Title:  .beta.-lactam granules free of organic solvents

United States Patent:  6,242,006

Assignee:  Gist-Brocades B.V. (NL)

Filed:  December 24, 1998

PCT NO:  PCT/EP97/03877

102(e) Date:  December 24, 1998

PCT PUB. Date:  January 22, 1998

Foreign Application Priority Data:  Jul 16, 1996[EP] (Jul 16, 1996[EP])

.beta.-Lactam granules free of organic solvents have been provided for. Also a process to prepare the same by applying during the granulation only water as binding solvent has been disclosed.

DETAILED DESCRIPTION OF THE INVENTION

The two granulation methods, wherein the use of organic solvents have been avoided, consist essentially of the application of a batch-wise operated fluidized bed granulator or a continuous high-shear mixer in combination with a fluidized bed dryer. The application of these two granulation methods results in granules of .beta.-lactams, for instance the potassium salt of penicillin V with a satisfactory particle size distribution, viz. mainly between 100 and 1400 .mu.m, bulk and tapped density and particle strength.

The first method comprises the following steps:

A certain amount of crystalline .beta.-lactam powder, for instance from the potassium salt of penicillin V, is added to a fluidized bed granulator wherein air, conditioned to a certain temperature and humidity, is passed as to move the solids vigorously. After adjustment of the temperature of the bed to the inlet air temperature (typically 0-60^oC.), water is added by using spray nozzles (top-spray). Preferably so called two-phase nozzles using compressed air are applied. Within approximately 30-60 minutes 5 to 200%, preferably 10-100 wt % of water is added to the bed mass during which the bed temperature drops, typically to 20-30^oC. The exact amount and temperature depend on the air humidity, air flow rate and air temperature. The amount of water can in principle be much larger but this may cause unpracticle long operating times. After reaching a satisfactory particle size (distribution) the water dosage is stopped and the bed mass is dried until the bed temperature reaches a predetermined value (e.g. 50-60^oC.).

The bed is emptied while the granulate is passed over a grinder-sieve in which the large (off-spec) particles are broken to a suitable size, viz. between 25 and 2000 .mu.m, preferably between 100 and 1400 .mu.m. The process can be carried out in fluid beds of different sizes.

According to the second method, the crystalline material is added on the front end by an adjusted flow rate (e.g. using a screw device) to a continuous high shear mixer granulator such as the Lodige CB type of machine. This consists of a horizontal axis provided with certain types of paddles, rotating at 1000-3000 rpm. Water is admixed (approximately 5-20 wt %, preferably 10-13 wt %) and after only a few seconds (1-30 s) the wet granulate leaves the machine at the rear end. It is subsequently transferred to a continuous type of dryer such as a continuous fluidized bed dryer. After passing this apparatus (typical residence time 1 hr) the material is milled and sieved and ready for use, preferably in a continuous mode. Several batches of the material can be mixed as to achieve one single batch and subsequently filled in a suitable package (e.g. boxes).

Claim 1 of 3 Claims

What is claimed is:

1. A process to prepare granules of penicillin VK compounds free of organic solvents and additives consisting essentially of:

adding a crystalline .beta.-lactam powder batch wise to a fluidized bed;

fluidizing said powder;

adding water as a binding agent to said powder during fluidization to produce granulates; and

drying the granules obtained to form penicillin VK having particle size between 25 and 2000 .mu.m.

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