Production of aprepitant nanocrystals by wet media milling and subsequent solidification

Abstract

The present study investigates the effects of formulation and process parameters on the production of aprepitant nanosuspensions applying wet media milling and subsequent solidification. Six stabilizers were used: two brands of hydroxylpropylmethyl cellulose (HPMC E-15LV and Pharmacoat 603), hydroxypropyl cellulose (HPC-SSL), polyvinylpyrollidone (PVP), D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS 1000), Poloxamer P188 and sodium dodecyl sulfate (SDS), while two diluents (mannitol and sucrose) were incorporated prior to solidification by two methods (spray- and freeze-drying). The polymorphic purity of the raw material, the particle size of nanocrystals, and the physicochemical properties of the final dried powders were assessed. Focus was placed on the energetic aspects of the crystal structure of aprepitant in order to rationalize particle breakage during wet milling. It was found that a combination of cellulosic polymers with SDS are suitable stabilizers for the production of aprepitant nanocrystals (∼300 nm or smaller) by wet media milling. Regarding the solidification of the nanosuspensions, spray-drying is advantageous compared to freeze-drying, as it leads to the production of almost spherical individual micron-sized agglomerates of nanocrystals and few secondary agglomerates of them which are expected to exhibit improved handling behavior. Spray-dried nanocrystal agglomerates containing Pharmacoat 603 and mannitol exhibit reduced hygroscopity compared to those prepared with sucrose and HPC-SSL, making them the excipients of choice.

Introduction

Nanocrystals possess enhanced dissolution rate due to the substantial surface area increase, which is also accompanied by a reduction in the thickness of the diffusion layer, and possibly an increase in the saturation solubility of the drug (Hasa, 2014, Hasa et al., 2013, Kesisoglou et al., 2007). Wet media milling for particle size reduction at the nano-scale was first applied to danazol in order to enhance its dissolution rate, leading to a ∼75% increase in oral bioavailability (Liversidge and Cundy, 1995). It is proven to be an efficacious technique for the nanonization and bioavailability enhancement of poorly water-soluble drugs (Liu, 2013, Merisko-Liversidge and Liversidge, 2011, Merisko-Liversidge and Liversidge, 2008). Wet media milling can be performed by a variety of equipment, including ball mills, planetary mills, vibration mills, attritors or stirred media mills etc., following few simple steps: the milling bowl is charged with media (small beads, spheres) usually up to 80% volume, a suitable dispersion liquid is added, and the content of the mill is set in motion by rotation or stirring, depending on the type of the mill. The energy input to the mill causes the development of stress and breakage of the primary crystalline particles to smaller ones. As the crystals get smaller, fracture occurs preferably by cleavage along slip planes, making the identification of slip planes an important predictive tool of the feasibility of nano-comminution. At the end of the milling run, the resultant suspension is inherently unstable due to the high surface free energy of the nanocrystals (Wu et al., 2011), which tend to aggregate or undergo Ostwald ripening. Therefore the use of additives, known as suspension stabilizers, is required in order to improve their stability. Suitable additives include polymers, surfactants and low molecular weight substances like sugars (Lee et al., 2008). The addition of polymers in the drug’s suspension stabilizes the produced nanocrystals, and can contribute to their redispersion. Stabilizers are thought to attach themselves on the drug crystal faces and prevent the subsequent aggregation, either by steric hindrance or by modification of the surface’s electrostatic properties. It is also thought that the stabilizers aid nano-comminution, acting directly on the surface via the Adsorption Induced Reduction of Strength of solids (AIRS) or Rehbinder effect, by disrupting the hardening surface layer, thus causing a marked reduction of the crystals’ mechanical strength (Andrade et al., 2002, Malkin, 2012, Monteiro et al., 2012).

Among several APIs that have been successfully formulated and marketed as nanocrystals, aprepitant represents a characteristic example of a poorly water-soluble substance whose bioavailability can be enhanced by nano-comminution (Kesisoglou et al., 2007). Aprepitant is a tachykinin receptor antagonist used against chemotherapy-induced emesis. It is classified as BCS Class IV drug, with an aqueous solubility <10 μg/ml (Wu et al., 2004), and it is marketed under the brand name Emend^® (Merck) in the form of nano-crystalline particles deposited on the surface of inert microcrystalline cellulose beads (Bosch et al., 2012, Kesisoglou et al., 2007). The nanocrystals are manufactured by the wet media milling method using aqueous hydroxypropyl cellulose and sodium dodecyl sulfate (SDS) as milling aids.

Up until now, several reports describing the production of aprepitant nanocrystals by various methodologies can be found in the literature. Attari et al. (2016) applied precipitation or milling combined with high pressure homogenization, using high amounts of polyvinyl alcohol (PVA), sodium dodecyl sulfate (SDS), tween 80, polyvinylpyrollidone (PVP), poloxamers as well as combinations of the aforementioned as nanosuspension stabilizers, and achieved a 90% yield of nanosuspension. The authors mention a change in the DSC behavior of milled aprepitant, however the polymorphic stability of aprepitant was not studied (Attari et al., 2016). Angi et al. (2013) applied a continuous flow precipitation method to produce amorphous nanostructured particles with diameter below 100 nm, while Bhavani et al. (2013) applied wet media milling using hydroxypropyl cellulose and SDS to stabilize the nanosuspensions, however no information about the mill operating conditions is given (Angi et al., 2013, Bhavani et al., 2013). Although it has been established that production of aprepitant nanocrystals is feasible by various methods, wet media milling remains the method or preference for industrial applications, and no sufficient information can be found in the literature, of the effects of composition and process parameters on the quality of the produced nanosuspensions and corresponding solidified product. Also, spray-drying is a single-step process for the conversion of a liquid feed into a dried particulate form. It is a popular process from an industrial perspective as it is more cost- and time-effective compared to freeze-drying (Mujumdar and Alterman, 1997).

Therefore, the present work aims to: a) fill the knowledge gap of the effects of different stabilizers on the aprepitant size reduction during wet nanomilling, b) focus on the energetic aspects of aprepitant’s crystal structure in order to rationalize particle breakage during nanomilling, and c) to compare freeze-drying and spray-drying as solidification methods of the aprepitant nanosuspension produced by using different stabilizer, after the addition of sucrose or mannitol as diluents.

For this purpose, aprepitant nanosuspensions are produced by a planetary ball mill, using brands of substituted cellulose stabilizers differing in their substitution (one hydroxylpropyl and two hydroxypropyl-methyl cellulose brands) alone or in combination of surfactant (SDS). Subsequently the produced nanosuspensions are solidified by freeze- or spray-drying, after addition of sucrose or mannitol as diluents.