Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-07-07
2002-11-19
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S450000, C562S593000
Reexamination Certificate
active
06482438
ABSTRACT:
This application claims priority to GB9828721.2 filed Dec. 24, 1998.
This invention relates to a novel apparatus for preparing crystalline particles, particularly particles of defined particle size distribution, especially particles of therapeutically useful or carrier substances of a size suitable for inhalation therapy. There is also provided a process for preparing the same.
Industrial processes for production of many products, particularly pharmaceutical products, require the preparation of pure substances of a defined particle size distribution. Pure substances are frequently prepared by precipitation from solutions of lesser purity. When precipitation takes place relatively slowly (eg over a matter of hours), crystals are grown which are frequently of an non-uniform shape and relatively large size.
In the field of inhalation therapy, therapeutic molecules are generally desired of a particle size “suitable for inhalation”, which is a term generally taken to indicate an aerodynamic diameter between 1 and 10 &mgr;m, especially 1 and 5 &mgr;m, particularly 1 and 3 &mgr;m. Carrier molecules (such as lactose) for inhaled therapeutic preparations are typically desired of a significantly larger aerodynamic diameter so that they do not penetrate into the upper respiratory tract to the same degree as the active ingredient and an aerodynamic diameter of 100 to 150 &mgr;m is generally considered suitable. However this is a generalisation and for some purposes it may well be preferred to use a lower particle size for the carrier, even one comparable to that of the therapeutic substance.
Particles of the desired particle size for inhalation therapy are conventionally prepared by milling or micronisation. These processes, depending on the precise conditions adopted, are capable of generating particles distributions which include fractions having particles with the appropriate size. Milling is suitable for preparing particles of the larger size indicated above and micronisation of the smaller size indicated above. However, there are a number of disadvantages associated with milling and micronisation processes including that the fraction having the desired particle size may be relatively small, that there may be generated a significant fraction of particles that are finer than is desired (which may be deleterious eg if it affects bioavailability) and that product losses generally may be considerable. A further property of micronised products is that the surfaces of the particles generated are generally substantially amorphous (i.e. have minimal crystallinity). This may be undesirable when there exists a tendency for the amorphous regions to convert to a more stable crystalline state.
Rapid precipitation (eg by dilution of a solution with an anti-solvent) may give rise to crystalline particles which could be of suitable size, however this technique is notoriously difficult to control and has not found widespread acceptance in the pharmaceutical industry, particularly in relation to inhalation products.
The use of ultrasonic radiation to increase effectiveness of crystallisation in purification of organic substances is described in Yurhevich, et al. (1972), Primen. Ul'trazvuka Met. Protsessakh, Mosk. Inst. Stali Splavov 67, 103-106.
We have now invented a novel process and apparatus for preparing particles which overcomes or substantially mitigates one or more of the above mentioned disadvantages.
Thus according to a first aspect of the invention there is provided a process for preparing crystalline particles of substance which comprises mixing in a continuous flow cell in the presence of ultrasonic radiation a flowing solution of the substance in a liquid solvent with a flowing liquid antisolvent for said substance which is miscible with the liquid, and collecting the resultant crystalline particles generated.
A particular advantage of the process is that is capable of running continuously (subject to adequate supply of solution and anti-solvent) even if, for a particular application, it may be desired to run it only for a relatively short time.
A feature of the process is that in a steady state the concentration of dissolved substance in the mixing chamber of the flow cell remains approximately constant since the precipitating substance is replaced by the inflow of further solution. This allows the process to be run continuously and reproducibly.
According to a second aspect of the invention there is provided an apparatus for preparing crystalline particles of a substance which comprises
(i) a first reservoir of said substance dissolved in a liquid solvent;
(ii) a second reservoir of liquid antisolvent for said substance which is miscible with the liquid solvent;
(iii) a mixing chamber having first and second inlet ports and an outlet port;
(iv) means for delivering the contents of the first and second reservoirs to the mixing chamber via the first and second inlet ports respectively at independent controlled flow rate;
(v) a source of ultrasonic radiation located in the vicinity of the first inlet; and
(vi) means for collecting crystalline particles suspended in the liquid discharged from the mixing chamber at the outlet port.
Preferably the apparatus further comprises means to mix the liquids delivered to the mixing chamber via the first and second inlets. The preferred means is a stirrer. Most preferably the mixing means should be non grinding eg a non-grinding magnetic stirrer or an overhead stirrer (particularly a non-grinding magnetic stirrer).
Desirably, stirring speed will be set a level that gives efficient mixing in the mixing chamber, but without inducing vortex effects. Vortex effects are undesirably since they have a tendency to disrupt the cavitation caused by the source of ultrasonic radiation. Furthermore they may cause particle size reduction through liquid micronisation-like processes.
Desirably the means for delivering the contents of the first and second reservoirs to the mixing chamber via the first and second inlet ports respectively at independent controlled flow rate comprises one or more pumps. Preferably a pump will be provided for each of the first and second reservoirs. A range of pumps are available and may be suitable for the apparatus according to the invention. The pump may, for example, be a peristaltic pump. Pumps which are essentially non-pulsing are preferred.
The contents of the first and second reservoirs may be delivered to the mixing chamber at a range of flow rates which will be selected and optimised according to the nature of the substance, the solvent, the antisolvent and the power and frequency of the source of ultrasonic radiation. Typically flow rates will be in the range of 0.5-50 ml/min.
Preferably the outlet port of the apparatus is disposed above the inlet ports in the mixing chamber such that the liquid in the mixing chamber flows from a lower to a higher point in the chamber before exiting. This arrangement optimises mixing and allows ready balance of the rates of inflow and outflow.
Preferably the mixing chamber is substantially circular in section and the first and second inlet ports are disposed diametrically opposite each other and at the same height relative to the base of the mixing chamber. Nevertheless, it may be conceived to orientate the two inlet ports in an off-set manner in order to give some circular motion to the inflowing liquids, although this is not generally preferred.
The position of the outlet port relative to the inlet ports is believed to have an influence on the size of the crystalline particles generated. Without being limited by theory, it is believed that the greater the distance between the inlet ports and outlet port, the greater the average residence time if the particles in the flow cell, the longer the crystalline particles have to mature and hence the larger the mean particle size. However it will be appreciated that mean particle size is subject to a number of other influences.
Preferably the exit port is located approximately half way up the side of the mixing chamber.
In one particular embodime
Lancaster Robert William
Singh Hardev
Theophilus Andrew
Fubara Blessing
Page Thurman K.
Riek James P.
SmithKline Beecham Corporation
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