Process for the preparation of phenacetin granules

Method for producing spherical phenacin granules and device for carrying out the method

The present invention relates to the production of spherical phenacetate granules from the molten phase. And the device for carrying out the method.

It is already known to convert organic substances into granules via the melt by atomization using one- and two-component nozzles or disc atomizers and subsequent solidification in gases or liquids. (ZBW Boretzky, Fette-Seifen-Anstrichmittel, 69 Year No. 4, 1967, pages 263-268; G. Matz, Crystallization in Process Engineering, Springer 1954, pages 284-291) · These processes are preferably carried out with temperature-insensitive substances , W. Boretzky reports on stearic acids, paraffins and synthetic resins that were granulated in this way.

This procedure is not possible for temperature-sensitive substances, since they tend to discolour and decompose when heated to or above the melting point. Until now, they could only be kept and processed in the melting phase without damage by adding suitable reducing agents. In German Offenlegungsschrift 1 617 933 it is described that pharmaceutical agents, with reducing agents such as aqueous hydrazine solutions or ammonium formate solutions, were melted and then solidified.

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This procedure requires that the additives be completely removed from the phenacetin because of the purity requirements that apply to pharmaceuticals. The disadvantage of this process is that the pure active ingredient must first be contaminated in order to melt and. to allow subsequent solidification.

It has been found that spherical phenacetine granules are obtained if crystalline phenacetin is added without the addition of a reducing agent in a continuously operating melting device with a short product residence time and a narrow residence time spectrum, preferably in a heated, intermeshing and self-cleaning multi-shaft screw with little play between the screw flanks and between screw combs and housing melts at wall temperatures between 150 and 500 ° C. and the melt is then atomized in a known manner in inert gases or liquids.

It is extremely surprising. to call,. that the thermally sensitive phenacetin, which according to the published patent application 1,617,933 is destroyed near the melting point, if no suitable reducing agent is present. is not discolored or decomposed only by choosing the appropriate melting device and suitable dimensions, even at wall temperatures of over 100 ° C above the melting point.

The production of phenacin granules according to the invention represents a technical advance, since it can now be easily produced without chemical aids, which were previously required to protect the melt from discoloration or decomposition. There is no longer any need to remove the additives previously required from the melt.

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A heated, intermeshing and self-cleaning multi-shaft screw with a narrow dwell time range with little play between the screw combs and the housing and the screw flanks can preferably be used as the melting element. According to the invention is a co-rotating twin-shaft screw with a diameter-related play of preferably 4 · 10 5 to 30 · 10-5_{to the SC}H_onmelting ends are particularly suitable.

Such a twin-shaft screw has, on the one hand, because of its special mixing intensity, large heat transfer numbers and thus small product-filled volumes and, on the other hand, due to its self-cleaning kinematics, only slight deviations from the mean, anyway very short, residence time.

The entrance zone of this melting screw is expediently to be cooled so that pasty, unwieldy material states do not impede the flow of the crystalline phenacetin powder in the funnel area by premature melting. This feed zone is followed by a closed, externally heated housing area in the conveying direction. Here, the powder is heated to the melting point in the case of strong forced convection. It then runs through a melting range in which the consistency changes from the powder to pasty states to the low-viscosity melt. Precisely because of these difficult-to-handle material states, the use of the worm system described is advantageous. In principle, in addition to the external housing heating mentioned, the worm shafts themselves can also be heated.

The two-shaft screw mentioned allows very large temperature differences between the heating medium and phenacetin, without this exiting the screw heated to an average of more than 2 to 3 ° C. above the melting point. In view of the short dwell time and low thermal stress, it is advisable to place the end of the melting range as close as possible to the screw outlet. The melt emerging from the screw is either fed via a small intermediate container or directly to a heated pump, which brings it to the atomizing pressure.

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-3 The parts of the apparatus arranged between the screw end and the atomizing element may only be heated to a few degrees above the melting point. The total residence time in the liquid phase should not exceed 20 minutes.

The atomized phenacetin is solidified in a known manner in a gas (such as air, nitrogen, noble gas, carbon dioxide) or a liquid (such as water). When solidified in a gas, the final product is formed. If it solidifies in a liquid, it must then be dried.

In contrast to the crystalline phenacetine, the spherical phenacetin granules obtained in this way can be tabletted directly, ie the active ingredient can be compressed into tablets with good mechanical properties even on modern high-performance tablet presses by simply adding conventional tabletting aids.

The following exemplary embodiments show some variants of the method according to the invention with different temperatures and residence times.

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- 4 Example 1

Crystalline phenacetin was melted in a co-rotating, combing two-shaft screw with 32 mm outer screw diameter, 17 mm core diameter and 770 mm screw length at wall temperatures of 190 ° C and a residence time in the screw of 3.2 minutes. The throughput was 8 kg / h. The melt was atomized by means of a piston pump at temperatures around 140 ° C through a swirl chamber nozzle in air of 20 ° C. The total residence time of the product under thermal stress was 13 minutes.

The product had the required purity according to USP XVIII or BP 73 and had the following particle size distribution:

% ^<Z 126 // m% </ 242 Z (m ^J % C 332 / im

It was very free flowing and not dusty.

Example 2

Crystalline phenacetin was melted in the two-shaft screw described in Example 1 at wall temperatures of 210 ° C. with a residence time in the screw of 1.4 minutes. The throughput was 18 kg / h. The melt was atomized by means of a piston pump at temperatures of around 140 ° C. via a swirl chamber nozzle in air of 20 ° C. The total residence time of the product under thermal stress was 6 minutes. The solidified product met the purity requirements according to USP XVIII or BP 73 and had the following particle size distribution:

80 Am% d 160 Am 90% </ 212 km

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- 5 I.

Example 5

Crystalline phenacetin was melted in the twin-screw screw described in Example 1 at wall temperatures of 270 ° C. with a residence time in the screw of 1 minute. The throughput was 26 kg / h. Using a piston pump, the melt was atomized at temperatures around 140 ° C through a swirl chamber nozzle in air at 20 ° C. The total residence time of the product under thermal stress was 4 minutes. The solidified product had the required purity and had the following particle size distribution:

% <Z. 91 km% 168 at% 247 km

Example 4

Crystalline phenacetin was melted in the twin-screw screw described in Example 1 at wall temperatures of 210 ° C. with a residence time in the screw of 1.5 minutes. The throughput was 17 kg / h. The melt was atomized at a temperature of 142 ° C. by means of a swirl chamber nozzle in water of 20 ° C. by means of a piston pump. The total residence time of the product under thermal stress was 6 minutes. That froze^r and dried product had the required purity and

<td></td><td colspan="2">had the following particle size distribution:</td>

<td> ¥</td><td> 10 %</td><td>58 am</td>

<td></td><td> 50 %</td><td>104 am</td>

<td></td><td> 90 %</td><td>230 am</td>