University of Helsinki
Optimization of particle size distribution in continuous wet granulation process (ConsiGma25).
Degree: Farmaceutiska fakulteten, 2016, University of Helsinki
There is a growing interest towards continuous manufacturing in pharmaceutical industry. When considering solid dosage form manufacturing and continuous wet granulation, twin screw granulation is the most studied technology. In spite of this, process knowledge is not as comprehensive as it is for batch granulation technologies such as high shear granulation. One problem with twin screw granulation seems to be bimodal and broad particle size distribution of granules. Specific causes of bimodal distribution and the ways to possibly gain unimodality either in granulation step or via dry milling are not fully understood.
The purpose of this study was to optimize the ConsiGma25 continuous twin screw wet granulation process and study dry milling as a possible way of gaining unimodal particle size distribution in order to optimize particle size for tablet compression purposes. One aim was also to compress tablets from the obtained twin screw granules and evaluate the quality against high shear and direct compressed tablets of same formulation.
Central composite circumscribed design was used as a design of experiments for twin screw wet granulation process. Factors (powder feed rate, screw speed, liquid to solid ratio (L/S ratio) and mill screen size) were varied in two levels. In total, 29 experiments were conducted. Tablet compression design was fractional as only 11 experiments from the twin screw granulation design were tableted. High shear granulation was conducted with Diosna P-1/6 using three different L/S ratios. All of these batches were compressed to tablets. Also direct compression was carried out. Formulation used had ibuprofen as active pharmaceutical ingredient, mannitol and MCC as fillers, HPC as binder and croscarmellose sodium as disintegrant. Lubricant, sodium stearyl fumarate, was blended to granules before tablet compression.
Torque was measured during granulation in order to evaluate equilibration of the twin screw granulation process. It stabilized quickly and stayed stable after parameter changes and increased as L/S ratio and barrel fill rate increased. Particle size distribution and flowability of granules were analysed and tablets were analysed according to European and United States pharmacopoeias. Also tensile strengths and compactibilities were evaluated.
Particle size distributions of unmilled twin screw granules were bimodal and broad. After dry milling, QicPic dynamic image analysis results showed unimodal particle size distributions for all experiments whereas Mastersizer laser diffraction analysis showed more unimodal distributions for experiments milled with smaller mill screen sizes. Mill screen size had the largest effect on particle size and as increased mill screen size increased particle size. Results showed that dry milling was a way to optimize particle size distribution for tablet compression purposes. Also flowability of formulation and process parameters needed to be optimized as granulation parameters had an effect on particle size and manufacturability was enhanced with…
Subjects/Keywords: continuous granulation; wet granulation; twin screw granulation; ConsiGma; dry milling; Industriell farmaci; Industrial pharmacy; Teollisuusfarmasia; continuous granulation; wet granulation; twin screw granulation; ConsiGma; dry milling
to Zotero / EndNote / Reference
APA (6th Edition):
Häkkinen, A. (2016). Optimization of particle size distribution in continuous wet granulation process (ConsiGma25). (Masters Thesis). University of Helsinki. Retrieved from http://hdl.handle.net/10138/161269
Chicago Manual of Style (16th Edition):
Häkkinen, Aino. “Optimization of particle size distribution in continuous wet granulation process (ConsiGma25).” 2016. Masters Thesis, University of Helsinki. Accessed September 15, 2019.
MLA Handbook (7th Edition):
Häkkinen, Aino. “Optimization of particle size distribution in continuous wet granulation process (ConsiGma25).” 2016. Web. 15 Sep 2019.
Häkkinen A. Optimization of particle size distribution in continuous wet granulation process (ConsiGma25). [Internet] [Masters thesis]. University of Helsinki; 2016. [cited 2019 Sep 15].
Available from: http://hdl.handle.net/10138/161269.
Council of Science Editors:
Häkkinen A. Optimization of particle size distribution in continuous wet granulation process (ConsiGma25). [Masters Thesis]. University of Helsinki; 2016. Available from: http://hdl.handle.net/10138/161269