GB2077268A

GB2077268A - A Process for the Preparation of Anhydrous Stable Lactose

Info

Publication number: GB2077268A
Application number: GB8018991A
Authority: GB
Original assignee: DMV Campina BV
Current assignee: DMV Campina BV
Priority date: 1980-06-10
Filing date: 1980-06-10
Publication date: 1981-12-16
Also published as: GB2077268B

Abstract

Anhydrous stable lactose is obtained by extruding crystalline alpha - lactose hydrate as a dry product in an extruder the jacket of which is heated to temperatures above 100 DEG C. Preferably an extruder is used in which a gradual controlled build-up of shear takes place. The lactose may be extruded together with a pharmacologically active substance, e.g. sodium fluoride, and tablets or capsules prepared therefrom.

Description

SPECIFICATION A Process for the Preparation of Anhydrous Stable Lactose Usually lactose is obtained on an industrial scale by cooling a supersaturated solution of lactose at temperatures below 930C and separating and drying the resulting solid substance. The resulting lactose is obtained in the form of a-lactose hydrate containing 1 molecule of hydrate water per molecule of lactose, which means about 5 percent by weight of hydrate water.

An important field for the use of lactose is the pharmaceutical industry, where lactose is used when manufacturing tablets and capsules.

However, it is generally known that the presence of moisture in any form in tablets and capsules may have a negative influence upon the quality of these tablets or capsules, for example because the water reacts with the active ingredient in the tablet or the capsule. Thus the use of a-lactose hydrate may encounter difficulties. Moreover, strong tablets can only be formed with difficulty with the usual a-lactose hydrate crystals.

Therefore, normally binders and/or lubricants and optionally water are added to the lactose, whereafter by tabletting in the conventional way sufficiently strong tablets can be manufactured (cf. for example German patent application 2,1 5,116). It is also known from the German patent application 1,667,038 to knead lactose powder with 20 percent by weight of water, to extrude the kneaded product to form granules and to subject these granules in a special way to centrifugal forces in an apparatus with rotating disks.

From Chemical Abstracts, 65(1966), 8681 c it is known that anhydrous lactose is very suitable as a diluent in tablets.

This invention is based on the observation that anhydrous stable lactose having a specific physical structure can be obtained when crystalline a-lactose hydrate is introduced.as a dry product into an extruder, the jacket of which is heated to temperatures above 1 O00C. At these temperatures above 1 000C the a-lactose hydrate is heated under pressure, whereafter it is extruded. Immediately thereafter evaporation of water takes place. The resulting product has a dry solids content of more than 99 percent by weight.

It has further been found that the extrusion of the dry a-lactose hydrate can only take place with a satisfactory result, if an extruder is used of a type in which a gradual controlled build-up of shear takes place. Extruders of this type are for example extruders of the so-called Battenfeed-design, in which the diameter of the worm shaft first increases conically, whereafter a cylindrical portion follows, as shown in Fig. 1 and explained in more detail in Example 1. However, other extruders with a single worm shaft or with double worm shafts are also useful in process of the invention provided that a gradual controlled buildup of shear takes place therein. This means that abrupt variations in the build-up of shear must be avoided. Such abrupt variations occur for example, when the cross-section of the space between worm shaft and jacket of the extruder is subject to sudden changes.Thus, extruders of the type, which is often used in the preparation of foodstuffs (extrusion cooking) shown in Fig. 2 and explained in more detail in Example 2, appear to be not suitable for use in the process of the invention. In these extruders the build-up of shear does not take place gradually, because the annular space between worm shaft and jacket through which the lactose mass is pressed, is narrowed at one or more places over a very short distance by increase of the diameter of the worm shaft.

Using an extruder of the lastmentioned type a mixture of a-lactose hydrate and water may be extruded provided at least 1.5 percent by weight, but preferably more than 4 percent by weight of water are added. By this process, however, a product is obtained, which after cooling contains at least 1 percent by weight of water and therefore must be dried in a separate step, before it can be considered as anhydrous. Such afterdried products often show unacceptable hygroscopic properties, possibly as a result of the presence of instable or amorphous forms of lactose. Because in the process of the invention water is not added, an anhydrous product can be obtained without afterdrying, the water of hydration being evaporated from the extruded product immediately after it leaves the extruder.

The hot extrusion product is preferably cooled with the aid of dry air.

By a proper selection of the shape of the orifice of the extruder the extruded product may be obtained as a filament or a rod. By variation of the conditions and of the shape of the orifice the product may also be extruded as a ribbon or in any other shape. The dimensions of the extruded products may be varied.

Optionally the resulting filament, rod or ribbon can be comminuted by means of a rotating knife to obtain granules the size of which can be adjusted as desired. It is also possible to mill the resulting extruded product and to obtain the desired particle size by a proper selection of the miliing intensity.

All the above mentioned methods of shaping, comminuting and milling the extruded products are generally known the act.

Tablets may be manufactured on an ex-center press from the milled anhydrous product with the addition of 0.5 percent by weight of a lubricant.

The resulting tablets resist a pressure of 10--13 kg.

When carrying out the process of the invention it is also possible to extrude other substances.

such anhydrous lactose or certain substances with a pharmacological action, together with the a-lactose hydrate. In this way a product may be obtained for example, in which a small amount of a pharmacologically active substance is distributed homogeneously in the carrier of anhydrous stable lactose and may be pressed therewith immediately to form tablets. In this way, for example, sodium fluoride may be dispersed in lactose.

With the an hydros lactose prepared according to the invention stable capsules may also be prepared.

The following examples illustrate the invention.

Example I (According to the invention) Crystalline a-lactose hydrate was extruded in an extruder of the so-called Battenfeld-design having a conical-cylindrical worm shaft, as shown in Fig. 1. In the space between the conical portion (1) of the worm shaft (2) and the jacket (3) of the extruder the product to be extruded is subjected to an increasing shear in a gradual way which is controlled by the shape of the worm shaft and the jacket. Thereafter the product is pressed through the space between the cylindrical portion (4) of the worm shaft and the jacket, where shear remains constant. The jacket was heated at 1 620C. In a period of two hours 26 kg of anhydrous lactose having a moisture content of less than 0.3% by weight were prepared. The product was not hygroscopic and contained 82.8% by weight of p-lactose.

Example Il (For comparative purposes.) Crystalline a-lactose hydrate was introduced into an extruder as shown in Fig. 2. The cylindrical worm shaft (5) is enlarged at two places by abrupt annular enlargements (6), indicated at steamlocks. In the space between these steamlocks and the jacket (7) the product is suddenly and in an uncontrolled way subjected to a strong shear.

The jacket was heated at 1 640C. It was impossible to process the a-lactose hydrate in a dry state with this extruder. However, when 4% by weight or more of water was added to the a- lactose hydrate, the mixture could be extruded without difficulties. As soon as the addition of water was stopped, however, the extrusion process was interrupted and no further extruded product was obtained.

Claims

1. A process for the preparation of anhydrous stable lactose, wherein crystalline a-lactose hydrate is introduced as a dry product into an extruder, the jacket of which is heated to temperatures above 1 000C, and is extruded from the extruder.

2. A process according to claim 1, wherein the extruder used is one in which a gradual controlled build up of shear takes place.

3. A process according to claim 1 or claim 2, wherein water evaporates from the extruder product immediately after it leaves the extruder.

4. A process according to any one of claims 1 to 3, wherein the a-lactose hydrate is introduced into the extruder in admixture with anhydrous lactose or a small amount of a pharmacologically active substance.

5. A process according to any one of claims 1 to 4, wherein the extruded product is brought in the desired shape and/or size in a way known per se.

6. A process according to claim 1 conducted substantially as described in Example 1 herein.

7. A tablet or capsule manufactured acceding to claim 6.

7. A process for manufacturing tablets or capsules with the use of lactose, wherein anhydrous lactose prepared according to any one of the preceding claims is used as excipient.

8. A tablei or capsule manufactured according to claim 7.

New Claims or Amendments to Claims filed on 30 January 1981 Superseded Claims 1 to 8 New or Amended Claims:

1. A process for the preparation of anhydrous stable lactose, wherein crystalline a-lactose hydrate is introduced as a dry product into an extruder of the type in which a gradual controlled build-up of shear takes place, the jacket of which is heated to temperatures above 1000C and is extruded from the extruder.

2. A process according to claim 1, wherein water evaporates from the extruder product immediately after it leaves the extruder.

3. A process according to claim 1 or claim 2, wherein the a-lactose hydrate is introduced into the extruder in admixture with anhydrous lactose or a small amount of a pharmacologically active substance.

4. A process according to any one of claims 1 to 3, wherein the extruded product is brought in the desired shape and/or size in a way known per se.

5. A process according to claim 1 conducted substantially as described in Example 1 herein.

6. A process for manufacturing tablets or capsules with the use of iactose, wherein anhydrous lactose prepared according to any one of the preceding claims is used as excipient.