Publication
Multivariate analysis of a direct compression pharmaceutical tablets continuous manufacturing process
| Summary: | In the last decade, there have been significant advances in the areas of engineering and science, allowing the implementation of pharmaceutical continuous manufacturing (CM). These advances are coupled with the adoption of the quality by design paradigm for pharmaceutical development and the advances on process analytical technology to improve design, analysis and control. These advances have contributed significantly to advances on the design and manufacturing of pharmaceutical, namely the adoption of continuous processing. Continuous manufacturing can be used for the production of medicines in multiple pharmaceutical forms. If advances are being operated in the field of continuous manufacturing, it is also true that substantial efforts are still required to fully understand how this manufacturing paradigm can be efficiently integrated within industry, for full advantages to be achieved. This work had the objective of pursuing the goal to better understand how materials behave under continuous processing. It aimed at evaluating the performance of a direct compression process for tablets production in continuous mode. Direct compression, a unit operation especially interesting for the manufacturing of tablets, has the ability to be efficiently integrated within a continuous manufacturing framework. The investigated continuous manufacturing process resourced to the continuous table production line located at the PROMIS Center at the School of Pharmacy of the University of Eastern Finland (Kuopio, Finland). The line was configured for direct compression purposes, encompassing multiple gravimetric feeders, a continuous mixer and a tableting machine. Tablets monitoring was accomplished with near-infrared spectroscopy. A formulation containing simultaneously caffeine (2.6%) and paracetamol (20%) was selected for this study. Selected process variables were varied according to an experimental design in order to understand the effects on tablets' properties. Mixer speed (350-1200 rpm), feed rate (5-10 kg/h) and the existence or not of premixture were the selected process variables. Tablets were evaluated according to the weight, hardness and thickness. Feed rate demonstrated as was expected to be fundamental for the stability of the direct compression process. For instance, experiments carried out at lower feed rates (lower than 5kg/h) revealed poor fluidity and tablets were not acceptable. The influence of process variables on tablets properties was modelled by partial least squares regression. Tablets mass is significantly affected, in a positive way, by the speed of the mixer and negatively affected by the feed rate. The range of coefficients of determination for the calibration (R2) and test (Q2) for the three responses were 0.78-0.94 for R2 and 0.56-0.88 for Q2. Near-infrared spectra collected from tablets allowed the development of PLS models for the caffeine and paracetamol content. Validation experiments reveal that the root mean square errors of prediction for caffeine and paracetamol were respectively 11.96% and 10.48%. |
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| Main Authors: | Miranda, Sílvia Maria Mesquita Ribeiro |
| Subject: | Continuous manufacturing Tableting Process analytical tecnhology Chemometrics Near infrared spectroscopy Teses de mestrado - 2018 |
| Year: | 2018 |
| Country: | Portugal |
| Document type: | master thesis |
| Access type: | open access |
| Associated institution: | Universidade de Lisboa |
| Language: | English |
| Origin: | Repositório da Universidade de Lisboa |
| Summary: | In the last decade, there have been significant advances in the areas of engineering and science, allowing the implementation of pharmaceutical continuous manufacturing (CM). These advances are coupled with the adoption of the quality by design paradigm for pharmaceutical development and the advances on process analytical technology to improve design, analysis and control. These advances have contributed significantly to advances on the design and manufacturing of pharmaceutical, namely the adoption of continuous processing. Continuous manufacturing can be used for the production of medicines in multiple pharmaceutical forms. If advances are being operated in the field of continuous manufacturing, it is also true that substantial efforts are still required to fully understand how this manufacturing paradigm can be efficiently integrated within industry, for full advantages to be achieved. This work had the objective of pursuing the goal to better understand how materials behave under continuous processing. It aimed at evaluating the performance of a direct compression process for tablets production in continuous mode. Direct compression, a unit operation especially interesting for the manufacturing of tablets, has the ability to be efficiently integrated within a continuous manufacturing framework. The investigated continuous manufacturing process resourced to the continuous table production line located at the PROMIS Center at the School of Pharmacy of the University of Eastern Finland (Kuopio, Finland). The line was configured for direct compression purposes, encompassing multiple gravimetric feeders, a continuous mixer and a tableting machine. Tablets monitoring was accomplished with near-infrared spectroscopy. A formulation containing simultaneously caffeine (2.6%) and paracetamol (20%) was selected for this study. Selected process variables were varied according to an experimental design in order to understand the effects on tablets' properties. Mixer speed (350-1200 rpm), feed rate (5-10 kg/h) and the existence or not of premixture were the selected process variables. Tablets were evaluated according to the weight, hardness and thickness. Feed rate demonstrated as was expected to be fundamental for the stability of the direct compression process. For instance, experiments carried out at lower feed rates (lower than 5kg/h) revealed poor fluidity and tablets were not acceptable. The influence of process variables on tablets properties was modelled by partial least squares regression. Tablets mass is significantly affected, in a positive way, by the speed of the mixer and negatively affected by the feed rate. The range of coefficients of determination for the calibration (R2) and test (Q2) for the three responses were 0.78-0.94 for R2 and 0.56-0.88 for Q2. Near-infrared spectra collected from tablets allowed the development of PLS models for the caffeine and paracetamol content. Validation experiments reveal that the root mean square errors of prediction for caffeine and paracetamol were respectively 11.96% and 10.48%. |
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