Systematic investigation of the cavi-precipitation process for the production of ibuprofen nanocrystals

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Abstract

Cavi-precipitation process is a combinative particle size reduction technology based on solvent-anti-solvent precipitation coupled high pressure homogenization (HPH). The cavi-precipitation can be used for the efficient production of drug nanocrystals (NC) with improved dissolution rate leading to better bioavailability. The work presented here demonstrates the advantage of cavi-precipitation process over the standard HPH processes and standard combination process (decoupled process) where precipitation is performed outside the homogenizer. The model compound ibuprofen (IBP) was solubilized in isopropanol (IPA) to constitute the solvent phase and mixed with the anti-solvent phase (0.1% (w/v) hydroxypropyl methylcellulose with 0.2% (w/v) sodium dodecyl sulphate) at different ratios to carry out the precipitation step. IBP-IPA-Water composition was selected from ternary diagram for a highly supersaturated zone to obtain smaller size particles. The mean particle size [d(0.5)] obtained by this process (300 nm) was much smaller when compared to that obtained from the decoupled process (1.5 μm). Optimization of the solvent-anti-solvent ratio and drug concentration was necessary to achieve a smaller particle size. PXRD and DSC results revealed that the solid state properties of the original IBP and the prepared NC samples by cavi-precipitation samples were similar.

Introduction

Poor water solubility of compounds has become a major challenge in the drug development process. The presence of hydrophobic moieties makes a compound less water soluble and thereby often less orally bioavailable. Nanosizing as a technological approach has proved to be a successful drug delivery platform for poorly water soluble compounds, as several drug nanocrystal products have been introduced on the pharmaceutical market in the last decade (Van Eerdenbrugh et al., 2008).

In general, four different ways are used to produce drug nanocrystals, i.e., chemical reactions, top-down, bottom-up, and combination approaches. Top-down technologies are mostly used now-a-days, because of their universal applicability (Moschwitzer and Muller, 2007). Bottom-up approaches are relatively old but have not been widely used for pharmaceutical products so far. However, they are gaining more attention since they have the potential to result in small size drug nanocrystals with less energy demanding processes (Rasenack and Muller, 2004, Sinha et al., 2013). Especially, in recent times, the liquid anti-solvent precipitation process has drawn attention of various research groups (D’Addio and Prud’homme, 2011, Dong et al., 2009, Liu et al., 2012, Thorat and Dalvi, 2012, Xu et al., 2012). The possibility of using cheaper process equipments, faster processes, and avoidance of contamination from the grinding material are the major driving forces behind the shift of the attention. Inspite of being a primitive process (Franke and Mersmann, 1995) and easy to perform, it is still difficult to control the particle size in this process.

Furthermore, there are still more opportunities of generating intellectual property in the field of drug nanocrystals production (Moschwitzer, 2012). This can also be seen with some newer precipitation techniques that have been developed more recently (D’Addio and Prud’homme, 2011, Liu et al., 2008).

The combination of precipitation with top-down methods is another way to preserve the small size of particles after precipitation. It was demonstrated that combining a top- down method with solvent-anti-solvent precipitation method could generate smaller size particles than either of the conventional approaches. This process was first described and used by a research group at Baxter and patented as NANOEDGE™ (Kipp et al., 2001, Rabinow, 2004). The NANOEDGE™ process is essentially a decoupled process where the bottom-up step is used first to generate a fragile material which is homogenized in the next step to reduce the particle size and to anneal the particles to stabilize their surfaces. Hence, there is a significant time difference between the precipitation and the high pressure homogenization (HPH) technique. This time difference between the precipitation and the high energy application step is suspected to allow the particles sufficient time to grow in size.

The importance of the time difference was realized by our research group. Hence, the cavi-precipitation process was developed and later used to produce drug nanocrystals for few compounds (Kakran et al., 2012, Müller and Möschwitzer, 2009). In this process, a precipitation step is carried out in proximity to the high energy zone of a homogenizer. When high pressure is applied during a precipitation process, it serves dual functions. On one hand, it breaks down newly formed, fragile but comparatively larger crystals and on the other, it could be helpful to achieve faster mixing of the solvent and the anti-solvent phase in the timescale of μs (Mohr, 1987). However, as the process is relatively new, it has not been investigated in detail and parameters are not well established yet.

As pointed out by many research articles, there are multiple interconnected factors in the precipitation process that affect the final particle size (Shelar et al., 2012, Sinha et al., 2013, Xu et al., 2012). However, the degree of supersaturation and the mixing efficiency are inarguably the two most influential factors. Changing the solvent-anti-solvent ratio and the drug concentration are often the common ways to alter the degree of supersaturation during precipitation process.

Drug concentrations and solvent-anti-solvent ratios are selected in such a way which causes immediate precipitation of the dissolved solute. Conventionally, although, the process parameters are changed to assess their effect on the particle size, the solvent-anti-solvent system condition is always kept in the precipitation zone to generate a high degree of supersaturation. On other hand, precipitation from a high supersaturation region is often difficult to control and generates bigger particles at the end. On the other hand, a sub-saturated system remains stable and precipitation of the solute phase does not take place from such a system in normal condition. Does application of high energy to such a system might induce a controlled precipitation leading to smaller particle size? To the best of our knowledge, no one had ever investigated this situation. Additionally, to the best of our knowledge, no report exists which demonstrates how the constitution of solvent anti-solvent combination affects the final particle size after HPH.

Because of ductile nature and associated challenge in particle size reduction, ibuprofen (IBP) was used as a model compound in this study (Larsson and Kristensen, 2000, Plakkot et al., 2011). It has also been extensively investigated for solvent-anti-solvent precipitation studies (Rasenack and Muller, 2002, Rasenack et al., 2004, Verma et al., 2009). Even IBP is poorly water soluble but it has good solubility in several organic solvents, hence, it is very well suited for solvent-anti-solvent precipitation study.

The objective of the study was to investigate the different physical conditions which results from mixing the solvent phase (S-phase) and the anti-solvent phase (AS-phase) in different ratios. It was investigated which particle size can be achieved when mixtures at different conditions are processed with high pressure homogenization. Another objective was to investigate whether it was possible to achieve controlled precipitation from specific, sub-saturated mixtures (i.e. the oiling-out phases) of the S and the AS phases by applying high energy (using HPH). The most important objective of this study was, however, to assess the effect of different time intervals between the precipitation and the HPH process on the resulting final particle size of nanosuspensions. Therefore, the particle sizes obtained by different processes such as standard HPH, de-coupled precipitation, and HPH process as well as cavi-precipitation were compared.

Section snippets

Materials

IBP was used as a model compound and purchased from BASF (Ludwigshafen, Germany). Isopropanol (IPA) was used as the organic solvent phase and purchased from VWR International GmbH (Dresden, Germany). The AS-phase was constituted of 0.1% (w/v) hydroxypropyl methylcellulose (HPMCE5, Colorcon, Orpington, UK) and 0.2% (w/v) sodium dodecyl sulphate (SDS) (granular) (Sigma–Aldrich Chemie GmbH, Munich, Germany).

Construction of the ternary phase diagram for IBP-IPA-Water system

To study a wide range of solvent-anti-solvent compositions, a ternary phase diagram was

Ternary phase diagram of IBP-IPA-Water

The ternary diagram was constructed with three major components; drug (IBP), solvent (IPA), and anti-solvent phase (Water). Fig. 2I shows the ternary diagram of different physical compositions with different color coded zones. Five different zones were identified. Among them, two were bigger zones, i.e., insoluble zone [red zone (A)] and solution zone [blue zone (E)] and three were relatively smaller zones, i.e., the precipitation zone [grey zone (B)], the biphasic zone one [light green zone

Ternary phase diagram of IBP-IPA-Water

The ternary diagram gives a clear idea of the physical conditions of the different blends of the three components mixtures. The borderline of the blue zone in the diagram indicates the minimum IPA content required to obtain a solution system with a certain amount of IBP. A reduction of the IPA content (shift to right hand side) in the mixture caused precipitation. The bi-phasic zone, appeared in some compositions, also known as “Oiling out” phenomenon, has been reported earlier (Kiesow et al.,

Conclusion

Bottom-up processes are difficult to control and often generate bigger particles. Hence, these processes are not used widely at commercial scale. We have studied the combination of precipitation and HPH in a systematic manner by splitting the study into several parts. It was found that a ternary diagram can be used to select the suitable S/AS ratio to obtain solid particles by the precipitation step. It was systematically established that the IBP-IPA-Water composition should be selected from a

Acknowledgement

Funding support provided by the Erasmus Mundus External Co-operation Window Lot-13 programme to the first author is thankfully acknowledged.

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