NL1002493C2 - Microcrystalline starch products, process for their preparation as well as the use of those products as tableting excipient. - Google Patents

Description

VO 9063

Title: Microcrystalline starch products, process for their preparation as well as the use of those products as tableting excipient.

The invention relates to microcrystalline starch products which are suitable as a tabletting aid, in particular as a filler and / or binder. Tablets, in addition to the active ingredient such as a drug, vitamin, detergent, colorant, insecticide or herbicide, usually also contain certain inert components, often referred to by the term tableting excipients (excipients). These tableting aids are classified according to their functional properties such as binders, fillers, disintegrants, lubricants, flavors and dyes. Suitable starch products can also perform multiple functions such as the combination of binder and filler (often referred to as filler / binder).

The starch products according to the invention are particularly suitable as filler / binder in tablets, pellets, pills, capsules and granules. For the manufacture of the tablets one can use the usual production techniques, namely dry granulation, wet granulation and direct compression. The starch products of the invention are particularly useful in the manufacture of tablets via direct compression. The powder mixture to be tableted is filled into the molds of a tablet press and then pressed into tablets with a stamp under pressure. Most starches consist of granules containing two types of glucose polymers, namely amylose (15 - 35 wt.% On dry matter) and amylopectin (65 - 85 wt.% On dry matter). Amylose consists of mainly linear molecules with an average degree of polymerization (DP) of 1000 - 5000 (depending on the starch type). Amylopectin consists of very large, highly branched molecules with an average degree of polymerization of approximately 2,000,000.

1002493 - 2 -

Most starches occur in plants as semi-crystalline granules, which are practically insoluble in cold water. The starch granules have a diameter ranging between 1 and 100 micrometers, starch granules usually consist partly of amorphous regions (approximately 70 to 80% by weight of the granules) and partly of small crystalline regions (approximately 20 to 30% by weight of the granules ). The crystalline material consists essentially of radially oriented, linearly adjacent chain portions of amylopectin molecules. The crystalline areas are sometimes referred to as micelles or as crystallites. These crystallites are relatively very small, averaging only about 0.02 micrometers. The amorphous regions contain both amylose and amylopectin.

On the action of acids and / or enzymes on starch granules in an aqueous medium below the gelatinization temperature, mainly the amorphous part of the starch granules is attacked (etched away) by hydrolysis and dissolution. The crystallites are practically unaffected by their compact crystalline structure. With the progressive action of acids and / or enzymes on the starch granules, the grain structure is increasingly weakened, while the content of crystalline material increases. After the desired degree of action, the starch product obtained, preferably after neutralization, separation and washing, can be dried into a powder of microcrystalline starch. If desired, the microcrystalline starch can be reduced to the desired particle size by mechanical processing (eg, by homogenization or grinding) before or after drying. Methods of manufacturing microcrystalline starch are described in International Patent Publication 92/21703 and in U.S. Patent 4,551,177.

By the term microcrystalline starch is meant here the starch products, which can be obtained by the action of acids and / or enzymes on starch granules, ion 2493-3 - below the gelatinization temperature. Due to this action, partial hydrolysis and dissolution of the amorphous parts of the starch granules take place, whereby the content and accessibility of the crystallites increases. The term 5 microcrystalline starch was probably first used by acclaimed starch chemist Roy L. WhistIer.

The term is further described in International Patent Publication 92/21703.

The use of microcrystalline starch as a tabletting aid is known from US patent 4,551,177. The dried starch powders described therein have the drawback that they do not have optimum tabletting properties with regard to the binding force and that the breaking strength of the obtained tablets leaves something to be desired. The microcrystalline starch products according to the invention have improved properties with regard to the binding force and the breaking strength.

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

All granular starches are suitable as starting material for the manufacture of microcrystalline starch according to the invention, for example: 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, it is also possible to use modified granular starches obtained by chemical, enzymatic substance and / or physical modification of the aforementioned native '10 * 24 ° 3 '- 4 starches. These modified starches also fall under the term "starch" as used herein. Grain starches are preferably used as the 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 using water-miscible organic solvents and drying of the products obtained. If necessary, the dried product can be ground to the desired fineness.

The acidic hydrolysis of the starting granular starches can be carried out in a suspension of the starch in a dilute or concentrated acid, such as sulfuric acid or hydrochloric acid. Preferably, the starch concentration is between 1 and 45% by weight, 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, for example, by filtration or centrifugation, and then washed.

In the enzymatic process, an aqueous suspension of granular starch is treated with a starch-splitting enzyme such as alpha amylase or amyloglucosidase. The starch concentration to be used is preferably between 1 and 45% by weight. The reaction temperature is below the gelatinization temperature of the starch suspension and preferably between 10 and 65 ° C. The pH of the reaction medium is preferably between 3 and 9 and the reaction time is preferably between 2 and 48 hours. As the enzyme 30, it is possible to use, for example, the alpha-amylase preparations of NOVO Nordisk A / S (Bagsvaerd, Denmark) BAN 240 L or Maltogenase 4000 L. The reaction can be stopped by lowering the pH to, for example, 2 to 2.5. The amount of soluble carbohydrate (depolymerized starch) depends on the starting starch and the reaction conditions and can vary from 5 to 80% by weight of the starting starch material. The reducing power 1002493-5 of the enzymatically treated starch determined as Dextrose Equivalent (DE) can vary between 5 and 40. After stopping the reaction, the reaction medium can be neutralized to, for example, pH 6. Then the starch product 5 can be filtered or centrifugation are separated from the reaction medium.

The starch granules treated with acids and / or enzymes, which have been separated from the reaction medium, have a dry matter content of, for example, 10 to 40% by weight. In order to incorporate the microcrystalline starch products into tablet formulations, the dry matter content must be increased to about 85 to 95% by weight.

It has been found that the dehydration method influences the properties of the dehydrated microcrystalline starches. According to the invention, dehydration takes place by treating the microcrystalline starch with water-miscible organic solvents such as ethanol, isopropanol, n-propanol, methanol or acetone. This treatment can be carried out, for example, by stirring, extracting and / or washing, in which the water originally present in the starch product is partly or almost completely replaced (substituted) by the organic solvent used. By subsequent drying of the dehydrated microcrystalline starch, products are obtained which have the desired dry matter content. The starch products thus obtained have improved tabletting properties, in terms of compression binder and tablet hardness, compared to corresponding starch products which are dehydrated immediately after separation from the aqueous reaction medium by air drying, vacuum drying, spray drying or pneumatic drying.

The microcrystalline starch products 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.

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To prevent friction of the tableting powder with the tabletting machine during the preparation of tablets, magnesium stearate is often added as a lubricant. However, magnesium stearate negatively affects the bonding properties of most binders, including microcrystalline cellulose. It has been found that according to the invention microcrystalline starch products are obtained, the binding properties of which, compared to those of microcrystalline cellulose, deteriorate less in the presence of magnesium stearate. These starch products thus have a relatively lower magnesium stearate sensitivity.

Of course, the fillers / binders should not bind so strongly that the tablets once made in liquids no longer decompose. The tablets, which have been manufactured with the aid of starch products according to the invention, usually have a sufficiently short break-up time.

If desired, the disintegration time can be further reduced by including disintegrants in the tabletting formulation (BU / SW 54).

The invention is further illustrated by the following examples. In the text, examples and claims a number of terms, preparation methods and determination methods are mentioned which are further described hereinafter.

To dry

The starch products obtained after air drying or dehydration with an organic solvent are spread on a sheet of filter paper and dried in a drying oven at 40 ° C to a moisture content of 6-8%. Then the product is re-moistened in a climate cabinet at 20 ° C and 50% RH (Relative humidity of the air) to a moisture content of 11-12%. This method is used because in this way all products have the same moisture content during further tests.

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Moisture content

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

Specific surface area (BET)

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

10 Tablets

From the starch products to be tested, mixtures are made with alpha-lactose monohydrate (a filler) in a 1: 1 weight ratio. a tablet is manufactured from this mixture with a hand press at a compression force of 2000 kg. The tablets have a weight of 500 mg and a diameter of 13 mm. When using magnesium stearate as a lubricant, the mixture of starch product and lactose is first mixed with 0.5% by weight (based on the starch / lactose mixture) of magnesium stearate for 20 minutes at 90 rpm in a Turbula mixer. Tablets are made from the resulting mixed product as described above.

Breaking strength

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

Lubricant aenaivitv ratio_ (LSR)

The lubricant sensitivity of a tableting formulation can also be determined from the LSR value. This value is determined by dividing the difference between breaking strength with and without lubricant by breaking strength without lubricant.

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Opoeloat 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 5 (g / L). This content is determined by measuring the refraction of the filtrate. The percentage that has gone into solution is calculated by dividing the dissolved carbohydrate by the original amount and multiplying by 100.

io v 1 te.aav.al tld-d

The disintegration time of the tablets is measured in an Erwèka device, performed according to the standards of the USP (United States Pharmacopeia). The discs have not been used. The medium is water (37 ° C).

15 Example_I

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

A 100 g sample of the wet filtered starch product was suspended in 800 ml of ethanol and stirred for 30 minutes. Then the starch product was filtered off and air-dried. Another 100 g sample of the wet filtered starch product was air dried directly without stirring in ethanol. Tablets were made from both dehydrated microcrystalline 1002493-9 line starch products by direct compression (as described above). Table 1 lists a number of properties of the microcrystalline starch products (MCZ) based on potato starch, corn starch, wheat starch and rice starch. Some properties of the tablets made with these starch products are also mentioned. The fracture 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 1 also lists the disintegration time and the lubricant sensitivity ratio (LSR). For comparison, the product Avicel PHioi is listed in Table 1. This is a type of microcrystalline cellulose, which is often used as a filler / binder in tablets.

15 Table 1

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

I-1-1-1— “Ί - ^ - 1 — I

20 I Produkt- Zet · Method Specific Breaking strength Breakdown LSR

I designation of area (kg) time I

I thing kind of dehydra- ------------------------- (min) 1

I ___ teren__mi2 / g 0% MS 0.5% MS ___ I

25 I MCZ-1 Earth air 0.1 7 <1 n.a. 1 I

apple |

I MCZ-2 Earth ethanol 0.2 13 <1 n.a. 1 D

apple R.

30 I

MCZ-3 Maize air 0.6 13 7 4 0.46 MCZ-4 Maize ethanol 1.1 17 10 4 0.41 35 MCZ-16 Wheat ethanol n.a. 17 13 2 0.24 MCZ-5 Rice air 0.7 17 10 7 0.41 MCZ-6 Rice ethanol 1.5 22 21 7 0.05 40 _______

Avicel 0.93 20 9 1 0.55

PH101 ill III

note: does not mean 1002493 - 10 -

Table 1 shows that microcrystalline starch dehydrated using ethanol imparts higher breaking strength to tablets, compared to corresponding microcrystalline starch dehydrated with air, without ethanol treatment.

Example 2

This example relates to microcrystalline starch produced by enzymes. As 10 starch-splitting enzymes, 2 commercial bacterial alpha-amylase enzyme preparations from NOVO Nordisk A / S (Bagsvaerd, Denmark), namely BAN 240 L and Maltogenese 4000 L (a maltogenic alpha-arnylase), were used.

1500 g of a starch in water suspension (36% by weight of starch) was placed in 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 dosed. Depending on the starch type, the reaction was carried out at a temperature of 58 ° C for 4 to 6 hours. Table 2 lists the reaction conditions.

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

1002493 - 11 - label 2

Application of enzymatically manufactured microcrystalline starches in tablets 5 I || B Brewing- Enzyme- Reac- Method Sped- Breaking strength Out- LSR I flour preparation tie-loose from peak (kg) a

Isooit (dosing duration carbon- dehydre- ------------------- fall- B% v / g As.) (Hours) hydrate wearing 0% 0, 5% time 10 I ____ (wt%) t n £ / g MS MS (min) __ fl I Rice BAN 240L 5 16.2 air 1.23 11 9 13 0.1S 1

(0.2) B

Rice BAN 240L 5 16.2 ethanol 1.66 17 14 1.5 0.18 K.

15 (0.2) [

Rice Maltogenase 5 123 ethanol n.a. 13 12 2 0.08 Π

1 (0.2) I

Maize BAN 240L 6 18.0 air 0.75 8 5 1 0.38 H

(0.2) U

Maize BAN 240L 6 18.0 ethanol 1.19 11 7 1 0.36 | (0.2) fl

Maize Maltogenase 6 n.a. ethanol n.a. 12 5 1 038 |

(0.2) I

Wheat BAN 240L 4 30 ethanol n.a. 11 7 1 0.36 Π

(0.25) || B

Table 2 shows that microcrystalline starch products, which have been dehydrated using ethanol, which have been dehydrated using ethanol, yield better tablets (with respect to breaking strength) compared to corresponding microcrystalline cereal starch products which are dehydrated by air treatment (without ethanol treatment).

1002493

Claims (7)

1. Microcrystalline starch 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 of the dehydrated starch product. Microcrystalline starch according to claim 1, wherein a grain starch is used as granular starch. Microcrystalline starch according to claim 1 or 2, characterized by a specific surface area of at least 10. m2 / g. 4. A process for preparing a microcrystalline starch, characterized in that granular starch in an aqueous suspension is treated with an acid and / or enzyme, the hydrated microcrystalline starch obtained is dehydrated by a water-miscible organic solvent, and the dehydrated starch product then dries. 5. A method for making tablets, characterized in that a microcrystalline starch according to claims 1-3 or prepared according to claim 4 is used as tableting aid. Tablets containing as a tableting excipient a microcrystalline starch according to claims 1-3 or prepared according to claim 4. Use of a microcrystalline starch according to claims 1-3 or prepared according to claim 4 as a tabletting aid. 1002493 REPORT ON NEWNESS RESEARCH OF INTERNATIONAL TYPE ΙΟΕΝΠΡΙΚΑΤ1Ε OF OE NATIONAL APPLICATION Characteristic of applicant ol van da gemmcnogo · _NW 9063__ NtMUnou application no. BA Date of the request for an examination of intamaaaiai type By ae tnsanse for Intemasonaat OnurzoeK (ISA) to the request for an investigation of interna na na ai type begeaend nr SN 27260 NL I. CLASSIFICATION OF THE SUBJECT (at The passing of versenilenoe classifications , specify all the dassificaoe symbols) According to the international aassihcaoe (IPC) Int. Cl. 6: C 08 B 30/12, C 12 P 19/14 _J II. UNRESERVED FIELDS OF TECHNIQUE. Untested minimum classification. Classification system I. Cl.6 C 08 B, C 12 P Unusual anoere aocumemaoe can ae mtnmum oocumeneoe insofar as such documents are included in the investigated sense III. ! i NO EXAMINATION FOR ANY PARTICULAR CONCLUSIONS (additions to supplemental additions) IV. LACK OF UNITY OF INVENTION (Notes or Supplementary)! = orm PCT / ïSAr'2D1 / a) CS * 95 «*