Single-crystal – oriented-crystal – and epitaxy growth processes; – Processes of growth from liquid or supercritical state – Liquid phase epitaxial growth
Reexamination Certificate
2000-01-27
2001-10-16
Kunemund, Robert (Department: 1765)
Single-crystal, oriented-crystal, and epitaxy growth processes;
Processes of growth from liquid or supercritical state
Liquid phase epitaxial growth
C422S245100, C023S29500G, C023S300000
Reexamination Certificate
active
06302958
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a crystallization apparatus and process for producing submicron-sized particles.
BACKGROUND OF THE INVENTION
Producing uniform, very small particles is a common processing challenge for pharmaceutical substances. In general, smaller particles provide two very desirable qualities of pharmaceuticals, namely higher bioavailability and a higher dissolution rate. In U.S. Pat. No. 5,314,506 there is described a method using two impinging jets to achieve uniform particles. However, the particles formed using the process in U.S. Pat. No. 5,314,506 are only as small as 3 microns in size and the majority of the crystals formed are in the range of 3-20 microns.
The general process by which these prior art small particles are produced involves two impinging liquid jets positioned within a well stirred flask to achieve high intensity micromixing. At the point where the two jets strike one another a very high level of supersaturation exists. As a result of this high supersaturation, crystallization occurs extremely rapidly within the small mixing volume at the impingement point of the two liquids. Since new crystals are constantly nuceleating at the impingement point, a very large number of crystals are produced. As a result of the large number of crystals formed, the average size remains small, although not all the crystals formed are small in size.
The novel apparatus and process of this invention utilizes impinging jets to achieve high intensity micromixing in the crystallization process. The background of high intensity micromixing is discussed in detail in U.S. Pat. No. 5,314,506, which is incorporated by reference herein.
SUMMARY OF THE INVENTION
The present invention pertains to a novel apparatus and process for crystallizing submicron-sized particles, having an average size of less than 1 micron, and which provides high surface area end product crystals with greatly improved stability and purity. The pure, high surface area particles produced by the process of the present invention display superior crystal structure when compared with particles formed by standard slow crystallization plus milling methods known in the art which use the same quality and kind of feed compounds. These improvements in crystal structure result in decreases in decomposition rate and therefore longer shelf-life for the crystallized product or pharmaceutical composition. Moreover, the smaller size of the pharmaceutical crystals formed using the apparatus of the present invention provide for crystals having a higher bioavailability and higher dissolution rate.
More specifically, the novel apparatus and process of this invention relate to the addition of a sonication probe along with impinging jets to achieve high intensity micromixing of fluids so as to form a homogeneous composition prior to the start of nucleation in a continuous crystallization process.
The novel apparatus and process of the present invention provide for direct crystallization of high surface area submicron sized particles of high purity and stability.
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Kim Soo-jin
Lindrud Mark D.
Wei Chenkou
Bristol--Myers Squibb Company
Kunemund Robert
Makujina Shah R.
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