Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1996-03-28
1998-08-18
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424400, 424434, A61K 914
Patent
active
057955948
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 PCT/GB94/01425 filed Jun. 30, 1994.
The present invention relates to particulate products which may be prepared by methods and apparatus using supercritical fluids. More particularly, the invention relates to novel crystalline forms of salmeterol xinafoate.
The use of supercritical fluids (SCFs) and the properties thereof has been extensively documented, see for instance, J. W. Tom and P. G. Debendetti, "Particle Formation with Supercritical Fluids--A Review", J. Aerosol Sci., 22 (5), 555-584 (1991). Briefly, a supercritical fluid can be defined as a fluid at or above its critical pressure (Pc) and critical temperature (Tc) simultaneously. Supercritical fluids have been of considerable interest, not least because of their unique properties. These characteristics include:
High diffusivity, low viscosity and low surface tension compared with liquids.
Large compressibility of supercritical fluids compared with the ideal gas implies large changes in fluid density for slight changes in pressure, which in turn results in highly controllable solvation power. Supercritical fluid densities typically range from 0.1-0.9 g/ml under normal working conditions. Thus, selective extraction with one supercritical fluid is possible.
Many supercritical fluids are normally gases under ambient conditions, which eliminates the evaporation concentration step needed in conventional liquid extraction.
Most of the commonly used supercritical fluids create non-oxidising or nondegrading atmospheres for sensitive and thermolabile compounds, due to their inertness and moderate temperatures used in routine working conditions. Carbon dioxide is the most extensively used SCF due to its cheapness, non-toxicity, non-flammability and low critical temperature.
These characteristics have led to the development of several techniques of extraction and particle formation utilising supercritical fluids. In particular, two processing methods have been identified for particle formation.
Rapid Expansion of Supercritical Solution (RESS) (see, for instance, J. W. Tom and P. G. Debendetti, supra) involves the dissolution of the solute of interest in the supercritical fluid, followed by rapid expansion of the supercritical solution to atmospheric pressure, resulting in the precipitation of particles.
Gas Anti Solvent (GAS) Recrystallisation (P. M. Gallagher et al, Supercritical Fluid Science and Technology, ACS Symp. Ser., 406, p.334 (1989)) is particularly useful in situations when the solid of interest does not dissolve, or has a very low solubility in a supercritical fluid or a modified supercritical fluid. In this technique, the solute of interest is dissolved in a conventional solvent. A supercritical fluid such as carbon dioxide is introduced into the solution, leading to a rapid expansion of its volume. As a result, the solvent power decreases dramatically over a short period of time, triggering the precipitation of particles.
Both of these techniques, when applied to particle formation, have their limitations. Thus, when using RESS, the product yield is usually low due to the low solubility of many polar solutes (e.g. many pharmaceutical products) in supercritical carbon dioxide under normal working conditions. This, together with difficulties in collecting the products makes the technique time consuming and unattractive as a method of routine particle formation. In practice, the combination of high energy requirements of RESS and low yield has greatly limited the application of this technique.
Regarding GAS, the selection of solutes, solvents and the supercritical fluid requires careful consideration. The solubility of the solute in the sub/supercritical fluid should be low whilst, at the same time, the sub/supercritical fluid should expand the solvent appreciably. These operating criteria, in addition to experimental difficulties and high energy costs, have limited the use of this technique, as have problems with product recovery and solvent recovery/recycling every time the system is depressurised, see for instance P.
REFERENCES:
patent: 5509404 (1996-04-01), Lloyd et al.
Hanna Mazen
York Peter
Benston, Jr. William E.
Glaxo Group Limited
Page Thurman K.
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