JP2002512117A - Fluid energy grinding method and apparatus - Google Patents

Abstract

  (57) [Summary] Fluid energy mills that include means for adjusting the humidity of the compressed air used to mill provide improved micronized products, especially hydrates for use as drugs in pharmaceutical compositions.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD [0001] The present invention relates to a method and an apparatus for producing a finely divided powder, particularly a finely divided powder of a drug. In particular, the invention relates to improvements in fluid energy grinding.

BACKGROUND OF THE INVENTION Fluid energy milling, also known as micronization, is a method commonly used to produce micronized powders. It is particularly suitable for drug preparation, since there is no abrasive to contaminate the product. Particle size reduction in a fluid energy mill is caused by using the energy imparted by the compressed air to create abrasion between the particles of the material being milled. Since the compressed air used for fluid energy milling is likely to liquefy in the compressed air system, the humidity of the compressed air should be very low. To avoid the problems associated with liquefaction in devices that use compressed air, moisture is removed from the compressed air. Generally, the compressed air after compression is liquefied by cooling to remove water, and then the compressed air is passed through a drying tower, and the air is generally fed into a fluid energy mill. Typically, the compressed air used for fluid energy milling will have a pressure of about 6 bar and a dew point (at atmospheric pressure) of -40C or less. It can be as low as -70 ° C.

[0003] Ultrafine grinding methods can disrupt the crystal structure of the treated material due to the grinding that occurs during grinding. When grinding crystalline hydrates and solvates, the combination of fines and extremely dry air may remove water / solvate molecules from the crystal structure during processing, causing further damage. . After milling, the ultrafine material may be able to regain its original crystal structure after a period of time, depending on storage conditions. Thus, crystalline hydrate drug may return to its original properties after fluid energy milling, perhaps only after storage for an unpredictable period, and not its original properties. In addition, damage caused by grinding / desolvation may affect the intended properties of the product, such as surface energy, stability, bioavailability. In each case, the milled powder was aggregated rather than evenly dispersed during further processing.

DISCLOSURE OF THE INVENTION [0004] The present invention provides a method for controlling the humidity of the compressed air used in fluid energy milling to a range which is significantly higher than commonly used but lower than that which causes liquefaction problems in the mill. Is based on the finding that the damage to the crystallinity of the pulverized product is reduced by adjusting. As a result, the operation of drying the substance during the milling process is reduced or avoided, and it is also easier to regain the original level of crystallinity after milling. Thus, the present invention provides a more consistent and improved quality control ultrafine effluent. This significantly reduces the in-batch variables,
This leads to a reduction in batch operations redo or failure. In addition, the method of the present invention has no adverse effect on the particle size reduction obtained by the micronization method. In its broadest aspect, the present invention provides a fluid energy grinding device that includes means for adjusting the humidity of the compressed air used for grinding.

[0005] The present invention is also a pulverization method in which compressed air is fed into a mill chamber containing granules and the substance is subjected to fluid energy pulverization. To reduce the damage to the milled product. Adjustments made in accordance with the present invention are typically those that increase humidity. However, once the optimal value has been determined and the apparatus has been set to obtain the desired increase in humidity of the compressed air supply, adjustments are made during milling and the humidity is adjusted to maintain the optimal value. You may need to raise or lower the level. A typical fluid energy milling system consists of a source of compressed air, a drying tower, and a mill that includes a mill chamber and collector. The collecting device may be a filter sock at the outlet of the air flow, or it may be an expansion chamber that dissipates the energy of the air flow and immobilizes the comminuted material. The humidity of the process air in the mill can be increased by designing it to bypass the drying tower so that compressed air is fed directly into the mill from the source. However, the system preferably provides a bypass loop and a regulating valve around the drying tower so that it can be regulated by distributing the air flow between the bypass loop and the drying tower, thereby allowing the bypass and drying tower to be adjusted. The relative proportion of compressed air moving through can be varied. By monitoring the humidity of the air entering the mill, a regulating valve can be used to regulate the amount of air passing through the bypass and through the drying tower to achieve the desired humidity in the mill chamber.

In another embodiment, the non-dried air is mixed with the dry air at the individual compressed air outlets, such that the humidity control is performed only on the process air occupying an individual part of the apparatus. May be. In a further embodiment, the humidity is adjusted before the air stream reaches the mill by injecting the water into the compressed air-line, preferably as a mist or spray, at an upstream location where the moisture is dispersed throughout the air stream. be able to. The humidity is preferably evaluated by measuring the dew point. The present invention includes a method of adjusting the humidity so that the process air in the mill has a dew point higher than the dew point of the compressed air at the time of formation. Typically, the humidity is increased by raising the dew point (at atmospheric pressure) to a range from -30C to 5C, preferably from about -15C to 0C. The optimum value for a particular material can be determined by conventional procedures for testing and varying the dew point and assessing product quality.

[0007] Humidity is typically measured with a dew point hygrometer. For example, measurements can be taken continuously by a sensor placed in the airflow before entering the mill chamber, or intermittently, for example, by sampling the air in the airflow before entering the mill chamber. The present invention may be used, for example, in systems where the inner classifier releases particles when the particles have reached a predetermined size, or once the product is milled until all the particles are in the desired size range. It can be used in any fluid energy milling method of a classifier-free system that can pass through. A further advantage of the present invention is that it improves the micronization process itself, in addition to the quality of the micronized effluent, making it easier to maintain a balance between feed rate and air pressure. Furthermore, the method of the present invention improves the hardness and quality of the micronized drug effluent measured over a continuous production period. In addition, the present invention is particularly effective for preparing micronized drugs for use in pharmaceutical compositions. Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising a drug obtainable by a method as described above.

The present invention will improve the quality of the micronized effluent of most substances, but is particularly applicable to the micronization of substances sensitive to crystal damage during the process. Removing the water of the crystallinity itself (if any) can make the crystal structure unstable,
The potential for crystal damage during conventional methods of micronizing crystalline hydrates is a significant problem and the present invention addresses such problems. In a preferred embodiment, the method of the invention is used for the preparation of micronized calcium mupirocin dihydrate (EP01678856-A2, Beecham Group plc).
Previously, fluid energy milling of this material produced a micronized product that formed an undesirable mass when mixed into the ointment base. This is thought to be due to the change in surface energy due to the loss of water of crystallization and the damage to the crystal structure by grinding in extremely dry air. This problem was solved by adjusting the humidity of the processing air under atmospheric pressure so that the dew point was about -15 ° C to about 0 ° C. The ultrafine calcium mupirocin dihydrate produced by the method of the present invention has a water content of preferably 3.0 to 4.0, more preferably 3.4 to 3.7%, and has recovered the crystallinity. Thereafter, the degree of amorphousness is low, preferably 5% or less.

Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising micronized calcium mupirocin dihydrate obtained by the above-described method. Such a composition containing a more matched drug would have the advantage of avoiding in the ointment, for example, the aggregation formation of calcium mupirocin dihydrate. Such preferred compositions include ointments, creams and nasal sprays, for example,
EP 0231621-A2 (Beecham Group plc), WO 95/10999 (Smi
thKline Beecham Corp) and WO 98/14189 (SmithKline Beecham). A preferred composition is an ointment comprising calcium mupirocin dihydrate in a white soft paraffin base containing glycerin esters, available from SmithKline Beecham under the product: Bactroban Nasal. More preferred compositions are from SmithKline Beecham,
Products: Mineral oil, available as Bactroban Cream
Polyethylene glycol (1000) monocetyl ether, cetyl alcohol,
A cream comprising calcium mupirocin dihydrate in a base comprising stearyl alcohol, xanthan gum and water.

(Example) The present invention will be described using the following examples. Example 1 In a commercial scale plant for micronizing calcium-mupirocin dihydrate, compressed air is passed through a micronization mill through a silica gel column. A loop is provided during the process of supplying air to the mill, bypassing the silica gel drying column. The proportion of air that bypasses the drying column can be varied using a valve, thereby adjusting the humidity of the process gas. A batch of calcium mupirocin is taken and divided into three parts and subjected to three separate micronization treatments. The first ultra-pulverizing process (sub-batch A) was performed using process air normally pumped from a plant compressor. The dew point of the air was -58 ° C. A further 2 parts of the inflow are micronized and one part (sub-batch B) is -10 ° C. using air.
Was adjusted to the target dew point, and the other part (sub-batch C) was adjusted to a dew point of 0 ° C. (the upper limit of humidity obtained in this plant). Each operation produced about 5 kg of micronized product. In each case, the dew point was measured by sampling the air upstream of the mill adjacent to the air inlet and evaluated as a dew point at atmospheric pressure.

[0011] All three micronized sub-batches met the required particle size specifications. The effluent is then subjected to solution calorimetric crystallinity and Karl Fis
cher) analysis for the water content measured. Sub-batch A micronized at a dew point of -58 ° C is dry (water content: 3.1-3.2% w / w) and has an amorphousness of about 15% (non-ultrafine dihydrate) 2%). The dew point is -1
Subbatches B and C produced at 0 ° C. and 0 ° C. were not dried (water content: 3.6% w / w) and had an amorphousness of about 9%. When the sub-batches were continuously monitored, it was found that the amorphousness of the sub-batches B and C decreased steadily over the next two to three weeks, but the sub-batch A was dry and could not recover the crystal damage. I understand. Sub-batches A and B were blended with the ointment base. The ointment prepared from sub-batch A showed multiple aggregates; the ointment prepared from sub-batch B showed no aggregates.

Example 2 In another experiment, the effects on moisture content and crystal damage (amorphous drug content) were determined using air generally obtained from a compressed air system with a dew point of about -50 ° C. A portion of the batch of calcium mupirocin, when micronized with air adjusted to a temperature range of -15 ° C to -5 ° C, was simulated and compared for the process pressure while changing other micronized variables. Some of the batches micronized using air with a controlled dew point (-15 ° C to -5 ° C) have an average moisture content of 3.5.
% W / w and the amorphous drug content averaged 16.5%. Some of the micronized batches using standard compressed air (dew point about -50 ° C) have an average moisture content of 2.9.
% And the average amorphous drug content was 38.3%. With the method of controlling humidity, the spilled drug is much more consistent in quality than with the compressed air generally produced, indicating that the present invention has improved the inconsistency of the micronization method. It is shown.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS , JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZWF terms (reference) 4D067 CA02 CA05 GA20

Claims (22)

[Claims] 1. A fluid energy mill comprising means for adjusting the humidity of compressed air used for milling. 2. The apparatus of claim 1, further comprising means for monitoring the humidity of the compressed air upstream of the inlet to the grinding chamber. 3. A compressed air supply, a drying tower, a grinding chamber, a means for monitoring the humidity of the compressed air upstream of the grinding chamber, and a means for adjusting the humidity of the compressed air to a desired level. A fluid energy milling system comprising a collection device including means. 4. The apparatus according to claim 3, wherein the means for monitoring the humidity is a humidity detector placed in contact with the compressed air flow. 5. The apparatus according to claim 3, wherein the means for monitoring the humidity comprises means for sampling a flow of compressed air upstream of the grinding chamber and a hygrometer installed off-line. 6. Apparatus according to claim 3, wherein the means for adjusting the humidity of the compressed air is an injector for introducing water, mist or spray into the compressed air line. . 7. The control valve according to claim 3, wherein a bypass valve is used to change the path of the compressed air around the drying tower by using a bypass loop, and to switch an air flow between the drying tower and the bypass loop. An apparatus according to any one of the preceding claims. 8. The apparatus of claim 7, wherein the control valve is adjustable such that a variable proportion of compressed air can be sent through the drying tower and the bypass loop. 9. Feeding compressed air into a mill chamber containing the particulate matter,
A grinding method comprising subjecting the granules to fluid energy grinding, wherein the humidity of the compressed air is monitored and, if necessary, adjusted to reduce damage to the grinding product. Grinding method. 10. The method of claim 9, wherein the milling is performed in a system consisting of a compressed air supply, a drying tower, a mill chamber, and a collector. 11. The method according to claim 9, wherein the means for monitoring the humidity is a humidity detector placed in contact with the compressed air flow. 12. The method according to claim 9 or 10, wherein the means for monitoring the humidity comprises means for sampling the compressed air flow upstream of the mill chamber and a hygrometer placed off-line. 13. The method according to claim 9, wherein the means for adjusting the humidity of the compressed air is an injector for introducing water, mist or spray into the compressed air line. 14. A control valve for redirecting compressed air around a drying tower by using a bypass loop and for switching airflow between the drying tower and the bypass loop. A method according to any one of the preceding claims. 15. The method according to claim 14, wherein the regulating valve can be adjusted so that a variable proportion of compressed air can be sent through the drying tower and the bypass loop. 16. The method according to claim 9, wherein the substance to be pulverized is a drug. 17. The method according to claim 16, wherein the drug is a crystalline hydrate. 18. The method according to claim 10, wherein the crystalline hydrate is calcium mupirocin dihydrate. 19. A low-crystalline calcium mupirocin dihydrate having a water content of 3.0 to 4.0%, more preferably 3.4 to 3.7%. 20. Ultrafine calcium mupirocin dihydrate obtainable by the method according to any one of claims 9 to 18. 21. The composition according to claim 9, which is dispersed in a pharmaceutically acceptable carrier.
A pharmaceutical composition comprising a drug pulverized by any one of the above methods. 22. The pharmaceutical composition according to claim 21, wherein the drug is calcium mupirocin dihydrate.