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A stochastic global formulation for the description of antisolvent mediated crystal growth processes is discussed based on the Fokker-Planck equation (FPE). The obtained global model is used to define an operating map of the crystallization process, where asymptotic iso-mean and iso-variance curves are reported in an antisolvent flowrate – temperature plane. Using the obtained asymptotic operational map, three different CSDs have been predicted and compared, both in asymptotic and then dynamic conditions, using experimental results.

The use of in-line near-infrared (NIR) measurements for tablet potency monitoring and diversion was studied. First, the optimal sample size for in-line NIR measurements inside the feed chute and the dosing and filling chamber of the tablet press feed frame was determined to allow proper comparison between these different measurement positions. Because of the considerably longer measurement time needed to obtain the same sample size inside the feed chute compared to the feed frame, the possibility of powder segregation inside the feed chute and the additional powder mixing inside the feed frame, the latter is preferred over the feed chute for in-line blend potency monitoring. Next, a design of experiments (DoE) was performed to evaluate the effect of paddle speed, turret speed, overfill level and formulation properties upon the lead-lag and the time it takes before the powder blend that is expelled at the dosing station is measured by the NIR inside the dosing chamber. Lead-lag is defined as the difference in time and API concentration between the measured in-line NIR response inside the filling chamber of the feed frame and the off-line NIR tablet response. Paddle speed and turret speed were the only compression parameters affecting lead-lag. Lead-lag decreased with increasing paddle speed for the first formulation. For the second formulation, lead-lag decreased with decreasing paddle speed and/or increasing turret speed. Formulation properties did not have an effect on the lead-lag. The in-line NIR response inside the dosing chamber of the feed frame was found to be closely following the tablet NIR response. Therefore, the dosing chamber could be used as an additional in-line NIR position for tablet potency monitoring and diversion. It can provide an extra layer of confidence about the final tablet quality. To demonstrate this potential benefit of simultaneous in-line NIR measurements inside the filling and dosing chamber of the feed frame, a tableting experiment was performed where a surrogate API spike was introduced into the product stream to mimic a potential process disturbance. The in-line NIR measurements inside the filling chamber allow diverting tablets in-time when the blend potency crosses the predefined control limits. And because the NIR response inside the dosing chamber closely follows the tablet NIR response, tablet diversion can discontinue when the blend potency inside the dosing chamber is again within the control limits. This could increase the yield of the tableting process by avoiding a longer than needed wash-out period and rejecting tablets that meet the release limits., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The ongoing transition from batch to continuous manufacturing offers both challenges and opportunities in the field of oral solid dosage form production. In turn, Process Analytical Technology (PAT) offers a path towards the successful deployment of continuous tablet manufacturing in rotary tablet presses. One promising PAT tool for this endeavour is the NIR-derived potency measurement. However, the high degree of noise in the data may hamper the extraction of useful information. For this reason, this work focused on the implementation of an adaptive Kalman filter algorithm that incorporates and reconciles the potency prediction given by one or more NIR probes with those of a semi-mechanistic compartmental model developed for the application at hand. This approach allowed for more robust concentration estimations. Furthermore, it was observed that potency levels in multiple locations in the studied tablet press (including those in the finished tablets) could be appropriately inferred using a single in-line measurement data stream. This methodology thus opens the door to advanced process control applications., (Copyright © 2021 Elsevier B.V. All rights reserved.)

For continuous pharmaceutical manufacturing of oral solid dosages, it is essential that product quality is measured inline. In this application, a continuous rotary tablet press is used. The goal is a model-based assessment of the quality of the blend in the feed frame to determine whether the concentration of the active pharmaceutical ingredient (API) will be within the prescribed limits. This is to achieve a better quality assurance than by offline testing of a small sample of tablets. In this way, product quality for real-time release (RTR) could be implemented. With a near-infrared (NIR) probe, the concentration of the API in the feed chute and the feed-frame were measured, as well as the API concentration of the tablets by an offline NIR measurement. These different data sets are connected and used for the residence time distribution characterization of the mixing dynamic of the tablet press. A residence time distribution model is fitted to the data, and is further used to compute the lead-lag time. This yields information on how long it takes for a quantity of product to go from being measured in the feed frame until ending up in tablets. Further, it gives information on the occurrence of mixing in the feed-frame itself. These models allow making accurate predictions of whether tablets fall within specified concentration range in real-time. The real-time prediction can be used in combination with a control system both to maintain the quality of the blend as well as to know which tablets to discard. This real-time quality assurance will lead to less material waste and fewer declined batches of tablets., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The influence of different tableting process parameters on lead-lag was studied by collecting in-line near-infrared (NIR) spectra in the filling chamber of the tablet press feed frame and off-line NIR tablet data. Lead-lag is defined as the difference in time and API concentration between the measured in-line feed frame NIR response and the off-line NIR tablet data. Lead-lag results from the product formulation blend undergoing additional mixing after passing the NIR probe inside the feed frame, before being filled into the dies of the tablet press. A design of experiments (DoE) was performed to evaluate the effect of the tableting process factors paddle speed, turret speed, overfill level, paddle speed ratio and feed frame type upon lead-lag. Paddle speed and turret speed were identified as the only tableting parameters affecting lead-lag. Lead-lag decreased with increasing paddle speed or turret speed and became negligible at high paddle speed and high turret speed. Overfill level, paddle speed ratio and feed frame type did not affect lead-lag, suggesting that the amount and the trajectory of the recirculating powder in the feed frame did not significantly vary and hence influence the lead-lag within the examined process factor ranges. Finally, a methodology was developed using the in-line feed frame NIR measurements for the continuous monitoring and control of blend potency and tablet content uniformity. Tablet diversion should start when the in-line feed frame monitored blend potency exceeds the predefined control limits and can discontinue when this blend potency is again within the control limits for a duration equal to the lead-lag time. A combination of continuous blend potency monitoring inside the feed frame and in-process tablet weight control allows real-time tablet content uniformity assurance. Although the findings of this study are restricted to the specific equipment, tableting parameter ranges and product formulation used, the suggested approach for lead-lag determination and continuous tablet content uniformity monitoring can be applied to any rotary tablet press and product formulation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Continuous powder mixing technology (CMT) application during continuous direct compression has emerged as a leading technology used in the development and manufacture of solid oral dosage forms. The critical quality attributes of the final product are heavily dependent on the performance of the mixing step as the quality of mixing directly influences the drug product quality attributes. This study investigates the impact of blend material properties (bulk density, API particle size distribution) and process parameters (process throughput, hold up mass and impeller speed) on the mixing performance. Mixing of the blend was characterized using the Residence Time Distribution (RTD) of the process by trending the outlet stream of the mixer using a near-infrared (NIR) probe after the injection of a small mass of tracer at the inlet stream. The outcomes of this study show that the RTDs of the mixer with throughput ranging between 15 and 30 kg/h; impeller speed ranging between 400 and 600 rpm and hold up mass (HUM) ranging between 500 and 850 g can be described by a series of two ideal Continuous Stirred Tank Reactors (CSTRs) with different volumes, and correspondingly, different mean residence times. It is also observed that the mixing is mainly occurring in the lower chamber of the CMT and the normalized RTDs of the mixer are similar across the range of process conditions and material attributes studied. The results also showed that the formulation blend with different API particle sizes and bulk properties, like bulk density and flowability, provide insignificant impact on the mixing performance. The CMT allows independent selection of target set points for HUM, impeller rotational speed and line throughput and it shows great robustness and flexibility for continuous blending in solid oral dose manufacturing., (Copyright © 2021 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

One of the critical quality attributes of the solid oral dosage forms produced in continuous direct compression operations is the tablet potency. A novel soft sensor comprising of a combination of first principle-based and empirical models has been developed to enable real-time monitoring of blend and tablet potency, and concentrations of other excipients at various stream levels along the direct compression line. The soft sensor model has only three adjustable parameters, primarily associated with the equipment design and operation, so the model is product agnostic which is key to enable flexible manufacturing. The estimation accuracy of the soft sensor is demonstrated through a series of real time experiments which include steady state and dynamic transitions of potency during the runs, compared with offline analytically tested tablet cores. The results indicate that the proposed soft sensor can be utilized as a robust tool for real-time monitoring of potency, suggesting an extension of its utilization to higher levels of control. Two potential applications of the soft sensor are: 1. An element of a control strategy for product diversion; 2. A predictive model for advanced process control strategy to minimize the variability in tablet composition., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Near Infrared (NIR) spectroscopy is commonly utilized for continuous manufacturing as Process Analytical Technology (PAT) tool. This paper focus on a continuous direct compression manufacturing process, in which an NIR PAT probe is integrated into the tablet press feed frame and into the tablet diversion control system to ensure continuous monitoring of the potency and homogeneity of the blend within the process line. The quantification of NIR spectra is achieved through Partial Least-Squares (PLS) modeling, calibrated with offline analyzed tablet cores at different potency levels. Because the NIR measurements are often sensitive to sample physical properties caused by raw materials or process conditions, etc., adopting a data-driven approach will require a large amount of representative data throughout the method lifecycle. During the early stages of process development, whenever new uncaptured source of variability in the model space are encountered, the chemometric predictions can deviate from the offline reference, requiring frequent model updates. These deviations can be reduced by integrating process and physico-chemical knowledge in the on-line potency estimation. This paper presents a novel hybrid method combining the online NIR PLS and a potency soft sensor estimation, enabling a robust potency prediction whilst minimizing maintenance downtimes and facilitating cross-site method transfer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Assessment of quality of life in patients with different degrees of chronic kidney disease is an important issue because of its impact on clinical decisions and financial resource management in the health-care system. The aim of this study was to assess whether a generic instrument like the SF-36 questionnaire is able to discriminate three different populations of patients with different degrees of renal disease (pre-ESRD, ESRD, TxR). Five hundred sixty-three patients from 12 Italian nephrology units completed the SF-36 scales by themselves. The results from these samples were compared with those from the general population. Univariate analysis and multivariate regression were used. The generic SF-36 questionnaire proved to be a powerful instrument to discriminate populations with different degrees of chronic renal failure. The quality of life of patients on dialysis is significantly worse than that of the normal population and other patients with less severe renal function impairment.

This paper completes the 2004 national survey of Renal and Dialysis Units organised by the Italian Society of Nephrology (SIN), and presents data from the last three Italian Regions, Campania, Sicilia and Sardegna. The major purpose of this initiative was to obtain a benchmark reference on national and regional basis. Main findings in the 3 Regions, respectively: A) STRUCTURAL RESOURCES: Renal Units = 28, 30, 19; Private Dialysis Units = 126, 95, 4; total Renal and Dialysis Units 27, 26, 21 pmp (per million population); % of private facilities = 81, 74, 12%; hospitalization beds = 35, 40, 32 pmp; dialysis stations = 337, 356, 265 pmp., B) Personnel Resources: physicians = 88, 75, 67 pmp; dialysis nurses = 162, 136, 247 pmp; each physician treats 10, 12, 12 dialysis patients and each dialysis nurse treats 4.7, 4.0, 3.3 dialysis patients. C)., Activity: hospitalizations = 1334, 1911, 1851 pmp; renal biopsies = 50, 66, 100 pmp. D)., Epidemiology: prevalence of dialysis patients = 842, 915, 822 pmp; prevalence of transplanted patients = 269, 212, 327 pmp; incidence of dialysis patients = 187, 199, 150 pmp; gross mortality rate of dialysis patients = 12.9%, 12.1%, 12.5%; distribution of vascular accesses in prevalent dialysis patients: arteriovenous fistulas = 93%, 84%, 77%; central venous catheters = 6%, 12%, 15%,; vascular grafts = 1%, 3%, 8%. Compared to other Regions, Campania and Sicilia have an abnormal high rate of private Dialysis Units, resulting in difficulties in optimizing structural and economic resources. Furthermore, the independence of some of these structures from a Renal Unit interferes with an adequate treatment of dialysis patients.

Background: Hyperphosphatemia in the uremic patient undergoing dialysis causes and makes the secondary hyperpharatyroidism progress. Nowadays it has a very important role in predicting mortality. The aim of the study was to assess by "Audit" to analyse adequacy of the Sardinian dialytic patients with reference to the optimal objective of the national and international guidelines., Patients and Methods: The questionnaire of the audit was composed of 11 questions about the percentage distribution of: calcium in the dialysate, values of phosphoremia), Ca x P product, patients treated with vitamin D taking one or more phosphate binders, average dose, spKt/V > or = 1.2, serum aluminium, parathiroidectomy., Results: We examined 1274 dialysis patients (93% on hemodialysis and 7% in CAPD) in 26 dialytic centers in our region (age 63.8 anni +/- 32.4; dialytic age 5.15 +/- 5.06. Phosphorus ranges (mg/dL) P < 5.5: 61.3 +/- 23%; between 5.5 e 6.5: 28.2 +/- 17.7%; and P > 6.5: 10.4 +/- 7.7%; Ca x P (<60): 77.8% +/- 16.6%; between 60-70: 16.8 +/- 13.4%; > 70: 4.99 +/- 4.7%. The more prescribed dialysate calcium was 1.5 mmol/L in HD (58.8%) HF (60.6%), HDF (51.6%) and CAPD (5.6%). PTH levels were: 31.1% (<120); 29.5% (120-250); 21.1% (250-450); 8% (450-600); 10.3% (>600). Patients on vitamin D: os daily 23.04 +/- 28%; post-dialysis boluses: os 32.6 +/- 28, i.v. 10.6 +/- 9%; no therapy 32.7 +/- 22.7%. The percentage use of phosphorus binders: 48.5% calcium carbonate (2.9 g/d); 7.12% calcium acetate (1.34 g/d); 13.5% sevelamer (2.79 g/d); 10% total aluminium based (0.62 g/d). The aluminium is dosed in 11/26 dialysis units (32.3% of the population); 2.3% +/- 0.9% of patients having Aluminium > 30 mcg/L. The dialytic patients have a Kt/V > or = 1.2: 80.1 +/- 19%. Parathyroidectomy incidences 1.8%., Conclusions: The data show good control of the average phosporous, there is a worrying percentage of patients with PTH values compatible with hypodynamic bone condition, lower and therefore safer calcium levels in the dialysate, poor aluminium control and low incidence of parathyroidectomy. In our experience the audit is a good way to verify and to correct the therapeutic choice in uremic osteodistrophy.

A congenital diverticulum of the small intestine is a condition with only a low morbidity and is generally a Meckel's diverticulum. There is, however, another congenital malformation, which can closely resemble a Meckel's diverticulum, but has another etiology, the tubular duplication of the small intestine. The authors point out the embryologic, anatomic and histological findings between these different but very similar malformations. It seems that the diagnosis of duplication is not often considered when finding a diverticulum of the small intestine and such a malformation is too easily called a Meckel's diverticulum.

The Authors report a case of leiomyosarcoma of the small bowel, a rare neoplasm with severe limitations of pre-operative diagnosis. A discussion of the pathological staging, diagnosis and surgical therapy follows. At the moment, better diagnostic techniques and greater awareness of the disease notwithstanding, the prognosis remains severe due to the presence of local or distant metastases at laparotomy.

The authors describe two cases of celiac disease that simulated mesangial IgA nephropathy (Berger's disease). In both cases, gluten-free diet rapidly abated the histological and clinical picture, renal as well as intestinal. The authors conclude that all patients with Berger's disease should be tested systematically for antigliadin antibodies of the IgA class with a view to more accurate clinical classification and therapeutic planning.