Ultrasonic technologies are being exploited to improve the manufacture of drug particles for inhaled medicines. Dr Graham Ruecroft, chief technical officer at Prosonix, explains how
For many drug particles where the lung is the mode of delivery, the usual method of manufacture involves taking large crystals and physically breaking them into smaller particles. Prosonix offers technologies that enable small particles for inhaled medicines to be made through advanced particle engineering.1
Particles must be in the right size range to reach the right place in the upper or lower airways of the lung, otherwise, when released from the inhaler, they reach only the tongue and are simply swallowed. Of course, they must get out of the inhaler in the first place - and Prosonix can deliver improvement in asthma inhaler performance.
For respiratory diseases, the constit-uent bronchodilator long acting beta-agonists (LABAs), short acting derivatives (SABAs) and steroidal ingredients can be prepared by a number of new techniques. These drug components operate with a synergistic action at molecular and cellular level and need to be delivered in an exact ratio: the bronchodilator opens the airways and the steroid reduces inflammation.
However, it is important that the two medicines arrive in the lung together for maximum effect. Prosonix technologies ensure that the two components effectively chaperone each other to the site of action. Unfortunately, the standard technique of dry blending means they do not always arrive together and some particles do not arrive at all.
Active pharmaceutical ingredients (APIs) are, in essence, performance chemicals and it is size, morphology, surface energy and, critically, surface three-dimensional geometry that govern particle performance in inhaled medicines formulation. Fluid energy milling and micronisation are crystal-destructive techniques that are capable of achieving the target size range, but the high energy required for such processes often damages the crystal surface.
This leads to highly charged and co-hesive particles, resulting in the chemical and physical instability of the drug, not to mention undesirable surface polymorphological transformation and formation of amorphous domains, as well as generation of heat which may be incompatible with the API.
Conversely, API particles can be engineered via controlled crystallisation, leading to simpler drug delivery platforms. In this respect Prosonix sonocrystallisation4 technologies DISCUS,2 SAX3 and the newer UMAX, facilitate control of size, shape, surface geometry, surface free energy, and crystallinity. They are also ideally aligned with the new FDA directives for
Quality by Design, aimed at guiding5 the pharmaceutical industry to improved invention, development and commercialisation of structured products using technologies that will result in superior product quality.
Rather than the historic approach to design, manufacture and optimisation of an API process via a "process down" view, we need a newer "molecule-to-product" approach, whereby there is molecular design of the product property - particle engineering.
Crystallisation is a critical operation in API manufacture and almost every chemical process that produces solid forms involves at least one crystallisation step. Yet crystallisation processes are poorly understood and are difficult to control. However, sonocrystallisation assisted particles engineering can help when producing inhaled mesoscopic particles.
For greater systematic availability or local effect in the deep lung, drug delivery requires particles that are below 3µm. The upper respiratory tract is ideal for the treatment of diseases such as asthma and COPD, as well as respiratory infections, and requires
particles in the 1-5µm range. However, many delivery devices are unnecessarily complicated. Prosonix can deliver superior particles that allow the use of less complex dry powder inhalation (DPI) devices.
The ideal respiratory particle requirements are suitably high fine particle fraction (FPF), emitted dose (ED), dose consistency and uniformity, and should be achieved independently of the type of device and inhalation flow rate.6 These can be achieved by having:
- Correct aerodynamic particle size (mass medium aerodynamic diameter)
- Right aerodynamic diameter - function of density and dynamic shape factor
- Narrow particle size distribution
- Low aerodynamic dispersion forces to aerosolise
- Good physical and chemical stability - crystallinity, polymorphism
- Low density and large volume diameter for better dispersion and efficient lung delivery.
While spherical particles can have the ideal properties for inhalation, rod and needle-like particles, and indeed twinned-type crystals, as shown in Fig. 1, can have a useful aerodynamic performance, as they can orientate in the air flow and behave like smaller particles.
DPI formulations generally consist of two parts: the drug - micronised or engineered, typically cohesive and ideally 1-5µm, and an inert carrier - generally micronised lactose used to carry the drug, but much larger at 60-150µm. The materials are typically low-shear blended.
In these formulations the surface texture plays a crucial role and has a significant effect on the cohesive-adhesive balance (CAB), which governs the ease or difficulty by which the drug particles are released from the carrier particles under the force of inspiration. With Prosonix engineered particles, the CAB can be controlled and more useful drug formulations can be developed. In addition, ultrasonic Particle Rounding Technology (PRT)7 can be used to prepare the lactose carrier.
PRT is used in combination; this process technology, the Prosonix Prosonitron1,4,8 process and reactor technology represent an ideal solution to a range of common manufacturing issues and classical dry milling or micronisation problems.
The judicious application of ultrasound to crystal slurry using a Prosonitron configured in a recirculation loop, (see Fig. 2), with existing batch crystalliser can lead to remarkable changes in crystal morphology. The effects can be attributed to a number of concomitant events including in situ ultrasonic (cavitation) milling, Ostwald ripening and inter-particle collision (like pebbles on a beach). This technique can lead to improvement in particle features by changing their shape but not the volume. Benefits include:
- Improved packing density of powders
- Enhanced flow of powders
- Reduced electro-static charges
- Manufacturing by direct compression without granulation
- Higher filler loading in composite pastes.
Prosonix has used PRT technology for a variety of pharmaceutical materials with excellent results. The application to alpha-lactose leads to significantly enhanced morphology (Fig. 3), flowability and improved stability on storage (no agglomeration). A new product, LactoSonic will soon be commercially available for inhalation drug therapy. Peter York, at Bradford University, has demonstrated an in vitro performance increase of over 100% for FPF and a 20% increase in ED when sonocrystallised lactose was used with micronised salbutamol sulphate in impactor studies (Anderson cascade impactor).9 Engineered salbutamol sulphate when used with suitably prepared lactose should give an incremental increase in performance.
For inhaled corticosteroids, such as budesonide, Prosonix has carried out rigorous in vitro inhalation studies on engineered material using external partners and the Next Generation Impactor (NGI).10 The aerosolisation efficiency of SAX and DISCUS budesonide has been assessed in binary (with micronised lactose) DPI formulations. In all cases Prosonix powders were over 100% more efficient in terms of fine particle dose (FPD) and certainly superior in terms of ED (Fig. 4).
Similarly, the company has shown an increase of more than 50% in FPD and ED when engineered particles of some well-known beta-2-adreno receptor agonists (both long and short-acting bronchodilators) were subject to in vitro inhalation studies using external partners.
SAX1,3 and some of the second generation atomisation-based particle engineering technologies (such as UMAX) for the production of microcrystalline particles with narrow size distribution show great promise in applications for preparing particulate pharmaceuticals with defined physicochemical properties. These techniques involve the formation of a drug substance solution followed by its atomisation, controlled evaporation of the solvent, collection of droplets in a vessel containing non-solvent, and crystallisation via nucleation with power ultrasound. The product slurry is then transferred for solid isolation, preferably through spray-drying or supercritical CO2 drying.
Atomisation and sonocrystallisation techniques for the preparation of micro and nano-crystalline particles for drug delivery take things to a different level in terms of crystallinity and morphology control. The latest techniques are scalable, economic, operate at generally ambient temperature and pressure. The technologies are undergoing rapid development and the industry can expect to see multi-kg cGMP production during 2009.
Antisolvent precipitation is an indispensable tool for the process chemist: often crystallisation can be achieved by mixing a solution of the drug substance to be crystallised with an antisolvent, so that, after mixing, the solution is supersaturated and crystallisation occurs. Usually it is precipitation - or "crashing out of solution" - of amorphous and ultrafine particles due to extremes of supersaturation.
Molecule-to-particle techniques using power ultrasound, such as antisolvent precipitation, take advantage of the excellent dispersive and crystal nucleation properties of transient cavitation. The precipitation conditions must be chosen to maximise crystal nucleation at the expense of growth.
Prosonix takes advantage of these effects by mixing in the presence of an ultrasonic field. The two streams can be mixed either in continuous mode or in a recirculation loop using the ultrasonic devices shown in Fig. 5. In recirculation mode the antisolvent stream is re-circulated rapidly through the flow-cell while the optional feed API solution is fed slowly into the flow cell whereby flow rates are often over 100:1.
This leads to rapid dispersion and crystallisation of micron and sub-micron sized particles that can then be isolated by spray drying, for example. This "reverse" antisolvent process is essential to avoid growth of particles in a "normal" antisolvent process whereby antisolvent is added to the API solution (Fig. 5). Prosonix has a range of dispersive technologies using ultrasound called DISCUS.2
The company has produced various microcrystalline steroids by this "reverse" process and sees this as an effective means of preparing mesoscopic crystalline particles at industrial scale. The options are quite diverse: the non-solvent-solvent system may be miscible, such as an ethanol solution dispersed into heptane, or immiscible, such as dichloromethane or toluene dispersed into water, with continuous removal of the more volatile solvent. A melt of the API can be fed in (as long as the melting point is not too high). All these methods can be used for preparing aqueous nanosuspensions often with the use of stabilisers.
DISCUS sonocrystallisation can be applied to the preparation of aqueous nanosuspensions, or sub-micron colloidal dispersions of pure drug. These are ideal formulations to improve bioavailability. Nanosizing is the size reduction of the API down to sub-micron range in an aqueous media; typically down to 100-200nm and stabilised with surfactants or polymers.11 The nanosuspensions can be dried using conventional techniques, such as spray-drying or lyophilisation.
This ultrasound mediated emulsion crystallisation, developed by Prosonix, is a novel particle engineering technique that facilitates formation of submicron to micron-sized particles to improve therapeutic efficiency. This technique is beneficial for poorly water-soluble drug candidates.
In a typical process, a drug is dissolved in organic solvent, which is immiscible with the non-solvent of choice. Ultrasound is applied to achieve a stable emulsion. Each emulsified droplet can be subjected to heat or mass transfer effects, so as to achieve evaporation, cooling or diffusion, to bring about the required degree of supersaturation and crystal nucleation. Use of ultrasound assists in the dispersion and stabilisation of the drug particles in non-solvent.
There is also a drive to produce formulations of two or more drugs - combination particles - where two or more APIs in an exact ratio can be converted to a particle formulation containing the very same drug substances as separate crystalline entities. Prosonix has developed a platform for this. The company can also use dispersive techniques, such as DISCUS, to achieve similar results. The synergy of action of steroid and bronchodilators combinations for asthma and COPD suggest that it should be highly beneficial to have them prepared together.
Prosonix" process virtually eliminates the variability associated with blending two or more micronised powders. Multiple APIs in the correct dose ratio can be symbiotically crystallised in a single perfect particle. In vitro delivery has been assessed (using NGI) for individual components derived from combination particles via carrier based DPI formulations using a monohaler. In all cases the FPD was consistently higher than when using individual micronised powders. Importantly, the overall particle stability over a four-week period was significantly greater for Prosonix engineered particles (Fig. 6). For Seretide equivalent particles a 30% increase in FPD can be shown when using well-engineered combination particles compared with micronised Fluticasone propionate and Salmeterol xinafoate 5:1 powders dry blended.
Full industrialisation of these techniques will require the build of new ultrasonication equipment for lab and production use. Industry can expect to see major inroads into cGMP manufacture by 2010. With Prosonix flow-cell technology1,4,8 many processing opportunities for inhaled medicines can be tackled. Techniques discussed here should become the default methodology for producing perfect mesoscopic particles that will lead to pharma products with improved performance, stability and ease of manufacture.