GB2172006A - Excipient composition - Google Patents

Abstract

Excipients for use in compression molding are prepared by dispersing cellulose powder and hydroxypropyl starch powder in an aqueous medium so as to provide a weight ratio in the range from 9:1 to 4:6, and then spray drying the dispersion. In a preferred embodiment, the excipients are prepared by dispersing the cellulose powder and hydroxypropyl starch powder in a 0.5 to 5% by weight aqueous solution of starch or of hydroxypropyl starch.

Description

SPECIFICATION Excipient useful in compression molding and process for preparing same This invention relates to excipients useful in compression molding and a process for preparing the excipients.

When powder or granules are to be molded by compression, there are instances where the main ingredients to be molded are too small in quantity for successful molding, or where the main ingredients are difficult to mold be compression. In these cases, it is common to first mix the main ingredient with an inert substance, called an excipient, which has good moldability. This technique is often practiced in the production of pharmaceuticals, veterinary drugs, agricultural chemicals, food products and cosmetics, and some other chemical products. Lactose, microcrystalline cellulose powder and and calcium hydrogen phosphate have been widely used as the excipient.

However, difficulties exist in using these substances. For example, lactose has advantages of low cost and chemical inertness and gives compression moldings of high hardness, but the moldings do not possess disintegrability. For pharmaceuticals, veterinary drugs and agricultural chemicals, it is frequently necessary for the molding to disintegrate in a relatively short time in water or in digestive juice. Moldings using lactose as the excipient, usualiy do not disintegrate or require a long time for disintegration and frequently cannot be put to practical use. In order to overcome the disadvantage, disintegrants, such as starch, calcium carboxymethylcellulose and low-substituted hydroxypropyl methylcellulose etc., must be added in appropriate proportions.

However, adding disintegrants is complicated, because a suitable combination has to be selected from vast number of possible combinations of main ingredients plus excipients plus disintegrants in various ratios. Conventionally, determination of the formulation including selection of the type and proportion of disintegrant has depended on many tests, conducted by trial and erro technique. This is costly and inefficient.

Microcrystalline cellulose powder has excellent properties as an excipient because it is chemically inert, and able to give moldings of relatively high hardness and good disintegration time. However, it has poor flowability which causes difficult handling. It cannot be poured smoothly into the mold. Moreover, microcrystalline cellulose powder is expensive.

Calcium hydrogen phosphate produces moldings with high hardness but it is an ionic substance which cannot be regarded as chemically inert. The means that the range of applications employing it is limited. In addition to this disadvantage, it gives moldings of poor disintegrability.

The aim of this invention is to provide an improved excipient.

The excipient of this invention may be prepared by dispersing proportions of cellulose powder and hydroxypropyl starch powder in an aqueous medium so as to provide a weight ratio in the range of from 9:1 to 4:6; and spray drying the obtained dispersion. This process can be carried out readily on an industrial scale.

The aqueous medium may be water or it may be an aqueous solution of starch or hydroxypropyl starch.

Hydroxypropyl starch powder used in this invention is well known as a filler for pharmaceutical tablet molding. It gives moldings having disintegrability but low strength. Therefore, hydroxypropyl starch by itself is inadequate as a molding excipient.

Cellulose powder used in the invention is well known as a filler in pharmaceutical tablet compression. It gives molds having strength. However, it has one disadvantage, in that it is lacking in flowability. Therefore, it is difficult to mix with other ingredients and difficult to pour into a mold. This eliminates its use in high speed, continuous tablet compression processes.

In accordance with the invention, hydroxypropyl starch and cellulose powder are combined to form a composite material which, unexpectedly, is free flowing, giving mouldings of high hardness and high disintegrability. The excipient is physiologically harmless, chemically inert and of low production cost. It is useful in high-speed automatictableting machine molding, for example.

Because of all these characteristics, the excipients of the invention can be used as an excellent excipient in the compression molding of active ingredients.

The hydroxypropyl starch powder used in this invention is advantageously the propylene glycol ether of starch containing from 1-8% by weight of hydroxypropoxyl groups. If the hydroxypropyl group content exceeds 8% by weight, it forms a paste in the presence of water, at room temperature, which makes it undesirable. The cellulose powder is advantageously commercially available pulverized pulp of such particle size that 90% of particles pass through a 250-mesh screen or higher. Microcrystalline cellulose powder also may be used.

The first step in carrying out the process of this invention is to disperse the above-described hydroxypropyl starch and the cellulose powders in the aqueous medium.

Thus, these powders may be dispersed in water in any order of mixing. If the two powders are dispersed independently in water, this can be followed by combining the two dispersions. Also, if these powders are formed first into a concentrated dispersion, this step may be followed by dilution with water. The most appropriate range of concentration of the solid components in the dispersion is normally within the range of 10-30% to achieve a smooth supply of the dispersion to the spray dryer, but no particular limitations exist. In addition, the apparatus used for dispersion can be selected from generally known equipment such as paddle-type or turbine-type high speed agitators.

Heating is not required for preparations of the dispersion. It is only essential to maintain the temperature of the mixture of hydroxypropyl starch and water below its glue-forming point. The temperature at which hydroxypropyi starch forms glue varies according to the content of hydroxypropyl groups. In general hydroxypropyl starch used herein forms a glue at about 50"C. Advantageously, therefore, the temperature should not rise above 30"C.

It is desirable to conduct continuous agitation of the dispersion obtained as described above to prevent sedimentation of the solid powder components, because if the dispersion is left to stand for 48 hours or longer, the powder forms a sediment layer with strong dilatancy.

In the next step, the dispersion is spray dried. Both a spray drier mounted by the spray nozzle and one mounted by a high speed rotary disc may be employed. However, the latter is recommended as it can be- used for dispersions with high solids content and the size of particles obtained is more suitable as an excipient. There is no particular limitation in the temperature of the air used for spray drying. Atemperature up to the levei of 400"C at the spray drier inlet does not cause any problems. It is inevitably desirable to decrease the outlet temperature for heat energy economy in order to reduce production costs. To achieve this, a well-known established technique involves controlling the outlet air temperature, by regulating the flow rate of the drying air.

Thus, the outlet temperature is advantageously controlled to 400C i 50C. Excessively high outlet temperature (over 100"C) may cause discoloration.

As described above, in accordance with the process of this invention, an excipient may be easily obtained on an industrial scale, which has high flowability and which imparts excellent hardness and disintegrability to compression molded products.

An advantageous embodiment ofthis invention comprises using an aqueous solution of starch or hydroxypropyl starch, instead of just water, as the aqueous medium in preparing the above-described dispersion. This changes the property of the dispersion from dilatancy to thixotropy which permits easy agitation, leading to stabilization of the dispersion and good effect on the product.

It is generally known that the addition of protective colloids to dispersions which have dilatancy will alleviate that condition and also impartthixotropy. It is also generally known that water-soluble high polymers can be added to an aqueous dispersion. We have found, however, that many water-soluble polymers such as polyvinyl alcohol, water-soluble cellulose derivatives (methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or combined derivatives thereof), hydroxypropyl starch or starch, can change the property of the dispersions ofthis invention from dilatancy to thixotropy. Polyvinyl alcohol and water-soluble cellulose derivatives are well known to tbe excellent binders for molding and are often used for binding purposes in wet granulation processes to make hard and strong granules.Contrary to this generally known fact, when these substances are used in a dispersion to make it thixotropic according to this invention, the resulting excipients give only very weak molds by compression. Only starch and hydroxypropyl starch gave excellent results.

This is an unusual phenomenon, the reason forwhich is not completely understood. However, it seems likely that the film strength of such polymers as polyvinyl alcohol and the water-soluble cellulose derivatives, is extremely strong and so these polymers impart toughness to the particles obtained on spray drying, leading to the phenomenon of a repulsive force against compression during the compression molding operation. In contrast, starch and its derivatives, which are remarkably weaker in film strength than polyvinyl alcohol and the water-soluble cellulose derivatives, can be considered as substances that do not prevent the production of a molded product with high hardness, because this repulsive force does not act.

The starch used in this embodiment of the invention can be corn starch, potato starch or sweet potato starch. Hydroxypropyl starch having a hydroxypropoxyl group content within the range of 1% to 25% by weight suitably may be used. The amount of the starch or hydroxypropyl starch to be used with the water employed as the dispersing medium is appropriately within the range of 0.5% to 5% by weight. This is because at concentrations below 0.5%, the dispersion lacks the capacity for conversion of dilatancy to thixotropy which means that the purpose of this embodiment cannot be achieved easily. In addition, at concentrations above 5%, the dispersion can adaquately convert to thixotropy, but the dispersion's viscosity increases remarkable, necessaitating excessive power for agitation and transportation.Furthermore, atomization of the dispersion into fine droplets in the spray dryer becomes difficult, and with their adhesion to the wall of the dryer, considerable loss cannot be avoided. Dissolving starch or hydroxypropyl starch in water can be achieved readily by using a well-known procedure of adding these substances to water and heating to a temperature equal to or above its glue forming temperature while performing agitation.

The cellulose and hydroxypropyl starch powders are dispersed in the aqueous solutions of starch or hydroxypropyl starch which has been obtained using this process, and this dispersion can be conducted in the same way as that described above for the case where the medium is water only.

The spray drying of the dispersion so obtained can also be performed in exactly the same way as that described for the embodiment where water is used as the dispersing medium. Naturally, sedimentation of the starch and hydroxypropyl starch powder in the dispersion is remarkably slower compared with those embodiments where water is used as the dispersing medium. In addition, this embodiment has the advantage that dilatancy does not occur, so that prevention of sedimentation by means of very gentle agitation is possible The spray dried products obtained in accordance with this invention posses good flowability, while the excellent and advantageous properties of each component are enhanced. The mixture obtained is thus extremely useful as an excipient for automatic continuous compression molding.

The invention is illustrated by the following Examples.

Where given, tablet hardness was determined using a Schreuniger hardness tester. Tablet disintegration times were determined in water at 25"C using the apparatus designated for that purpose in the Japanese Pharmacopoeia, X.

The Angle of repose: Where reported, the angle of repose of a composition is determined by measurement of the angle made between the surface of the loose, granular or powdery composition and the horizontal after rotation for 2 minutes at 2 r.p.m. in the glass vessel of a Miwa's Rotary Cylinder Type Repose Angle Tester.

Example 1 5.5 kgs of hydroxypropyl starch powder having 2.98% by weight of hydroxypropoxyl groups and a loss on drying of 13.8% (HPS-101 by Freund Industrial Co., Ltd.) and 5.5 kgs of cellulose powder (KC FlocW-300 by Sanyo Kokusaku Pulp Co., Ltd.; minimum 90% passes through a 300-mesh screen) are added in small portions to 28.5 kgs of water while vigorously agitating the mixture. An aqueous dispersion with a 25.2% solids content is obtained. The dispersion is spray dried to obtain a white, free flowing powder. Loss on drying of the product is 4.0%.

The condition settings for the rotary disc type spray dryer used are shown in Table 1, below.

Table 1 Feed speed of dispersion 16.7 kgs/hr.

Speed of disc rotation 20,000 r.p.m.

Hot air flow rate 5.0 Nm3/min.

Temperature of hot air inlet 350"C Temperature of hot air outlet 50"C Operation time 2 hrs. 20 min.

Amount of powdered product obtained 9.8 kgs The flowability of the powder obtained in this example is good. As criterion for this flowability evaluation, measurements of the angle of repose are made and compared to the angle of repose measured on the starting materials (hydroxypropyl starch and cellulose powder) and also compared with the angle of repose of a product obtained by simple mechanical mixing of the same hydroxypropyl starch and cellulose powder in the same proportions given above in this example (control).

The comparative test results are given in Table 2 below.

Table2 Test Material Angle of Response Hydroxypropyl starch 8590" Cellulose powder 7580" Product of this invention (Example 1) 35 Mechanical mixture of hydroxypropyl starch and cellulose powder (control) 75 -80 Where the angle of repose is less than 45" the material has very good flowability. Where the angle is between 4555", the flowability of the powder is less satisfactory, while within the range of 5575", flowability is almost lacking. At 75" or above, flowability is completely lacking.

Next the test materials described in Table 2, above are molded by compression using a rotary tableting machine. The results are shown in Table 3, below.

Table3 Test Material Molding Hardness of Disintegration Character the molded time for the product molded product Hydroxypropyl Smooth starch handling not possible Cellulose Rough to Too weakfor powder mold measurement Product of Molded well 8.1 kgs 40 seconds this invention (Example 1) Mechanical Rough to mold 4.2 kgs 63 seconds mixture of with yield of hydroxypropyl only 25% starch and cellulose powder (control) The product of this invention prepared in Example 1 showed exceptionally good performance in every test item, as shown in Table 3, above.

Example 2 0.5 kg hydroxypropyl starch having 2.98% by weight of hydroxypropoxyl groups and a loss on drying of 13.8% (HPS-101 by Freund Industrial Co., Ltd.), is added to 24.5 kgs of water. The temperature of the mixture is raised to 85"-90"C while agitating and maintained at that temperature for 5 minutes to produce a solution.

Afurther 25 kgs of water is added and the resulting solution cooled to room temperature. As a result, 49.5 kgs of 0.87% hydroxypropyl starch solution is obtained. To 11.52 kgs of this solution there is added 2.24 kgs of hydroxypropyl starch having 2.98% by weight of hydroxypropoxyl groups and a loss on drying of 13.8% (HPS-101 by Freund Industrial Co., Ltd.) and 2.24 kgs of powder pulp (KC Floc w-300 by Sanyo Kokusaku Pulp Manufacturing Co., Ltd.; minimum 90% passes through 300 mesh screen, loss on drying 5.0%).

The mixture is agitated to produce 16.0 kgs of a dispersion containing 26.0% solids. The dispersion is then spray dried under the same conditions given in Table 4, below, employing the rotary disc type of spray dryer used in Example 1, supra. The spray dried product is a free-flowing powder, showing a loss on drying of 4.8%.

Table4 Feed speed of dispersion 21.4 kgs/hr.

Speed of disc rotation 20,000 r.p.m.

Hot air flow rate 5.8 Nm3/min.

Temperature of hot air inlet 345"C Temperature of hot air outlet 53"C Operation time 40 minutes Amount of powdered product obtained 3.5 kgs The flowability of the powder obtained in this Example 2 is good. The angle of repose of the product is 33 .

The powder product obtained and also the same powder mixed with lactose powder is molded by compression using a rotary type tableting machine. The tablet results obtained are shown in Table 5, below.

TableS Test Material Molding Hardness of Disintegration Character the molded time for the product molded product Product of Smoothly 8.0 kgs 40 seconds this example molded Mixture of the Smoothly 11.3 kgs 55 seconds product of molded this example with lactose powder* (in the ratio of 1:1 by weight) *Lactose powder is produced by DMV of Holland, minimum of 95% passes through a 100-micron screen.

Both the product powder and the mixture of the product and lactose powder showed good tablet properties. The mixture with no-disintegrable lactose underwent rapid disintegration.

Example 3 This Example is not an Example of the invention, but is made for comparative purposes.

The procedure df Example 2, supra., is repeated, except that a 0.2% aqueous solution of hydroxypropyl cellulose is used instead of the 0.87% aqueous solution of hydroxypropyl starch used in Example 2. A powder was produced, with an angle of repose of 379 The product's flowability is good. However, when the powder is molded into tablets using a rotary tableting machine, the tablets obtained give a hardness of only 1.2 kg, indicating poor strength.

Example 4 To 12.52 kgs of a 1.2% aqueous hydroxypropyl starch solution, there is added 1.34 kg of hydroxypropyl starch (having 5.88% by weight of hydroxypropoxyl groups; 11.5% loss on drying; HPS-1 Ol by Freund Industrial Co., Ltd.) and 3.14 kgs of cellulose powder (KC-Floc W-250 by Sanyo Kokusaku Pulp Manufacturing Co., Ltd.; minimum 90% passes through 250 mesh screen, loss on drying 3.8%). The mixture is agitated to form a dispersion. The dispersion obtained is then spray dried in a rotary disc spray dryer under the conditions shown in Table 6, below. Afree4lowing powder is obtained, having a loss on drying of 3.8%.

Table6 Feed speed of dispersion 21.4 kgs/hr.

Speed of disc rotation 20,000 r.p.m.

Hot air flow rate 5.8 Nm2/min.

Temperature of hot air inlet 348"C Temperature of hot air outlet 51"C Operation time 40 minutes Amount of powdered product obtained 2.6 kgs Both the powder obtained and a 1:1 by weight mixture of this powder with lactose powder (DMV, supra.) is molded by compression using a rotary tableting machine. Molding proceeds smoothly and the table results obtained are shown in Table 7, below.

Table 7 Test Material Table Tablet Disintegration Hardness Time Powder Product of 8.2 kgs 44 seconds this Example 4 Mixtureofthe 12.1 kgs 63 seconds product of this example with lactose powder (1:1) Example 5 A 0.82% aqueous solution of corn starch is produced by dissolving corn starch in hot water to 12.50 kgs of this solution there is added 0.71 kg of hydroxypropyl starch, having 4.63% by weight of hydroxypropoxyl groups and a 12.4% loss on drying (HPS-101 by Freund Industrial Co., Ltd.), and 2.82 kgs of powder pulp (KC-Floc W-300 bySanyo-Kokusaku Pulp Manufacturing Co., Ltd., minimum 90% passes through 300 mesh screen, 4.2% loss on drying) the mixture is agitated to form a dispersion. The-dispersion thus prepared is spray dried in a rotary disc type spray dryer under the conditions given in Table 8, below. A free-flowing powder is obtained having a loss on drying of 4.5%.

Table8 Feed speed of dispersion 21.4kgs/hr.

Speed-of disc rotation 20,000 r.p.m.

Hot air flow rate 5.8 Nm3/min.

Temperature of hot air inlet 348"C Temperature of hot air outlet 51"C Operation time 40 minutes Amount of powdered product obtained 2.8 kgs The powder obtained has extremely good flowability with an angle of repose of 45 . When the powder is molded by compression using a rotary tableting machine, the molding is smooth and the tablet test results are given in Table 9, below.

Table9 Test Material Table Hardness Tablet Disintegration Time Product of this 8.3 kgs 40 seconds Example 5

Claims (7)

1. A process for the preparation of an excipient useful in compression molding, which comprises dispersing cellulose powder and hydroxypropyl starch powder in an aqueous medium in a weight ratio of the cellulose to hydroxypropyl starch powder in the range of from 9:1 to 4:6, and spray drying the obtained dispersion.

2. A process according to Claim 1, wherein the aqueous medium is water.

3. A process according to Claim 1, wherein the aqueous medium is a 0.5 to 5% weight aqueous solution of starch or of hydroxypropyl starch.

4. A process according to any preceding Claim, wherein the hydroxypropyl starch powder has a content of hydroxypropyl groups of from 1-8% by weight.

5. A process according to any preceding Claim, wherein the dispersion which is spray dried has a solids content of from 10-30%.

6. A process for the preparation of an excipient, substantially as described in any one of the Examples herein.

7. An excipient useful in compression molding and comprising a spray-dried mixture of cellulose powder and hydroxypropyl starch powder in a weight ratio in the range of from 9:1 to 4:6.