Occurrence and prevention of Pickering foams in pharmaceutical nano-milling.

Particle size reduction to sub-micrometer dimensions in stirred media mills is an increasingly common formulation strategy used for improving the bioavailability of poorly aqueous soluble active pharmaceutical ingredients (APIs). Due to their hydrophobic character, the API particles need to be stabilised by a surfactant in order to form a stable nano-suspension. This work is concerned with the understanding of an undesired phenomenon often encountered during the development and scale-up of wet nano-milling processes for hydrophobic APIs - the formation of foams. We investigate the microstructure, rheology and stability of these foams, and find them to be Pickering foams stabilised by solid particles at the gas-liquid interface rather than by a surfactant. By exploring the effect of surfactant concentration on the on-set of foaming in conjunction with the milling kinetics, we find a relationship between the specific surface area of the nano-suspension, the quantity of surfactant present in the formulation and the occurrence of foaming. We propose a mechanistic explanation of foam formation, and find that in order to prevent foaming, a large surfactant excess of approx. 100x above the critical micelle concentration has to be present in the solution in order to ensure a sufficiently rapid coverage of freshly exposed hydrophobic surfaces formed during the wet nano-milling process.

The influence of thermal treatment and type of insoluble poly(meth)acrylates on dissolution behavior of very soluble drug from hypromellose matrix tablets evaluated by multivariate data analysis.

Hypromellose matrices exhibit extended burst effect immediately after contact with aqueous medium, especially when a water-soluble drug is incorporated. The objective of this study was to reduce burst effect and maintain complete dissolution of a very soluble levetiracetam over 12 h period from hypromellose K4M matrices to obtain zero-order kinetics. Desired changes were achieved by applying water dispersions of insoluble Eudragits® (NE, NM, RL, RS) as a granulation liquid to the drug/microcrystalline cellulose mixture during high-shear granulation (non-thermal treated set) and consequently by thermally treating granules or final tablets (TT), respectively. Applying Eudragit® water dispersions to the drug/microcrystalline cellulose mixture was recognized as an effective method of significantly reducing the burst release (25.4-33.7%) of levetiracetam in comparison with a reference sample without Eudragit®. Multivariate data analysis showed that the addition of Eudragit® reduced burst effect, increased fitting with zero-order kinetics, and supported matrix erosion as the supplementary mechanism to predominant diffusion. Moreover, resulting PCA sub-model revealed the addition of Eudragit® RL and thermal treatment of tablets to be the most suitable method of all. For a 12 h dissolution profile, characterized by low burst effect and drug release close to 100% at the 12th hour, sample RL_TT was the most suitable.

Scale-up from batch to flow-through wet milling process for injectable depot formulation.

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 scale-up 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 30ml maximum working volume, and a flow-through mill with a 250ml 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 d50 particle size in the range of 200-300nm. 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.

Effect of hydrophobic inclusions on polymer swelling kinetics studied by magnetic resonance imaging.

The rate of drug release from polymer matrix-based sustained release formulations is often controlled by the thickness of a gel layer that forms upon contact with dissolution medium. The effect of formulation parameters on the kinetics of elementary rate processes that contribute to gel layer formation, such as water ingress, polymer swelling and erosion, is therefore of interest. In the present work, gel layer formation has been investigated by magnetic resonance imaging (MRI), which is a non-destructive method allowing direct visualization of effective water concentration inside the tablet and its surrounding. Using formulations with Levetiracetam as the active ingredient, HPMC as a hydrophilic matrix former and carnauba wax (CW) as a hydrophobic component in the matrix system, the effect of different ratios of these two ingredients on the kinetics of gel formation (MRI) and drug release (USP 4 like dissolution test) has been investigated and interpreted using a mathematical model.