Optimization of formulation and process parameters for the production of carvedilol nanosuspension by wet media milling

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Abstract

The aim of this study is to develop nanosuspension of carvedilol (CRV) by wet media milling. Concentration of polymeric stabilizer (hydroxypropyl cellulose-HPC-SL), milling speed and size of milling beads were identified as critical formulation and process parameters and their effect on CRV particle size after 60 min of milling was assessed using a Box-Behnken experimental design. Optimized nanosuspension was solidified using spray drying and freeze drying and subjected to solid state characterization. Low stabilizer concentration (10%), low milling speed (300 rpm) with small milling beads (0.1 mm) were found as optimal milling conditions. Crystal lattice simulation identified potential slip plane within CRV crystals, where fractures are the most likely to occur. Calculated mechanical properties of CRV crystal indicates that low energy stress is sufficient to initiate fracture, if applied in the correct direction, explaining the advantage of using smaller milling beads. Only spray dried nanosuspension redispersed to original nanoparticles, while particle agglomeration during freeze drying prevented sample redispersion. Wet milling and spray drying did not induce polymorphic transition of CRV, while there is indication of polymorphic transition during freeze drying, making spray drying as the preferred solidification method.

Introduction

Amongst numerous approaches for overcoming problems caused by the poor solubility of drugs, formulation of nanosuspensions made the fastest breakthrough from development to industrial scale, whereby the first product based on nanosuspensions appeared on the market in only about 10 years after the first patent application (Shegokar and Müller, 2010). Nanosuspensions are considered as dispersions of drug particles with size lower than 1 µm (most commonly between 200 and 500 nm) stabilized by the addition of suitable polymer and/or surfactant (Peltonen and Hirvonen, 2010, Wang et al., 2013). The basic idea of this approach is that particle size reduction to nano size will increase drug dissolution rate due to increase of surface area in contact with medium, according to well-known Noyes–Whitney equation. Additionally, it has been reported that decreasing in particle size to nano level leads to increase in saturation solubility, whereby this effect is more significant for particles with size below 100 nm (Shegokar and Müller, 2010). Other benefits of nanosuspensions (i.e. nanocrystalline suspensions or nanocrystals) include broad applicability to molecules of different physicochemical properties, high drug loading, reproducibility of oral absorption, improved dose-bioavailability proportionality, reduced toxicity and side effects, greater adhesiveness to biological membranes and tissues and improved patient compliance via a reduction in the number of oral units that must be administered (Müller et al., 2001, Rabinow, 2004, Shegokar and Müller, 2010).

Available techniques for production of drug nanosuspensions are grouped into bottom up and top down techniques, whereby using of both types of techniques in combination has been also reported. Although bottom up approach, in which drug precipitation from solution into nanosized precipitate is induced by the addition of anti-solvent, looks much simpler, use of this method has not resulted in any formulation that reached market yet. Due to numerous limitations of bottom up approach, such as, using of high volumes of organic solvents and problems associated with solvent residues, necessity for drug solubility in one solvent, lower drug loading, difficult particle size control and possible precipitation in the unstable amorphous state, top down techniques are considered as the first choice for the industrial production of nanocrystals (Müller et al., 2011, Shegokar and Müller, 2010, Möschwitzer, 2013). Wet media milling is an efficient method for the production of drug nanocrystals, where particle size diminution of coarse drug suspension with added stabilizer is achieved by impaction, collision and shear force as a result of the moving of the milling beads (Liu et al., 2015b). Due to its high particle size reduction capability (down to 100–300 nm), cost-effectiveness, ability to run continuously, high versatility, easy scalability and diversity of the available equipment that meets different requirements, wet media milling has been used for the production of the most nanosuspensions currently presented on the market (Peltonen and Hirvonen, 2010, Merisko-Liversidge and Liversidge, 2011, Möschwitzer, 2013). Wet media milling can be performed using variety of equipment, including ball mills, planetary mills, vibration mills, attritors or stirred media mills etc., depending on whether moving of the milling media (small beads, spheres) is induced by rotation of the external stirring device or moving of the whole milling chamber. The selection of the suitable equipment is predominantly determined by the formulation properties (particularly suspension viscosity), as well as batch size, where the mills with external stirring device are preferred choice for high viscosity formulations and larger batch size, due to high shear forces provided by rotation of the external stirrer. Despite absence of the external stirrer, the planetary ball milling is also considered as a high energy milling process due to the two simultaneous rotations of the milling vessel, with the milling beads reaching very high linear velocities. Although the planetary ball mills are particularly suitable for the small scale development studies with low amount of available material, milling process in this equipment is highly scalable. In their recent study, Toziopoulou et al. (2017) obtained similar particle size of aprepitant nanosuspension prepared in the lab scale planetary ball mill and commercial product described in patent US8258132B2 (Bosch et al., 2012), which proved scalability of milling process in the planetary ball mills. Since particle size achieved by the wet media milling is affected by numerous formulation and process parameters, such as the number and size of milling beads, the amount of drug and stabilizers, milling time, speed, and temperature (Peltonen and Hirvonen, 2010), implementation of Quality by Design (QbD) concept with the use of experimental design techniques is strongly recommended in the formulation development. Despite this, only a few studies describe optimization of wet media milling process for the production of drug nanosuspensions using experimental design techniques (Singare et al., 2010, Singh et al., 2011, Ghosh et al., 2012, Ahuja et al., 2015).

It is well established that liquid nanosuspensions are associated with physical instability, such as sedimentation, crystal growth (i.e. Ostwald ripening), aggregation and solid state transformation. Crystal growth and particle aggregation cause changes of particle size in the nanosuspensions diminishing all benefits of these systems and finally result in the fluctuations of bioavailability. Additionally, large water content makes this preparation sensitive to microbial growth upon storage (Malamatari et al., 2016). In order to avoid these problems and formulate more convenient dosage forms, liquid nanosuspensions are undergone to solidification techniques, among which spray drying, freeze drying and spray coating of neutral pellets are the most commonly used.

Carvedilol (CRV) is an α1, β1 and β2 adrenergic receptor antagonist used in the treatment of essential hypertension, congestive heart failure and systolic dysfunction after myocardial infarction (Frishman, 1998). CRV is a weak base with pH-dependent solubility, with extremely low solubility in alkaline pH, that prevents the drug from being available for absorption in small intestine and colon and limits CRV bioavailability (Chakraborty et al., 2009, Planinšek et al., 2011). Thus, numerous approaches have been applied to overcome problems with CRV poor solubility, such as formulation of solid dispersions (Shamma and Basha, 2013), self-emulsifying drug delivery systems (Wei et al., 2005), complexation with cyclodextrins (Hirlekar and Kadam, 2009, Alonso et al., 2016) and adsorption onto porous carriers (Planinšek et al., 2011). Since it has been shown that CRV dissolution rate and bioavailability can be significantly improved with particle size reduction (Liu et al., 2015a), formulation of nanosuspensions is also a very promising approach in the development of CRV formulations for oral delivery. However, currently available literature describes preparation of CRV nanosuspensions only using an antisolvent precipitation (Rana and Murthy, 2013, Saindane et al., 2013, Liu et al., 2012, Liu et al., 2014, Liu et al., 2015a, Abdelbary et al., 2015) as well as high pressure homogenization (Kumar et al., 2015). Therefore, this study describes for the first time the preparation of CRV nanosuspension using wet media milling technique. Preparation process was optimized using Box-Behnken experimental design with regards to formulation (concentration of stabilizer) and process parameters (rotation speed of mill and size of milling beads) in order to achieve the lowest CRV particle size. Additionally, molecular modeling techniques have been applied to analyze mechanical properties of CRV and rationalize particle size reduction mechanisms at the molecular level. Due to possible polymorphic transitions of CRV during milling and drying, comprehensive solid state characterization has been performed.

Section snippets

Materials

CRV (Hemofarm AD, Serbia) was used as a model poorly soluble drug, while hydroxypropyl cellulose-HPC-SL (Nisso HPC-SL, Nippon Soda Co., Japan) and sodium lauryl sulphate (SLS) were used in combination as nanosuspension stabilizers. Mannitol (Pearlitol® 160C, Roquette Frères, Lestrem, France) was used as matrix for spray drying and freeze drying of the nanosuspension in order to prevent aggregation of CRV nanocrystals during solidification process.

Preparation of CRV nanosuspensions

CRV nanosuspensions were prepared by wet media

Wet media milling

Measured CRV particle size after 60 min of milling (Table 2) was in the range between 241 and 564 nm, showing that a nanosuspension was generated in all experimental runs. PDI values for all formulations were below 0.5, which is reported as acceptable for nanosuspensions (Mohammadi et al., 2011), while 12 out of 15 formulations showed PDI below 0.3, which is indicator of good particle size uniformity (Patel et al., 2014). Both CRV particle size and PDI after 7 days storage of nanosuspensions in

Conclusion

Production of CRV nanosuspension with particle size below 250 nm and uniform size distribution is feasible with wet media milling process with careful selection of polymeric stabilizer concentration and processing conditions. Analysis of experimental results using Box-Behnken experimental design showed that CRV particles of the lowest size is produced using either small size milling beads (0.1 mm) in combination with low HPC-SL concentration (10%) and low milling speed (300 rpm), or larger

Acknowledgements

This work was done under the project No. TR 34007, supported by the Ministry of Education, Science and Technological Development, Republic of Serbia. The authors would like to thank to Nippon Soda Co., Ltd. for providing gift sample of Nisso HPC-SL. Djordje Medarević would like to acknowledge to Ministry of Education, Science and Technological Development, Republic of Serbia for providing scholarship for postdoctoral research.

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