CHAPTER 2 LITERATURE REVIEW AND BACKGROUND
2.1.5 Applications of High Power Ultrasound
2.1.5.1 Implementations in pharmaceutical and technological processes
In the area of pharmaceuticals, the most common application of HPU mainly focuses on particle engineering techniques such as crystallization from solution, slurry (Sono- crystallisation, sonic slurry) and particle engineering from the melt phase (melt sonocrystallisation, ultrasound assisted melt extrusion). (Guo et al. 2003; Dhumal et al. 2009; Park* and Yeo 2010). Particle engineering under the effect of HPU can change and improve the primary and secondary physical properties associated with solids such as: a) Primary physical properties like particle size, shape, density, crystal habit and porosity etc.
b) Secondary physical properties like flowability, compactability and compressibility.
Particle uniformity is also particularly important in the pharmaceutical industry because it can directly impact the processability of the powder and the final product.
Crystallisation methods are an essential part of manufacturing APIs. Achieving small and uniform API particles is essential for pharmaceutical dosage uniformity. Dry milling processes are used to reduce particle size, but there can be undesirable outcomes such as physical instability of the crystals caused by the stress applied. Large scale manufacturing of APIs cannot be achieved using dry milling and an extra cost related to special equipment for safety is also necessary. Small API particles can be obtained by the application of ultrasound during slurry crystallisation. In this process, an ultrasonic probe is operated at 20 KHz frequency with an effective energy
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input of 100-200W for 10g of material. It has been found that crystals with an initial particle size of 100-200
µ
m can be reduced to particles smaller than20µm using this technique
.
Overall, the HPU approach can significantly reduce the particle size of APIs whilst having no effect on the crystallinity (Kim et al. 2003).Crystal morphology can influence various physical and chemical properties of APIs such as flowability, packing, compaction, solubility and dissolution rate. A melt sonocrystallisation (MSC) process was designed by Manish et al for ibuprofen, where ultrasonic energy was applied to a molten state of ibuprofen causing a significant increase in the kinetic energy of the molecules and number of collisions, leading to an increased rate of crystallisation of the API. Different morphologies, such as hollow tubes and plates, during the application of ultrasound energy to the molten state of the API, were also observed. The results concluded that the crystal size decreased with an increase in US treatment time. The solubility of MSC IBU agglomerates was found to be significantly higher than pure IBU, because of the smaller crystal size. Furthermore, pure IBU is known to have a sticking problem to the punch during compression. This is due to surface roughness and large cracks between crystals. MSC IBU was proposed as an ideal solution to avoid sticking and to improve compressibility through smoother particle surfaces and a lower number of cracks (Manish et al. 2005).
The direct compression of tablets can be a cost effective and simple method to use which can also increase the stability of the API. Certain APIs which have poor flowability properties are difficult to directly compress, for example,
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theophylline. This is because tablet size and weight are limited and tablets are at risk of capping. The application of high intensity ultrasound can overcome those limitations and allow for direct compression techniques to be used on those drugs that failed to be tableted by conventional compression methods. For example, high anhydrous theophylline content formulations are unsuitable for direct compression, ultrasound assisted compaction has been introduced to help produce them (Levina et al. 2000).
Many pharmaceutical powders, such as IBU and paracetamol (PAR), during conventional compression techniques, can experience plastic or elastic deformation and can fragment into smaller particles. In 2002, a study conducted by Levina and Rubinstein used an ultrasound-assisted compaction machine operating at 20 KHz and 20-30 MPa. The simultaneous application of HPU with compression force was found to be better than applying HPU before and after the conventional compression process. It was found that pressure should be applied simultaneously with HPU to improve acoustic contact, which is required to allow ultrasound vibrations to pass from the horn to the material. It was also demonstrated that ultrasound- assisted compaction was influenced by the formulation and sonication time. When IBU was mixed with microcrystalline cellulose (MCC), a stronger tablet was obtained by ultrasound-assisted compaction compared to compaction of IBU alone. The increase in the mechanical strength was due to HPU induced bonding between IBU and MCC molecules. The temperature of the tablet surface increased from 43°C to 60°C when the ultrasound amplitude was increased and sonication times were increased from 1 to 5 seconds. The resulting effects of HPU can cause particles rearrangement, interparticulate
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bonding and incorporation of the API into the thermoplastic material. Therefore the dissolution rate can be decreased (Levina and Rubinstein 2002).
Dry powder inhaler formulations require drug particles with an aerodynamic particle size below 5
µ
m. Particle size below 5µ
m provides deep lung deposition and good flow properties which enables accurate dose metering. In 2009, Dhumal et al compared an elongated crystal of Salbutamol Sulphate (SS) that was prepared by sonocrystallisation (SC) with a micronized spray drying method (SD) and without sonication. SS is a short acting B-adrenergic receptor agonist used for the treatment of asthma. It has been demonstrated in a lung simulator (cascade impactor) that the fine particle fraction (FPF) of the formulation increased from 16.66% for micronized SS to 31.2% for SDSS (achieved by spray drying of an aqueous solution of SS) and 44.2% for SD- SCSS. The elongated crystals of SS obtained by SD-SCSS caused a reduction in the cohesive/adhesive forces and subsequently lead to more FPF deposition in the lung. In summary, the SC process was shown to be a rapid and simple method which could produce SS crystals suitable for pulmonary delivery (Dhumal et al. 2009).Anti-solvent processes have been widely used to crystallise pharmaceutical compounds, the simultaneous application of ultrasound with anti-solvent crystallisation of roxithromycin has had a significant effect on the agglomeration and crystal habit of roxithromycin when compared with the anti-solvent crystallisation on its own (Park* and Yeo 2010). Agglomeration was decreased under the action of HPU; nucleation and the probability of
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contact between the nuclei was also decreased. Additionally, crystals grown in a well-mixed condition did not agglomerate and particles with large sizes formed.
Hot melt extrusion is the most widely used technique in the polymer industry. Many efforts have been made to develop extrusion technology for improving product quality. Guo et al used ultrasound-assisted extrusion for the dispersion of nanocomposites within a molten polymer. The ultrasound apparatus was constructed at the die zone and was parallel to the direction of the melt flow. It was demonstrated that significant changes occur to polymeric materials by subjecting HPU to polymer melts during the extrusion process (Guo et al. 2003). In addition, Isayev et al found that the application of HPU to polymers provided advantages such as the reduction in structural defects, enhancement of mechanical properties and an increase in crystallinity (Isayev et al. 2009).