CELLULOSE ETHERS FOR SOLIDS FORMULATIONS

The present invention relates to a novel process for preparing cellulose ethers which have a particularly low proportion of fine dust and a compressibility which is particularly advantageous for the pressing of tablets.

The controlled release of active compounds from tablet formulations has been known in principle for a long time and encompasses various liberation profiles. These include an immediate release, a delayed release or a controlled release of the respective active compound by means of matrix formulations and/or coatings.

To prevent liberation of the active compound in the stomach and to effect targeted release in the intestine, enteric coatings, for example, are used. For this purpose, it is possible to utilize, for example, hydroxypropylmethylcellulose mixed with ethylcellulose (US 2,887,440).

Liberation distributed over time is referred to as "sustained release" or "controlled release". To provide such liberation characteristics from tablet formulations, various approaches based on cellulose ethers have been pursued in the past:

Thus, the use of carboxymethylcellulose or hydroxypropylmethylcellulose (HPMC) was proposed as early as 1962 in US 3,065,143. On contact with water, these formulations form a gel barrier which prevents spontaneous liberation of the active compound and effects liberation of the active compound over a period of at least 4 hours.

US 3,870,790 discloses HPMC, if appropriate in mixtures with ethylcellulose, with the HPMC being moistened under controlled conditions in thin layers over a period of more than 24 hours before use. Liberation is influenced both by the degree of moistening and by the pressing pressure in the tableting step.

US 4,226,849 describes sustained release formulations based on HPMC which has previously been subjected to a hydrolysis and oxidation step.

US 4,369,172 discloses the use of low-viscosity HPMC having a hydroxypropoxyl content of from 9 to 12% and a molecular weight of less than 50 000 g/mol in order to achieve sustained release characteristics.

EP-A 0 223 590 discloses the use of finely divided hydroxypropylcellulose and its optional mixing with HPMC in sustained release tablet formulations. Here, the fineness of the HPMC is not described as critical to the liberation. The finely divided HPC is, for example, obtained by milling of coarser HPC in a ball mill.

US 2005/0260267 discloses the use of HPMC having a bimodal or multimodal molecular weight distribution for the purpose mentioned at the outset.

However, the abovementioned approaches based on cellulose ethers for providing tablet formulations having a sustained release character suffer from disadvantages. Thus, in tablet production there are relatively distinct quality fluctuations of the cellulose ethers which result, inter alia, in sustained release behavior which is not uniformly satisfactory.

In addition, the known finely divided cellulose ethers of the Methocel grades from DOW and Metolose grades from ShinEtsu have, at satisfactory compressibility, relatively high proportions of dust which are undesirable for reasons of workplace contamination and occupational hygiene.

The production processes described in EP-A 1 127 910, US 6,509,461 ,

US 6,872,820 make it possible to obtain, for example, methylhydroxyethylcelluloses (MHEC) having small proportions of dust. However, these have a low compressibility and are therefore unsuitable as matrix material for sustained release tablets.

For the milling and drying of moist cellulose ethers, EP-A 0 370 447 describes a process which is based on simultaneous impact and frictional comminution and has the objective of largely preventing a decrease in viscosity during comminution.

EP-A 0 835 882 describes a further development of this process with the objective of effecting a further decrease in the proportion of oversize particles. This is achieved by an altered flow of air in the mill. However, the documents do not reveal the extent to which such finely divided cellulose ethers can be produced with low proportions of dust and good compressibility as are desirable for the production of sustained release formulations in the form of tablets.

GB 2 262 527 describes a process for the drying and milling of cellulose ethers after gelling, but unfortunately the cellulose ethers described there do not have the desirable high compressibility. The comparative products without gelling before drying and milling described in GB 2 262 527 do give a high compressibility but have a low bulk density which is unsuitable for industrial use.

It was an object of the present invention to provide cellulose ether particles which are suitable for the industrial production of sustained release formulations and do not have the abovementioned disadvantages of the prior art, e.g. high proportions of dust and/or unsatisfactory compressibility, and also have bulk densities of at least 280 g/l.

This object has now been achieved by the process described below and the cellulose ether particles obtainable by the process.

The present invention provides a process for producing cellulose ether particles, which comprises comminuting and drying a cellulose ether which is moist with water and/or alcohol and has a moisture content of from 20 to 50% by weight in a mill, wherein this mill comprises a concentrically arranged beater wheel provided with a plurality of beater blades and a screen basket arranged concentrically with the beater wheel and in addition the circumferential velocity of the beater wheel is from 90 to 140 m/s and the circumferential velocity of the screen basket is from 30 to 60 m/s.

The relative velocity of beater wheel and screen basket is thus at least 120 m/s.

The invention further provides the cellulose ethers which can be obtained in this way themselves.

Such an apparatus for the comminution and drying of cellulose ethers has been described in principle in EP-A 0 370 447 or EP-A 0 835 882. However, it has been found according to the present invention that the ratio of impact comminution to frictional comminution which can be achieved by means of a high circumferential velocity of the beater wheel and a high relative velocity of beater wheel and screen basket is critical for achieving high compressibilities together with satisfactorally high bulk densities of the product. It is particularly advantageous for both the circumferential velocities and also the cross-sectional area of the perforations of the friction plates to be particularly high, i.e. for the friction plates to have, in a longitudinal direction, an opening of at least 2 mm and a gap width of at least 2 mm.

In such an apparatus to be used according to the invention, the beater wheel and screen basket are typically located in a housing having a side inlet opening for coaxial introduction of the material to be milled and the transport gas and also a discharge opening for the milled and dried material and the transport gas. To introduce a further gas stream which flows through the space between screen basket and housing, a further opening can be installed tangentially on the housing.

Meaning of the numbers in figures 1 to 3:

1. housing

2. beater wheel

3. beater blades

4. friction plates

5. sawtooth segment

6. tooth projections

7. shaft of beater wheel

8. shaft of screen basket

9. discharge opening

Furthermore, an inlet opening for introduction of the feed and for introduction of the transport gas is present in the housing axially to the shaft of the beater wheel in the interior of the screen basket (not drawn in separately in the figures).

The screen basket has, in successive sections around the circumference, sawtooth segments (5) and friction plates (4) provided with openings. The beater wheel and the screen basket are driven in a contrarotating fashion by means of shafts.

The moisture content with respect to water and/or alcohol of the cellulose ether used as feed in the process of the invention is preferably from 35 to 48% by weight.

However, moisture contents of the feed of less than 20% by weight based on the total weight are undesirable in the process of the invention since excessively high temperatures are then obtained in the region of the mill and undesirably low residual moisture contents are obtained in the milled and dried end product.

As cellulose ether, preference is given to using methylcellulose (MC) having a methoxyl content of from 15 to 40% and also mixed derivatives thereof, e.g. hydroxyethylmethylcellulose (HEMC) and hydroxypropylmethylcellulose (HPMC), in the process of the invention.

The determination of the chemical etherification of the cellulose ethers is carried out in accordance with USP 29 (United States Pharmacopeia 29, The United States Pharmacopeial Convention, meeting at Washington, D. C March 9 - 13, 2005).

The HPMC here has a degree of substitution corresponding to a methoxyl content of from 15 to 40%, preferably from 17% to 30%, particularly preferably from 19% to 24%, and a hydroxypropoxyl content of from 4 to 12%. The hydroxypropoxyl content of the HPMC is preferably from 6 to 9%, particularly preferably from 6.5 to 8.5%, very particularly preferably from 7.0 to 8.0%.

The viscosity of these cellulose ethers can be varied within a wide range and is typically from 1 to 500 000 cps as 2% by weight solution in water measured using an Ubbelohde viscometer at 20 ⁰ C.

Such cellulose ethers can be obtained by processes known per se from the prior art in which a raw cellulose is alkalized, etherified and subsequently washed and finally subjected to milling with drying. The viscosity of such grades is typically from 1000 to 150 000 cps at 20°C. Viscosities of 400 cps and below are, for example, possible by means of acid-hydrolytic degradation by means of HCI.

After the etherification reaction, the crude product is, if appropriate, washed a number of times with hot water and separated from the washing solution by means of a separation apparatus corresponding to the prior art. Possible separation apparatuses are, for example, continuously operating belt filters or rotary pressure filters.

Such a cellulose ether obtained in the form of a filter cake normally has a residual moisture content based on water and/or alcohol of ≥ 50% by weight. To separate off moisture, it is then dewatered, for example by means of a mechanical press or a gas stream, to a residual moisture content of < 50% by weight. The gas stream can be, for example, compressed air or steam. This after-treatment can be carried out either on apparatuses downstream of the filtration apparatus or on the filtration apparatus itself.

A moist cellulose ether which can generally be obtained in this way as filter cake preferably has a moisture content of from 35 to 50% by weight, particularly preferably from 40 to 48% by weight, and can be used directly in the process of the invention for producing the finely divided cellulose ether having a low proportion of dust and a high compressibility.

If the moisture content of the filter cake is undesirably low, it can be adjusted to the desired value by addition of water in order to produce the feed. To avoid

undesirable gelling, hot water, preferably in the temperature range from 60 to 90 ⁰ C, can be used for this purpose.

To adjust the moisture content of the cellulose ether as feed, it can also be mixed with a cellulose ether having a lower moisture content, with the ratio of the two cellulose ethers being selected so that the resulting feed then preferably has a from 3 to 12% by weight, particularly preferably from 4 to 9% by weight, lower moisture content.

To effect the abovementioned reduction in the moisture content, it is possible to use a cellulose ether which has already been milled and dried, which can be either coarse or finely divided. As coarse fraction, preference is given to using the cellulose ether obtained in a sieving step following the milling and drying step. The particle size of the coarse fraction is from about 150 to 500 μm.

Possible mixing apparatuses are continuously or discontinuously operating mixers having a horizontal or vertical shaft. Preference is given to using mixing tools of the plowshare or scoop type; screw mixers or ribbon mixers can likewise be used.

During washing, filtration, dewatering and the discontinuous or continuous production of the feed, gelling caused by excessive shearing or cooling or shearing and cooling has to be avoided at all costs. The mixing apparatuses following washing should therefore be heatable or insulated.

Predrying and/or precomminution before the milling and drying step is possible and can be carried out by means of apparatuses according to the prior art. For example, introduction into the mill can be effected by means of a transport gas which is preheated. Depending on the distance from introduction of feed into the gas stream to introduction into the mill, it is possible to realize, for example, flow drying in this way. Precomminution can be carried out using, for example, crossbeater mills or hammer mills.

Furthermore, additional drying within the mill can be realized by the introduction of an additional preheated gas stream which does not transport feed to be milled into the mill.

Control of the temperature of the mill, either heating or cooling, is likewise conceivable.

The transport gas conveys the milled material into a separation device, e.g. a filter or cyclone separator or a combination of the two.

The circumferential velocity of the beater wheel is preferably from 90 to 130 m/s, particularly preferably from 95 to 120 m/s.

The circumferential velocity of the screen basket is preferably from 33 to 55 m/s, particularly preferably from 35 to 50 m/s.

The screen basket is a drum-like device whose circumference is formed by successive sawtooth segments (5) and friction plates (4) provided with openings (fig. 1 ). These friction plates preferably have oblique punchings so as to form tooth projections (6) on one side (pointing outward or inward) (fig. 2). The punchings form isosceles trapezoidal to hemielliptical (rounded isosceles trapezoid) openings. The longitudinal direction corresponds to the height of the trapezoid, while the gap width corresponds to the base of the trapezoid. The punchings preferably have an opening of from 2 to 8 mm in the longitudinal direction and a gap width of from 2 to 8 mm. The punchings particularly preferably have an opening of from 2.5 to 6 mm in the longitudinal direction and a gap width of from 2.5 to 6 mm.

Preference is given to the same number of sawtooth segments and friction plates, particularly preferably 4 sawtooth segments and 4 friction plates or 6 sawtooth segments and 6 friction plates, forming the circumference of the screen basket.

A mixed provision of friction plates which have different sizes of the punchings is possible. In the case of 4 friction plates, 2 of the friction plates in this case have

punchings having an opening of from 3 to 6 mm in the longitudinal direction and a gap width of from 3 to 6 mm. In the case of 6 friction plates, 2 or 3 of the friction plates in this case have punchings having an opening of from 3 to 6 mm in the longitudinal direction and a gap width of from 3 to 6 mm. The friction plates are then distributed symmetrically around the circumference of the screen basket, with each friction plate being followed by a sawtooth segment.

The saw teeth of the sawtooth segments have a height of from 1 to 10 mm, preferably from 2 to 5 mm.

The spacing between beater wheel (upper edge of beater blades) and screen basket (upper edge of tooth of friction plate or tooth of sawtooth segment) is from 1 to 12 mm, preferably from 1.5 to 8 mm, most preferably from 2.0 to 6 mm.

The screen basket generally has a diameter of from 800 to 1600 mm and a width of from 100 to 700 mm.

The milled and dried, pulverulent product obtained by the process of the invention is then preferably sieved to reduce the proportions of particles of > 140 μm, preferably > 180 μm (coarse fraction). The coarse fractions separated off in this way can be recirculated to the mill and/or to the filter cake for producing the feed. Sieves used for the separation have mesh openings of from 140 to 400 μm, preferably from 160 to 250 μm, particularly preferably from 180 to 220 μm.

The cellulose ether particles obtained by this process have a particularly low proportion of fine dust and a compressibility which is particularly advantageous for tablet pressing and at the same time have a satisfactory bulk density immediately after production even without downstream classification steps.

The cellulose ether particles are characterized using a laser light scattering method (instruments HELOS with powder dispersion RODOS from Sympatec). The particle size distribution of the collection of cellulose ether particles is calculated here from the intensity distribution of the scattered light. The evaluation is carried out

according to the Fraunhofer theory assuming a shape factor of 1. The result obtained is a laser light scattering particle diameter. Average volume diameters are measured and the resulting particle size distribution is a distribution in percent by volume (% by volume).

The invention further provides the cellulose ether particles which can be obtained in this way and have a proportion of particles smaller than 180 μm of at least 80% and a proportion of dust particles smaller than 15.5 μm of not more than 4%, in each case determined by means of laser light scattering, and a compressibility of the cellulose ether particles according to Test F in accordance with ASTM D6393-99 "Carr Compressibility" of at least 29%.

The particles preferably have a compressibility of from 30 to 50%, particularly preferably from 31 to 43% and very particularly preferably from 32 to 39%.

The compressibility can, for example, be determined by means of the "Powder Tester" from Hosokawa Micron Ltd, Runcorn, Cheshire, UK.

The cellulose ether particles which can be obtained by the process of the invention preferably have the abovementioned fineness, with at the same time the proportion of particles smaller than 90 μm determined by means of laser light scattering being at least 50%. In addition, the proportion of particles smaller than 45 μm is particularly preferably at least 25%.

In addition to the abovementioned proportion of dust particles smaller than 15.5 μm, the proportion of particles smaller than 5.5 μm is preferably not more than 2%, particularly preferably not more than 1 %.

The bulk density of the products is at least 280 g/l, preferably from 280 to 600 g/l, particularly preferably from 290 to 500 g/l, very particularly preferably from 300 to

450 g/l.

The moisture contents of the products, based on water and/or alcohol content, are typically from 1 to 10% by weight, preferably from 2 to 7% by weight, particularly preferably from 2.5 to 5% by weight.

The cellulose ethers of the invention are highly suitable as additive or binder in solids formulations, especially in solids formulations of the pharmaceutical industry, the food supplements and food industry and the feedstuff or agrochemical industry.

The cellulose ethers of the invention are preferably used in solids formulations which are subsequently brought into a defined shape by means of mechanical processes or thermal and mechanical processes. In particular, such solids formulations are brought into tablet form by pressing.

The solids formulations are either pressed directly or, if appropriate, compacted, e.g. by rolling, or granulated, e.g. with addition of polymeric granulation aids such as HPMC, hydroxypropylcellulose or polyvinylpyrrolidone dissolved in solvents before the actual pressing step to produce the tablet.

The cellulose ethers of the invention are preferably used to alter the release behavior of substances such as pharmaceutical active compounds, crop protection agents, fragrances and flavors, vitamins, minerals, trace elements. In particular, sustained release of these substances should be effected.

Examples

The viscosities reported below for the products correspond, unless indicated otherwise, to the product designation according to United States Pharmacopeia 29, The United States Pharmacopeial Convention, meeting at Washington, D. C March 9 - 13; 2005 (USP 29).

The viscosities of the cellulose ethers used were measured on 2% by weight solutions in water using an Ubbelohde viscometer at 20 ⁰ C.

The particle fractions were determined by means of laser light scattering using a HELOS instrument from Sympatec. Dispersion was carried out by means of the RODOS dispersing section from Sympatec. The light scattering pattern is evaluated according to the Fraunhofer theory. The result obtained is a laser light scattering particle diameter. Average volume diameters are measured and the resulting distribution is a volume distribution.

The compressibility of the cellulose ether particles was determined by Test F in accordance with ASTM D6393-99 "Carr Compressibility". The number of "Taps" was in each case 180.

The HPMC used in the experiments was prepared by processes of the prior art by etherification of cellulose. Processes for the etherification of cellulose are described, for example, in EP-A 1 180 526, EP-A 1 279 680 and EP-A 1 589 035 and the references cited therein.

The subsequent washing of the HPMC obtained by etherification of cellulose was likewise carried out according to the prior art.

In the experiments, an HPMC of the substitution type 2910 was used as filter cake moist with water. To set the moisture content required according to the invention, this filter cake was mixed either with HPMC having a lower moisture content (e.g.

the coarse fraction separated off in sieving of the product) or with water. The milling and drying apparatus was operated using the following parameters:

Circumferential velocity of beater wheel: 94 m/s

Number of beater blades at the circumference of the beater wheel: 90

Circumferential velocity of screen basket: 33.5 m/s

Friction plates: 2χ 4.0 mm and 2χ 5.0 mm

Sawtooth segments: 4χ 2.5 mm

Spacing between beater wheel and screen basket: 2.0 mm

The product was sieved through a 220 μm sieve.

The moisture contents of the product were from 1.5 to 3.5% by weight based on the total mass. As example C5 shows, a moisture 5 content of the feed which is too high leads to unsatisfactory compressibilities.

The following table summarizes the results of a milling with drying of HPMC of the substitution type 2208 carried out analogously on the same apparatus. As a change from the above-described configuration, the following equipment was selected here: friction plates: 2χ 2.5

The moisture contents of the product were from 2.0 to 4.0% by weight based on the total mass.

Example 11

For comparison, an HPMC having a methoxy content of 22.3% and a hydroxypropoxy content of 9.2% and a viscosity of 4000 cps was milled and dried by the same process at a feed moisture content of 60% by weight and 55% by weight. The products had moisture contents of 27.2 and 28.6% by weight, respectively, and did not display satisfactory compressibilities.

Example 12

For comparison, an HPMC having a methoxy content of 22.7%, a hydroxypropoxy content of 6.0% and a viscosity of 4000 cps was milled and dried by the same process at a feed moisture content of 45% by weight, but the circumferential velocities of beater wheel and screen basket were changed:

Circumferential velocity of beater wheel: 83 m/s

Circumferential velocity of screen basket: 31 m/s

Friction plates having openings having a gap width of 2.5 mm were used.

The product obtained was an HPMC having the texture of absorbent cotton and an unsatisfactory bulk density of only 220 g/l and a compressibility of 36.2%.

Example 13

The same HPMC as in example 11 in the form of a filter cake having a moisture content of 48% by weight was milled and dried on a screenless mill of the UltraRotor type in accordance with the method of GB 2 262 527 but without gelling of the material to be milled. The product obtained was an HPMC having the texture of absorbent cotton and an unsatisfactory bulk density of only 210 g/l and a compressibility of 41.0%.

Example 14

In a further comparative experiment, the same HPMC was gelled according to the process of GB 2 262 527 and milled and dried on a screenless mill of the UltraRotor type. The product had a satisfactory bulk density of 395 g/l but displayed a compressibility of only 23.1 %.

The following listing shows that commercial cellulose ethers have a comparatively high proportion of fine dust at particle sizes of < 5.5 μm or < 15.5 μm.

The commercial products Methocel® and Metolose® are trademarks of DOW Chemical Company or Shin Etsu Chemical Company.

In contrast, the following commercial Walocel® products (Wolff Cellulosics GmbH & Co. KG, Walsrode, Germany) have a remarkably low proportion of fine dust and acceptable bulk densities, but the compressibility is not satisfactory.

To evaluate tableting, powder mixtures were pressed by the direct tableting method to give round tablets having a diameter of 12 mm (highly convex) on a rotary tableting press at a pressing force of 25 kN.

Composition of powder mixture in parts by weight:

The HPMCs were of the type 2208 having a viscosity of 4000 cps and were distinguished by different compressibilities, particle size distribution curves, fine dust contents and bulk densities:

* In the case of the commercial cellulose ethers, weighing out, mixing and tableting resulted in increased pollution of the surrounding air with corresponding effects on employees and increased coating of the machines by fine HPMC dust.