Process for the preparation of phenacetin granules

PATENT DESCRIPTION

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PATEHTOWT

PRL

Additional patent to patent No. Pending: 04.04.75 (P.179331)

Priority: 06.04.74 Federal Republic of Germany

The application was announced: 27.03.76

Patent description published: 31.01.1979

Int. Cl.² C07C 103/38 _ B01J 2/02

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Creator of the invention Patent holder: Bayer Aktiengesellschaft, Leverkusen (Federal Republic of Germany)

Method for producing spherical phenacetin and granules

The invention relates to a process for the preparation of spherical phenacetin granules.

It is known that 'organic substances can be converted into granules by melting and dispersing, with the aid of dispersing devices with one or two nozzles or disc dispersing apparatus and subsequent solidification in a gas or liquid environment (e.g. W. Boretzky, Fette-Seifen-Anstriehmittel, 69 year, no. 4, 1967, pp. 263-268; G. Natz, Kristallisation in der Verfahrcnsteehmk, Springer 1954, pp. 284-291). These methods are suitable primarily for substances insensitive to elevated temperatures.

W. Boretzky gave granulation of stearic acid, paraffins and synthetic resins in this way. This procedure cannot, however, be used for substances sensitive to the effects of elevated temperature, because when heated to the melting point or above they tend to stain and decompose. Therefore, until now, these substances could only be kept in the melt phase and further processed without the addition of suitable reducing agents.

In German Patent DOS No. 1 617 933 it is described that pharmaceutical active substances treated with reducing agents, such as aqueous solutions of hydrazine or ammonium formate solutions were melted and then solidified. However, due to the required purity of the therapeutic agents, it is necessary to completely remove these additives from phenacetin again due to this procedure. The disadvantage of this procedure is that the pure active substance must first be contaminated to allow it to melt and finally solidify.

It has been found that spherical phenacitin granules can be made without adding reducing agents by fusion in a heated comb, one-sided rotating and self-cleaning two-shaft screw conveyor with clearance 4.10-³ until 30.10-3 between the combs of the screw and the body of the device and between the edges of the screw in relation to the cross-section of the screw, if phenacetin is melted in a short period of time the product is in the conveyor, namely within 1-5 minutes at a wall temperature of 150-300 ° C and stop then in a known manner chap_M is washed in gas or liquid.

As completely unexpected, it should be emphasized that phenacetin, which is temperature-sensitive and which, according to German Patent DOS No. 1 617 933, if no reducing agent is added to it, decomposes near the melting point as a result of choosing the right melting equipment and its proper Dimensioning does not spontaneously color or decompose at wall temperatures more than 100 ° C above the melting point.

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The production of phenacetin granules by the process according to the invention is therefore technical progress, since the granules can henceforth conveniently be produced in a simple manner without the use of chemical auxiliaries which have hitherto been used to protect the alloy from staining or decomposition. There is no need to remove alloys previously needed from the alloy.

The two-shaft screw used in the method according to the invention has, due to the particular intensity of mixing, both a high heat transfer coefficient, and therefore has a small volume of product filling, and as a result of self-cleaning kinematics is characterized only by small deviations from the average, moreover very short product retention period.

The entry zone of this melting scroll should be cooled in an appropriate manner so as not to inhibit the inflow of a stream of phenacetin crystal powder through a premature, bulky pasty melting in the funnel area. A closed, externally heated housing area is connected to this introduction zone in the supply direction. Here, the powder is heated to the melting point with high forced consistency, after which it flows through a melting area in which the consistency of the powder changes through pastes to a low-viscosity alloy. Precisely because of the difficulty of handling these transiently forming pasty products, the advantage is the use of the described screw system. In principle, along with the said external heating of the housing, the screw shaft itself can also be heated.

Said twin shaft screw permits the use of temperatures with a very large difference between the heating environment and phenacetin, so that phenacetin, when heated, on average above ₄₀2-3 ° C above melting point exits the screw. Due to the short residence time and low thermal requirements, it is expedient for the end of the melting area to be as close as possible to the screw outlet. The melt leaving the screw is fed either through a small intermediate tank or directly to a heated pump, which brings it to a pressure suitable for dispersion. Parts of the apparatus between the screw outlet and the dispersion device may be carefully heated to a temperature only a few degrees above the melting point. The entire period of product remaining in. liquid phase must not exceed 20 minutes.

Solidification of dispersed phenacetin occurs in a known manner in gas (like air, nitrogen, rare gases, carbon dioxide) or in liquid (like water). When solidifying in gas, the product is obtained in the final form. When solidifying in a liquid₆θ mtfsi product to be dried. The spherical phenacetin granulate thus produced, in contrast to the crystalline phenacetin, can be directly tabletted, i.e. the active substance, after simply mixing with the generally used auxiliary agents for tableting, can. also be pressed on modern, high-performance tablet presses ensuring that tablets with good mechanical properties are obtained.

In the following embodiments, several variants of the method of the invention are given, at different temperatures and times for the product to remain in the melting apparatus. '

Example 1. Crystalline phenacetin was melted in a one-sided rotating, combing double-shaft screw conveyor with a length of 770 mm, core cross-section 17 mm and external screw dimension 32 mm, at a wall temperature of 190 ° C and holding the product in the screw for 3.2 minutes. The throughput was 8 kg / hour. The molten product was forced by a piston pump at 140 ° C through a dispersing nozzle and dispersed in air at 20 ° C. The period of time during which the product remained in the required temperature conditions was 13 minutes. The resulting product corresponded to the purity required by USP XVIII or BP 73 and had the following particle size distribution

10% 126 in m2

50% &lt;242 μτη 90% &lt;332 μτη

The product had good wettability and was not dusty.

Example II Crystalline phenacetin was melted in the twin shaft screw conveyor described in Example 1 at a wall temperature of 210 ° C and the product was held in the screw conveyor for 1.4 minutes. The throughput was 18 kg / hour. The molten product was forced by a piston pump at 140 ° C through a dispersing nozzle and dispersed in air at 20 ° C.

The period of savory during which the product remained in the required temperature conditions was 6 minutes. The solidified product corresponded to purity. required by USP XVIII or BP 73 and had the following particle size distribution:

10% &lt;80 μτη 50% &lt;160 μτη 90% &lt;212 μτη

Example III. Crystalline phenacetin was melted in the example described. And a twin shaft screw conveyor at 270 ° C wall temperature and maintenance. product in a screw conveyor within 1.0. minutes. The throughput was 26 kg / hour. The molten product was pumped by means of a piston pump at 140 ° C through a dispersing nozzle and dispersed in air at 20 ° C.

The total period of time during which the product remained in the required temperature conditions was 4 minutes. The solidified product had the desired purity and the following particle size distribution:.

10% &lt;Ζ 91 50⁰% C 168 μτη 90% &lt;247 μτη

Example IV Crystalline phenacetin was melted in the two-shaft screw conveyor described in Example 1 at a wall temperature of 210 ° C and holding the product in the screw conveyor for 1.5 minutes. The throughput was 17 kg / hour.

The molten product was pumped using a piston pump at 142 ° C through a dispersing nozzle and dispersed in water at 20 ° C. The period of time during which the product remained in the required temperature conditions was 6 minutes. The solidified and dried product had the required purity and had the following particle size distribution:

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T0 %% &lt;38 μτη 50 %% &lt;104 μτη

90 °% &lt;230 μτη