Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-03-01
2002-10-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S400000, C424S484000, C514S951000, C264S005000, C264S006000, C264S011000
Reexamination Certificate
active
06461642
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a process for preparing essentially crystalline particles containing a substance in a solvated form, the resulting particles being useful e.g. for oral or nasal inhalation.
BACKGROUND OF THE INVENTION
The increasing production and use of fine powders in the pharmaceutical industry has high-lighted the need for reliable methods for assessing their physicochemical and technical handling. Particles obtained by spray drying, freeze drying, rapid solvent quenching or from controlled precipitation will often be in an amorphous state or in a meta-stable crystalline form. For crystalline substances, a diminution operation, e.g. micronization, will give particles with amorphous regions.
The usefulness of amorphous and/or meta-stable crystalline particles is limited due to their thermodynamic instability. For example, such particles tend to fuse in the presence of moisture, thereby forming hard agglomerates which are difficult to break up. Furthermore, amorphous and/or meta-stable crystalline particles exhibit larger batch-to-batch variations as regards bulk density than do well-defined crystalline particles. This may cause problems e.g. in inhalers for treating respiratory disorders, due to lower dosing accuracy.
It is therefore desirable to produce crystalline or at least essentially crystalline particles, which exhibit a good dosing accuracy and storage stability.
Methods to convert the amorphous or meta-stable crystalline particles into crystalline particles are known. Examples are disclosed in U.S. Pat. Nos. 5,709,884 and 5,562,923 both to Astra AB of Sweden.
The known methods to produce crystalline particles are, however, often time consuming requiring substantial space. Therefore, there is a need for a more efficient technique for producing crystalline particles with a high shelf life.
SUMMARY OF THE INVENTION
The object of the present invention is to provide a process for preparing essentially crystalline particles containing a substance in a solvated form, comprising dissolving the substance in a first solvent, introducing into an apparatus under supercritical or subcritical conditions the solution containing the substance with an anti-solvent and a second solvent, which is water and recovering the essentially crystalline particles formed containing the substance in a solvated form.
According to a preferred embodiment of the invention, the anti-solvent is carbon dioxide.
According to another preferred embodiment, the relative solvent saturation of the anti-solvent lies in the range of from 15% up to 50% of total solvent saturation at the prevailing pressure and temperature.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for preparing essentially crystalline particles containing a substance in a solvated form, comprising
(a) dissolving the substance in a first solvent;
(b) introducing into an apparatus the solution containing the substance together with a supercritical or subcritical fluid comprising an anti-solvent and a second solvent which is water, and
(c) recovering the essentially crystalline particles formed.
The inventors of the present process, have surprisingly found that by applying a supercritical or subcritical fluid comprising an anti-solvent and a second solvent, which is water to a solution containing the substance at issue, essentially crystalline particles can be obtained. This is especially true if the particles are post-conditioned with the supercritical or subcritical fluid.
The process of the present invention can be performed in accordance with fluid gas anti-solvent techniques, wherein fluid gas includes material in its supercritical, near critical and subcritical states as well as compressed gases. Suitable fluid gas anti-solvent techniques, include but are not limited to, GAS (gas anti-solvent precipitation), a modified version of the GAS technique known as SEDS (solution enhanced dispersion by supercritical fluid), ASES (aerosol solvent extraction system), SAS (supercritical anti-solvent) and PCA (precipitation with compressed fluid anti-solvent). Preferably use is made of the SEDS technique.
The traditional SEDS technique employs an apparatus comprising a particle-forming vessel with means for controlling the temperature and pressure of said vessel, together with a means for co-introduction into said vessel of a supercritical or subcritical fluid and a vehicle containing at least one substance in solution or suspension, such that dispersion and extraction of the vehicle occur simultaneously by the action of the fluid.
To make the present invention work, especially if it is performed in accordance with the SEDS technique, the following criteria apply to the combination of first solvent, second solvent, anti-solvent, and the substance at issue:
i) the substance at issue must be essentially soluble in the first solvent,
ii) the first solvent must be miscible with the anti-solvent, e.g. carbon dioxide,
iii) the second solvent must be miscible with the anti-solvent,
iv) the substance at issue should be insoluble in the anti-solvent,
v) the amount of second solvent in the anti-solvent must not exceed that needed for saturating the supercritical or subcritical anti-solvent.
The latter criterion is essential for avoiding formation of a two-phase system containing supercritical solvent-saturated anti-solvent, e.g. water-saturated carbon dioxide, and a liquid phase containing e.g. water, solvent and dissolved active substance.
In the SEDS technique, the substance at issue is dissolved in the solvent and co-introduced into an apparatus via a nozzle having at least two channels, one channel for a solvent and one channel for an anti-solvent i.e. the supercritical or subcritical fluid. Mixing and dispersion occur at the spot where the fluids meet. The supercritical fluid dissolves the solvent but not the substance since the substance must be insoluble in the anti-solvent. Therefore, the substance will precipitate as particles with a suitable size.
A suitable apparatus for the SEDS process is described in WO 95/01221. The SEDS technique is further described in WO 96/00610. WO 95/01221 and WO 96/00610 (both to the University of Bradford, GB), are hereby incorporated by reference.
A “supercritical fluid” is a fluid at or above its critical pressure (P
c
) and critical temperature T
c
) simultaneously. Supercritical fluids also encompass “near supercritical fluids”, which are above but close to its critical pressure (P
c
) and critical temperature T
c
) simultaneously. A “subcritical fluid”
0
is above its critical pressure (P
c
) and close to its critical temperature (T
c
).
The anti-solvent is suitably one or more of carbon dioxide, nitrous oxide, sulfur hexafluoride, ethane, ethylene, propane, n-pentane, xenon, trifluoromethane, chlorotrifluoromethane, a fluorocarbon compound, a chlorofluorocarbon compound, nitrogen, or water. The anti-solvent is preferably carbon dioxide.
In the present invention, the supercritical or subcritical fluid contains an anti-solvent and a second solvent, which is water, is miscible with said anti-solvent.
Immediately before the supercritical or subcritical fluid is introduced in the particle-forming vessel, the relative solvent saturation of the anti-solvent may be in the range of from about 50% up to 100%, i.e. total, solvent saturation at the prevailing pressure and temperature. Immediately before treating the particles in the conditioning vessel, the relative solvent saturation of the anti-solvent is suitably in the range of from 70% up to 100%, preferably from 90% up to 100%, and more preferably from 95% up to 100% of total solvent saturation at the prevailing pressure and temperature.
A particularly preferred combination of anti-solvent and solvent is carbon dioxide and water, advantageously when the relative water-saturated supercritical carbon dioxide (RWSSC) lies in the range of from about 50% up to 100%, i.e. total saturation, especially when the RWSSC lies in the range of from 90% up to 100%, and more especially when the RWSSC lies in
Bisrat Mikael
Demirbüker Mustafa
Moshashaee Saeed
Nyqvist Håkan
AstraZeneca AB
Evans Charesse
Page Thurman K.
White & Case LLP
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