A novel approach to support formulation design on twin screw wet granulation technology : understanding the impact of overarching excipient properties on drug product quality attributes

The overall objective of this work is to understand how excipient characteristics influence the drug product quality attributes and process performance of a continuous twin screw wet granulation process. The knowledge gained in this study is intended to be used for Quality by Design (QbD)-based formulation design and formulation optimization. Three principal components which represent the overarching properties of 8 selected pharmaceutical fillers were used as factors, whereas factors 4 and 5 represented binder type and binder concentration in a design of experiments (DoE). The majority of process parameters were kept constant to minimize their influence on the granule and drug product quality. 27 DoE batches consisting of binary filler/binder mixtures were processed via continuous twin screw wet granulation followed by tablet compression. Multiple linear regression models were built providing understanding of the impact of filler and binder properties on granule and tablet quality attributes (i.e. 16 DoE responses). The impact of fillers on the granule and tablet responses was more dominant compared to the impact of binder type and concentration. The filler properties had a relevant effect on granule characteristics, such as particle size, friability and specific surface area. Binder type and concentration revealed a relevant influence on granule flowability and friability as well as on the compactability (required compression force during tableting to obtain target hardness). In order to evaluate the DoE models' validity, a verification of the DoE models was performed with new formulations (i.e. a new combination of filler, binder type and binder concentration) which were initially not included in the dataset used to build the DoE models. The combined PCA (principle component analysis)/DoE approach allowed to link the excipient properties with the drug product quality attributes

Prediction of first test day milk yield using historical records in dairy cows

The transition between two lactations remains one of the most critical periods during the productive life of dairy cows. In this study, we aimed to develop a model that predicts the milk yield of dairy cows from test day milk yield data collected in the previous lactation. In the past, data routinely collected in the context of herd improvement programmes on dairy farms have been used to provide insights in the health status of animals or for genetic evaluations. Typically, only data from the current lactation is used, comparing expected (i.e., unperturbed) with realised milk yields. This approach cannot be used to monitor the transition period due to the lack of unperturbed milk yields at the start of a lactation. For multiparous cows, an opportunity lies in the use of data from the previous lactation to predict the expected production of the next one. We developed a methodology to predict the first test day milk yield after calving using information from the previous lactation. To this end, three random forest models (nextMILKFULL, nextMILKPH, and nextMILKP) were trained with three different feature sets to forecast the milk yield on the first test day of the next lactation. To evaluate the added value of using a machine-learning approach against simple models based on contemporary animals or production in the previous lactation, we compared the nextMILK models with four benchmark models. The nextMILK models had an RMSE ranging from 6.08 to 6.24 kg of milk. In conclusion, the nextMILK models had a better prediction performance compared to the benchmark models. Application-wise, the proposed methodology could be part of a monitoring tool tailored towards the transition period. Future research should focus on validation of the developed methodology within such tool

Twin-screw granulation – a systematic analysis of process parameters

Twin-screw granulation has a significant advantage over traditional granulation methods leading to the possibility of continuous manufacturing. Although this technology has drawn attention in recent years, the general understanding of the process is limited. This study gives a brief overview of the most important process parameters and their influence on product quality. Experimental results from a benchtop granulator and an in-line particle size measurement have been analysed. From this basic study conclusions can be drawn how to tailor the particle size distribution in twin-screw granulation. The most crucial parameters are the liquid-to-solid ratio and the filling level of the screws

Sustainable Materials and Biorefinery Chemicals from Agriwastes

This is an open access chapter distributed under the terms of the Creative Commons Attribution License.-- et al.Countries with economies based on agriculture generate vast amounts of low or null value wastes which may even represent an environmental hazard. In our group, agricultural industrial wastes have been converted into value added liquid substances and materials with several aims: decreasing pollution, giving added value to wastes and working in a sustainable manner in which the wastes of an industry can be used as the raw materials of the same or others, as the “cradle to cradle” philosophy states [1]. Sub-products from the agricultural food industry are being employed as renewable low cost raw materials in the preparation of Ecomaterials, designed for use in a number of industrial processes of great interest. Given their origin, these materials may compete with conventional ones since with this process a sustainable cycle is closed, in which the residues of one industry are used as raw materials in the same or other industries [2]. With regards to the composition of the residues produced from agriculture, the pH of soil is of great importance, since plants can only absorb the minerals that are dissolved in water and pH is mandatory for the physical, chemical and biological properties of soil and the main cause of many agronomic questions related to nutrient assimilation [3-5]. Variations of pH modify the solubility of most elements necessary for the development of crops and also influence the microbian activity of soil, which will affect the transformation of elements that are liberated to the soil and can be assimilated to form crops or not [3]. For example at pH lower than 6 or higher than 8 bacterian activities are lowered, the oxidation of nitrogen to nitrate is reduced and the amount of nitrogen available for plant food is decreased. However Al, Fe and manganese are more soluble at low pHs, reaching even toxic concentrations. Potassium and sulphur are easily adsorbed at pH higher than 6, calcium and magnesium between 7 and 8.5 and iron at pH lower than 6. For alkaline pH in soil, the availability of H2PO4-can be reduced through precipitation of phosphorous containing salts withcations such as calcium Ca2+ or magnesium Mg2+. However when soils have acid pH other compounds with HPO42-and iron (Fe2+), aluminium (Al3+) and manganese (Mn2+) can form, with increased solubility. The main factors that influence soil pH are the mineral composition and how it meteorizes, the decomposition of organic matter, how nutrients are partitioned among the solution and aggregates and of course the pluviometryof the zone and atmospheric contamination.Lower pHs are found in places with high pluviometry, with high organic matter decomposition, young soils developed on acid substrates, and places with high atmospheric contamination (acid rain). Depending on the species, crops can benefit from calcareous soils with high calcium carbonate content such as alfalfa, but other plants prefer soils with acid pH such as potatoes, coffee or tobacco. It is clear that different seasons will produce plants with a varying composition depending on the atmospheric conditions and therefore the materials derived from them need to be characterised and analysed to determine their possible uses.Given its multidisciplinary approach, this work is being carried out through the collaboration among national (Institute of Materials Science of Madrid (ICMM, CSIC), Institute of Catalysis (ICP, CSIC), Centre of Molecular Biology Severo Ochoa (UAM-CSIC), Polytechnic University of Madrid (UPM), University at distance (UNED), University Complutense of Madrid (UPM) and international (University of Sheffield and University of Ghent) research groups, in addition to various industries interested in the transformation of their residues and or sub-products into “value added materials”, with whom various research projects have been and are being sponsored by the MICINN and CDTI.Peer Reviewe