HK1021144A - β-LACTAM GRANULES FREE OF ORGANIC SOLVENTS - Google Patents

Description

Beta-lactam granules without organic solvents

The invention relates to beta-lactam granules free of organic solvents and a method for the production thereof.

Background and field of the invention

For the manufacture of tablets or capsules containing oral grade penicillins or cephalosporins it has generally been found that the dosage to be controlled during the manufacture of the tablets or capsules cannot be guaranteed due to the unsatisfactory flowability of the crystalline material. Thus, a granule is often first prepared by mixing crystalline powder (1-30 μm) with a small amount of organic solvent (e.g. ethanol), sometimes diluted with water. And then mixed with other components as a binder (e.g., PVP) and a filler (e.g., lactose) to obtain granules having satisfactory particle size distribution and strength. However, unless larger tablets are made, it is not possible to have a high dose per tablet.

The granulation process is typically carried out in a high shear mixing granulator, which produces dense granules with a suitable particle size distribution. The material was dried after the granulation process (particles with an average diameter of about 400-500 μm). It was found that when water alone was used as the binding liquid (i.e. no ethanol, no binder) in which Pen VK was dissolved, which liquid resulted in binding to granules during drying, batch-operated high shear granulators could not produce a satisfactory particle size distribution but rather excessive fouling of the equipment.

The use of organic solvents in this process is a significant disadvantage because low solvent levels are required in the final dosage form and one must adequately dry the final product. From a process point of view, environmental problems can be greatly reduced if the use of organic solvents can be avoided.

In addition, the absence of binder may result in granules that may be used in high potency tablets or capsules.

We have now found two granulation processes in which no organic solvent is required to obtain water-soluble penicillin granules (e.g. Pen VK granules). Granulation of Pen VK without other additives (e.g., binding materials) using only water as the binding solvent, yields beta-lactam granules that are substantially free of organic solvent, i.e., no more organic solvent than is contained in the beta-lactam prior to granule formation.

Summary of The Invention

The present invention provides organic solvent-free beta-lactam granules, in particular beta-lactam potassium salt granules, preferably penicillin V potassium salt granules. Also provided is a process for preparing the beta-lactam granules, i.e. using substantially only water as binding solvent during granulation. Preferably in a batch-operated fluid bed granulator, more preferably by using top water sprays. Furthermore, the process is carried out in a continuous mixer. Finally, tablets or capsules containing the granules also form an aspect of the invention. Detailed Description

Two granulation processes, in which the use of organic solvents is avoided, essentially comprise: a batch-wise operated fluid bed granulator or a continuous high shear mixer in combination with a fluid bed dryer is used. The two granulation methods can be used to obtain beta-lactam granules (such as penicillin V potassium salt) with satisfactory particle size distribution (most of which are between 100 and 1400 mu m), bulk density (bulk density) and tap density (tap density) and particle strength.

The first method comprises the following steps:

a quantity of crystalline beta-lactam powder (e.g. from penicillin v potassium salt) is added to a fluid bed granulator into which air adjusted to a specific temperature and humidity is passed to vigorously mobilize the solid. After adjusting the bed temperature to the inlet air temperature (typically 0-60 ℃), water is added using a nozzle (top nozzle). Preference is given to using so-called two-phase nozzles using compressed air. 10-100 wt.% water is added to the bed material over about 30-60 minutes, during which the bed temperature typically drops to 20-30 ℃. The exact amount of water and temperature depends on the air humidity, air flow and air temperature. In principle the amount of water can be large, but this can cause unrealistically long operating times. After a satisfactory particle size (distribution) is achieved, the water dosing is stopped and the bed material is dried until the bed temperature reaches a predetermined value (e.g. 50-60 ℃).

The fluidized bed is emptied and the granules are passed through a mill-sieving system in which large (out of specification) granules are crushed to a suitable size, i.e. between 25-2000 μm, preferably between 100 and 1400 μm. The process can be carried out in fluidized beds of different sizes.

According to a second method, the crystalline material is fed at the front end into a continuous high shear mixing granulator (e.g. a Lodige CB type machine) by adjusting the flow rate (e.g. by means of a screw device). The machine consists of a horizontal shaft with some type of paddle, 1000-. After a few seconds (1-30 seconds) of incorporation of water (about 5-20% by weight, preferably 10-13% by weight), the moist granulate leaves the granulator at the rear end. And then transferred to a continuous type dryer such as a continuous fluidized bed dryer. After passing through the apparatus (typically with a residence time of 1 hour), it is preferred to grind the material in a continuous manner and screen it for use. Batches of the material may be mixed into a batch and subsequently filled into a suitable package (e.g., a box).

The following examples merely illustrate the invention.

Example 1

In a GPCG1 (Glatt powder coating and granulating machine, Glatt Co., Ltd.), 1 kg of oral grade PenVK (Gist-brocades) was heated to the inlet temperature of air (50 ℃) and the fluidization process was started (superficial air velocity 8 cm/s). After 6 minutes water addition (30 g/min, nozzle pressure 1.5bar) was started and the bed temperature was reduced to 26 ℃. Drying started after 35 minutes (air inlet temperature 70 ℃) and was terminated after 44 minutes. The bulk density of the product was 0.5g/ml, and the tap density was 0.58 g/ml. Particle size distribution: 200g is more than 1400 μm,0.6g is less than 100 μm,100 μm is less than 677g is less than 1400 μm.

Example 2

In a GPCG15 (Glatt Co., Ltd.), 10 kg oral grade PenVK (Gist-brocades) was heated to the inlet temperature of air (55 ℃ C.) and the fluidization process was started. After 40 minutes the granules were dried and 10.7 kg of water were added; the process was ended after 59 minutes. The bulk density of the product was 0.47g/ml and the tap density was 0.55 g/ml. Particle size distribution: 425g is more than 1400 μm,185g is less than 100 μm,100 μm is less than 8111g is less than 1400 μm.

Example 3

Oral grade PenVK (Gist-seconds) was added continuously to Lodige CB 20(1500 rpm) at 116 kg/h and mixed with water (11 wt%). The material was transferred directly to a continuous fluid bed dryer (Heinen) operating at 70 ℃. The material was passed through the dryer and after about 1.5 hours a sample was taken. The bulk density of the product was 0.52g/ml and the tap density was 0.57 g/ml. Particle distribution: 15% > 1400 μm, 11% < 100 μm,100 μm < 74% < 1400 μm.

Claims (11)

1. Beta-lactam particles, wherein the particles are substantially free of organic solvents.

2. The granule of claim 1, wherein the granule is a potassium salt of β -lactam.

3. The particles of claim 1, wherein the particles are penicillin.

4. Granules according to claim 3, wherein the granules are penicillin V potassium salt.

5. A process for the preparation of the beta-lactam particles according to any one of claims 1 to 4, comprising:

-batchwise addition of crystalline beta-lactam powder to a fluidized bed

-fluidizing the powder

-adding water to the powder to prepare granules and

-drying the obtained granules.

6. A process as claimed in claim 5, wherein the amount of water is typically 5-200% by weight of the crystalline material.

7. A process for the preparation of the beta-lactam particles according to any one of claims 1 to 4, comprising:

-adding crystalline beta-lactam powder to a continuous mixer;

-simultaneously adding water to the continuous mixer;

-granulating the mixture;

-feeding the obtained granules to a continuous dryer; and is

-drying the obtained granules.

8. A process as claimed in claim 7, wherein the amount of water is from 5 to 20% by weight of the added solids.

9. A process as claimed in claim 7, wherein the amount of water is from 10 to 13% by weight of the added solids.

10. A method as claimed in claim 9, wherein the dryer is a continuous fluid bed dryer.

11. A tablet or capsule comprising the granules as claimed in claims 1 to 4.