The compression of a powder is a complex process that is usually affected by different kinds of problems. These problems have been widely investigated and mainly concern the volume reduction and the development of strength between the particles of the powder sufficient to ensure tablet integrity. The application of ultrasonic energy shows a great ability to reduce and even avoid these problems. Ultrasound refers to mechanical waves with a frequency above 18 kHz (the approximate limit of the human ear). In an ultrasound compression machine, this vibration is obtained by means of a piezoelectric material (typically ceramics) that acts as a transducer of alternate electric energy of different frequencies in mechanical energy. An acoustic coupler, or “booster, ” in contact with the transducer increases the amplitude of the vibration before it is transmitted (usually in combination with mechanical pressure) to the material to be compressed. Ultrasound – assisted powder compression has been widely employed in metallurgy as well as in the plastic and ceramic industries. The first references in the pharmaceutical industry are two patents in 1993 and 1994.

Two main objectives are pursued nowadays by means of the application of ultrasound – assisted compression:

  1. Increase in the drug dissolution rate due to amorphization of the drug
  2. Preparation of controlled – release dosage forms with thermoplastic excipients

As a consequence of the application of ultrasonic energy, the drug can loose its crystalline structure. This will result in an increase of the dissolution rate of the active substance, which can be very adequate for slowly dissolving drugs. Nevertheless, depending on the storage conditions, the drug can recover, at least partially, its crystallinity. To overcome this problem, it has been proposed to use an adequate excipient, preventing the recovery of the crystallinity, leading in some cases to the preparation of solid solutions into the die of the tableting machine. Several analytical techniques, such as infrared (IR) spectroscopy, differential scanning calorimetry, HPLC, and thin – layer chromatography (TLC), have been used to investigate possible drug degradation due to ultrasonic energy. No important permanent modification of the drug has been found, with the exception of the loss of crystallinity. Concerning the design of controlled – release dosage forms, using a thermoplastic excipient (e.g., copolymers of acrylic and metacrylic acid), an important decrease in the release rate has been found for tablets compressed with the assistance of ultrasonic energy in comparison with traditional tablets. Although the effects of the ultrasonic energy on the material are not completely clarified, this slow release rate has been attributed to different phenomena:

Mechanical Pressure This pressure is exerted by the punches of the ultrasound – assisted tableting machine. This is the main compression mechanism when low ultrasonic energies are employed. Rodriguez et al. or when the materials used are not thermoplastic. In these cases the machine acts as a multiple – impact mechanical press.

Thermal Effects Due to the poor conductivity for ultrasounds (low module of elasticity and high quantity of air trapped inside) usually exhibited by the materials included in pharmaceutical formulations, a fast decay of ultrasonic energy to thermal energy is obtained. This process has been studied, monitoring the temperature inside the compression chamber by means of a thermistor. In the studied mixtures , a fast rise in temperature was obtained in tenths of a second followed by a relatively fast decrease. In this respect it must be mentioned that a recent modification of the ultrasound – assisted tableting machine that involves the suppression of Teflon isolators in contact with the powder must result in a faster decrease in temperature inside the compression chamber. Thermal effects can cause the total or partial fusion of some components of the formulation. Nevertheless, in the assayed controlled – release formulations, the components are usually below its melting points.

 Plastic Deformation Plastic deformation results from the combination of thermal and mechanical effects. The thermoplastic excipient was subjected to a temperature above its glass transition temperature ( T g ) and to a high – frequency mechanical pressure that can avoid the elastic recovery of the material.

 Sintering The combination of temperature, pressure, and friction effects can result in the sintering of particles, so that the limits between them are no longer evident . Recent studies have shown that, for one component of the system undergoing thermoplastic deformation, the continuum percolation model can be used to predict the changes in the system with respect to a traditional pharmaceutical formulation.


FIGURE 1. SEM micrograph of matrix tablet containing potassium chloride as drug model and commercial acrylic – metacrylic copolymer. The white KCI particles are surrounded by an almost continuous dark gray mass of excipient

The continuum percolation model dispenses with the existence of a regular lattice underlying the system; therefore, the substance is not distributed into discrete lattice sites. This model deals with the volume ratio of each component and a continuum distribution function. The volume ratio is expressed as a space – occupation probability to describe the behavior of the substance. The continuum percolation model predicts an excipient percolation threshold around 16% v/v. This can explain the important decrease in the critical point corresponding to the excipient percolation threshold, a critical point that governs the mechanical and release properties of the matrix. Ultrasound compaction lowers the percolation threshold of the thermoplastic excipient, resulting in a drastic reduction (about 50%) in the amount of matrix – forming excipient  needed to obtain the controlled-release system as well as in a better control of the drug release. The structure of the excipient inside the US -tablets does not correspond to a particulate system but to an almost continuous medium; therefore, there is no an excipient particle size inside these matrices . Consequently, the percolation threshold of the active agent is higher than in traditional tablets. The insoluble excipient almost surrounds the active agent particles, slowing down the contact with the dissolution medium. These facts can involve important advantages for the pharmaceutical industry, such as the preparation of controlled – release inert matrices containing high drug doses, with very little increase in the weight of the system. This fact is especially interesting when a high drug dose has to be included in the dosage form, as frequently occurs in controlled – release systems. On the other hand, application of ultrasonic energy results in an increase in the temperature of the die during the compaction process. The consequences of this fact should be taken into account and cannot be neglected in the case of thermo labile drugs and/or excipients. Further research is needed in the area of ultrasound – assisted compression of pharmaceutical powders, including a higher number of drugs and excipients.


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