If vibration intensity—the mean power that is transmitted per surface unit—is sufficiently high, the amplitude of the capillary waves will also grow, and their shape will increasingly deviate from that of a sine wave due to nonlinearities. Finally, at high amplitudes, droplets will be propelled from the crests of the wave as they are unstable, and this leads to atomization of the liquid (3–5).

During ultrasonic nebulization, waves formed on the surface of the solution have a wavelength (1):

where f is the frequency of the ultrasonic vibrations, and   and   are the surface tension and density of the liquid, respectively. The diameter of the droplets formed from the waves is

where   is a proportionality coefficient.

For a given nebulizer, the vibration frequency of the transducer is fixed and is often in the range 1–2.5 MHz.

For a given vibration frequency, the intensity of the wave is proportional to the square of wave amplitude a and its frequency f:

In most cases, an adjustment in vibration intensity is possible by modifying the vibration amplitude of the transducer.

Although air is not involved in the initial formation of droplets by ultrasonic vibrations, a flow of air is used to expel the aerosol droplets. Ventilation,generally adjustable, sends an airflow through the nebulizer and carries out the aerosol produced.

The vibrations may be transmitted through a coupling liquid—commonly water—to a nebulizer cup containing the solution to be aerosolized (1,2,6–8).

     In a previous work, we studied the influence of technological parameters of jet nebulization, that is,the nebulizer and dynamic conditions (airflow and pressure), on the quality of nebulization. Our results showed the importance not only of defining the formulation, but also of associating it with the proper nebulizer(s) and conditions of use (9). It seemed of interest, as a corollary to this study, to consider the influence of the technological parameters of ultrasonic nebulization on nebulization quality to improve the efficiency of ultrasonic nebulizers.

EXPERIMENTAL

Materials

Nebulization was carried out with a 9% sodium chloride solution and 2% aqueous solution of   protease inhibitor (  PI) (LFB, Lille, France). The   PI is a glycoprotein of human origin with a molecular weight of 52,000 Da.

The characteristics of the ultrasonic nebulizers used are presented in Table 1. The three ultrasonic nebulizers were used to study the influence of the following technological parameters: vibration intensity,ventilation level, vibration frequency of the transducer, and presence of a coupling liquid.

The coupling liquid was water. It was used to transmit the ultrasonic vibrations to the solution to be aerosolized. It prevents the direct contact of the drug solution with the transducer.

Environmental temperature and relative humidity were maintained constant at 20 C and 40% and 45%, respectively.

Method

    As the three nebulizers studied had different vibration frequencies, we studied the influence of vibration frequency on droplet size for similar ventilation levels.

   A study was made of the influence of a coupling liquid on the solution temperature. For the other parameters (vibration intensity and ventilation level), we studied their influence on the size of droplets emitted, the quantity nebulized, and the nebulization time. Each result is the mean of three replicate measurements.

Evaluation of Nebulization Quality

 Size of Droplets Emitted

    Aerosol size distribution emitted from the solution was determined with a Mastersizer X (Malvern,Orsay, Paris) laser size analyzer. The solution was directly nebulized in the laser beam. After repeated testing, the measurement variation was 2.4%. The results are expressed as the percentage of droplets