CommentaryEnhancement of dissolution rate of poorly-soluble active ingredients by supercritical fluid processes: Part I: Micronization of neat particles
Introduction
As a growing number of new active compounds exhibit a very low solubility in biological media, the pharmaceutical industry is facing a major challenge to find means to formulate such compounds in order to reach an “acceptable” bio-availability (Liu, 2000). More than one-third of the drugs listed in the US Pharmacopoeia are considered to be “poorly-soluble”, and a recent study stated that 41% of failures in new drug development in seven UK-owned companies have been attributed to poor biopharmaceutical properties, including water insolubility (Prentis et al., 1999).
In fact, it has been shown that, for most orally administered poorly-soluble compounds, the bio-absorption process is rate-limited by dissolution in gastro-intestinal fluids; in the case of parenteral administration, the effective bio-availability of compounds is also limited by solubility issues (risk of precipitation at the injection point, slow dissolution in serum, …). Many parameters related to solid morphology influence the dissolution rate of a compound, among which the particle size and the crystal habit and crystal pattern have a key-role.
Here we review literature and present some of our own results on the dissolution rate enhancement of poorly-soluble active ingredients by using supercritical fluid (SCF) processes (Jung and Perrut, 2001, Perrut, 2003a, Perrut and Clavier, 2003b) in order to micronize these compounds into neat nano-/micro-particles (Part I), or to formulate them by microencapsulation, cyclodextrin (CD) inclusion and impregnation (Part II, Perrut et al., 2005).
For the purpose of dissolution enhancement, several supercritical fluid particle design processes can be used, classified according to the four main basic concepts (see details in Jung and Perrut, 2001), with the possibility to micronize neat particles with the first two processes and to prepare composite particles by the all four:
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Rapid expansion of supercritical solutions (RESS): A solution of the compound(s) in a supercritical fluid is rapidly depressurised through a nozzle, causing a rapid nucleation of fine particles (neat or composite) (Jung and Perrut, 2001).
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Supercritical anti-solvent (SAS): A solution of the compound(s) in an organic solvent is contacted with a supercritical solvent that causes solid precipitation by anti-solvent effect, the organic solvent being eventually entrained by the supercritical fluid; either neat particles of a unique compound, or micro-spheres of an ingredient embedded in an excipient, or CD-complex particles may be generated (Jung and Perrut, 2001).
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Particles from gas-saturated solutions (PGSS): The compound(s) are melted in presence of a compressed gas that dissolves in the liquid phase which is pulverized towards a low-pressure vessel, leading to precipitation of solid particles of compound(s); when a suspension of fine particles of an ingredient dispersed in a liquid excipient is processed, composite microcapsules are generated (Jung and Perrut, 2001).
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Impregnation: The compound is dissolved in a supercritical fluid that is then depressurized into a vessel containing a porous excipient on which the compound is adsorbed. In another concept called concentrated powder formulation (CFP), applicable to liquid compounds, the liquid viscosity is decreased by saturation with high-pressure CO2, and the liquid penetrates the carrier pores where it is adsorbed during the co-pulverization of the solid and liquid phases (Jung and Perrut, 2001).
We will not enter into the solubility theory and solubility prediction as the reader can find comprehensive accounts in Liu (2000) but here we simply recall some fundamental aspects.
Section snippets
Fundamentals (Liu, 2000)
Applying the Fick's law, it is easy to demonstrate that the mass transfer rate of a particulate solid of mass M (composed of particles with an average volume Vp) into a liquid of volume VL is proportional to the solid surface S:where h is the mass transfer coefficient (generally estimated by h = D/e where D is the diffusion coefficient of the compound in the liquid and e is the thickness of the diffusion layer), CS the solid solubility and Cb is the solute bulk concentration. This
Experimental issues
It must be emphasized that solid dissolution is a complex operation influenced by a great number of factors, not only the particle size. This can be illustrated in Fig. 1 (Crison, 2000) showing the dissolution curves of a poorly soluble compound as bulk or micronized, compared with the theoretical curve of the micronized form, according to the Hixson–Crowell cube-root equation (Eq. (3)). Further observations using a light microscope showed a high degree of re-agglomeration of the micronized
Dissolution rate of SCF-micronized particles
Among the hundreds of articles dealing with SCF particle design (Jung and Perrut, 2001, Perrut, 2003a, Perrut and Clavier, 2003b), it is rather surprising that very few disclose results on the difference in dissolution rate between unprocessed material and SCF micronized solid, as detailed below. Moreover, in many publications, data are not complete and the physical properties of the solid material are lacking. We have experienced difficulties in obtaining such comparisons, but some of our own
Discussion
From the results cited in this publication on 13 active compounds by a variety of researchers, we would conclude:
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Although the accepted theory tends to predict a rate quasi-proportional to the specific surface area a, micronisation alone cannot guarantee a significant enhancement of dissolution rate or bio-availability of hydrophobic drugs.
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Many other factors play a major role in the dissolution phenomenon among which the most important one is wettability; addition of a surfactant in the
Acknowledgements
The authors are grateful to Professor Jacques Fages (Ecole des mines d’Albi-Carmaux, France) for valuable discussions and for reviewing this article.
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