Modelling the effect of L/S ratio and granule moisture content on the compaction properties in continuous manufacturing

The pharmaceutical field is currently moving towards continuous manufacturing pursuing reduced waste, consistency, and automation. During continuous manufacturing, it is important to understand how both operating conditions and material properties throughout the process affect the final properties of the product to optimise and control production. In this study of a continuous wet granulation line, the liquid to solid ratio (L/S) and drying times were varied to investigate the effect of the final granule moisture content and the liquid to solid ratio on the properties of the granules during tabletting and the final tensile strength of the tablets. Both variables (L/S and granule moisture) affected the tablet tensile strength with the moisture content having a larger impact. Further analysis using a compaction model, showed that the compactability of the granules was largely unaffected by both L/S and moisture content while the compressibility was influenced by these variables, leading to a difference in the final tablet strength and porosity. The granule porosity was linked to the L/S ratio and used instead for the model fitting. The effect of moisture content and granule porosity was added to the model using a 3d plane relationship between the compressibility constant, the moisture content and porosity of the granules. The tablet tensile strength model, considering the effect of moisture and granule porosity, performed well averaging a root mean squared error across the different conditions of 0.17 MPa

A Model for Information Representation and Retrieval in Large Organizations. Technical Report 2010-03

In this report, the focus will be on the generation and use of taxonomies for knowledge representation and discovery in organizations. A model for the taxonomic organization, and subsequent use and manipulations, of compound terms is presented. More specifically, the presented model envisions the organization of compound terms into multiple taxonomies which can be dynamically related in various ways based on the context of usage. We will be referring to the set of interrelated taxonomies as facetted taxonomies, following the traditional usage of this term, with the nuance that the set is not static and is dynamically adapting to the usage context

Dissolution and Release Behavior of Swellable Matrix Tablets: Influence of the solubility and dissolution rate enhancement of model substance

Tablets exhibiting extended drug release have in many therapeutical applications shown both compliance and clinical advantages. One way of achieving extended drug release from a tablet is by employing the concept of swellable matrices. These formulations have been a primary candidate for oral dosage forms, due to their advantages in regulatory, manufacturing and drug delivery. Numerous studies in regards to the influence of drug dissolution on the release mechanism of these formulations are a testament of their complexity and also the industrial need for exploring this subject. The aim of this thesis was to shed light on the effect of i) the solubility of additives (components other than the polymeric back bone of the tablets) and ii) the dissolution rate improvement of poorly soluble model drugs on the release from these tablets. A mechanistic view of the influence of solubility on the dissolution and release robustness of swellable matrices was presented. High rate of water transport into the matrix rendered the dissolution characteristics of the tablets significantly more sensitive to shear forces in the dissolution medium. This behavior was seen below the so called polymer percolation threshold of the polymer in the composition. Employment of solid dispersion technology enhanced the dissolution rate and inhibited crystallization of amorphisized model substances. This effect was observed in different degrees, depending on the type of polymeric carrier used in the dispersions. The carriers used in this thesis were PEG 4000, HPMC 100 cps and HPMCAS-MF. In terms of the release of the amorphisized model substance from the matrix, two findings were observed; 1) a balance, which can alter the release mechanism from the matrix can exist between the rate of aqueous dissolution and the crystallization of molecularly dispersed drug, 2) by choosing a proper crystallization inhibitor, drug substances can be delivered in a more readily dissolvable state than that of the crystalline form to the gastrointestinal bulk. The findings in this thesis can help formulators to design more robust tablets and new concepts for prevailing over the issue of low dissolution rate as bioavailability limiting factor

Dissolution and Release Behavior of Swellable Matrix Tablets: Influence of the solubility and dissolution rate enhancement of model substance

Tablets exhibiting extended drug release have in many therapeutical applications shown both compliance and clinical advantages. One way of achieving extended drug release from a tablet is by employing the concept of swellable matrices. These formulations have been a primary candidate for oral dosage forms, due to their advantages in regulatory, manufacturing and drug delivery. Numerous studies in regards to the influence of drug dissolution on the release mechanism of these formulations are a testament of their complexity and also the industrial need for exploring this subject. The aim of this thesis was to shed light on the effect of i) the solubility of additives (components other than the polymeric back bone of the tablets) and ii) the dissolution rate improvement of poorly soluble model drugs on the release from these tablets. A mechanistic view of the influence of solubility on the dissolution and release robustness of swellable matrices was presented. High rate of water transport into the matrix rendered the dissolution characteristics of the tablets significantly more sensitive to shear forces in the dissolution medium. This behavior was seen below the so called polymer percolation threshold of the polymer in the composition. Employment of solid dispersion technology enhanced the dissolution rate and inhibited crystallization of amorphisized model substances. This effect was observed in different degrees, depending on the type of polymeric carrier used in the dispersions. The carriers used in this thesis were PEG 4000, HPMC 100 cps and HPMCAS-MF. In terms of the release of the amorphisized model substance from the matrix, two findings were observed; 1) a balance, which can alter the release mechanism from the matrix can exist between the rate of aqueous dissolution and the crystallization of molecularly dispersed drug, 2) by choosing a proper crystallization inhibitor, drug substances can be delivered in a more readily dissolvable state than that of the crystalline form to the gastrointestinal bulk. The findings in this thesis can help formulators to design more robust tablets and new concepts for prevailing over the issue of low dissolution rate as bioavailability limiting factor

Dissolution Rate Enhancement of Parabens in PEG Solid Dispersions and Its Influence on the Release from Hydrophilic Matrix Tablets

The dissolution rate of a homologous series of parabens and their dispersions inPEG 4x103 was examined. In light of these measurements, the release behavior of thesubstances from extended release hydrophilic matrix tablets based on PEO 5x106 was studied.Tablet release was examined for matrices comprising either a physical mixture of PEG, paraben,and PEO, or a solid solution of each paraben in PEG, incorporated in the PEO matrix.Considerable increase of the dissolution rate for the eutectic and in particular solid solutionform of the parabens was observed. The hydration rate of all matrices, as well as polymer release,was the same. The release rate of methyl, ethyl, and butyl parabens in solid solution form wassimilar to that of their crystalline form. However, the release rate of the solid solution form ofpropyl paraben was higher than that of its crystalline form, especially in the initial part of therelease. The results indicate that all parabens crystallized in the gel layer of the solid solutionformulations upon the process of tablet dissolution. This was proposed to be an effect ofdifferences in the dissolution and crystallization kinetics of the parabens

The Impact of Dose and Solubility of Additives on the Release from HPMC Matrix Tablets-Identifying Critical Conditions

Purpose. The dissolution of HPMC matrix tablets containing different amounts of highly soluble (mannitol) or poorly soluble (dicalcium phosphate, DCP) was studied to deduce the parameters critical to release robustness. Methods. The release of HPMC and additives was studied using a modified USP II method at two paddle stirring rates, 50 and 125 rpm, at HPMC content varying from 15% to 100%. Results. At HPMC contents between 30% and 35% a critical point was identified and found crucial to the release from the HPMC/mannitol tablets. Below this point the matrix rapidly disintegrated in a non robust manner. At higher HPMC contents the mannitol release became increasingly diffusion controlled with maintained matrix integrity. The release robustness was lower for HPMC/DCP than HPMC/mannitol tablets at high HPMC contents, however, lacking critical points. The critical point was interpreted as the percolation threshold for HPMC and differences explained in terms of water transport into the matrix. Conclusion. The release robustness was lower for formulations with additives of low solubility having an erosion controlled release than for additives with higher solubility and a diffusion controlled release. However, for additives creating a steep osmotic pressure gradient, an HPMC content above the percolation threshold becomes vital for maintaining the release robustness