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.     

Spectrophotometric analysis of disintegration mechanisms (abrasion and crushing) of agglomerates during the disc granulation of dolomite

The analysis of mechanisms which affect the formation of agglomerates and determine the granulation process in a broad sense encounters difficulties related to the many ways of the formation of granules. The aim of the study was to perform a qualitative and quantitative analysis of granulation mechanisms with special reference to agglomerates’ disintegration in the disc granulation process. This paper contains an analysis of disintegration mechanisms (abrasion and crushing) of agglomerates during the disc granulation of dolomite. The analysis of the mechanisms taking place during the process concerns the granulation stage after wetting. During the research, each time after the wetting stage, the size fraction 10–12.5 mm was substituted with an analogous fraction wetted by means of an aqueous solution of a coloring agent and the process was continued. After the specified time of granulation, the obtained product was sieved through laboratory sieves and then the content of the provided coloring agent in different size fractions was analyzed by means of a spectrophotometer. Measuring the absorbance of the analyzed samples and granulometric composition of the bed, the level and cause of the migration of material of the tested fraction into other size classes were determined, and at the same time, the occurring granulation mechanisms were analyzed. The proposed model and measurement method consisting of determining the absorbance of the tested granulometric fraction enable the qualitative and quantitative analysis of granulation mechanisms are encountered during the carrying-out of the process after wetting the bed.     

Formalizing process-based risk with Value-Focused Process Engineering

Following calls to advance the integration of risk and business process modeling paradigms, this paper formalizes the process of incorporating risk into business process models through the principles of Value-Focused Process Engineering (VFPE). In doing so, the paper aims to extend the existing VFPE modeling notation to reflect a set of necessary constructs required to adequately represent risk in goal-oriented business-process models. The extended set of constructs is proposed to support a formal systems view of process-based risk. Process-based risk is formalized on the one hand, as a product of complex interactions between activity-based elements, and on the other hand, as a natural component of the value creation mechanism of an elementary function or a complex process. The proposed risk-aware VFPE formalism also formulates rules for decomposing risk in process models according to the organizational values, thereby enabling better risk visibility, reducing process complexity, and ensuring continuity of business processes.     

Implementation of a strain energy-based nonlinear finite element in the object-oriented environment

The objective of the paper is to describe a novel finite element computational method based on a strain energy density function and to implement it in the object-oriented environment. The original energy-based finite element was put into the known standard framework of classes and handled in a different manner. The nonlinear properties of material are defined with a modified strain energy density function. The local relaxation procedure proposed as a method used to resolve a nonlinear problem is implemented in C++ language. The hexahedral element with eight nodes as well as the adaptation of the nonlinear finite element is introduced. The chosen numerical model is made of nearly incompressible hyperelastic material. The application of the proposed element is shown on the example of a rectangular parallelepiped with a hollow port.     

Fixed points of the RSA encryption algorithm

In this paper the problem of the number of fixed points for an RSA algorithm is considered. This is an important question from the point of view of any cryptosystem. We have estimated the expected value of this number for randomly chosen RSA parameters. It turned out that it is O(ln²n), and the probability of finding such a point is O(ln²n/n). Thus, these values are really negligible, which had been intuitively expected.     

Immune-based algorithms for dynamic optimization

The main problem with biologically inspired algorithms (like evolutionary algorithms or particle swarm optimization) when applied to dynamic optimization is to force their readiness for continuous search for new optima occurring in changing locations. Immune-based algorithm, being an instance of an algorithm that adapt by innovation seem to be a perfect candidate for continuous exploration of a search space. In this paper we describe various implementations of the immune principles and we compare these instantiations on complex environments.