CN1108151C - Fluid energy milling process and apparatus - Google Patents

Abstract

This invention relates to a fluid energy grinding apparatus comprising means for regulating the humidity of compressed air used for grinding, the apparatus providing improved micronized products, particularly hydrates used as pharmaceuticals in pharmaceutical compositions.

Description

Fluid energy grinding method and equipment

The present invention relates to a method and an apparatus for producing finely divided powders, especially pharmaceutical powders. In particular the present invention relates to improvements in fluid energy milling.

Fluid energy milling, also known as micronization, is a procedure commonly used to prepare finely divided powders. It is especially suitable for the micronization of pharmaceuticals as there is no abrasive media to contaminate the product. In fluid energy grinding, the particle size reduction is caused by the inter-grinding between the particles of the material to be ground by using the energy generated by compressed air.

The compressed air used in fluid energy milling has very low humidity due to the increased condensation capacity in the compressed air system. After compression, moisture is removed from the air to avoid condensation in equipment using compressed air. Moisture removal is typically accomplished by condensation, cooling the compressed air after compression, and then passing the compressed air through a drying tower before entering the fluid energy mill. The pressure of compressed air used in fluid energy grinding is usually about 6 bar, and its dew point is below -40°C, and can be as low as -70°C.

During milling, micronization methods can destroy the crystal structure of the substance being processed. When grinding crystalline hydrates and solvates, the combination of intergrinding and very dry air can cause additional damage due to the removal of water/solvate molecules from the crystal structure during processing. After milling, the micronized substance regains its original crystalline structure over time depending on the storage conditions. Thus, a drug in the form of a crystalline hydrate may not be in its original strength after fluid energy milling, and may return to its original strength after an unforeseeably long storage time. Furthermore, damage caused by intergrinding/desolvation can affect the intended properties of the product, eg surface energy, stability, bioavailability. In certain cases, the ground powder agglomerates during further processing rather than being homogeneously dispersed.

The present invention is based on the discovery that controlling the humidity of the compressed air used in fluid energy milling to a range significantly higher than normally used, but below that which would cause condensation to occur during grinding, can affect the crystallinity of the ground product. cause minor damage. The consequent reduction or avoidance of drying of the material during milling also facilitates reacquisition of its original level of crystallinity after milling. Thus, the present invention provides a micronized product with more consistent properties and better quality control. This greatly reduces variation between batches, resulting in fewer rework processes or batch failures. Furthermore, the method of the present invention has no detrimental effect on the particle size reduction achieved by micronization.

Most importantly, the present invention provides a fluid energy grinding apparatus including means for adjusting the humidity of the compressed air used for grinding.

The invention also provides a grinding method comprising feeding compressed air into a grinding chamber containing particulate matter and subjecting the material to fluid energy grinding, characterized in that the humidity of the compressed air is monitored and adjusted if necessary to Reduces damage to abrasive products.

The adjustments made in accordance with the present invention are generally increases in humidity. However, once the optimum value has been determined, and the equipment has been adjusted so that the compressed air produces the desired humidity increase, all that needs to be done during the grinding process is to calibrate the humidity level up and down to maintain its optimum value.

A typical fluid energy grinding system includes a compressed air source, a drying tower, and a grinder with a grinding chamber and collection device. The collection device may be a filter bag in the outlet air stream or an expansion chamber in which the energy of the air stream is dissipated to deposit ground material. The humidity of the process air in the mill is increased by the arrangement of the bypass drying tower so that the compressed air enters the mill directly from the air source. However, the system is preferably designed to be controllable by providing a bypass circuit around the drying tower and having control valves to reverse the flow of air between the bypass circuit and the drying tower, whereby, through the bypass The relative proportion of compressed air to the column is variable. By monitoring the humidity of the air entering the grinder, the amount of air passing through the bypass and through the drying tower can be adjusted using control valves to achieve the desired humidity in the grinding chamber.

In another embodiment, undried air can be mixed with dried air at a specific compressed air outlet to humidify only the process air supplied to specific equipment.

In other embodiments, humidity can be adjusted by spraying water, preferably in the form of a mist or shower into the compressed air line at an upstream location, which disperses the moisture throughout the air stream before it enters the mill. middle.

Humidity is best estimated with dew point measurements. The present invention includes any process that regulates humidity so that the dew point of the process air in the mill is higher than the dew point of the compressed air produced. Typically the humidity is increased to a dew point of -30°C to 5°C, preferably about -15°C to 0°C. The optimum value for a particular substance can be determined by routine trials to vary the dew point and assess product quality.

Humidity is usually measured by a dew point hygrometer. For example, continuous measurement can be performed by placing the probe in the air stream before entering the grinding chamber; or intermittent measurement can be performed by sampling the air stream before entering the grinding chamber.

The invention can be applied to any fluid energy grinding process, for example in systems where the particles are discharged by an internal classifier when the particles reach a predetermined size or in systems provided with classifiers in which the product passes through the mill several times until the particles are in the desired size range.

In addition to the beneficial effect of the present invention on the micronized product, another advantage is that it improves the micronization process itself, making it easier to maintain the feed rate and air pressure balance. Furthermore, the method of the present invention improves the consistency and quality of the micronized drug product in a continuous production cycle.

Furthermore, the present invention is particularly effective for the preparation of finely powdered drugs for use in pharmaceutical compositions. Therefore, in another aspect the present invention provides a pharmaceutical composition comprising a medicament obtained by the above method.

The invention will improve the quality of micronized products of most substances, but has particular application in the micronization of substances which are susceptible to crystallization damage during processing. The possibility of crystal damage is a serious problem during the conventional micronization process of crystalline hydrates because the removal of water of the crystallization itself (if present) can destabilize the crystal structure, and the present invention will overcome this problem.

In a preferred embodiment, the procedure of the present invention is used for the preparation of micronized mupirocin calcium dihydrate (EPO167856-A2, BEECHAM Group plc). Previously, fluid energy milling of such materials produced micronized products that formed undesirable aggregates when mixed into ointment bases. This has been postulated to be caused by a change in surface energy resulting from loss of crystallization water and damage to the crystal structure by grinding in very dry air. Controlling the humidity of the process air to an atmospheric dew point of -15°C-0°C overcomes this problem. The moisture content of the micronized mupirocin calcium dihydrate produced by the procedure of the present invention is preferably 3.0-4.0%, more preferably 3.4-3.7%, and has a low amorphous content after recovery of crystallinity, most preferably 5% or less.

Therefore, in another aspect the present invention provides a pharmaceutical composition comprising micronized mupirocin calcium dihydrate obtained by the above process. Such compositions have the advantage of comprising a more consistent quality profile of the drug and avoiding the formation of aggregates of mupirocin calcium dihydrate, eg in ointments.

Preferably, such compositions include ointments, creams and nasal sprays as described in EPO231621-A2 (Beecham Group plc), EP0251434-A2 (Beecham Group plc), WO95/10999 (Smithkline Beecham Corp) and WO98/14189 (Smithkline as described in Beecham). A preferred composition is an ointment containing mupirocin calcium dihydrate in a white soft paraffin base containing glycerides, commercially available from Smithkline Beecham Company under the product Bactroban Nasal. Another preferred composition is a composition containing An emulsion of mupirocin calcium dihydrate, commercially available from Smithkline Beecham under the product Bectroban Cream.

The invention is illustrated by the following examples.

Example 1

An industrial-scale plant for the micronization of mupirocin calcium dihydrate feeds compressed air through a column of silica gel into a micronization grinder. A circuit bypassing the silica gel drying column is provided in the supply of process air to the grinder. A valve is used to vary the proportion of air bypassing the drying column so that the humidity in the process air can be controlled.

Take a single batch of mupirocin calcium and divide it into thirds for three separate micronizations. The first micronization (sub-batch A) was using the process air normally supplied by the plant compressor. The dew point of air is -58°C. The other two feeds were micronized: one (sub-batch B) with air controlled at -10°C dew point and one (sub-batch C) with air controlled at 0°C dew point (available at the plant). humidity limit). Each run produced approximately 5 kg of micronized product. In each case, the dew point was determined by sampling the air upstream of the mill near the air inlet and rated as the dew point at atmospheric pressure.

All three micronized sublots met the desired particle size specification. The product was evaluated for its crystallinity with a solution calorimeter and its moisture content was determined with Karl Fischer analysis. Micronization of sub-batch A at dew point -58°C showed a drying effect (moisture content: 3.1-3.2% (w/w)) and an amorphous content of about 15% (2% in unmicronized dihydrate ). Subbatches B and C were produced at dew points of -10°C and 0°C respectively, showed no drying (moisture content: 3.6% (w/w)), and had an amorphous content of about 9%. Continuous monitoring of the sublots showed that, for sublots B and C, the amorphous content continued to decrease over the ensuing weeks, while sublot A did not recover its crystalline damage due to drying.

Sublots A and B were mixed with the ointment base. Significant aggregates were present in the ointment made from sublot A; no aggregates were found in the ointment made from sublot B.

Example 2

In another experiment, aliquots of a batch of mupirocin calcium micronized using air with a controlled dew point of -15°C to -5°C and air micronized with a dew point of -50°C typically produced by a compressed air system Experiments were carried out to compare the effect on moisture content and crystal damage (amorphous drug content) while varying other micronization parameters to simulate the stress regime of the process. Experiments with batches using air micronization with controlled dew point (-15°C to -5°C) showed an average moisture content of 3.5% (w/w) and an average amorphous drug content of 16.5% . Experiments with batches micronized using standard compressed air showed an average moisture content of 2.9% (w/w) and an average amorphous drug content of 38.3%. When the humidity-controlled process was used, the product drug was of more consistent quality than when conventional compressed air was used, demonstrating the improved stability of the micronization process of the present invention.

Claims (10)

1. micronized Calcium mupirocin dihydrate., its moisture are 3.0-4.0%, and its amorphous content is 5% or lower.

2. according to the micronized Calcium mupirocin dihydrate. of claim 1, its moisture is 3.4-3.7%.

3. be used to prepare the Ginding process of the micronized Calcium mupirocin dihydrate. of claim 1, it comprises the grinding chamber that compressed air is infeeded mupirocin calcium dihydrate particulate matter, and make this material through fluid energy milling, it is characterized in that, monitor this compressed-air actuated humidity, regulate this humidity when needing to reduce infringement to abrasive product.

4. according to the method for claim 3, wherein grinding is to carry out in the system that comprises compressed air source, drying tower, grinding chamber and gathering-device.

5. according to the method for claim 3 or 4, the device of wherein monitoring humidity is to be in and the contacted drimeter probe of compressed air stream.

6. according to the method for claim 3 or 4, the device of wherein monitoring humidity comprises the device of the compressed air stream sampling of grinding chamber upstream and the drimeter that off-line is provided with.

7. according to the method for claim 3 or 4, the device of wherein regulating compressed air humidity is a kind of syringe, and it is introduced water, water smoke or spray quinoline water in the compressed air line.

8. according to the method for claim 3 or 4, bypass circulation is set wherein, makes compressed air walk around drying tower, and it is mobile with commutation air between drying tower and bypass circulation that control valve is set.

9. method according to Claim 8, wherein control valve is adjustable, so that be variable by the compressed-air actuated ratio of drying tower and bypass circulation.

10. Pharmaceutical composition, it comprises the micronized Calcium mupirocin dihydrate. of claim 1, and this medicine is dispersed in the pharmaceutical carrier.