CN1198926A - Process for manufacturing hydropropyl cellulose powder with low substitution - Google Patents
Process for manufacturing hydropropyl cellulose powder with low substitution Download PDFInfo
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- CN1198926A CN1198926A CN 98107964 CN98107964A CN1198926A CN 1198926 A CN1198926 A CN 1198926A CN 98107964 CN98107964 CN 98107964 CN 98107964 A CN98107964 A CN 98107964A CN 1198926 A CN1198926 A CN 1198926A
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Abstract
The invention provides a process for producing a low substitution degree hydroxypropyl cellulose powder which is capable of easily removing impurities in production stages, is good in a pulverizing property at the of forming the powder and is good in the flow property of the powder obtained by pulverization. Alkaline cellulose contg. sodium hydroxide and propylene oxide are brought into reaction and the sodium hydroxide is at least partly neutralized with an acid. Next, the product after the neutralization is washed and is then dehydrated to obtain cake having a moisture content of 70 to 90 wt.%. The cake is pulverized after drying. The cake has a compression degree of <=42% and an angle of repose of <=48 deg..
Description
Background of invention
1. invention field
The present invention relates in pharmaceutical lozenge or granule the manufacture method of the hydropropyl cellulose powder with low substitution that adds as disintegrating agent, binding agent and excipient.
2. description of related art
The lozenge of pharmaceuticals or granule after administration because of wherein contained disintegrating agent generation swelling disintegrate.As disintegrating agent, can enumerate such as low degree of substitution hydroxypropyl cellulose, carboxymethyl cellulose and calcium salt thereof, starch and derivant thereof.Wherein, low degree of substitution hydroxypropyl cellulose is the nonionic disintegrating agent little with drug interaction.Low degree of substitution hydroxypropyl cellulose can be used as the pharmaceuticals additive and uses a thing, sees the record in the special public clear 57-53100 communique of special public clear 48-38858 communique of Japan and Japan for details.
Low degree of substitution hydroxypropyl cellulose can obtain by alkali cellulose and 1,2 epoxy prapane are reacted.When in and during the alkali that exists in the reaction product, if use usual way, for example, reaction product is dropped into method in the acidiferous hot water, then can produce following problem.That is, with the low degree of substitution hydroxypropyl cellulose that this method obtains,, be the cellulosic same, thereby washing performance is good with raw material paper pulp because substitution value is low, refining easily, but its reverse side is to pulverize difficulty, can not obtain the pulverizing product of good fluidity.
If it is poor to pulverize the flowability of product, then when when directly playing ingot legal system ingot, the lozenge deviation of weight increase of making ingot, and when using extruder grain manufactured granule, pelletize speed diminishes.
On the other hand, when the method put down in writing in the special public clear 57-53100 communique with Japan, the alkali that will in water, partly neutralize and use after etherification reaction finishes as catalyst, thus low degree of substitution hydroxypropyl cellulose is partly dissolved, with control cellulosic part.In the time of in this way, if remaining alkali number is many, then meltage increases and makes apparent density become big, flowability to improve.Yet if adopt this method, the granule that generates becomes hard, and the washing performance when removing impurity worsens, and not only needs with a large amount of washings, and can make the residual branch of heat-flash surpass specification value.
Summary of the invention
The present invention is for the shortcoming of eliminating above-mentioned prior art proposes, and aims to provide a kind of manufacture method of hydropropyl cellulose powder with low substitution that just can easily remove impurity, comminuted good when making powder and pulverize the good fluidity of the powder that obtains in manufacture process.
Manufacture method of the present invention, that the hydropropyl cellulose powder with low substitution of the following angle of repose of the degree of compression below 42% and 48 degree is arranged, it is characterized in that comprising and make the alkali cellulose and 1 that contains sodium hydroxide, the step of 2-propylene oxide reaction, this sodium hydroxide is used sour neutral step at least in part, dewater, obtain the step pulverized behind the step of filter cake of 70～90% (weight) moisture content and this filtration cakes torrefaction after the washing of product after this neutralization.
The manufacture method of hydropropyl cellulose powder with low substitution of the present invention just can easily be removed impurity in manufacturing process, and comminuted good when making powder.
In addition, the powder that obtains according to manufacture method of the present invention has the degree of compression and 48 below 42% to spend following angle of repose, and flowability is good.Therefore, allocate under the situation of directly beating in the ingot usefulness compositions, can obtain the little lozenge of deviation of weight, and under the situation in allocating the extruding granule into, pelletize speed increases, and has improved the production efficiency of granule at this powder.
The better detailed description of embodiment
Method of the present invention at first is to make alkali cellulose and the 1,2 epoxy prapane generation substitution reaction that contains sodium hydroxide.Alkali cellulose is by making lamellar paper pulp flood in sodium hydrate aqueous solution, squeeze, or the powder paper pulp in stirring sprays sodium hydroxide and obtains.Sodium hydroxide is that the catalyst as substitution reaction works.
The consumption of sodium hydroxide and cellulosic weight ratio are about 0.3～0.7.
The addition of 1,2 epoxy prapane during reaction is that cellulosic anhydrous glucose unit is about 0.2～1.0 mole for per 1 mole.
Reaction temperature is 40～80 ℃, and the response time is 1～5 hour.Reaction is carried out with pressure-resistant reaction vessel.
Then, with acid sodium hydroxide is completely or partially neutralized.As acid, can use acetic acid, hydrochloric acid etc.
In partly and the time; low degree of substitution hydroxypropyl cellulose is partly dissolved because of remaining sodium hydroxide; make the flowability when making powder subsequently become good; but its reverse side is partly can firmly associate, make washing to become difficult with the sour granule of separating out of measuring after a little while in the neutralization, thereby impurity content is increased.In partly and the time, increase by the dosis neutralisata that makes the initial stage in the full neutralization reaction, make the cellulosic that comes from raw cellulose remaining in a large number, the washing easily thereby product that neutralization reaction is obtained becomes also makes the moisture content of adjusting filter cake subsequently, the physical property of control powder etc. become easy.
In the part and the addition of acid under the situation be more than 20% (mole) of neutralization whole alkali needed acid.
The content of propoxyl is 5～16% (weight), better is 7～13% (weight) in the low degree of substitution hydroxypropyl cellulose that obtains.Because if less than 5% (weight), then the character of hydroxypropyl cellulose and raw cellulose is similar, and because if surpass 16% (weight), then the water solublity of hydroxypropyl cellulose increases, swelling ratio is reduced, and disintegrative is all insufficient being used under the situation of lozenge etc.
Then, the product washing back dehydration after the neutralization is adjusted to 70～90% (weight) to the moisture content of filter cake.
During the product washing, use 60～100 ℃ hot water usually.If 60 ℃ of the temperature deficiencies of hot water, then owing to low degree of substitution hydroxypropyl cellulose generation swelling, thereby washing becomes difficult.Usually, washing be the hydroxypropyl cellulose after the neutralization with hot water be made into 3～7% slurry, filter make filter cake after, from it spray hot water or be made into slurry once more, dehydration is carried out like this.
The moisture content of the low degree of substitution hydroxypropyl cellulose filter cake after the dehydration is adjusted to 70～90% (weight), better 75～85% (weight).If less than 70% (weight), then comminuted poor, and the degree of compression and the degree of resting in peace of powder is big after pulverizing, mobile poor.If surpass 90% (weight), then drying load is too big, thereby bad.
For moisture content being adjusted in this scope, can adjust the operating condition of dewaterer.For example, hanging down under the situation that subtracts the dehydration of agent machine, can adjust rotating speed or dewatering time with centrifugalize.Perhaps, make it to reach, can in mixer, add water and adjust moisture content than after the low moisture content of target moisture content.
Transfer at moisture content under the state of 70～90% (weight), better below 15 ℃ if temperature is reached below 20 ℃, then can carry out the hydration of low degree of substitution hydroxypropyl cellulose, thereby better.
As the method for putting down in writing in the special public clear 57-53100 communique of above-mentioned Japan, in order to improve liquidity, rely on remaining alkali to make the partly soluble method of low degree of substitution hydroxypropyl cellulose if adopt, the granule of then separating out firmly associates sometimes, makes Impurity removal become difficult sometimes, but according to method of the present invention, after washing finishes, flowability when making powder in order to improve there is no need to make the particle hardening of separating out, thereby can improve washing performance.
Then, pulverize behind the filtration cakes torrefaction.
Drying can adopt drying machines such as agitating type or box, carries out with usual way.
Pulverizing can adopt impingement pulverizers such as hammer mill to carry out.
According to the hydropropyl cellulose powder with low substitution that the manufacture method of the present invention of above explanation obtains, its degree of compression below 42%, angle of repose below 48 degree, flowability is good.Therefore, directly beat under the situation of ingot legal system ingot in usefulness, the good fluidity of gradation composition, the lozenge deviation of weight of system ingot is little, and is obtaining with the extruder grain method under the situation of granule, and pelletize speed increases.
Here, the degree of compression is calculated with { (closely knit apparent specific gravity)-(loose apparent specific gravity) }/this formula of (closely knit apparent specific gravity) * 100 (%), and it becomes the value of estimating powder flowbility with angle of repose.The degree of compression is worth more little, mobile just good more with angle of repose.
Closely knit apparent specific gravity, mean that sample is filled in certain container gently afterwards with the real-time apparent specific gravity of tup battering ram, be, to measure the sample weight of filling in 100 ml containers and calculate after 3 minutes with 50 compactings of per minute with powder test machine (thin river Micron corporate system).
Loose apparent specific gravity means to allow sieve vibration and proportion when making sample fall into certain container, calculates with the sample weight of filling in powder test machine (thin river Micron corporate system) mensuration 100 ml containers.
Angle of repose means that sample falls the bus of the circular cone of piling up on the plane and the angle of horizontal plane, is to use the powder test machine, and the height from 75mm on the discoideus platform of diameter 80mm flows out, and measures the powder piled up and the angle of platform and obtains.
The mean diameter of hydropropyl cellulose powder with low substitution normally 5～150 μ m, better be 40-100 μ m.Less than 5 μ m persons are mobile poor.If surpass 150 μ m, the anxiety of heterogeneity is arranged under the situation of hydroxypropyl cellulose and medicament mixed then.The cell size of sieve was adjusted when mean diameter can be sieved by suitable selection.
Hydropropyl cellulose powder with low substitution can be made granule by cooperating medicine, excipient, binding agent, coloring agent, lubricant etc. and carrying out pelletize.In addition, cooperated medicine etc. and made compositions person, both can also can after making the pelletize thing, play ingot, and make lozenge with its former state.
Example
Below describe embodiments of the invention in detail.
Embodiment 1～2
A) low degree of substitution hydroxypropyl cellulose is synthetic
Paper pulp floods the back squeezing in the sodium hydrate aqueous solution of 49% (weight), obtain containing the alkali cellulose of 24.2% (weight) sodium hydroxide.This alkali cellulose 100 weight portions join in the reaction machine, carry out nitrogen replacement.After the displacement, in the reaction machine, add 1,2 epoxy prapane 9.0 weight portions, while stirring 40 ℃ of reactions 1 hour, 50 ℃ of reactions 1 hour with 70 ℃ of reactions 1 hour, obtain reaction product 109 weight portions.
Hot water 2.5 weight portions and acetic acid 0.08 weight portion that in kneading machine, add 65 ℃, and to wherein disperseing reaction product 1 weight portion.Temperature is transferred to 30 ℃, make the dissolving of a part of reaction product after, add 0.25 weight portion acetic acid, make it to separate out.Precipitate with 90 ℃ of hot washes after, press dewatering is pulverized in ribbon blender, obtains the washing product of moisture content 65%.
Washing product is added in the ribbon blender, make ribbon blender while rotate Jia Shui, make moisture content reach 75% (sample No.1) or 85% (sample No.2), then drying.Dry product is with there being the high speed rotating impact grinder of 0.3mm screen cloth to pulverize near load current value, sieves with the sieve of cell size 75 μ m, obtains attritive powder.Calculate grindability from the percent of pass of charging rate to pulverizer and sieve.These values are listed in the table 1.When carrying out the substituent group analysis, the containing ratio of propoxyl is 10.7%.
B) rerum natura of low degree of substitution hydroxypropyl cellulose
With apparent specific gravity and the angle of repose of PD-T type powder test machine (thin river Micron corporate system) mensuration sample No.1 and sample No.2, in addition, with laser-bounce formula determinator HELOS﹠amp; RODOS (hot Paques B. V. system) measures mean diameter.The results are shown in Table 1 for it.
Table 1
| Embodiment 1 | Embodiment 2 | Comparative example 1 | ||
| Sample No. | ????1 | ????2 | ????3 | |
| Comminuted | Charging rate (kg/hr) | ????4.0 | ????4.3 | ????3.6 |
| 75 μ m sieve percent of pass (%) | ????77 | ????81 | ????70 | |
| Grindability (kg/hr) | ????3.1 | ????3.5 | ????2.5 | |
| Powder property | Mean diameter (μ m) | ????42 | ????37 | ????47 |
| Loose apparent specific gravity | ????0.38 | ????0.41 | ????0.31 | |
| Closely knit apparent specific gravity | ????0.64 | ????0.67 | ????0.56 | |
| The degree of compression (%) | ????40 | ????39 | ????45 | |
| Angle of repose (°) | ????46 | ????44 | ????50 | |
| Lozenge deviation of weight (%) | ????0.7 | ????0.5 | ????1.2 | |
| Granule pelletize speed (g/min) | ????150 | ????160 | ????110 | |
C) with directly playing ingot legal system ingot
With aspirin prilling powder (aspirin/corn starch=95/5) as base, with sample No.1 or sample No.2 is that 10 weight portions, aspirin prilling powder are that 90 weight portions, magnesium stearate are the match ratio of 0.5 weight portion, and the ingot compositions is directly beaten in preparation.
With RT-S15K-T35 (chrysanthemum water make institute corporate system), with rotating speed 30rpm, beat 0.6 ton of ingot pressure this direct ingot of beating is played ingot with compositions, obtain the lozenge of diameter 9mm, weight 300mg.Measure deviation of weight, hardness, the disintegration time of this lozenge.The results are shown in Table 1.
D) extruder grain
10 weight portion sample No.1 or sample No.2 and 90 weight portion Phenacetins mix with the Heng Saier mixer, after adding 52 weight parts waters again and mediating, with 5 inches cylinder extruders pelletize that 0.6mm aperture sieve plate is arranged.The results are shown in Table 1 for pelletize speed.
Comparative example 1
Except that moisture content being adjusted to the washing product of 75% (weight) or 85% (weight) moisture content 65% before with adding water among the embodiment 1～2, use with the same method of embodiment 1～2 and obtain attritive powder, with this as sample No.3.Its grindability is listed in the table 1.For the sample No.3 method same, carry out the physical property measurement of powder, directly beat ingot legal system ingot and extruder grain with embodiment 1～2.The results are shown in Table 1.
The low degree of substitution hydroxypropyl cellulose of embodiment 1,2 be comminuted (grindability: the crushing quantity of time per unit) excellent, the lozenge deviation of weight is little, granule pelletize speed is big.This is to make dry preceding moisture content be transferred to the above cause of 70% (weight).
Claims (1)
1. there is the degree of compression and 48 below 42% to spend the manufacture method of the hydropropyl cellulose powder with low substitution of following angle of repose, it is characterized in that comprising: make the alkali cellulose and 1 that contains sodium hydroxide, the step of 2-propylene oxide reaction, with acid with the neutral at least in part step of this sodium hydroxide, dewater, obtain after the washing of product after this neutralization 70～90% (weight) moisture content filter cake step and make the step of pulverizing behind this filtration cakes torrefaction.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11893997A JP3408398B2 (en) | 1997-05-09 | 1997-05-09 | Method for producing low substituted hydroxypropylcellulose powder |
| JP118939/1997 | 1997-05-09 | ||
| JP118939/97 | 1997-05-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1198926A true CN1198926A (en) | 1998-11-18 |
| CN1163213C CN1163213C (en) | 2004-08-25 |
Family
ID=14748978
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB981079644A Expired - Lifetime CN1163213C (en) | 1997-05-09 | 1998-05-08 | Process for manufacturing hydropropyl cellulose powder with low substitution |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP3408398B2 (en) |
| CN (1) | CN1163213C (en) |
| TW (1) | TW364849B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924609A (en) * | 2012-12-04 | 2013-02-13 | 新疆光大山河化工科技有限公司 | Method for producing low-substituted hydroxypropyl cellulose via fractional step method |
| CN107266592A (en) * | 2016-04-04 | 2017-10-20 | 信越化学工业株式会社 | The manufacture method of water-soluble nonionic cellulose ether powder with high-bulk-density |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8343547B2 (en) | 2006-08-08 | 2013-01-01 | Shin-Etsu Chemical Co., Ltd. | Solid dosage form comprising solid dispersion |
| US8343548B2 (en) | 2006-08-08 | 2013-01-01 | Shin-Etsu Chemical Co., Ltd. | Solid dosage form comprising solid dispersion |
| US8519120B2 (en) * | 2006-08-08 | 2013-08-27 | Shin-Etsu Chemical Co., Ltd. | Methods for producing a low-substituted hydroxypropylcellulose powder |
| EP3031451B1 (en) | 2009-01-26 | 2018-03-07 | Shin-Etsu Chemical Co., Ltd | Wet granulation tableting method using aqueous dispersion of low-substituted hydroxypropyl cellulose |
| JP5324302B2 (en) * | 2009-04-22 | 2013-10-23 | 信越化学工業株式会社 | High moldability, high fluidity, low substituted hydroxypropyl cellulose and solid preparation containing the same |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5163927A (en) * | 1974-11-28 | 1976-06-02 | Shinetsu Chemical Co | Ketsugoseiryokonajozaihokaizaino seizohoho |
| JP3534130B2 (en) * | 1994-03-01 | 2004-06-07 | 旭化成ケミカルズ株式会社 | Pharmaceutical composition |
| JPH08229103A (en) * | 1995-02-27 | 1996-09-10 | Shin Etsu Chem Co Ltd | Fluidizing method of low replaceability hydroxy propylcellulose and manufacture of solid preparation |
-
1997
- 1997-05-09 JP JP11893997A patent/JP3408398B2/en not_active Expired - Lifetime
-
1998
- 1998-05-06 TW TW087106990A patent/TW364849B/en not_active IP Right Cessation
- 1998-05-08 CN CNB981079644A patent/CN1163213C/en not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102924609A (en) * | 2012-12-04 | 2013-02-13 | 新疆光大山河化工科技有限公司 | Method for producing low-substituted hydroxypropyl cellulose via fractional step method |
| CN107266592A (en) * | 2016-04-04 | 2017-10-20 | 信越化学工业株式会社 | The manufacture method of water-soluble nonionic cellulose ether powder with high-bulk-density |
| US11299557B2 (en) | 2016-04-04 | 2022-04-12 | Shin-Etsu Chemical Co., Ltd. | Method for producing water-soluble nonionic cellulose ether powder having high bulk density |
| CN107266592B (en) * | 2016-04-04 | 2022-05-31 | 信越化学工业株式会社 | Process for producing water-soluble nonionic cellulose ether powder having high bulk density |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH10305084A (en) | 1998-11-17 |
| CN1163213C (en) | 2004-08-25 |
| TW364849B (en) | 1999-07-21 |
| JP3408398B2 (en) | 2003-05-19 |
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Granted publication date: 20040825 |