most involved were: physicians (41%), followed by nurses (33%) and healthcare assistants (HCAs, 10%). The incidence proportion was calculated for these highest-risk categories in three defined time points (at the beginning, in the middle and at the end of the study period): 104/2149 (4.86%) in 1995, 41/2498 (1.64%) in 2005 and 25/2057 (1.22%) in 2015. Most injuries occurred in General Surgery (14.21%), Gynecology and Obstetrics (9%) and Pediatrics (6.49%). In about 34% the HCWs had been exposed to HCV infected fluids. Over time, a significant decrease in accidental exposure was recorded for physicians (p= 0.019), nurses (p< 0.0001) and HCAs (p< 0.0001). Our results confirm that some profiles, namely physicians, nurses and healthcare assistants, are still at risk of needlestick injuries, especially in surgical areas, including obstetric wards. Further primary and secondary prevention strategies are needed to decrease the incidence of new cases of needlestick injuries

MED1/BDNF/TrkB pathway is involved in thalamic hemorrhage-induced pain and depression by regulating microglia

Central post-stroke pain (CPSP) and associated depression remain poorly understood and pharmacological treatments are unsatisfactory. Recently, microglia activation was suggested to be involved in CPSP pathophysiology. The goal of this study was to investigate the effectiveness of a co-ultramicronized combination of N-palmitoylethanolamide and luteolin (PEALut) in a mouse model of thalamic hemorrhage (TH)-induced CPSP. TH was established through the collagenase-IV injection in thalamic ventral-posterolateral-nucleus. PEALut effects in CPSP-associated behaviors were evaluated during a 28-days observation period. We found that repeated administrations of co-ultra PEALut significantly reduced mechanical hypersensitivity after TH, as compared to vehicle, by reducing the early microglial activation in the perilesional site. Moreover, PEALut prevented the development of depressive-like behavior (21 days post-TH). These effects were associated with the restoration of synaptic plasticity in LEC-DG pathway and monoamines levels found impaired in TH mice. Hippocampal MED1 and TrkB expressions were significantly increased in TH compared to sham mice 21 days post-TH, whereas BDNF levels were decreased. PEALut restored MED1/TrkB/BDNF expression in mice. Remarkably, we found significant overexpression of MED1 in the human autoptic brain specimens after stroke, indicating a translational potential of our findings. These results pave the way for better-investigating depression in TH- induced CPSP, together with the involvement of MED1/TrkB/BDNF pathway, proposing PEALut as an adjuvant treatmen