FIELD

The present specification is directed to a process for producing microcrystalline cellulose having a reduced content of nitrite salts.

BACKGROUND

Microcrystalline cellulose, commonly referred to as “MCC”, is widely used in the food and pharmaceutical industry to enhance the properties or attributes of final products. Applications of MCC include, for example, as a binder or stabilizer in beverages, as a binder or disintegrant in pharmaceutical tablets, as a suspending agent in liquid pharmaceutical formulations, as a binder, disintegrant or processing aid in industrial applications, in household products such as detergents or bleaches, in agricultural formulations, or in personal care products such as dentifrices or cosmetics.

Microcrystalline cellulose is typically produced by hydrolyzing cellulosic materials, obtained from fibrous plant materials, preferably with a high alpha content, with mineral acids, preferably hydrochloric acid (acidic hydrolysis). The mineral acid preferentially attacks the amorphous regions of the cellulosic material, thereby exposing, freeing and leaving behind the paracrystalline regions, which form crystalline aggregates constituting microcrystalline cellulose. The aggregated crystalline mass is then separated from the reaction mixture and washed to remove degraded by-products. The resulting wet mass typically contains 40% to 60% moisture and is generally referred to by people skilled in the art as ‘hydrolyzed cellulose wet cake’ or ‘microcrystalline cellulose/MCC wet cake’.

Processes for producing microcrystalline cellulose by acidic hydrolysis are disclosed in U.S Patent Nos. 2,978,446; 3,023,104; and 3,146,168. Alternative methods to reduce cost while maintaining quality of microcrystalline cellulose have been proposed. These include steam explosion (U.S Patent No. 5,769,934), one-step hydrolysis and bleaching, reactive extrusion and partial hydrolysis of semi-crystalline cellulose and water reaction liquor in a pressurized reactor at high temperatures (100 to 200°C) (U.S. Patent No. 5,543,511).

It is well-known that impurities in microcrystalline cellulose are glucose, formaldehyde, nitrates and nitrites (‘‘Impact of Excipient Interactions of Solid Dosage Form Stability” by Ajit S. Narang et al., P/?a/777acet/frca/ 7?esearc/7 volume 29, pages 2660-2683 (2012)). Formation of nitrosamines is possible in the presence of secondary, tertiary, or quaternary amines and nitrite salts under acidic reaction conditions. There is the great need to minimize the concentration of nitrosamines in food and pharmaceutical applications because nitrosamines are considered to be probable human carcinogens. Due to the wide usage of MCC in food and pharmaceutical applications, there is also the urgent need to reduce the concentration of nitrite salts that are present in MCC.

Several methods are known to reduce the concentration of nitrites in aqueous solutions, such as ozonization, catalysis, passing the aqueous solution through activated charcoal, passing the aqueous solutions through ion exchange resins, making use of microalgae or subjecting water/glycol mixtures at elevated pressure and temperatures above 120°C. Evidently these methods are not useful for reducing the concentration of nitrites in MCC when the MCC is in powder form. Thus, there is still the urgent need to find a method of reducing the concentration of nitrite salts that are present in tMCC rr/ttrrbcr

SUMMARY

One aspect of the present invention is a process for reducing the content of nitrite salts in microcrystalline cellulose which comprises the step of subjecting microcrystalline cellulose to a heat treatment.

Another aspect of the present invention is a process for producing microcrystalline cellulose which comprises the steps of i) acidic hydrolysis of cellulosic material to produce crude microcrystalline cellulose (MCC); ii) washing and at least partially neutralizing the crude MCC obtained in step i) to obtain an MCC wet cake; and iii) spray-drying the MCC wet cake, wherein after step ii) or step iii) or both of steps ii) and iii) MCC is subjected to a heat treatment.

It has surprisingly been found that a simple heat treatment of MCC significantly reduces the concentration of nitrite salts in MCC, even when the MCC is present in its powder form. Surprisingly, no chemical adjuvants, such as charcoal or glycols are needed for the reduction of nitrite salts.

DETAILED DESCRIPTION

In some embodiments, MCC is subjected to heat treatment in the process of the present invention when the MCC is in its powder form. When MCC is in its powder form, it generally has a moisture content of up to 30%, up to 20%, up to 10%, or up to 5%, based on the weight of dry MCC. The moisture content generally is 0% or more, typically 1 % or more, and more typically 2% or more, based on the weight of dry MCC. In the most preferred embodiment of the invention the moisture content is 3% or more, based on the weight of dry MCC. Alternatively, an MCC wet cake can be subjected to heat treatment. An MCC wet cake typically contains 30% to 90%, more typically 40% to 80% moisture, based on the weight of moist MCC. It has surprisingly been found that the moisture content of the MCC before heat treatment has an impact on the concentration of nitrite salts in MCC after heat treatment. When the moisture content of the MCC before heat treatment is from 3 to 30%, more preferably from 5 to 30%, and most preferably from 9 to 25 %, based on the weight of dry MCC, the nitrite salts in MCC can be reduced in the heat treatment in a shorter time period and to a lower concentration than when the moisture content is below 3%, based on the weight of dry MCC. The moisture content typically is the water content in the MCC.

In some embodiments, the temperature of the heat treatment depends on the duration of the heat treatment. The shorter the duration of the heat treatment is, the higher is generally the applied temperature, and vice versa. Generally, MCC is subjected to heat treatment at a temperature of at least 35°C. The maximum temperature of the heat treatment is not very critical, except that it should not cause significant degradation of the MCC. Generally, the heat treatment is conducted at a temperature of up to 400°C, typically at a temperature of up to 350°C. In some embodiments, the heat treatment is conducted in the absence of a chemical adjuvant.

In some embodiments, the duration of the heat treatment depends on the temperature during the heat treatment. The higher the temperature generally is, the shorter is generally the duration of the heat treatment and vice versa. Generally, the MCC is subjected to heat treatment for at least 1 minute, typically for at least s minutes. In some embodiments, the MCC is subjected to heat treatment for at least 30 minutes.

In one embodiment of the present invention, the MCC is subjected to heat treatment at a temperature of from 35 to 50°C (or from 40 to 45°C) for a time period of from 2 weeks to 12 months, from 1 to 10 months, or from 2 to 8 months.

In another embodiment, the MCC is subjected to heat treatment at a temperature of from 50 to 150°C, from 60 to 120°C, or from 70 to 100°C for a time period of from 1 to 300 hours, from 1 to 200 hours, or from 2 to 100 hours.

In yet another embodiment, the MCC is subjected to heat treatment at a temperature of from 150 to 350°C (or from 200 to 300°C) for a time period of from 1 minute to 1 hour (or from 5 to 30 minutes).

Typical nitrite salts that are reduced by the process of the present invention are ammonium and/or alkali metal nitrite salts, such as ammonium nitrite and/or sodium nitrite, preferably ammonium nitrite. By the process of the present invention the content of nitrite salts in MCC is typically reduced by at least 50% by the heat treatment, based on the weight of the nitrite salts in MCC prior to the heat treatment. In some embodiments, the content of nitrite salts in MCC is reduced by at least 80%, at least 90%, or at least 95%. In general, microcrystalline cellulose (MCC) from any source may be used in the process of the present invention. Typically, suitable sources of MCC include, for example, wood pulp (such as bleached sulfite and sulfate pulps), straw, cotton, flax, cotton linters, hemp, ramie, corn husks, bagasse, seaweed cellulose and fermented cellulose. Other sources include bleached softwood Kraft pulps, bleached hardwood Kraft pulps, bleached Eucalyptus Kraft pulps, paper pulps, fluff pulps, dissolving pulps, and bleached non-wood cellulosic pulps. In one embodiment, the MCC used is one approved for human consumption by the United States Food and Drug Administration.

If desired, low-cost pulp or mixtures of low-cost pulp and specialty pulp may be used as sources of MCC. If so, then, for example, about 30-80% of the total MCC can be made up of low-cost pulp. In some embodiments, the colloidal content of the resulting MCC product is at least 60%. Examples of low-cost pulp include paper grade pulps, fluff pulp such as Southern Bleached Softwood Kraft Pulp, Northern Bleached Softwood pulp, Bleached Eucalyptus Kraft pulp, Bleached Sulfite pulps, Bleached Hardwood Kraft pulp, Bleached Soda Pulps, and bleached non-wood pulps.

The process for producing MCC comprises a step i) wherein cellulosic material is subjected to acidic hydrolysis to produce crude MCC. The term “acidic hydrolysis” as used herein does not imply limitation to a complete hydrolysis but encompasses partial hydrolysis that is generally applied in known processes for producing MCC. Crude MCC is typically produced by partially hydrolyzing the above-described cellulosic source material with an acid (in some embodiments with a mineral acid, or in some embodiments with hydrochloric acid (acidic hydrolysis)). Processes for producing microcrystalline cellulose by acidic hydrolysis are disclosed in U.S Patent Nos. 2,978,446; 3,023,104; and 3,146,168. The mineral acid preferentially attacks the amorphous regions of the cellulosic source material, thereby exposing, freeing and leaving behind the paracrystalline regions, which form crystalline aggregates constituting microcrystalline cellulose. During partial hydrolysis of the cellulosic source material the average degree of polymerization (= D. P.) drops down to a level-off value which reflects a destruction of the original fibrous structure of the cellulosic source material. The level-off values which can be obtained by means of partial hydrolysis depend mainly on the choice of the above-mentioned raw materials. MCC having an average level-off D.P. in the range of 15 to 60, for example, can be produced from regenerated forms of cellulose. MCC having an average level-off D.P. in the range of 60 to 125 may be obtained from alkali swollen natural forms of cellulose such as cotton linters and purified wood pulps. Sulfite pulp as a source material will typically produce MCC having an average level-off D.P. in the range of 200 to 400. The average level-off degree of polymerization (= D.P.) is determined in agreement with DIN 54 270, parts 1 and 2.

MCC can be made more suitable to the optional attrition described further below by chemical or mechanical treatments. For example, during or after acid hydrolysis of MCC, the MCC can be treated with carboxymethyl cellulose (CMC), peroxide, per-acetic acid, persulfate, performic acid, or ozone at acidic pH. Other additives such as iron salts, may be added to enhance the hydrolysis of MCC. Enhanced hydrolysis may also be achieved through extended cooking of MCC or by changing reaction conditions such as temperature of cooking, acid concentration, etc.

The process for producing MCC further comprises a step ii) wherein after partial hydrolysis the aggregated crystalline mass, i.e., the crude MCC, is washed and at least partially neutralized with an aqueous liquid to remove degraded by-products and to at least partially neutralize excess acid that has been used in the acidic hydrolysis. Typically, the washing step involves filtration, followed by dilution to produce an MCC wet cake that is suitable for spraydrying. The neutralizing agent can be added to the washing liquor. In some embodiments, it is added to the liquor used for dilution. Examples of neutralizing agents are, e.g., ammonium bicarbonate or ammonium carbonate. In some embodiments, the neutralizing agent comprises ammonia or ammonium hydroxide.

In some embodiments, the washing liquors are water, brine, or organic solvents in admixture with water, such as aqueous mixtures of isopropanol, ethanol or methanol. In some embodiments, the washing liquors are water or brine. The resulting wet mass typically contains 30% to 80%, more typically 40% to 70% moisture, based on the total weight of moist MCC. Optionally MCC is modified for certain uses in food, pharmaceutical or cosmetic applications, such as use as a gelling agent, thickener, fat substitute, non-caloric filler, as suspension agent, texturizer or stabilizer in emulsions. In some embodiments, the MCC is modified for such uses by subjecting hydrolyzed wet MCC to high shear mixing called ‘attrition’. The process of attrition typically subdivides microcrystalline crystallites into fine particles (in some embodiments, in the colloidal range). Colloidal microcrystalline celluloses such as those modified with CMC are described in U.S. Patent No. 3,539,365. Typically, the optionally attrited MCC is subsequently diluted before spray-drying. In some embodiments, the diluting agent is water, which, in some embodiments comprises an above-described neutralizing agent. A diluted MCC suitable for spray drying is generally in the form of an aqueous slurry of MCC and typically comprises about 10% to 20% MCC and about 80% to 90% water, based on the total weight of dry MCC and water. Both the moist MCC containing 30% to 80% moisture, based on the total weight of moist MCC, as well as the diluted MCC comprising about 10% to 20% MCC and about 80% to 90% water, based on the total weight of dry MCC and water, are designated herein as “MCC wet cake”.

In step iii) of the process the MCC wet cake is spray-dried. The desired commercial grades of MCC are obtained by varying and controlling the spray drying conditions in order to manipulate the degree of agglomeration (particle size distribution) and moisture content of the MCC product. [G. Thorens, Int. J. Pharm. (2015), 490, 47-54; G. Thorens, Int. J. Pharm. (2014), 473, 64-72)]. Suitable spray drying devices and conditions are known in the art.

Thus, the process for producing MCC comprises the steps of i) acidic hydrolysis of cellulosic material to produce crude microcrystalline cellulose (MCC); ii) washing and at least partially neutralizing the crude MCC obtained in step i) to obtain an MCC wet cake; and iii) spray-drying the MCC wet cake. Embodiments of steps i) - iii) of the process are as described above. After step ii) or step iii) or both of steps ii) and iii) MCC is subjected to a heat treatment as described further above wherein the content of the nitrite salts in MCC is reduced.

In one embodiment, the MCC is subjected to a heat treatment as described further above after step ii) and before step iii). In this embodiment, the concentration of nitrite salts can be reduced that potentially originate from the starting material used for producing the MCC and/or that potentially originate from step ii) that involves the partial or complete neutralization of the crude MCC obtained in step i).

In another embodiment, the MCC is subjected to a heat treatment as described further above after the spray-drying step iii). In this embodiment, not only the concentration of nitrite salts potentially originating from the starting material used for producing the MCC can be reduced but also the concentration of nitrite salts that potentially originate from the partial or complete neutralization of the crude MCC obtained in step i) and the concentration of nitrite salts that potentially originate from the spray-drying step, for example from the drying gas utilized in the spray-drying step.

Other features and advantages of the present invention will be apparent from the following Examples. The disclosed embodiments are for the purpose of explanation and are only exemplary and are not to be considered as limitations of the invention. Unless otherwise mentioned, all parts, percent and ratios are by weight.

EXAMPLES

Determining the Content of Nitrites in MCC

The measurements of nitrite salts were performed on an ion exchange chromatography system (Dionex ICS-6000 system consisting of AS-AP autosampler, quaternary pumps, KOH eluent generator, anion suppressor, conductivity detector, and Chromeleon 7.2.9 Chromatography Data System) with microbore analytical and guard columns (Dionex lonPac AS 19, 2 x 250 mm, Catalog number 062886 and Dionex lonPac AG 19, 2 x 50 mm, Catalog number 062888). KOH gradient was simultaneously generated by a KOH eluent generator: - 10 min at 1 mmol for equilibration (meaning 10 min pre-equilibration time for the IC column to get equilibrated before the IC method starts to run), 0-15 min from 1 mmol to 20 mmol, 15.1 min to 50 mmol and hold at 50 mmol until 28 min, 28-29 min from 50 mmol to 1 mmol and the run stops at 30 min. The flow rate is at 0.5 mL/min. Anion suppression with ADRS 2mm suppressor was applied with dynamic mode with starting voltage at 3.8 V. The column temperature was 30°C and compartment temperature was 15°C. The injection was done with 25 pL sample loop.

For nitrite analysis, the microcrystalline cellulose (MCC) samples were prepared by extracting 1 g of MCC with 15 g of high purity water (electrical resistivity greater than 18 megohm-cm at 25°C, prepared by filtering deionized water through any reliable laboratory water purification system such as the Milli-Q IQ 7003/7005/7010/7015 system from Millipore Sigma) on a shaker at low shaking speed for 30 minutes in a 50-mL centrifuge tube. The tube was then centrifuged at 10000 rpm for 10 min to precipitate MCC (Sorvall Legend XT/XF Centrifuge Series, Catalog 75004541). The clear extraction solution was filtered through 0.45 pm PTFE filter and put into IC autosampler vials for analysis by ion exchange chromatography (IC). The samples were calibrated with external calibration standards prepared at 0.5 pg/g, 0.05 pg/g and 0.005 pg/g with IC analytical standards purchased from Inorganic Ventures (1000 pg/g nitrite (NO2-), Part numbers ICNO31-125ML and ICNO21-125ML).

Moisture analysis

Moisture analysis was performed using a Mettler-Toledo HB 43-S halogen moisture analyzer with moisture calculated as % loss on drying (LOD) at 110°C.

MCC Production Process

The MCC used as starting material for the heat treatment was produced by acid hydrolysis of commercially available high purity wood pulps, with alpha contents above 90%. The acid hydrolysis was conducted with aqueous hydrochloric acid. The resultant MCC was separated from the reaction by-products and washed using water during a filtration step to produce an MCC wet cake of about 35% - 40% solids having an average degree of polymerization (DP) of about 240. The MCC wet cake was diluted with water to about 20% solids and anhydrous ammonia was added with the water to neutralize residual acid and obtain a pH of between 5.5 - 7.0 in the final powder. Finally, the diluted MCC was spray dried to produce a powder. Example 1

MCC samples were produced according to the MCC Production Process described above, but with an extra filtration after ammonia neutralization and before spray drying.

10 g of MCC samples were weighed into each of 2 oz (about 60 ml) HDPE bottles. These samples were heated at 50°C, 70°C and 90°C for 1 or 2 or 3 hours, respectively in a commercial oven wherein the humidity was not controlled. At each designed experiment point, such as after heating at 90°C for 1 hour, the specific bottle used only for this testing condition was taken out of the oven and let cool down before determining the content of nitrites as described above. The results in Table 1 below show the nitrite content in ppm after various time periods and various temperatures of the heat treatments.

Table 1

Example 2

MCC samples were produced according to the MCC Production Process described above, except that hydrogen peroxide at a concentration of 3 wt.-%, based on the weight of dry MCC, was added after ammonia neutralization and before spray drying. An extra filtration was applied after addition of hydrogen peroxide and before spray drying.

The results in Table 2 below show the nitrite content in ppm after various time periods and various temperatures of the heat treatments. Table 2

Example 3

MCC samples were produced according to the MCC Production Process described above. No hydrogen peroxide addition and no extra filtration were applied.

The results in Table 3 below show the nitrite content in ppm after various time periods and various temperatures of the heat treatments.

Table 3

Example 4

Commercial MCC material was evaluated which was produced according to the MCC Production Process described above.

The results in Table 4 below show the nitrite content in ppm after various time periods and various temperatures of the heat treatments. Table 4

The results in Tables 1 - 4 above illustrate the surprising finding that by simple heat treatment the nitrite content can be almost completely removed in bulk MCC powders although nitrite salts are only present in traces in the MCC powders before the heat treatment. Surprisingly, the expectation was not met that the nitrite salts would be stabilized in the MCC matrix which would prevent the reduction of the nitrite level to a large degree.

Example 5

MCC powder that was commercially available under the trademark AVICEL PH-102 was used for the heat treatment experiments. AVICEL PH-102 microcrystalline cellulose has a nominal particle size of 100 pm, a moisture content of 3.0 - 5.0 % LCD (loss on drying) and a bulk density of 0.28 - 0.33 g/ml.

MCC sample 5-I was obtained by drying AVICEL PH-102 MCC in a vacuum oven at ambient temperature over several days to the desired final LCD of 0.4 %, based on the weight of absolutely dry MCC.

MCC sample 5-II was AVICEL PH-102 MCC that had a moisture content, i.e. , a LCD (loss on drying), of 4.2 %, based on the weight of absolutely dry MCC.

MCC samples 5-III, 5-IV and 5-V were obtained by humidification of AVICEL PH-102 MCC in a Lodige ploughshare reactor unit at room temperature. The desired amount of deionized (DI) water was sprayed (60psig air pressure through a hollow cone nozzle with a 30° spray angle) onto the agitated MCC powder over 1-2 minutes. Stirring was continued for an additional hour to blend/homogenize. Then the humified MCC was removed from the reactor. The humification was conducted 3 times adding three different amounts of DI water. The LCD of each humified MCC was measured to determine the new moisture level. MCC sample 5-III had an LCD of 9.3%; MCC sample 5-IV had an LCD of 12.4%; and MCC sample 5-V had an LCD of 24.9%. The samples were then subjected to heat treatment. The heat treatment experiments were run in an agitated Lodige VT10 ploughshare blender. The jacket system was heated using a stand-alone heater/chiller system using a glycol/water mix. The jacket system was set to 99°C to give an internal temperature of about 90°C. The unit was pre-heated before adding MCC powder to the unit. Each of the MCC samples 5-I to 5-V was separately added to the preheated Lodige reactor and stirred at that temperature over the course of Day 1 and twice on Day 2. All samples were measured for LCD and nitrite content immediately after they were removed from the reactor. The nitrite content is based on the weight of dry MCC. The results are listed in Table 5 below.

Table 5

The results in Table 5 above confirm the surprising finding that by simple heat treatment the nitrite content can be almost completely removed in bulk MCC powders although nitrite salts are only present in traces in the MCC powders before the heat treatment. The results in Table 5 above also illustrate the surprising finding that the speed and extent of the reduction of nitrite content depends on the humidity of the MCC sample before the heat treatment. Example 6

MCC samples that were commercially available under the trademark AVICEL PH-102, AVICEL PH-112 and AVICEL SMCC 90 were used for the heat treatment experiments. AVICEL PH-102 microcrystalline cellulose has a nominal particle size of 100 pm, a moisture content of 3.0% - 5.0% and a bulk density of 0.28 - 0.33 g/ml. AVICEL PH-102 originated from a different batch than in Example 5, therefore the nitrite content at the start was slightly different than in Example 5. AVICEL PH-112 microcrystalline cellulose has a nominal particle size of 100 pm, a moisture content of not greater than 1.5% and a bulk density of 0.28 - 0.34 g/ml. AVICEL SMCC 90 has a mean particle size (d50), determined by laser diffraction, of 90 - 150 pm and a bulk density of 0.25 - 0.37 g/ml. AVICEL SMCC 90 is a co-processed spray- dried excipient comprising 98% of MCC and 2% of colloidal silicon dioxide.

10 g of MCC samples were weighed into each of 2-oz (about 60 ml) HDPE bottles. The bottles were put into an oven wherein the temperature was maintained at 40°C and 75% humidity. The bottles designed for each specific experiment point, such as month 1 treatment at 40°C and 75% humidity, were taken out of the oven. The content of nitrites was analyzed as described above. The results in Table 6 below show the nitrite content in ppm after various time periods of the heat treatments.

Table 6

The results in Table 6 above illustrate that even at a very moderate heating at only 40°C a drastic reduction in nitrite content can be achieved when the MCC is kept over an extended time period at this temperature. For example, the reduction in nitrite content can be very conveniently achieved by storing the MCC at a temperature-controlled warehouse. Example 7

MCC that was commercially available under the trademark AVICEL PH-101 was used for the heat treatment experiments. AVICEL PH-101 microcrystalline cellulose has a nominal particle size of 50 pm, a moisture content of 3.0% - 5.0% and a bulk density of 0.26 - 0.31 g/ml. For heat treatment 10 g of Avicel PH 101 microcrystalline cellulose was stored in a cabinet oven at high temperatures for a very short time. The results in Table 7 below show the nitrite content in ppm after various time periods and various temperatures of the heat treatments.

Table 7

The results in Table 7 above illustrate that at high temperatures a drastic reduction in nitrite content can be achieved within a very short time period.

Examples 8 and 9

The experiments in Examples 8 and 9 were conducted to evaluate whether the content of nitrite salts in MCC could also be reduced by a simple heat treatment of MCC at large scale. In Example 8 a drum comprising about 50 kg of MCC that is commercially available under the trademark AVICEL PH-112 was placed in a warehouse that had at a temperature of 40°C. The MCC originated from a different batch than in Example 6, therefore the nitrite content at the start was slightly different than in Example 6. The drum was simply kept standing in the warehouse without agitation. At weekly intervals MCC samples were taken from the drum and analyzed for the nitrate content as described further above. The results are listed in Table 8 below. Table 8

In Example 9 a box comprising about 20 kg of MCC that is commercially available under the trademark AVICEL PH-102 was placed in a warehouse that was had a temperature of 40°C. The MCC originated from a different batch than in Examples 5 and 6, therefore the nitrite content at the start was slightly different than in Examples 5 and 6. The box was simply placed in the warehouse without shaking or other agitation. At weekly intervals MCC samples were taken from the box and analyzed for the nitrate content as described further above. The results are listed in Table 9 below.

Table 9 The results Tables 8 and 9 illustrate the surprising finding that the content of nitrite salts in MCC can be reduced by about 50% or even more by simple heat treatment, even at large scale and even if the MCC is only kept standing.