Injectable depot formulations are aimed at providing long-term sustained release of a drug into systemic circulation, thus reducing plasma level fluctuations and improving patient compliance. The particle size distribution of the formulation in the form of suspension is a key parameter that controls the release rate. In this work, the process of wet stirred media milling (ball milling) of a poorly water-soluble substance has been investigated with two main aims: (i) to determine the parametric sensitivity of milling kinetics; and (ii) to develop scaleup methodology for process transfer from batch to flow-through arrangement. Ball milling experiments were performed in two types of ball mills, a batch mill with a 30 ml maximum working volume, and a flow-through mill with a 250 ml maximum working volume. Milling parameters were investigated in detail by methodologies of QbD to map the parametric space.Specifically, the effects of ball size, ball fill level, and rpm on the particle breakage kinetics were systematically investigated at both mills, with an additional parameter (flow-rate) in the case of the flow-through mill. The breakage rate was found to follow power-law kinetics with respect to dimensionless time, with an asymptotic d 50 particle size in the range of 200-300 nm.In the case of the flow-through mill, the number of theoretical passes through the mill was found to be an important scale-up parameter.
The advantage of magnetic resonance imaging (MRI) is mainly the direct visualization of the physico-chemical processes occurring during the polymer dissolution in real time. Nowadays, polymeric matrices as a means to control the release of the active pharmaceutical ingredient (API) are widely used. Hence it seems necessary to describe the polymer swelling and find the relationship between the type of used polymer and the dissolution profile of API.The aim of our research was to monitor the dissolution kinetics of polymeric matrices with the different ratio of hydrophilic and lipophilic components utilizing MRI technology. For this purpose, six different matrices were prepared. For the dissolution experiments in MRI magnet, plastic flow through cell and tablet holder were designed and manufactured using a 3-D printer. The experiments were performed under specific conditions i.e. phosphate buffer saline pH 6 as a medium, medium temperature - 37°C, the flow rate of medium - 4 ml/min, the time of experiment - 8 hours. To improve the visibility of the erosion front, composite magnetic nanoparticles SiO2/FeOx as a MRI contrast agent were used. Each matrix was measured three times and the thickness of gel layer was evaluated in three different regions. Results from MRI experiments were compared to the results obtained by utilizing the texture analyzer, and then the relationship between polymer swelling and drug release was evaluated.To sum up, MRI turned out to be a suitable imaging method for polymer swelling quantification. For the future measurements, the effect of different additives on the polymer swelling kinetics will be evaluated. The results from the whole research should lead to the database of matrix components and conditions of technological processes and their effects on the dissolution profile of API, thus simplifying the formulation of dosage forms with the desired drug release.
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