SubscribeImproved Crystallization and Particle Engineering.
Power ultrasound within chemical processing has particular importance in crystallisation control, including nucleation, size distribution down to micron-size and morphology.
Drug microcrystalline particles for inhalation can also be prepared using new power ultrasound assisted technologies such as the Solution Atomisation and sonoXtallisation (SAX) technology being developed by Prosonix in conjunction with the University of Bath, UK. This allows the production of spherical drug particles with superior geometrical, surface and performance properties.
Pharmaceutical manufacturing is committed to making particles and then modifying their properties in order to turn them into structured products, but surprisingly 5 - 10 % of manufactured formulations fail to meet specifications.
Typically mesoscopic particles for drug inhalation are manufactured by some very primitive pharmaceutical technologies such as micronisation; a "sledgehammer" and energy-inefficient technique to turn large, regular crystals into irregular 1 - 5 μm particles that can undergo morphological change and surface polymorph transformations leading to amorphicity and decreased stability. The particles can also be highly charged which undermines the flow-rates essential for aerosolised and dry powder inhalers.
We must learn to engineer such mesoscopic crystals, control their micro and macro structure and fully characterise their performance enhancing attributes. This will allow control of surface characteristics and surface geometry while maintaining high throughput, low cost and industrial scalability. Emerging crystallisation and particle engineering technologies are now being developed to assist in both drug development and manufacture.
The production of drug particles using supercritical fluids has generated significant interest, albeit with limited success to date. Questions are being asked about scalability, cost effectiveness due to high pressure, limited productivity and inherent amorphicity. Conversely, the SAX technology, developed in conjunction with the inventor, Dr. Rob Price of the University of Bath, avoids all these issues to give superior engineered drug particles.
Ultrasound And Crystallisation
Almost all chemical processes utilise crystallisation - cooling, evaporative, anti-solvent or reactive - and can be one of the most difficult unit operations to control. Ultrasound is used routinely in areas such as medical imaging, diagnostics and biological cell disruption and now the application of power ultrasound (20 - 100 kHz) has risen to prominence in sonochemistry (modify chemical reactions) and sonocrystallization (nucleation via transient cavitation).
The latter is particularly effective for primary nucleation and reproducibly generating microcrystalline seed crystals (to avoid conventional seeding). As a result, we can control crystal size distribution, morphology, impurities and solid-liquid separation. The in-line continuous flow or batch mode process can be applied to intermediates, excipients, APIs, binders and sugars and importantly can be validated across scale in current Good Manufacturing Practice (cGMP) environments.
Polymorph Control
An understanding of the metastable zone (MZ) and the zone width (MZW) is fundamental to controlling crystallization. The application of high-intensity 20 kHz ultrasound can lead to narrowing of the MZW and by doing so it is possible to "tailor" a crystal size distribution using a short burst of ultrasound to nucleate at low supersaturation and then allow growth to large crystals, and the production of small crystals via continuous insonation and mechanical disruption of crystals or loosely bound agglomerates. The optimum needs to be determined by experimental investigation.
Ultrasound can also induce secondary nucleation by mechanically disrupting crystals or loosely bound agglomerates. The overall technique lends itself extremely well to polymorphic systems. Polymorphism is common amongst organic materials resulting in the existence of two or more crystalline phases with different packing in the crystal lattice. Isolation of the "wrong" polymorph brings substantial problems in pharmaceutical applications but by careful application of ultrasound the ground state polymorph (the most thermodynamically favoured and least soluble) can be isolated.
For example, in a system that exhibits enantiotropic polymorphism (fig. 1) sonocrystallisation, using a pilot scale recirculation system (~500 l crystalliser and 5 l Prosonitron), allows us to prepare the thermodynamically stable polymorph (cool along blue line), which has cubic type crystal habit, at low supersaturation.
Sonocrystallisation for enantiotropic (with transition point) polymorphs.
Conversely, at high supersaturation (cool along red line) fast nucleation kinetics, along with poorly controlled crystallization, leads to the proliferation of the kinetic (metastable) polymorph, which has a distinct needle habit, and in turn results in poorly stirred slurries and variable product bulk density.
From Laboratory To Manufacture
One of the principal barriers to the adoption of power ultrasound technology in pharmaceutical manufacturing has been the lack of industrial scale equipment. To address this need we have designed industrial equipment to allow effective and focussed distribution of acoustic energy into a liquid by using a number of low-power transducers (now 21 in a 5 l flow-cell) bonded to the outside of a cylindrical duct.
This avoids the problems of using high-powered probe based equipment where metal particles can be shed into the crystallising liquor. Typical equipment for pharmaceutical manufacture fabricated from Hastelloy is shown in figure 2 alongside similar equipment, with the acoustic shield removed, where the piezoelectric transducers can be clearly seen. This equipment can be used as a recirculation or continuous flow-cell.
Manufacturing equipment for sonocrystallisation.
The technology can be applied from kilogram to tonne scale for fine chemical and pharmaceutical manufacture. The value-added benefits arising can include identification of new process patents for individual products, thus securing and extending marketing timescales. Sonocrystallisation can be applied at any stage in a product pipeline; the scale-out feature of the technology ensures that success in the lab can be replicated across scale.
SAX is a sonocrystallisation technique for production of particles with optimum size and morphology suitable for formu¬lation where microcrystallinity is essential. We have seen specific benefits in the production of particles for inhaled therapeutics, and also see potential in the production of nanosuspensions, pharmaceutical co-crystals and combination-based products. SAX allows production of spherical particles (fig.4) with a well-defined size range and with control of the macroscopic morphology, including polymorphism and surface topology. These properties are invaluable in defining aerodynamic properties of particles, shelf life, stability, bioavailability and efficacy.
SAX Particles of Budesonide and right: ICS / LABA combination particle Advanced.
It is particle geometry that is the central design principle in controlling surface forces and hence interfacial interactions. SAX aims to control the particle geometry, morphology and surface properties by a technique that is simple in philosophy but not without its challenges in terms of underlying physics and chemistry. In principle the atomised droplets undergo controlled evaporation to produce a highly concentrated viscous non-crystalline droplet. Only when power ultrasound is applied to the droplet by using a non-solvent medium does it undergo nucleation and crystallisation.
Combination Particles
Combination Particles are single particles containing two or more active pharmaceutical ingredients (API) or API and recipient such as lactose. These particles should have a high degree of crystallinity with respect to both ingredients. Often the two drugs have synergistic action and need to be delivered in an exact ratio such as in inhaled corticosteroid (ICS) and long acting beta agonist (LABA) formulations (fig. 4). For optimal interaction, the two drugs must be delivered to the same site of action in adequate doses since the synergistic action may be reduced with variable ICS and LABA doses.
SAX introduces the potential for a novel particle engineering solution whereby a single droplet containing the two APIs in an exact ratio can be converted to a particle containing the very same drug substances as separate crystalline entities. Indeed triple therapy should be possible with SAX.
The SAX Process
Power ultrasound can be applied to crystallisation at manufacturing scale and now in technologies to produce micron-sized particles for drug inhalation. Sonocrystallisation can become a core technology in the pharmaceutical industry, and we can expect to see many more industrial applications in the near future. Power ultrasound has a significant part to play in pharmaceutical particle science.
Dr. Graham Ruecroft
Prosonix Ltd
Oxford, UK
Tel.: +44 1865 784250
Fax: +44 1865 784251
graham.ruecroft@prosonix.co.uk
www.prosonix.co.uk