Micronization of antibiotics by supercritical assisted atomization

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Abstract

Supercritical assisted atomization (SAA) was used to produce tetracycline (TTC) and rifampicin (RF) microparticles with controlled particle size and particle size distributions in the range of aerosolizable drug delivery. The process is based on the solubilization of a fixed amount of supercritical carbon dioxide in the liquid solution; then the ternary mixture is sprayed thought a nozzle, and, as a consequence of atomization, solid microparticles are formed. Water was used as liquid solvent for TTC and methanol was used for RF; heated nitrogen was also delivered into the precipitator in order to evaporate the liquid droplets and generate the microparticles. SAA of these compounds was optimized with respect to the process parameters; then, the influence of the solute concentration in the liquid solution on particle size and particle size distribution was studied. The produced powders were characterized with respect to their morphologies and particle size: spherical particles with controlled particle size ranging between 0.5 and 3 μm were obtained for both drugs at optimized operating conditions. HPLC and GC-Head Space analyses confirmed that no chemical degradation occurred in the drugs after the SAA processing and, in the case of methanol, a solvent residue of 5 ppb remained in the product. The X-ray traces revealed that all the SAA micronized powders were amorphous whereas the untreated material shows crystalline patterns.

Introduction

Rifampicin (RF) and tetracycline (TTC) are antibiotics used in the treatment of several pulmonary diseases. RF is generally used to fight tuberculosis, whereas TTC is mainly used for the treatment of chronic bronchitis [1]. In particular, RF is practically insoluble in water, therefore, its dissolution in biological liquids is particularly difficult.

Extensive research has shown that the critical size of the particles for aerosol delivery formulations lays in the range from 1 to 5 μm. Particles larger than about 5 μm collide with the walls in the upper airways. Then, they are carried by ciliary flow to the mouth and reach the system primarily by ingestion. Particles smaller than 1 μm can remain suspended in the inspired and expired air and do not reach the lung. Only drugs with a size approximately between 1 and 5 μm are effectively delivered in the deep lung.

The production of microparticles, as in the case of RF and TTC aerosol delivery, can be useful to address these drugs directly to the lung. Moreover, an accurate engineering of their particle size can allow a selective deposition of these drugs within the human respiratory tract to maximize their effectiveness against diseases that did not manifest uniformly within the lung (for example bronchitis) and minimize the adverse side effects.

Conventional techniques like jet milling and spray drying are not able to produce very narrow and controlled particle size distributions and can cause thermal degradation of the drug. Therefore, in the last years, several supercritical fluids based techniques have been proposed for the production of micronic and nanometric particles of pharmaceuticals compounds. Supercrical Fluid micronization processes can take advantage of some specific properties of gases at supercritical conditions, like the modulation of the solubilization power, large diffusivities, solventless or organic solvent reduced operation and the consequent possibility of controlling powders size and distribution. The techniques proposed are: the rapid expansion of supercritical solutions (RESS) [2], [3], [4], [5], [6], the particles generation from gas saturated solutions (PGSS) [7], [8], [9] and the supercritical antisolvent precipitation (SAS) [10], [11], [12], [13], [14], [15], [16], [17], [18]. One of the prerequisites for a successful SAS precipitation is the complete miscibility of the liquid in the supercritical CO2 and the insolubility of the solute in it. For these reasons SAS is not applicable to the precipitation of water soluble compounds due to the very low solubility of water in CO2 at the operating conditions commonly used.

Very recently, a supercritical carbon dioxide assisted atomization technique has been proposed by Sievers and coworkers [19], [20], [21], [22], [23]. It allows the micronization of water-soluble compounds, but also ethanol and ethanol–water mixtures have been successfully used [22].

The process consists of contacting the liquid solution with supercritical or near critical CO2 in a tee connection with a very low internal volume (internal volume lower than 0.1 μl) followed by a capillary tube (internal diameters ranging between 75 and 127 μm, 50 mm long, as a rule). Flow rates commonly used by Sievers and coworkers are: liquid flow rate between 0.1 and 0.3 ml/min and CO2 flow rate between 0.3 and 10 ml/min. Therefore, the residence time of the two fluids in the atomization device is smaller than 0.1 s, and can be as small as 0.01 s. Moreover, a capillary and a low dead volume tee are devices designed to favor segregation not the mixing between two fluids. Thus, the atomization device used by Sievers and coworkers [19], [20], [21], [22], [23], [24] tends to minimize the contact and the duration of the contact between the two fluids. They specifically state (for example, in Xu et al. [24]) that tees with larger dead volumes cannot be used, otherwise the aerosol (in the way they operate) was not formed. Therefore, the addition of the supercritical fluid generates a two-phase flow and gas penetration (no dissolution) produces bubbles and a very efficient atomization is obtained.

Recently, we developed a different process arrangement [25] with respect to the one proposed by Sievers and coworkers, in which a thermostated saturator is added before the injection. This device is packed with stainless steel perforated saddles with a high specific surface. It provides a large contacting surface and an adequate residence time for the two fluids. Indeed, in the range of flow rates we use in the process, residence times from tenth of seconds to minutes are obtained in the saturator. Therefore, we can obtain an efficient, continuous solubilization of supercritical CO2 in the liquid solution and we can optimize the mixing and the residence time of two fluids, to obtain the solubilization of CO2 in the liquid, near the saturation limit at the operating conditions of temperature and pressure. As a result, CO2 dissolves in the liquid and tends to form a single fluid phase. The solution formed in the contacting device is then send to a thin wall injector and sprayed into the precipitator.

The aim of this work was to produce particles with a controlled size, suitable for aerosol delivery, of RF and TTC, using the SAA technique. Water was used as liquid solvent for TTC and methanol was used for RF. This last series of experiments represents a further improvement of the CO2 assisted atomization process, until now prevalently limited to the use of water-soluble compounds. The produced powders were characterized with respect to morphologies, particle size and particle size distribution. We also studied the influence of some process parameters on the particle size distributions. Particularly, the possibility of particle size tailoring varying some process parameters was studied. HPLC and GC-Head Space analyses were also performed to ascertain if chemical degradation occurred in the drugs after the SAA processing and in the case of methanol if solvent residue remained in the product.

Section snippets

Experimental apparatus

The apparatus used for SAA is reported schematically in Fig. 1. It consists of three fed lines used to deliver supercritical CO2, the liquid solution and warm N2 and three vessels: saturator (Sa), precipitator (Pr) and condensator (Co). Liquid CO2 is taken from a cylinder and sent to the high-pressure pump (Gilson mod. 305) equipped with a dampener (Gilson mod. 805) to avoid pressure oscillations, then CO2 is sent to a heated bath (Forlab, Carlo Erba mod. TR12) and to the saturator where it

Results and discussion

As discussed in the introduction, the solubilization of CO2 inside the liquid solution is one of the key parameters controlling the efficiency of SAA. The maximum quantity of CO2 that can be solubilized (solubility) depends on the liquid solvent and on the temperature and pressure in the saturation device. Therefore, some major process parameters to be considered in performing SAA experiments are pressure and temperature in the saturator. Another condition that has to be obtained in the

Conclusions

SAA process is very promising in producing micronic and submicronic particles of controlled diameter [28]. Water, but also organic solvents, as methanol in this work and acetone in a previous one [25], can be used; very sharp PSDs can be obtained as in the case of TTC and RF, that lie in the particle size range of aerosolizable drugs. Varying the operating conditions it is even possible to tailor the PS of SAA produced particles for different targets inside the lung.

Acknowledgements

The authors acknowledge the financial support from MiUR (Italian Ministry of Scientific Research) (PRIN 2000).

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