Recent progress in continuous and semi-continuous processing of solid oral dosage forms: a review

Context: Continuous processing is an innovative production concept well known and successfully used in other industries for many years. The modern pharmaceutical industry is facing the challenge of transition from a traditional manufacturing approach based on batch-wise production to a continuous manufacturing model.

Objective: The aim of this article is to present technological progress in manufacturing based on continuous and semi-continuous processing of the solid oral dosage forms.

Methods: Single unit processes possessing an alternative processing pathway to batch-wise technology or, with some modification, an altered approach that may run continuously, and are thus able to seamlessly switch to continuous manufacturing are briefly presented. Furthermore, the concept of semi-continuous processing is discussed. Subsequently, more sophisticated production systems created by coupling single unit processes and comprising all the steps of production, from powder to final dosage form, were reviewed. Finally, attempts of end-to-end production approach, meaning the linking of continuous synthesis of API from intermediates with the production of final dosage form, are described.

Results: There are a growing number of scientific articles showing an increasing interest in changing the approach to the production of pharmaceuticals in recent years. Numerous scientific publications are a source of information on the progress of knowledge and achievements of continuous processing. These works often deal with issues of how to modify or replace the unit processes in order to enable seamlessly switching them into continuous processing. A growing number of research papers concentrate on integrated continuous manufacturing lines in which the production concept of “from powder to tablet” is realized. Four main domains are under investigation: influence of process parameters on intermediates or final dosage forms properties, implementation of process analytical tools, control-managing system responsible for keeping continuous materials flow through the whole manufacturing process and the development of new computational methods to assess or simulate these new manufacturing techniques. The attempt to connect the primary and secondary production steps proves that development of continuously operating lines is possible.

Conclusion: A mind-set change is needed to be able to face, and fully assess, the advantages and disadvantages of switching from batch to continuous mode production.     

Microstructure and Processing of 3D Printed Tungsten Microlattices and Infiltrated W–Cu Composites

Tungsten is of industrial relevance due its outstanding intrinsic properties (e.g., highest melting‐point of all elements) and therefore difficult to 3D‐print by conventional methods. Here, tungsten micro‐lattices are produced by room‐temperature extrusion‐based 3D‐printing of an ink comprising WO₃–0.5%NiO submicron powders, followed by H₂‐reduction and Ni‐activated sintering. The green bodies underwent isotropic linear shrinkage of ≈50% during the thermal treatment resulting in micro‐lattices, with overall 35–60% open‐porosity, consisting of 95–100% dense W–0.5%Ni struts having ≈80–300 μm diameter. Ball‐milling the powders and inks reduced the sintering temperature needed to achieve full densification from 1400 to 1200 °C and enabled the ink to be extruded through finer nozzles (200 μm). Partial sintering of the struts is achieved when NiO is omitted from the ink, with submicron interconnected‐porosity of ≈34%. Several tungsten micro‐lattices are infiltrated with molten copper at 1300 °C under vacuum, resulting in dense, anisotropic W–Cu composites with 40–65% tungsten volume fraction. Partially sintered struts (containing nickel) with submicron open porosity are also infiltrated with Cu, resulting in co‐continuous W–Cu composites with wide W struts/Cu channels at the lattice scale (hundreds of micrometers), and fine W–Cu interpenetrating network at the strut scale (hundreds of nanometers) allowing for the design of anisotropic mechanical and electrical properties.

     

Labeling Schemes for Tree Representation

This paper deals with compact label-based representations for trees. Consider an n-node undirected connected graph G with a predefined numbering on the ports of each node. The all-ports tree labeling ℒ _all gives each node v of G a label containing the port numbers of all the tree edges incident to v. The upward tree labeling ℒ _up labels each node v by the number of the port leading from v to its parent in the tree. Our measure of interest is the worst case and total length of the labels used by the scheme, denoted M _up (T) and S _up (T) for ℒ _up and M _all (T) and S _all (T) for ℒ _all . The problem studied in this paper is the following: Given a graph G and a predefined port labeling for it, with the ports of each node v numbered by 0,…,deg (v)−1, select a rooted spanning tree for G minimizing (one of) these measures. We show that the problem is polynomial for M _up (T), S _up (T) and S _all (T) but NP-hard for M _all (T) (even for 3-regular planar graphs). We show that for every graph G and port labeling there exists a spanning tree T for which S _up (T)=O(nlog log n). We give a tight bound of O(n) in the cases of complete graphs with arbitrary labeling and arbitrary graphs with symmetric port labeling. We conclude by discussing some applications for our tree representation schemes. A preliminary version of this paper has appeared in the proceedings of the 7th International Workshop on Distributed Computing (IWDC), Kharagpur, India, December 27–30, 2005, as part of Cohen, R. et al.: Labeling schemes for tree representation. In: Proceedings of 7th International Workshop on Distributed Computing (IWDC), Lecture Notes of Computer Science, vol. 3741, pp. 13–24 (2005). R. Cohen supported by the Pacific Theaters Foundation. P. Fraigniaud and D. Ilcinkas supported by the project “PairAPair” of the ACI Masses de Données, the project “Fragile” of the ACI Sécurité et Informatique, and by the project “Grand Large” of INRIA. A. Korman supported in part by an Aly Kaufman fellowship. D. Peleg supported in part by a grant from the Israel Science Foundation.     

Theories of initial segments of standard models of arithmetics and their complete extensions

We investigate families of finite initial segments of standard models for various arithmetics. We give an axiomatization of the theory of sentences true in almost all finite models with addition. We also characterize its complete extensions and relate its infinite models to models of Presburger arithmetic.We also estimate the complexity of complete extensions of the arithmetic with addition and multiplication.     

Approximation algorithm for hotlink assignment in the greedy model

Link-based information structures such as the web can be enhanced through the addition of hotlinks. Assume that each node in the information structure is associated with a weight representing the access frequency of the node by users. In order to access a particular node, the user must follow a path leading to it from the root. By adding new hotlinks to the tree, it may be possible to reduce the access cost of the system, namely, the expected number of steps needed to reach a leaf from the root, assuming the user can decide which hotlinks to follow in each step. The hotlink assignment   problem involves finding a set of hotlinks (with at most K=O(1)$K=O\left(1\right)$ hotlinks emanating from every node) maximizing the gain in the expected cost. The paper addresses this problem in two user models, namely, the traditional clairvoyant user model employed in [P. Bose, J. Czyzowicz, L. Gasieniec, E. Kranakis, D. Krizanc, A. Pelc, M.V. Martin, Strategies for hotlink assignments, in: Proc. 11th Symp. on Algorithms and Computation, 2000, pp. 23–34; E. Kranakis, D. Krizanc, S. Shende, Approximating hotlink assignments, in: Proc. 12th Symp. on Algorithms and Computation, 2001, pp. 756–767; P. Bose, D. Krizanc, S. Langerman, P. Morin, Asymmetrical communication protocols via hotlink assignments, in: Proc. 9th Colloq. on Structural Information and Communication Complexity, 2002, pp. 33–39; R. Matichin, D. Peleg, Approximation algorithm for hotlink assignments in web directories, in: Proc. Workshop on Algorithms and Data Structures, 2003, pp. 271–280] and the more realistic greedy user model recently introduced in [O. Gerstel, S. Kutten, R. Matichin, D. Peleg, Hotlink enhancement algorithms for web directories, in: Proc. 14th Symp. on Algorithms and Computation, 2003, pp. 68–77], and presents a polynomial time 2-approximation algorithm for the hotlink assignment problem on rooted directed trees.     

Water Balance of the Upper Jordan River Basin

Sharing water in the Jordan basin has been a key topic in the recent peace talks between Israel and its neighbors. Knowing the quantity of water available is a prerequisite to water sharing. Many different values have been published in recent years. Different sources report Jordan's discharge flow into Lake Kinneret anywhere from 460 to 800 Mm³/year. The aim of this article is to present a water balance for the Jordan basin for a 15-year period. The years 1977–1978 to 1991–1992 were studied for the basin's water budget, as they represent the present day (1998) land use. The results show that Lake Kinneret has a yearly average input (= output) of 770 Mm³. Israel uses some 800 Mcm³/year from the entire Jordan basin, of which 440 Mm³ is used within the basin and the rest outside. There is about 100 Mm³ for future utilization in the watershed. The yearly Jordan's discharge to the Dead Sea is 220–250 Mm³. Reporting by various secondary data sources is compared to primary data findings to illustrate the great variability of data reporting and to provide annual flow estimates, based largely on primary sources, for the Upper Jordan River.     

Security Policy Conflicts in Service-oriented Systems

This paper considers methods for knowledge exploitation in security policies for Service-Oriented Architecture (SOA) environments, discovering the modality conflicts in particular. Two algorithms for discovering SOA-specific modality conflicts are proposed. First, a trivial (ad-hoc) approach is presented and further extended by the improved algorithm which offers lower time complexity. The formal verification of the proposal is followed by experimental results confirming the expected supremacy of the improved algorithm.     

Labeling Schemes for Dynamic Tree Networks

Distance labeling schemes are composed of a marker algorithm for labeling the vertices of a graph with short labels, coupled with a decoder algorithm allowing one to compute the distance between any two vertices directly from their labels (without using any additional information). As applications for distance labeling schemes concern mainly large and dynamically changing networks, it is of interest to study distributed dynamic labeling schemes. The current paper considers the problem on dynamic trees, and proposes efficient distributed schemes for it. The paper first presents a labeling scheme for distances in the dynamic tree model, with amortized message complexity O(log² n) per operation, where n is the size of the tree at the time the operation takes place. The protocol maintains O(log² n) bit labels. This label size is known to be optimal even in the static scenario. A more general labeling scheme is then introduced for the dynamic tree model, based on extending an existing static tree labeling scheme to the dynamic setting. The approach fits a number of natural tree functions, such as distance, separation level, and flow. The main resulting scheme incurs an overhead of an O(log n) multiplicative factor in both the label size and amortized message complexity in the case of dynamically growing trees (with no vertex deletions). If an upper bound on n is known in advance, this method yields a different tradeoff, with an O(log² n/log log n) multiplicative overhead on the label size but only an O(log n/log log n) overhead on the amortized message complexity. In the fully dynamic model the scheme also incurs an increased additive overhead in amortized communication, of O(log² n) messages per operation.