Modification of the API to Improve Respiratory Deposition

As previously discussed, in order to achieve efficient respiratory delivery, the drug powder requires an aerodynamic diameter of <6 ^m to avoid impaction and/or sedimentation in the upper airways (4). Historically, the method of producing particles in this size range is through high energy milling or micronization of a larger crystalline starting material. However, this method of production leads to irregular particle morphology and the potential for the formation of amorphous regions in the sample surface, as represented in Figure 11. Such regions can be highly unstable, and for small pharmaceutical molecules, this may result in spontaneous re-crystallization when exposed to environments that facilitate a lowering of the glass transition (such as elevated humidity) to ambient conditions (62).

Since these micronized particulates have a high surface area, the instability in any surface amorphous regions may lead to variations in surface energetics and, where re-crystallization occurs, the potential for particle fusion, which may affect the particle size distribution, and subsequent FPF. Consequently, there has been an impetus in the physical sciences to gain a greater understanding of surface induced amorphous material and to detect its presence at the low levels (63,64). In a drive to reduce surface instability, amorphous content, and high interfacial energies, in DPI drug, a significant amount of research into particle engineering has occurred.

yY /

Mechanically Induced Damage ^^^^^^ m ™™m m

Molecular reordering to a more thermodynamic stable state

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Figure 11 Schematic of mechanically induced molecular surface damage (amorphous regions) and recrystallization.

Figure 11 Schematic of mechanically induced molecular surface damage (amorphous regions) and recrystallization.

There are several approaches which have been successfully used to prepare respirable drug particles that have shown improved therapeutic outcomes, when compared to conventional micronized drugs. The most common approaches are to either precipitate material of the required size range (i.e. controlled crystallization), or to flash evaporate the drug from a solution with/without excipients, that facilitate a stable particulate system with chosen physical attributes.

Precipitation of Particles to Improve Respiratory Therapy

As previously discussed, the conventional bulk precipitation of small molecule type drugs will result in a product which exhibits a particle size distribution which is unsuitable for respiratory delivery (65). In order to precipitate respiratory sized particles from solution in a single-step, a high degree of micro-mixing and molecular diffusion is required. Many techniques have been developed recently to overcome the growth kinetics, and generally either involve high energy input, for rapid micro-mixing, and/ or rapid diffusion of solvent and anti-solvent. One area that has received considerable recent attention is the use of supercritical fluids to precipitate particles of respirable size (66). Supercritical fluids are at a temperature and pressure that result in them behaving like both a gas and liquid (i.e. they can diffuse through materials easily, like a gas, whilst maintaining a high solvation capacity, as a liquid). Furthermore, by modifying the temperature and/or pressure within this supercritical region, large variations in properties such as density can be controlled. Since physical properties, such as density can be directly related to the solubility (or anti-solvent power), a range of technologies have been patented that use supercritical fluids to prepare particulates of a respirable size range (66). One of the most successful approaches, in applying this technology to dry powder inhalation was the research group at Bradford University (UK) (67-69) whose spin-off company, Bradford Particle Design (later acquired by Inhale (now Nektar)) (70), utilized a process referred to as Solution Enhanced Dispersion by Supercritical Fluids (SEDS) (Fig. 12). The controlled precipitation of particles using supercritical fluids has been used to produce different drug polymorphs (68) and powders with more suitable morphologies for efficient aerosolization (69). In addition recent studies, comparing the aerosolization efficiency of SEDS and micronized drug powders from lactose carrier blends, has suggested, that while the aerosol performance of similarly sized SEDS and micronized powders were similar, the physical stability of the SEDS material was improved (71).

The difference in aerosolization performance between the micronized and SEDS sample was attributed to mechanically induced amorphous content, present in the micronized sample, re-crystallizing, and causing particle fusion (71). This would be expected to occur when the

Figure 12 Aerosolization efficiency of micronized and SEDS-produced albuterol sulphate from a lactose carrier formulation as a function of relative humidity. Abbreviation: SEDS, solution-enhanced dispersion by supercritical fluids. Source: From Ref. 71.

environmental storage humidity was increased sufficiently to reduce the glass transition to ambient temperatures (albuterol sulphate glass transition humidity at 25°C is estimated to be approximately 50% RH (72)) and could thus be observed in investigations conducted after storage at higher humidities (>60% RH).

Other methods capable of producing discrete particle precipitation, rapid nucleation, and high rates of micro-mixing include sonication (73), high gravity precipitation (74-76), and impinging jet methodology (77). Recent work by Kaerger and Price (73) has suggested that aerosol droplets produced via electro-hydrodynamic or an air pressure atomizer could be captured in a anti-solvent and crystallized via sonic energy. This method of atomization and crystallization via sonication (SAXS) was shown to produce uniform particles with nanoscopic morphology within a suitable size range for respiratory delivery (1-5 ^m).

High gravity precipitation has also been recently investigated (74,76) and relies on rapid mixing, in a high gravity rotating packed bed (HGRPB) rector, to produce micron and sub-micron particulates. As with all these high energy systems, such as SAX described above, the HGRPB relies on a high energy input (in this case intensified mass and heat transfer) to control the nucleation and crystallization of small particulates at a size suitable for respiratory therapy. Recently, this method has been successfully utilized to produce respiratory sized albuterol sulphate crystals, which depending on the operating conditions, can exhibit FPFs up to 55% (76).

Particle Formation via Rapid Drying

An alternative to precipitation and crystal formation of APIs with required size distributions for respiratory delivery is the rapid evaporation of the particles by spray drying (78). Spray drying has conventionally been used in the production of foodstuffs and pharmaceutical excipients, however, in recent years it has gained popularity as a means of preparing APIs in a suitable form for respiratory deposition. The most obvious commercial example of API spray drying is the recent Exubera® formulation (13).

By modifying the drug solution concentration and operating conditions it becomes possible to, with relative ease, alter the particle size or morphology of the final product. This has obvious implications, as reported by Chew et al. (79), where the altering of the spray drying conditions resulted in the control of the degree of particle corrugation of an serum albumin (BSA), and thus, the aerosolization efficiency. An example of the surface morphologies of these particles is shown in Figure 13, and the image suggests that the degree of particle interactions between contiguous surfaces will be altered.

Additionally, the aerosol performance can be improved by the addition of excipients so as to vary the particle density, aerodynamic size, contact area, and physico-chemical stability of the formulation. For example, a mixture of excipients is employed during the spray drying process for the preparation of the insulin formulation for the inhaled product Exubera (13). The excipients act as bulking agents and aid stabilization of the formulation (12).

The addition of other excipients, such as "blow-out" fluorocarbons, during the spray drying of formulations results in porous particles with reduced density and contact area (81). This approach was used in Nektars

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Figure 13 AFM topography image of spray-dried bovine serum albumin particles prepared using methodologies described by Chew et al. (A) Smooth particulates and (B) corrugated particulates. Source: From Refs. 79,80.

PulmoSphere® technology. In a recent study, dry powder budesonide PulmoSpheres were reported to exhibit improved in vivo respiratory deposition when compared to a conventional micronized formulation (14). These hollow, porous systems are designed to have reduced contact area and lower density. The culmination of these two factors will result in improved powder aerosolization efficiency and reduced aerodynamic diameter (82). However, it is important to note, such systems will still have a relatively high surface area to mass ratio and therefore will presumably be highly cohesive/ adhesive in nature. An approach to overcoming this is to produce larger particles, which have volume diameters of the order 20 ^m but with densities that result in aerodynamic diameters of around 5 ^m (15). An example of this approach is Alkermes Air® technology.

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