FI71951C - Process for the preparation of crystal anhydrous lactose powder. - Google Patents

Description

1 71951

This invention relates to a process for the continuous production of a substantially anhydrous non-hygroscopic lactose powder.

Lactose, i.e., O-β-D-galactopyranosyl- [1-> 4J-D-glucopyranose, can exist in several different physicochemical forms. In aqueous solution, it exists as two anomers, the α and β forms, with an β / α ratio of about 1.5 / 1. From its aqueous solution o lactose can be crystallized to α-lactose monohydrate at a temperature below 93.5 o C or to β-lactose at a temperature above 93.5 C. From the crystallized solution, the crystals can be separated by several commonly known methods, dried and thus prepared α-lactose monohydrate powder and β-lactose powder. In α-lactose monohydrate, the water of crystallization is 5% by weight of lactose.

It is also known that the crystals do not have to be separated, but that the slurry containing the crystals can be dried as such (U.S. Patent 3 b39 170). In this case, a mixture of crystals and amorphous or crystalline lactose formed from dissolved lactose is obtained. If no crystallization is carried out at all, but the aqueous lactose solution is dried quickly, a completely crystalline, i.e. amorphous, powder is obtained. According to the literature, amorphous lactose is highly hygroscopic and easily agglomerated.

Highly purified, pharmacopoeial lactose is used in the pharmaceutical industry as a tablet filler and binder. Several studies have shown that different tableting methods impose different requirements on lactose rnm. in terms of fluidity, moisture content and anomeric equilibrium. Anhydrous lactose powder has proved to be particularly suitable in the so-called suoratabletointimenetelmässä.

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It is known from the literature that water of crystallization can be removed by solvent treatment, for example by boiling in methanol. However, these methods have not reached industrial applications due to their impracticality and high cost.

Anhydrous lactose powder suitable for direct tableting can also be prepared by roller drying (U.S. Patent 3,802,914). In the process, a hot aqueous solution of lactose is dried on a rotating drum to obtain a powder containing about 50% amorphous lactose. Amorphous lactose is known to be hygroscopic and easily agglomerated.

It is known that by heating crystalline lactose at a sufficiently high temperature, the crystalline water is released and a crystalline anhydrous product is formed. Depending on the mode of heating, the resulting product is either hygroscopic or non-hygroscopic (U.S. Patent 2,319,562). If the product is hygroscopic, it absorbs moisture until the amount of water corresponding to the removal of crystalline water is again bound. At the same time, the powder usually agglomerates. A known method for producing anhydrous non-caking lactose powder by heating is extrusion (DE-A-2 949 216). In the process, the α-lactose monohydrate powder is extruded at a temperature above 100 ° C under pressure to form a product containing about 80% (3-lactose. However, the resulting product must be ground to obtain a structure suitable for tableting.

Another known method of preparing a permanent, non-hygroscopic, anhydrous lactose powder is two-stage heating (EP-A-124 928). In this case, an unstable, hygroscopic anhydrous lactose powder is first prepared by heating α-lactose monohydrate or a mixture of monohydrate and amorphous lactose in batches in a drying oven. In the second step, the volatile anhydrous powder is further heated in batches to form a stable 3,71951 anhydrous lactose powder. Such a method with two separate heaters is in practice difficult to implement on an industrial scale.

The object of the present invention is to provide a continuous process by which a non-crystalline non-hygroscopic lactose powder can be prepared directly without separate grinding, which remains anhydrous even in humid conditions and which has good tableting properties. These objects are achieved by the method according to the invention, which is characterized in that the aqueous lactic powder applied to the substrate is continuously conveyed through the heating zone at normal atmospheric pressure.

According to the invention, the heating can be carried out easily and quickly continuously and continuously, even on an industrial scale.

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The crystalline lactose powder is preferably a lactose powder that complies with pharmacopoeial regulations. For example, the substrate may be an endless moving belt on which the powder is conveyed in a thin layer through the heating zone. The thickness of the powder layer is preferably about 1 to 10 mm, typically about 2 to 5 mm. The heating can be done by heating placed above and / or below the strip, which can be, for example, electric heaters, oil coils or infrared lamps.

The resistors heat the strip and the air immediately above it so that the air temperature rises to about 150 to 200 ° C, typically to about 175 ° C. The powder preferably remains in the heating zone for about 0.5 to 5 minutes, typically about 2 to 3 minutes. During heating, crystalline water is removed from the powder and part of the α-form changes to the 3-form. After heating, the powder is cooled with cold air to room temperature. In the method, both heating and cooling are performed at normal atmospheric pressure. After cooling, the powder does not need to be ground, but can be screened to the desired particle size. In the following, the method and the powder obtained by it are described by means of examples.

Example 1 USP compliant α-lactose monohydrate powder was heated with a continuous belt heater. The thickness of the powder layer was 3 mm and the temperature of the bottom strip of the heater was 160 ° C and the temperature of the top strip was 160 ° C. The residence time of the powder in the heating zone was 5 minutes. The powder thus treated was white, easily flowable and remained non-agglomerated at 65% relative humidity. The crystal water of the powder was removed and at the same time part of the cx form changed to the 3 form. The tableting properties of the method-treated powder were substantially improved compared to the non-concept powder (Table 1).

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Table 1. Effect of heat treatment on α-lactose monohydrate powder Untreated Treated powder powder *

Free water% 0.04 0.01 **

Crystal water% 5.53 0.51 α-lactose 97.3 78.4 3-lactose 2.7 21.6

Optical rotation 53.1 55.0 * * ★

Moisture absorption% - 0.12

Tablet breaking strength 3.8 17.1 s.c.u. units o

* = oven heating 2 h 80 C

o ** = oven heating for 2 h 140 c *** = humidification at 65% rH for 24 h

Example 2 A USP-compliant lactose powder consisting of crystalline α-lactose monohydrate and an amorphous mixture of α- and 3-lactose was heated in a 2 mm thick layer with a strip heater. In the heater, the temperature of the upper belt was 190 ° C and the temperature of the lower belt o was 160 ° C. The residence time of the powder in the heating zone was 3 minutes. Upon heating, the crystal water of the powder was removed and part of the α-form was converted to the β-form (Table 2).

Table 2. Effect of heat treatment on lactose powder Untreated Treated powder powder

Free water% * 0.36 0.03 * *

Crystal water% 5.07 0.44 c 71951 6 α-lactose% 87.5 82.7 3-lactose% 12.5 17.3

Optical rotation angle 52.0 54.8 * * *

Moisture absorption% 0.50 0.50

Tablet breaking strength 15.2 19.5 s.c.u · units o

* = oven heating 2 h 80 C

o

** = oven heating 2 h 140 C

*** = humidification at 65% rH for 24 h

Claims (5)

7 71951 A method for producing a substantially anhydrous non-hygroscopic lactose powder, characterized in that the aqueous crystalline lactose powder applied to the substrate is continuously conveyed at normal atmospheric pressure through a heating zone. Method according to Claim 1, characterized in that the layer thickness of the lactose powder applied to the substrate is about 1 to 10 mm, preferably 2 to 5 mm. Process according to Claim 1 or 2, characterized in that the residence time of the lactose powder in the heating zone is about 0.5 to 5 minutes, preferably 2 to 3 minutes. Method according to one of the preceding claims, characterized in that the temperature in the heating zone is about 150 to 200 ° C, preferably about 175 ° C. Process according to one of the preceding claims, characterized in that the aqueous lactose powder consists essentially of α-lactose monohydrate.