Electrohydrodynamic atomization and spray-drying for the production of pure drug nanocrystals and co-crystals

Abstract

In recent years, nanotechnology has offered attractive opportunities to overcome the (bio)pharmaceutical drawbacks of most drugs such as low aqueous solubility and bioavailability. Among the numerous methodologies that have been applied to improve drug performance, a special emphasis has been made on those that increase the dissolution rate and the saturation solubility by the reduction of the particle size of pure drugs to the nanoscale and the associated increase of the specific surface area. Different top-down and bottom-up methods have been implemented, each one with its own pros and cons. Over the last years, the latter that rely on the dissolution of the drug in a proper solvent and its crystallization or co-crystallization by precipitation in an anti-solvent or, conversely, by solvent evaporation have gained remarkable impulse owing to the ability to adjust features such as size, size distribution, morphology and to control the amorphous/crystalline nature of the product. In this framework, electrohydrodynamic atomization (also called electrospraying) and spray-drying excel due to their simplicity and potential scalability. Moreover, they do not necessarily require suspension stabilizers and dry products are often produced during the formation of the nanoparticles what ensures physicochemical stability for longer times than liquid products. This review overviews the potential of these two technologies for the production of pure drug nanocrystals and co-crystals and discusses the recent technological advances and challenges for their implementation in pharmaceutical research and development.

Introduction

The pharmaceutical industry is found in a persistent and urgent search for new scalable and cost-effective technological strategies to overcome (bio)pharmaceutical drawbacks of drugs such as poor aqueous solubility, low physicochemical stability in the biological milieu, short half-life and reduced bioavailability [[1], [2], [3], [4], [5]]. For instance, >50% of the approved drugs and >70% of new chemical entities under development are classified into Classes II and IV of the Biopharmaceutics Classification System (BCS) [6, 7]. These limitations increase drug attrition rates [8, 9] and lead to a decline in the ability to translate them into new pharmaceutical products [[10], [11], [12]].

Numerous strategies have been applied to overcome these disadvantages. Nanonization of pure drug particles via top-down or bottom-up techniques to produce nanoparticles of amorphous or crystalline nature with sizes ranging from a few nanometers up to 1 μm enhances the dissolution rate and the saturation solubility by increasing the specific surface area-to-volume ratio [1, [13], [14], [15], [16]] (Fig. 1). The Noyes–Whitney Eq. (1) describes the dissolution rate of spherical particles. The process is controlled by diffusion and no chemical reaction takes place [10, [17], [18], [19], [20]].

$$\frac{d{C}_x}{\mathit{dt}}=A\frac{\mathrm{D}}{\mathrm{h}}\left(C_s-C_x\right)$$

where dC_x/dt is the dissolution rate, A is particle surface area, D is the diffusion coefficient, h is the effective thickness of the boundary layer, C_s is particle saturation solubility and C_x is concentration in the surrounding liquid at time x. The Ostwald–Freundlich Eq. (2) establishes the increase in saturation solubility of a given compound based on the increase of the interfacial energy at high curvatures or in other words, for very small particles.

$$S=S_{\infty }exp\left(\frac{2\mathit{\gamma M}}{\mathit{r\rho RT}}\right)$$

where S is the saturation solubility of the nanosized active pharmaceutical ingredient, S_∞ is saturation solubility of an infinitely large active pharmaceutical ingredient crystal, γ is the crystal-medium interfacial tension, M is the molecular weight of the compound, r is the particle radius, ρ is the density, R is the gas constant and T is the absolute temperature.

Thus, an increase in the specific surface area-to-volume ratio of the nanonized crystals leads to a faster dissolution rate. In addition, when the particle size is smaller than 100 nm, the saturation solubility increases exponentially. Both phenomena result in an enhancement in the oral bioavailability of the drug [13]. Moreover, the number of contact points with the surrounding tissues (e.g., mucus) increases substantially, favoring the adhesiveness to biological structures and the prolongation of the residence time in specific body sites such as mucosal tissues [13].

Over the last decades, nanosizing techniques have gained increased interest in terms of both new intellectual property and clinical impact [1, 5, 10, 13, 21]. Pure drug nanoparticles can be used dispersed in aqueous media in the so-called nanosuspensions [21, 22] or to produce solid formulations such as tablets [20]. The degree of crystallinity of the drug in the nanoparticle may vary widely and can be controlled by adjusting/optimizing the conditions of the production method [1, 10].

In some cases, the relatively slow dissolution rate of pure nanocrystals of highly hydrophobic drugs combined with their ability to undergo entrapment by the intestinal mucosa resulted in a dramatic increase of the drug half-life with respect to the unprocessed counterpart (Fig. 2), a concept that we coined nanocarrier-less delivery systems [23, 24].

Pure drug nanoparticles have been also used by other minimally-invasive administration routes such as inhalation, transdermal, ophthalmic and buccal [10, 25, 26]. For example, pure drug nanocrystals of hydrophobic drugs (e.g., pranlukat hemihydrate) have been investigated for the treatment of chronic bronchial asthma by pulmonary delivery [[27], [28], [29]]. Drug nanocrystals have been also assessed to improve skin deposition and permeation of the non-steroidal anti-inflammatory drug diclofenac by the transdermal route [30]. More recently, pure drug nanocrystals of hydrophobic drugs (e.g., the antiretroviral rilpivirine) have been investigated to sustain the release upon intramuscular injection in the chronic therapy of the human immunodeficiency virus infection [31, 32]. Unlike other drug nanocarriers that have been extensively researched (i.e., liposomes, nanoemulsions and polymeric nanoparticles) and for which encapsulation efficiency and drug loading have to be defined in the final product, pure drug nanocrystals/co-crystals offer a theoretical drug content of up to 100%. Thus, the encapsulation efficiency is not a constraint which increases the chances of bench-to-bedside translation [13, 33, 34]. On the other hand, small drug particles are thermodynamically instable and they tend to grow in size by agglomeration [25, 35, 36]. This is why they are usually physically stabilized using surfactants or other polymeric stabilizers [1, 25, 33] what brings the typical total drug content to ~50–90% w/w [34]. Another important advantage of drug nanocrystals is the maturity and scalability of their fabrication technologies, which can be demonstrated by multiple commercial products that are currently on the market. Table 1 summarizes oral pharmaceutical formulations based on pure drug nanocrystals currently on the market or under preclinical trials (Table 1) [45]. At the same time, it is important to mention that the administration of nanoparticles with increased oral bioavailability with respect to the unprocessed (non-nanonized) drug might lead to toxicity due to higher C_max. Thus, bioequivalence and dose adjustment studies need to be conducted to ensure efficacy and safety.

Another approach currently investigated to overcome drug solubility issues is micro/nano-co-crystallization [46, 47]. Pharmaceutical co-crystals are crystalline materials composed of at least two different molecules, typically a drug and a co-crystal former known as a co-former in the same crystal lattice [37, 48, 49]. There are several types of molecular interactions that can generate co-crystals such as π-π stacking, van der Waals forces, H-bonds and ionic bonds [49, 50]. The main advantage of drug co-crystallization is the ability to alter the physicochemical characteristics of the pure drug to improve its solubility, physicochemical stability, dissolution rate and oral bioavailability, while maintaining their therapeutic activity [37, 51]. Conventional co-crystals are formed by a drug and a pharmacologically inert co-former. More recently, drug-drug and multidrug co-crystals were introduced [52, 53]. Their advantage over conventional co-crystals is that the components display a synergistic pharmacological activity as well as enhanced physicochemical properties for at least one of the co-crystal components [52, 54, 55]. Moreover, the combination of multiple therapeutic agents in single unit doses facilitates patient management with complex diseases that require multidrug therapy and increases patient compliance [52, 56].

The techniques applied to nanosize drugs can be classified into three main categories: bottom-up (e.g., conventional nanoprecipitation), top-down (e.g., wet ball milling, high pressure homogenization) and combination techniques [57]. Each one presents pros and cons though in general, all of them have to fulfill similar requirements such as controlled and reproducible size, narrow size distribution, high purity, low content of solvent residues, good physicochemical stability and desired morphology and density [57]_. In cases where the nanoparticles are used in the production of solid formulations (e.g., tablets), the mechanical and flow properties of the nanoparticle will govern the tableting process and the final properties of the pharmaceutical product [58, 59]. Moreover, different production methods influence differently the solid state characteristics of the nanoparticles [60]. In general, once the production conditions have been optimized and validated, bottom-up techniques enable a better control of the particle crystallinity/amorphousness and shape, and thus, in recent years, they have gained significant impulse [38]. The current review revisits two bottom-up technologies based on the atomization of a liquid drug solution in a pharmaceutically compatible aqueous or organic solvent into small droplets that undergoes relatively fast drying, namely electrohydrodynamic atomization (EHDA) or electrospraying (these are equivalent terms used to describe the same technique) and spray-drying, for the production of amorphous or crystalline pure drug nanoparticles and nano-co-crystals and critically analyzes their potential to play a fundamental role in the production of innovative pharmaceutical formulations with improved (bio)pharmaceutical properties.