WO1997031627A1

WO1997031627A1 - Use of microcrystalline starch products as tabletting excipient

Info

Publication number: WO1997031627A1
Application number: PCT/NL1997/000097
Authority: WO
Inventors: Pieter Lykle Buwalda; Anna Willemina Arends-Scholte
Original assignee: Coöperatieve Verkoop- En Productievereniging Van Aardappelmeel En Derivaten Avebe B.A.
Priority date: 1996-02-29
Filing date: 1997-02-28
Publication date: 1997-09-04
Also published as: AU2235397A; NL1002493C2

Abstract

This invention relates to the use of a microcrystalline starch as tabletting excipient, wherein the microcrystalline starch used is obtainable by the action of an acid and/or enzyme on granular starch, preferably a cereal starch, in an aqueous suspension, dehydration by means of a water-miscible organic solvent and drying the dehydrated starch product. The microcrystalline starch preferably has a specific surface area of at least 1 m2/g.

Description

Title: Use of microcrystalline starch products as

tabletting excipient.

The invention relates to the use of specific

microcrystalline starch products as tabletting excipient, in particular as filler and/or as binder. In addition to the active ingredient, such as a medicine, vitamin, cleaning agent, coloring agent, insecticide or herbicide, tablets usually also contain specific inert components, often designated by the term tabletting excipients. These

tabletting excipients are classified according to their functional properties, such as binders, fillers,

disintegrating agents, lubricants, flavors and coloring agents. Suitable starch products may also perform several functions, such as the combination of binder and filler (often designated as filler/binder).

According to the invention specific starch products, obtainable as described below, are used as filler/binder in tablets, pellets, pills, capsules, and granules. For the manufacture of the tablets the conventional production techniques can be used, namely dry granulation, wet

granulation, and direct compression. The starch products according to the invention are particularly suitable in the manufacture of tablets via direct compression. In this process the powder mixture to be tabletted is filled into the molds of a tabletting machine and then compressed with a punch under pressure into tablets.

Most of the starch types consist of granules in which two types of glucose polymers occur, namely amylose

{15 - 35 wt.% on dry substance) and amylopectin

(65 - 85 wt.% on dry substance). Amylose consists of substantially linear molecules having an average degree of polymerization (DP) of 1000 - 5000 {depending on the starch type) . Amylopectin consists of very large, highly branched molecules having an average degree of polymerization of about 2,000,000. Most of the starch types occur in plants as semicrystalline granules, which are practically insoluble in cold water. The starch granules have a diameter varying between 1 and 100 micrometers. Starch granules usually consist partly of amorphous regions (about 70 - 80 wt.% of the granules) and partly of small crystalline regions (about 20 - 30 wt.% of the granules). The crystalline material consists substantially of radially oriented, linearly juxtaposed chain portions of amylopectin molecules. The crystalline regions are also designated as micelles or as crystallites. These crystallites are relatively very small, namely about only 0.02 micrometers on an average. The amorphous regions contain both amylose and amylopectin.

During the action of acids and/or enzymes on starch granules in aqueous medium below the gelatinization

temperature, substantially the amorphous portion of the starch granules is affected by hydrolysis and dissolution (etched away) . Because of their compact crystalline

structure, the crystallites are practically not affected. During continued action of acids and/or enzymes on the starch granules, the granular structure is more and more weakened, while the content of crystalline material

increases. After the desired degree of action the resulting starch product, preferably after neutralisation, separation, and washing, can be dried to a powder of microcrystalline starch. If desired, the microcrystalline starch can be reduced to the desired particle size by a mechanical

treatment (e.g. by homogenizing or grinding) before or after drying. Processes for manufacturing microcrystalline starch are described in WO 92/21703 and in US-A-4,551,177.

By the term microcrystalline starch, as used herein, are meant the starch products obtainable by the action of acids and/or enzymes on starch granules, below the

gelatinization temperature. By this action partial

hydrolysis and dissolution of the amorphous portions of the starch granules takes place, so that the content and the accessibility of the crystallites increase. The term microcrystalline starch was probably first used by the famous starch chemist Roy L. Whistler. The term is specified in WO 92/21703.

The use of microcrystalline starch as tabletting excipient is known from US-A-4, 551, 177 and the corresponding EP-A-0 159 631. The dried starch powders described therein have the drawback that they have no optimum tabletting properties with regard to the binding force and that the breaking strength of the resulting tablets is open to criticism. The microcrystalline starch products to be used according to the present invention have improved properties with respect to the binding force and the breaking strength.

It has in fact been found that microcrystalline starch obtains improved properties as tabletting excipient if the starch product obtained by the action of acids and/or enzymes on starch granules is first dehydrated by means of a water-miscible organic solvent and the resulting dehydrated microcrystalline starch is then dried. The thus obtained microcrystalline starch powder has an increased specific surface area and, with respect to binding force and breaking strength, have improved properties as tabletting excipient.

Example 2 of WO 89/04842 describes that crushed starch was hydrolyzed with x-amylase and the resulting dispersion was filtered, washed, first with water and then with

isopropanol, and dried at room temperature.

Example 2 of EP-A-0 539 910 discloses that x-amylase was caused to act on rice starch and the reaction mixture was centrifuged. The resulting starch product was washed twice with water, and acetone was added, and then the whole was dehydrated and dried under reduced pressure.

All granular starch types are suitable as starting material for the manufacture of microcrystalline starch for use according to the invention, e.g. : corn starch, waxy corn starch, rice starch, waxy rice starch, tapioca starch, wheat starch, potato starch, amylopectin-potato starch, sago starch, pea starch and high-amylose starch. As starting material there may also be used modified granular starches obtained by chemical, enzymatic substance and/or physical modification of the above-mentioned native starch types. These modified starches also fall within the term "starch" as used herein. Preferably, cereal starches are used as starting material, such as corn starch, wheat starch, rice starch or waxy corn starch.

The microcrystalline starch products according to the invention can be obtained by the action of acids and/or enzymes on the starch granules, dehydration of the

microcrystalline starch products by means of water-miscible organic solvents and drying the resulting products. The dried product can be ground to the desired fineness, if necessary.

The acid hydrolysis of the granular starting starches can be carried out in a suspension of the starch in a diluted or concentrated acid, such as sulfuric acid or hydrochloric acid. Preferably, the starch concentration ranges between 1 and 45 wt.%, the reaction temperature between 25 and 85°C and the reaction time between 5 and 48 hours. After the reaction the suspension can be neutralized. The starch product can be separated from the reaction medium, e.g. by filtering or centrifuging, and then be washed.

In the enzymatic process an aqueous suspension of granular starch is treated with a starch-splitting enzyme, such as alpha-amylase of amyloglucosidase. The starch concentration to be used preferably ranges between l and 45 wt.%. The reaction temperature is below the

gelatinization temperature of the starch suspension and preferably ranges between 10 and 65°C. The pH of the reaction medium preferably ranges between 3 and 9 and the reaction time preferably ranges between 2 and 48 hours. The enzyme used may be, e.g., the alpha-amylase preparations of NOVO Nordisk A/S (Bagsvaerd, Denmark) BAN 240 L of

Maltogenase 4000 L. The reaction can be stopped by reducing the pH to, e.g., 2 to 2.5. The amount of soluble

carbohydrate (depolymerized starch) depends on the starting starch and the reaction conditions and may vary from 5 to 80 wt.% of the starch starting material. The reducing power of the enzymatically treated starch determined as Dextrose Equivalent (DE) may vary between 5 and 40. After stopping the reaction the reaction medium can be neutralized to, e.g., pH 6. Subsequently, the starch product can be

separated from the reaction medium by filtering or

centrifuging.

The starch granules treated by means of acids and/or enzymes, separated from the reaction medium, have a dry substance content of, e.g., 10 to 40 wt.%. To enable the processing of the microcrystalline starch products in tablet formulations, the dry substance content must be increased to about 85 to 95 wt.%.

It has been found that the method of dehydrating influences the properties of the dehydrated microcrystalline starches. Properties that are very favorable to the present use as tabletting excipient can be obtained by carrying out the dehydration by treating the microcrystalline starch by means of water-miscible organic solvents, such as ethanol, isopropanol, n-propanol, methanol or acetone. This treatment can be carried out, e.g., by stirring, extracting and/or washing, with the water originally present in the starch product being largely, i.e. as to more than 50%, or nearly completely being replaced (substituted) by the organic solvent used. By subsequently drying the dehydrated

microcrystalline starch there are obtained products having the desired dry substance content. The resulting starch products have improved tabletting properties, with regard to binding force when compressing and tablet hardness, in comparison with corresponding starch products dehydrated directly after separation from the aqueous reaction medium by drying in the air, vacuum drying, spray drying or pneumatically drying.

The microcrystalline starch products for use according to the invention have a relatively high specific surface area. The specific surface area (BET) of the starch products according to the invention (as described below) is

preferably above 1 m²/g.

To prevent friction of the tabletting powder with the tabletting machine during the preparation of tablets, magnesium stearate is often added as lubricant. Magnesium stearate, however, has e negative effect on the binding properties of most of the binders, including

microcrystalline cellulose. It has been found that according to the invention microcrystalline starch products are obtained the binding properties of which, in comparison with those of microcrystalline cellulose, deteriorate less in the presence of magnesium stearate. These starch products therefore have a relatively lower magnesium stearate

sensitivity.

Of course, the fillers/binders must not bind so

strongly that the once manufactured tablets no longer disintegrate in liquids. The tablets manufactured by means of starch products according to the invention often show a sufficiently short disintegration time. If desired, the disintegration time can be further reduced by including disintegrating means in the tabletting formulation

(BU/SW 54).

The invention will be explained in more detail by means of the following examples. In the tekst, examples and claims, a number of concepts, preparation methods and determination methods are mentioned which will be described below in more detail.

Drying-

After drying in the air or dehydrating with an organic solvent the resulting starch products are spread on a sheet of filtering paper and dried in a drying stove at 40°C to a moisture content of 6-8%. Subsequently, in a climatic test cabinet the product is remoistened at 20°C and 50% RV

(relative humidity of the air) to a moisture content of 11-12%. This method is used because thus all products have the same moisture content during further tests. Moisture content:

The moisture content of the powders is determined by drying 5 g product on a moisture balance at 105°C to a constant weight. The moisture content is determined from the loss of weight.

Specific surface area (BET)

The specific surface area (BET) is determined by means of nitrogen adsorption with a Quantasorp gas adsorption apparatus (Quantachrome Corp., Syosset U.S.A.).

Tablets

From the starch products to be tested mixtures with alpha-lactose monohydrate (a filler) are made in a weight ratio of 1:1. From this mixture a tablet is made with a hand press at a compression force of 2000 kg. The tablets have a weight of 500 mg and a cross-section of 13 mm. When using magnesium stearate as lubricant, the mixture of starch product and lactose is first mixed with 0.5 wt.% (based on the starch/lactose mixture) magnesium stearate for 5 minutes at 90 rpm in a Turbula mixer. From the resulting mixing product tablets are made as described above.

Breaking strength

The breaking strength of the tablets is measured with a Schleuniger-4M tablet tester.

Lubricant sensivitv ratio (LSR)

The lubricant sensitivity ratio of a tabletting formulation can be co-determined by means of the LSR value. This value is determined by dividing the difference between breaking strength with and without lubricant by the breaking strength without lubricant. Dissolved carbohydrate

The amount of dissolved carbohydrate is measured by multiplying the volume of the filtrate after enzymatic treatment by the carbohydrate content of the filtrate (g/L). This content is determined by measuring the refraction of the filtrate. The percentage gone into solution is

calculated by dividing the dissolved carbohydrate by the original amount and multiplying it by 100.

Disintegration time

The disintegration time of the tablets is measured in an Erweka apparatus, carried out according to the standards of the USP (United States Pharmacopeia). No use has been made of the discs. The medium is water (37°C).

Exampl e 1

450 g of an aqueous suspension of starch (potato starch, corn starch, wheat starch, rice starch) (36 wt.% starch) was brought into a double-walled reaction vessel. To this suspension, 28 ml 6N HC1 were added dropwise with stirring. Subsequently, the reaction was conducted for 24 hours at 54°C. After cooling the microcrystalline starch product was separated from the reaction medium by means of vacuum filtration. On the vacuum filter the separated starch product was washed with 1 1 water. Then the starch product was suspended again in 250 ml water and brought to pH 6 with an NaOH solution. The starch product was separated by means of vacuum filtration and washed on the vacuum filter with 750 ml water.

A sample of 100 g of the wet starch product separated by filtration was suspended in 800 ml ethanol and stirred for 30 minutes. Subsequently, the starch product was separated by filtration and dried in the air. Another sample of 100 g of the wet starch product separated by filtration was directly dried in the air, without stirring in ethanol. From both dehydrated microcrystalline starch products tablets were made by means of direct compression (as described above) . Table 1 shows a number of properties of the microcrystalline starch products (MCS) on the basis of potato starch, corn starch, wheat starch and rice starch. Moreover, some properties of the tablets manufactured with these starch products are shown. The breaking strength was determined in the absence of a lubricant (0% MS) and in the presence of 0.5 wt.% magnesium stearate (0.5% MS). Table l further shows the disintegration time and the lubricant sensivity ratio (LSR). Table l

Effect of the action of hydrochloric acid and the drying method on the properties of granular starches.

n.d.: not determined Table l shows that microcrystalline starch dehydrated by means of ethanol imparts a higher breaking strength to tablets, in comparison with corresponding microcrystalline starch dehydrated with air, without an ethanol treatment. Example 2

This example relates to microcrystalline starch, manufactured by means of enzymes. The starch-splitting enzymes used were 2 commercial bacterial alpha-amylase enzyme preparations of NOVO Nordisk A/S (Bagsvaerd,

Denmark), namely BAN 240 L and Maltogenase 4000 L (a maltogenic alpha-amylase).

1500 g of an aqueous suspension of starch (36 wt.% starch) was brought into a double-walled reaction vessel. After adjusting the pH to 6.3, 0.1; 0.2 or 0.25% (v/g d.s.) of the enzyme preparation was dosed. Depending on the starch type, the reaction was conducted for 4 to 6 hours at a temperature of 58°C. The reaction conditions are shown in Table 2.

The enzymatic treatment was terminated by reducing the pH. Then the reaction medium was neutralized. Subsequently, the microcrystalline starch products were separated from the reaction medium. A part of the separated wet starch product was dried in the air. Another part of the wet separated starch product was stirred for 1 hour with a 4-fold excess of ethanol (g/g moisture). After filtration this ethanol treatment was repeated. The dehydrated filtered products were dried in the air. The specific surface area of the dried products and the properties of the tablets made therewith are shown in Table 2.

Table 2 shows that microcrystalline starch products enzymatically made from cereal starches, dehydrated by means of ethanol, give better tablets (with respect to the breaking strength) in comparison with corresponding

microcrystalline cereal starch products dehydrated with an air treatment (without an ethanol treatment).

Claims

1. The use of a microcrystalline starch as tabletting excipient, wherein said microcrystalline starch is

obtainable by the action of an acid and/or enzyme on

granular starch in an aqueous suspension, dehydration by means of a water-miscible organic solvent and drying the dehydrated starch product.

2. The use according to claim 1, wherein the granular starch used is a cereal starch.

3. The use according to claim 1 or 2, wherein the

microcrystalline starch has a specific surface area of at least 1 m²/g.

4. A process for making tablets, wherein the tabletting excipient used is a microcrystalline starch obtainable as set forth in claims 1-3.

5. A process according to claim 4, wherein the tablets are made by direct compression..