Filter and application therefor

Abstract

Provided is a novel filter that can be used in the production of pharmaceutical raw materials or pharmaceuticals. The filter is for removing nitrogen oxides from air having a nitrogen oxide concentration of 300 ppb or less. The filter contains activated carbon or a substance of the same quality as activated carbon.

Description

Filter and Its Application

[0001] The present invention relates to a filter and its application.

[0002] Conventionally, a technique for removing nitrogen oxides in exhaust gas using activated carbon is known (see Patent Document 1 for example).

[0003] On the other hand, it is known that nitrogen oxides in the atmosphere are one of the causes of nitrosocompounds mixed in pharmaceuticals (see Non-Patent Document 1 for example).

[0004] Japanese Patent Laid-Open No. 07-178316

[0005] Fukuda et al.(2023) "N-Nitrosodimethylamine Formation in Metformin Drug Products by the Reaction of Dimethylamine and Atmospheric NO2", Organic Process Research & Development, vol.27 issue 11, pp.2123-2133.

[0006] The conventional nitrogen oxide removal technology using activated carbon as seen in Patent Document 1 has been treating gases with relatively high nitrogen oxide concentrations (on the order of several ppm), such as exhaust from tunnels and parking lots. Therefore, it is usually to use activated carbon treated with an adhesive, but there are several problems with such activated carbon. First, the material cost increases by the amount of the adhesive used. Second, the activated carbon treated with the adhesive needs to be prepared at the time of use, so it is difficult to obtain. Third, there is a risk that the quality of the product will deteriorate due to the adhesive mixing into the manufacturing equipment.

[0007] On the other hand, as shown in Non-Patent Document 1, in the formation of nitrosocompounds in pharmaceutical production, nitrogen oxides at much lower concentrations (on the order of several tens of ppb) were the cause. Based on these findings, the inventors of the present invention have conducted intensive studies and conceived that it is not necessary to treat activated carbon with an adhesive if it is used for the purpose of reducing the formation of nitrosocompounds in pharmaceutical production, and have thus completed the present invention.

[0008] One aspect of the present invention aims to provide a novel filter that can be used in the manufacture of pharmaceutical raw materials or pharmaceuticals.

[0009] The present invention includes the following embodiments: <1> A filter for removing nitrogen oxides from air having a nitrogen oxide concentration of 300 ppb or less, wherein the filter contains activated carbon or the same. <2> The filter according to <1>, wherein the activated carbon or the same is substantially unmodified. <3> A manufacturing facility for pharmaceutical raw materials or pharmaceuticals, equipped with the filter according to <1> or <2>. <4> A manufacturing apparatus for pharmaceutical raw materials or pharmaceuticals, equipped with the filter according to <1> or <2>. <5> An air manufacturing apparatus or supply apparatus, equipped with the filter according to <1> or <2>. <6> A compressed air manufacturing apparatus or supply apparatus, equipped with the filter according to <1> or <2>. <7> A method for manufacturing pharmaceutical raw materials or pharmaceuticals, comprising the step of removing nitrogen oxides from air having a nitrogen oxide concentration of 300 ppb or less using the filter according to <1> or <2> to provide a low nitrogen oxide concentration atmosphere. <8> The manufacturing method according to <7>, comprising the step of manufacturing and / or storing pharmaceutical raw materials or pharmaceuticals under the low nitrogen oxide concentration atmosphere. <9> The manufacturing method according to <7> or <8>, wherein the pharmaceutical raw material is atomoxetine or a salt thereof, and the pharmaceutical is a pharmaceutical containing atomoxetine or a salt thereof. <10> The manufacturing method according to <7> or <8>, wherein the pharmaceutical raw material is duloxetine or a salt thereof, and the pharmaceutical is a pharmaceutical containing duloxetine or a salt thereof. <11> A method for reducing the generation of nitroso compounds in pharmaceutical raw materials or pharmaceuticals, comprising the step of removing nitrogen oxides from air having a nitrogen oxide concentration of 300 ppb or less using the filter according to <1> or <2> to provide a low nitrogen oxide concentration atmosphere. <12> The method according to <11>, comprising the step of manufacturing and / or storing pharmaceutical raw materials or pharmaceuticals under the low nitrogen oxide concentration atmosphere. <13> The method according to <11> or <12>, wherein the pharmaceutical raw material is atomoxetine or a salt thereof, and the pharmaceutical is a pharmaceutical containing atomoxetine or a salt thereof.<14> The method according to <11> or <12>, wherein the pharmaceutical raw material is duloxetine or a salt thereof, and the pharmaceutical is a pharmaceutical containing duloxetine or a salt thereof. <15> A method for producing a pharmaceutical raw material or a pharmaceutical, comprising the step of producing and / or storing the pharmaceutical raw material or a pharmaceutical in a low nitrogen oxide concentration atmosphere in which the nitrogen oxide concentration is adjusted to 10 ppb or less by the filter described in <1> or <2>. <16> The method according to <15>, wherein the pharmaceutical raw material is atomoxetine or a salt thereof, and the pharmaceutical is a pharmaceutical containing atomoxetine or a salt thereof. <17> The method according to <15>, wherein the pharmaceutical raw material is duloxetine or a salt thereof, and the pharmaceutical is a pharmaceutical containing duloxetine or a salt thereof. <18> A method for reducing the formation of nitroso compounds in a pharmaceutical raw material or a pharmaceutical, comprising the step of producing and / or storing the pharmaceutical raw material or a pharmaceutical in a low nitrogen oxide concentration atmosphere in which the nitrogen oxide concentration is adjusted to 10 ppb or less by the filter described in <1> or <2>. <19> The method according to <18>, wherein the pharmaceutical raw material is atomoxetine or a salt thereof, and the pharmaceutical is a pharmaceutical containing atomoxetine or a salt thereof. <20> The method according to <18>, wherein the pharmaceutical raw material is duloxetine or a salt thereof, and the pharmaceutical is a pharmaceutical containing duloxetine or a salt thereof. <21> A pharmaceutical raw material or a pharmaceutical containing the same that can produce and / or cause to produce a nitroso compound, and which is present in or has been present in a low nitrogen oxide concentration atmosphere in which the nitrogen oxide concentration is adjusted to 10 ppb or less. <22> The pharmaceutical raw material or a pharmaceutical containing the same as described in <21>, wherein the pharmaceutical raw material is atomoxetine or a salt thereof. <23> The pharmaceutical raw material or a pharmaceutical containing the same as described in <21>, wherein the pharmaceutical raw material is duloxetine or a salt thereof.

[0010] According to one aspect of the present invention, a novel filter is provided that can be used in the manufacture of pharmaceutical raw materials or pharmaceuticals.

[0011] It is a schematic diagram showing the configuration of an apparatus for evaluating the performance of a filter used in Examples 1 to 8. It is a graph examining the ability of unmodified activated carbon to remove high-concentration nitrogen oxides. It is a graph examining the ability of unmodified activated carbon to remove high-concentration nitrogen oxides.

[0012] Although one embodiment of the present invention will be described below, the present invention is not limited thereto. The present invention is not limited to each configuration described below, and various modifications are possible within the scope shown in the claims. Embodiments obtained by appropriately combining the technical means disclosed in different embodiments are also included in the technical scope of the present invention.

[0013] Unless otherwise specified in this specification, "A to B" representing a numerical range means "A or more and B or less".

[0014] In this specification, nitrogen oxides are a general term for compounds mainly composed of nitrogen atoms and oxygen atoms. Examples of nitrogen oxides include nitrogen monoxide (NO), nitrogen dioxide (NO ２ ), nitrogen trioxide (NO ３ ), dinitrogen monoxide (N ２ O), dinitrogen trioxide (N ２ O ３ ), dinitrogen tetroxide (N ２ O ４ ), dinitrogen pentoxide (N ２ O ５ ). Substances such as ions composed of nitrogen atoms and oxygen atoms are also included in nitrogen oxides. Examples of such ions include NO ＋ , NO ２ － , NO ３ － . In one embodiment, nitrogen oxides may contain atoms other than nitrogen and oxygen atoms (such as hydrogen atoms). The number of atoms other than nitrogen and oxygen atoms can be 5 or less, 4 or less, 3 or less, or 2 or less. Examples of nitrogen oxides having such different atoms include HNO ２ , H ２ NO ２ ＋Examples include: In one embodiment, the nitrogen oxide does not contain any atoms other than nitrogen and oxygen atoms.

[0015] In this specification, where specific nitrogen oxides are mentioned, the ions of those nitrogen oxides are also intended unless otherwise specified. For example, the expressions "nitric oxide" and "NO" include the ions. Similarly, "nitrogen dioxide" and "NO" also include the ions. ２ The expression "also includes the ion. In one embodiment, the nitrogen oxide is nitric oxide. In one embodiment, the nitrogen oxide is nitrogen dioxide. In one embodiment, the nitrogen oxide is nitric oxide and nitrogen dioxide.

[0016] In this specification, pharmaceutical raw materials include not only active pharmaceutical ingredients and pharmaceutical excipients, but also starting materials, intermediates, and impurities in the manufacturing process of said ingredients. Impurities in the manufacturing process include impurities that cannot be removed due to technical reasons, as well as impurities that cannot be removed due to cost reasons. In one embodiment, pharmaceutical raw materials are ingredients that serve as raw materials for pharmaceuticals. In one embodiment, pharmaceutical raw materials are starting materials, intermediates, and / or impurities in the manufacturing process of ingredients that serve as raw materials for pharmaceuticals. In this specification, pharmaceuticals refer to compositions obtained by combining pharmaceutical raw materials. Pharmaceuticals may contain starting materials, intermediates, and / or impurities in the manufacturing process of pharmaceutical raw materials.

[0017] In this specification, nitroso compounds are a general term for compounds in which a nitroso group is bonded to a nitrogen atom constituting an amine. Their general structure is N(R １ ) (Caution ２ ) - N = O. １ and R ２ The structures of each are independent, and for example, they are hydrocarbon groups that may have heteroatom-containing groups. Alternatively, R １ and R ２These may be bonded together to form a ring. Examples of hydrocarbon groups include alkyl groups, cycloalkyl groups, and aryl groups. Heteroatom-containing groups may consist of only one or more heteroatom atoms, or they may contain both one or more heteroatom atoms and carbon and / or hydrogen atoms.

[0018] Examples of nitroso compounds include N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodipropylamine (NDPA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodibutylamine (NDBA), N-nitrosoisopropylethylamine (NIPEA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitrosomethylphenylamine (NMPA), methylnitrosopiperazine (MeNP), and N-nitrosomorpholine (NMOR). These nitroso compounds are generally found as pharmaceutical raw materials or as impurities in pharmaceuticals.

[0019] Other examples of nitroso compounds include compounds in which the pharmaceutical raw material itself has been nitrosated. Examples of such compounds include nitrosoorphenadrine, nitrosoquinapril, nitrosorasagiline, nitrosopropranolol, nitrosoamoxapine, nitrosovarenicline, nitrosoduloxetine, and nitrosoatomoxetine.

[0020] In one embodiment, the pharmaceutical raw material is a pharmaceutical raw material that can produce and / or cause the production of nitroso compounds. Pharmaceutical raw materials that can produce and / or cause the production of nitroso compounds include the following types. However, these types do not encompass all pharmaceutical raw materials that can produce and / or cause the production of nitroso compounds. Furthermore, some pharmaceutical raw materials that can produce and / or cause the production of nitroso compounds may fall into multiple types.

[0021] ◆The first type of pharmaceutical raw material having an amino group or a substituted amino group is a pharmaceutical raw material having an amino group or a substituted amino group. An amino group is -NH ２This is a functional group represented by . A substituted amino group is a functional group in which one or two hydrogen atoms in an amino group are substituted with another group. Such pharmaceutical raw materials may be nitrosated themselves, or their decomposition products may be nitrosated. In one embodiment, the pharmaceutical raw material has a substituted amino group. In one embodiment, the pharmaceutical raw material has a secondary amine structure. Examples of such pharmaceutical raw materials include orphenadrine, quinapril, rasagiline, propranolol, amoxapine, varenicline, duloxetine, atomoxetine, and salts thereof.

[0022] ◆The second type of pharmaceutical raw material in which amines are used as starting materials, intermediates, and / or catalysts is a pharmaceutical raw material in which amines are used as starting materials, intermediates, and / or catalysts in the manufacturing of the pharmaceutical raw material. Such pharmaceutical raw materials may produce nitroso compounds through nitrosation of residual starting materials, intermediates, and / or catalysts. The amine may be a primary amine, a secondary amine, or a tertiary amine. Examples of amines used as starting materials, intermediates, and / or catalysts include dimethylamine, diethylamine, methyl-4-aminobutyric acid, N-methylaniline, ethylisopropylamine, diisopropylamine, N-methylpiperazine, dibutylamine, morpholine, dipropylamine, and salts thereof.

[0023] ◆The third type of pharmaceutical raw material whose decomposition products can be nitrosated is a pharmaceutical raw material whose decomposition products can be nitrosated. The pharmaceutical raw material before decomposition may or may not have a part that can be nitrosated. An example of such a pharmaceutical raw material (and its decomposition products) is sitagliptin (which decomposes to produce 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine).

[0024] ◆Impurities in pharmaceutical raw materials can cause nitroso compounds. Pharmaceutical raw materials sometimes contain nitrites as impurities. These nitrites can either change themselves to produce nitroso compounds, or they can change other substances to produce nitroso compounds. Examples of such pharmaceutical raw materials include sucrose / starch granules, hypromellose, hypromellose acetate succinate, talc, and titanium dioxide.

[0025] [1. Filters] Conventionally, filters for removing nitrogen oxides have been developed with the aim of removing nitrogen oxides from exhaust gases containing high concentrations of nitrogen oxides emitted from factories, vehicles, etc. In order to remove high concentrations of nitrogen oxides, it is necessary to use filters with superior nitrogen oxide removal capabilities. For this reason, conventional filters had to contain a modifier in addition to activated carbon or a similar material.

[0026] Under such conventional technology, even when removing nitrogen oxides in the manufacturing process of pharmaceutical raw materials or pharmaceuticals, a person skilled in the art would likely use a conventional filter containing a modifier. This is because even if unmodified activated carbon without a modifier, or an equivalent material, is used, trace amounts of nitrogen oxides at the tens to hundreds of ppb level will pass through the filter, and the removal capacity for very small amounts of nitrogen oxides is expected to be insufficient.

[0027] However, through diligent research, the inventors discovered that the amount of nitrogen oxides that need to be removed in pharmaceutical raw materials or during the pharmaceutical manufacturing process is very small compared to the nitrogen oxides contained in exhaust gas, and that even a filter containing activated carbon that is not modified with a modifier, or a similar material, has sufficient removal capacity. Based on this finding, the inventors conceived the invention.

[0028] A filter according to one aspect of the present invention is a filter for removing nitrogen oxides from air having a nitrogen oxide concentration of 300 ppb or less. This filter contains activated carbon or an equivalent material.

[0029] The nitrogen oxide concentration in the air before passing through the filter is 300 ppb or less, and may be 250 ppb or less, 200 ppb or less, 150 ppb or less, 130 ppb or less, 100 ppb or less, 70 ppb or less, or 50 ppb or less. This level of nitrogen oxide concentration is closer to that of normal atmosphere than to exhaust gas. In other words, the filter is intended to remove nitrogen oxides from normal atmosphere and other sources. Air that has passed through such a filter can become a low nitrogen oxide concentration atmosphere, which can contribute to reducing the generation of nitroso compounds in the manufacture of pharmaceutical raw materials or pharmaceuticals. In this specification, the air after passing through the filter may be referred to as a "low nitrogen oxide concentration atmosphere."

[0030] The filter does not contain a modifier as an essential component. The absence of a modifier reduces the manufacturing cost of the filter. As a result, the manufacturing costs of pharmaceutical raw materials or pharmaceuticals can also be reduced. In addition, filters without modifiers are expected to be more readily available and have a lower risk of quality degradation.

[0031] [1.1. Filter Configuration] The filter configuration can be a general filter configuration. One example is a configuration that includes an outer casing, with activated carbon or a similar material filled inside the outer casing. Examples of materials that make up the outer casing include metal and nonwoven fabric.

[0032] More specific examples of filter configurations include: • A configuration in which activated carbon or an equivalent material is packed into a metal column. • A configuration in which activated carbon or an equivalent material is woven into a nonwoven fabric. • A configuration in which activated carbon or an equivalent material is sandwiched between layers of nonwoven fabric.

[0033] The activated carbon or equivalent material contained in the filter is not particularly limited. Examples of raw materials for activated carbon include wood, sawdust, coconut shells, and coal. A substance equivalent to activated carbon refers to a material that can adsorb nitrogen oxides to the same or greater extent than activated carbon. Examples include alumina and silica gel.

[0034] In one embodiment, the activated carbon or equivalent is substantially unmodified. Conventional activated carbon or equivalent contained in filters is usually modified with modifiers or impurities (such as metal compounds), but substantially unmodified activated carbon or equivalent substantially does not contain modifiers or impurities. The content of modifiers and impurities per gram of activated carbon or equivalent may be 100 μg or less, 10 μg or less, 1 μg or less, or 0.1 μg or less. In one embodiment, the activated carbon or equivalent does not contain any modifiers or impurities at all.

[0035] The lower limit of the weight of activated carbon or equivalent material contained in the filter may be 5g or more, 10g or more, 20g or more, or 25g or more. Within these ranges, sufficient nitrogen oxide removal capacity can be obtained. The upper limit of the weight of activated carbon or equivalent material may be 35g or less, 25g or less, or 15g or less. Within these ranges, the manufacturing cost of the filter can be reduced. However, the amount of activated carbon or equivalent material contained in the filter may vary depending on the size of the filter. Therefore, for example, a scaled-up filter may contain more activated carbon or equivalent material than the above ranges.

[0036] The packing density of activated carbon or its equivalent in a filter is the ratio of the weight of activated carbon or its equivalent to the total volume of the filter. The lower limit of the packing density of activated carbon or its equivalent may be 0.1 g / mL or higher, 0.2 g / mL or higher, 0.3 g / mL or higher, or 0.4 g / mL or higher. Within these ranges, sufficient nitrogen oxide removal capacity can be obtained. The upper limit of the packing density of activated carbon or its equivalent may be 2 g / mL or lower, or 1 g / mL or lower. Within these ranges, the manufacturing cost of the filter can be reduced, and pressure loss can be reduced. In addition, when substantially unmodified activated carbon or its equivalent is used, improved availability and a reduction in the risk of quality degradation can be expected.

[0037] Examples of the form of activated carbon or similar material contained in the filter include powder, granular (spherical, nearly spherical, pelletized, irregularly shaped crushed, etc.), fibrous (thread-like, cloth-like, nonwoven fabric-like, etc.), rod-shaped, and honeycomb-shaped. From the viewpoint of implementation, it is preferable that the activated carbon or similar material be in the form of irregularly shaped crushed or pelletized material.

[0038] The lower limit of the average particle size of activated carbon or equivalent materials contained in the filter may be 100 μm or more, or 200 μm or more. The upper limit of the average particle size of activated carbon or equivalent materials may be 10 mm or less, 7 mm or less, 5 mm or less, 2 mm or less, or 1 mm or less.

[0039] The lower limit of the BET specific surface area of ​​activated carbon or equivalent material contained in the filter is 500 m². ２ / g or more, 700m ２ / g or more or 1000m ２ It may be more than / g. The upper limit of the BET specific surface area of ​​activated carbon or equivalent is 5000 m². ２ / g or less, 3000m ２ / g or less or 2000m ２ It may be less than / g. Within the above range, the nitrogen oxide removal capacity will improve.

[0040] The filters described above may be used individually or in combination. When combining multiple filters, the activated carbon or similar materials may be of the same type or properties, or of different types or properties. There is no particular limit to the number of filters used in combination. When combining two or more filters, they may be applied in layers or separately in different locations. It is preferable to use a number of layers of filters such that the pressure loss of the circulating air is sufficiently small.

[0041] [1.2. Air circulating through the filter] The air circulating through the filter is not particularly limited. For example, the air circulating through the filter may be pre-treated air. In one embodiment, the air circulating through the filter is outside air. In one embodiment, the air circulating through the filter is compressed air. In one embodiment, the air circulating through the filter is raw air that will later become compressed air.

[0042] Examples of pretreatment include adjusting the types and content of constituent components and compressing air. More specific examples include passing the air through a filter different from the filter according to one embodiment of the present invention and compressing the air using a compressor.

[0043] [2. Application of the Filter] A filter according to one aspect of the present invention can be applied to various uses. Illustrative examples of applications are described below.

[0044] [2.1. Manufacturing facilities and apparatus for pharmaceutical raw materials or pharmaceuticals] A manufacturing facility and apparatus for pharmaceutical raw materials or pharmaceuticals according to one embodiment of the present invention is equipped with the above-described filter. In this specification, manufacturing facilities and apparatus mean facilities and apparatus that provide a space for manufacturing pharmaceutical raw materials or pharmaceuticals, respectively.

[0045] Since the manufacturing facilities and equipment are equipped with the aforementioned filters, nitrogen oxides are removed from the atmosphere in the space where pharmaceutical raw materials or pharmaceuticals are manufactured. Therefore, pharmaceutical raw materials or pharmaceuticals can be manufactured in a low nitrogen oxide concentration atmosphere, and as a result, pharmaceutical raw materials or pharmaceuticals with reduced nitroso compound content can be manufactured.

[0046] As mentioned above, since the filter according to one embodiment of the present invention has low manufacturing costs, the manufacturing facilities and equipment also have low manufacturing and maintenance costs. In addition, filters that do not contain modifiers are expected to be more readily available and have a reduced risk of quality deterioration.

[0047] The placement of filters in manufacturing facilities and equipment is not particularly limited. For example, air can be drawn into the space where pharmaceutical raw materials or pharmaceuticals are manufactured (such as vents). By placing filters in such locations, a low nitrogen oxide concentration atmosphere can be created within the space where pharmaceutical raw materials or pharmaceuticals are manufactured.

[0048] Specific examples of manufacturing facilities and equipment include manufacturing plants, manufacturing rooms, manufacturing equipment, storage warehouses, storage rooms, storage cabinets, experimental facilities, laboratories, experimental equipment, medical facilities, medical rooms, medical equipment, packaging facilities, packaging rooms, packaging equipment, transportation facilities, transportation rooms, transportation equipment, clean rooms, and some of these.

[0049] [2.2. Air or Compressed Air Manufacturing Apparatus or Supply Apparatus] An air manufacturing apparatus or supply apparatus according to one embodiment of the present invention is equipped with the above-described filter. In this specification, an air manufacturing apparatus means an apparatus that manufactures air by adding some processing to raw material air (such as adding or removing components, increasing or decreasing pressure). In this specification, an air supply apparatus means an apparatus that supplies air into a certain space. The air manufacturing apparatus and the air supply apparatus may be the same apparatus.

[0050] A compressed air production or supply device according to one embodiment of the present invention is equipped with the above-described filter. The compressed air production or supply device is one embodiment of an air production or supply device. In this specification, a compressed air production device means a device that produces compressed air from uncompressed air. In this specification, a compressed air supply device means a device that supplies compressed air into a certain space. The compressed air production device and the supply device may be the same device.

[0051] Since the air or compressed air production and supply apparatus is equipped with the aforementioned filter, nitrogen oxides are removed from the air or compressed air. By supplying this air or compressed air into a certain space, a low nitrogen oxide concentration atmosphere can be provided. Therefore, pharmaceutical raw materials or pharmaceuticals can be manufactured under a low nitrogen oxide concentration atmosphere, and as a result, pharmaceutical raw materials or pharmaceuticals with reduced nitroso compound content can be manufactured.

[0052] Because the filter according to one embodiment of the present invention has low manufacturing costs, the air or compressed air production equipment and supply equipment also have low manufacturing and maintenance costs.

[0053] The placement of filters in air or compressed air production and supply equipment is not particularly limited. Examples include uncompressed air intake, uncompressed air flow path, uncompressed air supply port, compressed air intake, compressed air flow path, and compressed air supply port.

[0054] Specific examples of air production and supply devices include air supply devices. Specific examples of compressed air production and supply devices include compressors. Air or compressed air production and supply devices may also be components of a manufacturing facility or manufacturing equipment.

[0055] [2.3. Method for producing pharmaceutical raw materials or pharmaceuticals, Method for reducing the generation of nitroso compounds in pharmaceutical raw materials or pharmaceuticals] A method for producing pharmaceutical raw materials or pharmaceuticals according to one embodiment of the present invention includes a step of providing a low nitrogen oxide concentration atmosphere by removing nitrogen oxides from air having a nitrogen oxide concentration of 300 ppb or less using the above-mentioned filter. A method for reducing the generation of nitroso compounds in pharmaceutical raw materials or pharmaceuticals according to one embodiment of the present invention includes a step of providing a low nitrogen oxide concentration atmosphere by removing nitrogen oxides from air having a nitrogen oxide concentration of 300 ppb or less using the above-mentioned filter.

[0056] In one embodiment, the manufacturing method and reduction method include a step of manufacturing and / or storing pharmaceutical raw materials or pharmaceuticals under a low nitrogen oxide concentration atmosphere. By including such a step, the content of nitroso compounds mixed into the pharmaceutical raw materials or pharmaceuticals can be reduced.

[0057] As mentioned above, since the filter according to one embodiment of the present invention has low manufacturing costs, the manufacturing method and reduction method can also be implemented at low cost.

[0058] The manufacturing method and reduction method can be implemented, for example, using the manufacturing facilities or equipment described above. Specifically, the manufacturing method and reduction method can be implemented in a manufacturing facility or equipment by creating a low nitrogen oxide concentration atmosphere through a filter in the space where pharmaceutical raw materials or pharmaceuticals are manufactured.

[0059] If the nitrogen oxide concentration in the air before passing through the filter is taken as 100%, then the percentage of nitrogen oxide concentration in a low nitrogen oxide atmosphere represents the residual rate of nitrogen oxides after passing through the filter. By subtracting the residual rate from 100%, the removal efficiency of nitrogen oxides after passing through the filter can be calculated. The removal efficiency of nitrogen oxides may be 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more. In one embodiment, the removal efficiency of nitric oxide and / or nitrogen dioxide may be 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more.

[0060] In one embodiment, the nitrogen oxide concentration in a low nitrogen oxide atmosphere may be 40 ppb or less, 30 ppb or less, 20 ppb or less, 10 ppb or less, 8 ppb or less, 5 ppb or less, 4 ppb or less, 2.9 ppb or less, 1.9 ppb or less, or 0.9 ppb or less. In one embodiment, the concentration of nitric oxide and / or nitrogen dioxide in a low nitrogen oxide atmosphere may be 40 ppb or less, 30 ppb or less, 20 ppb or less, 10 ppb or less, 8 ppb or less, 5 ppb or less, 4 ppb or less, 2.9 ppb or less, 1.9 ppb or less, or 0.9 ppb or less.

[0061] In this specification, nitrogen oxides (NO, NO) contained in the atmosphere ２ The quantitative determination of nitrogen oxides (and these ions, etc.) is based on JIS B 7953. Examples of nitrogen oxide analyzers based on this principle include the NA-721 (Kimoto Electronics Co., Ltd.) and the APNA-380 (Horiba, Ltd.).

[0062] [2.4. Pharmaceutical Raw Materials or Pharmaceuticals] One embodiment of the present invention also includes pharmaceutical raw materials or pharmaceuticals. Pharmaceutical raw materials or pharmaceuticals are present in or have been present in a low nitrogen oxide concentration atmosphere in which the nitrogen oxide concentration is adjusted to 10 ppb or less. In one embodiment, the pharmaceutical raw materials or pharmaceuticals are pharmaceutical raw materials or pharmaceuticals obtained by the manufacturing method described above.

[0063] For example, a pharmaceutical raw material or pharmaceutical product that is present in a low nitrogen oxide concentration atmosphere by controlling storage conditions may be one embodiment of the present invention. Alternatively, a packaged pharmaceutical raw material or pharmaceutical product that is present in a low nitrogen oxide concentration atmosphere by controlling packaging conditions may be one embodiment of the present invention.

[0064] Pharmaceutical raw materials or pharmaceuticals present in a low nitrogen oxide atmosphere are pharmaceutical raw materials or pharmaceuticals that are currently in a reduced nitrogen oxide atmosphere. Pharmaceutical raw materials or pharmaceuticals that were present in a low nitrogen oxide atmosphere are pharmaceutical raw materials or pharmaceuticals that were previously in a reduced nitrogen oxide atmosphere. The period of being (or having been) in a low nitrogen oxide atmosphere may be 1 minute or more, 30 minutes or more, 1 hour or more, 6 hours or more, 12 hours or more, or 1 day or more. The elapsed time since the last time being in a low nitrogen oxide atmosphere may be 1 hour or less, 6 hours or less, 12 hours or less, 1 day or less, 3 days or less, 1 week or less, 2 weeks or less, 3 weeks or less, 1 month or less, 3 months or less, 6 months or less, 9 months or less, or 1 year or less.

[0065] The pharmaceutical raw materials or pharmaceuticals have a reduced nitroso compound content. Assuming the total weight of the pharmaceutical raw materials or pharmaceuticals is 100% by weight, the nitroso compound content is 1 × 10⁻⁶. －３ Weight% or less, 1×10 －４ Weight% or less, 1×10 －５ Less than or equal to % by weight or 1 × 10⁻⁶ －６ It can be less than a percentage by weight.

[0066] [3. Atomoxetine or its salts and pharmaceuticals containing the same] In the embodiments of the present invention described above, the pharmaceutical raw material may be atomoxetine or its salts. In the embodiments of the present invention described above, the pharmaceutical may be a pharmaceutical containing atomoxetine or its salts.

[0067] Atomoxetine or its salts may have a particularly reduced content of nitroso compounds. The content of nitroso compounds may be 1 ppm or less, 0.9 ppm or less, 0.85 ppm or less, 0.83 ppm or less, 0.5 ppm or less, 0.3 ppm or less, 0.2 ppm or less, 0.1 ppm or less, 0.08 ppm or less, 0.05 ppm or less, 0.04 ppm or less, 0.03 ppm or less, or 0.02 ppm or less. In one embodiment, the above numerical ranges represent the content of nitrosoatomoxetine. In one embodiment, the structure of nitrosoatomoxetine is as shown below.

[0068] Atomoxetine or a salt thereof, or a pharmaceutical containing the same, may have a particularly reduced content of nitroso compounds. The content of nitroso compounds may be 1 ppm or less, 0.9 ppm or less, 0.85 ppm or less, 0.83 ppm or less, 0.5 ppm or less, 0.3 ppm or less, 0.2 ppm or less, or 0.15 ppm or less. In one embodiment, the above numerical ranges represent the content of nitrosoatomoxetine. In one embodiment, the structure of nitrosoatomoxetine is as shown above.

[0069] Examples of atomoxetine salts include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate. In one embodiment, the pharmaceutical raw material is atomoxetine hydrochloride. In one embodiment, the pharmaceutical contains atomoxetine hydrochloride.

[0070] Atomoxetine or its salts may be crystalline or amorphous. If atomoxetine or its salts are crystalline, their crystalline form is not particularly limited.

[0071] Atomoxetine or its salt may be anhydrous or hydrated. If atomoxetine or its salt is hydrated, the number of water molecules is not particularly limited.

[0072] In one embodiment, atomoxetine or a salt thereof may be a free anhydrous form, a free hydrate, a salt anhydrous form, a salt hydrate, or any combination thereof.

[0073] Pharmaceutical raw materials or pharmaceuticals may contain adhering water. The presence or content of adhering water in pharmaceutical raw materials or pharmaceuticals is not particularly limited.

[0074] Pharmaceuticals may contain ingredients other than atomoxetine or its salts. Examples of such ingredients include active ingredients other than atomoxetine or its salts, and pharmaceutical additives. Examples of pharmaceutical additives include excipients, disintegrants, binders, lubricants or fluidizers (anti-adhesion agents), colorants, fragrances, sweeteners, preservatives or antiseptics, and coatings. Each of these ingredients may be present individually or in combination of two or more types.

[0075] [4. Duloxetine or its salts and pharmaceuticals containing the same] In the embodiments of the present invention described above, the pharmaceutical raw material may be duloxetine or its salts. In the embodiments of the present invention described above, the pharmaceutical may be a pharmaceutical containing duloxetine or its salts.

[0076] Duloxetine or its salts may have a reduced nitroso compound content. The nitroso compound content may be 1 ppm or less, 0.9 ppm or less, 0.85 ppm or less, 0.83 ppm or less, 0.5 ppm or less, 0.3 ppm or less, 0.2 ppm or less, 0.1 ppm or less, 0.08 ppm or less, 0.05 ppm or less, 0.04 ppm or less, 0.03 ppm or less, or 0.02 ppm or less. In one embodiment, the above numerical ranges represent the nitrosoduloxetine content. In one embodiment, the structure of nitrosoduloxetine is as shown below.

[0077] Pharmaceuticals containing duloxetine or a salt thereof may have a particularly reduced content of nitroso compounds. The content of nitroso compounds may be 2 ppm or less, 1.8 ppm or less, 1.67 ppm or less, 1.6 ppm or less, 1.4 ppm or less, 1.2 ppm or less, 1 ppm or less, 0.9 ppm or less, 0.85 ppm or less, 0.83 ppm or less, 0.5 ppm or less, 0.3 ppm or less, 0.2 ppm or less, or 0.15 ppm or less. In one embodiment, the above numerical ranges represent the content of nitrosoduloxetine. In one embodiment, the structure of nitrosoduloxetine is as shown above.

[0078] Examples of duloxetine salts include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate. In one embodiment, the pharmaceutical raw material is duloxetine hydrochloride. In one embodiment, the pharmaceutical contains duloxetine hydrochloride.

[0079] Duloxetine or its salts may be crystalline or amorphous. If duloxetine or its salts are crystalline, their crystalline form is not particularly limited.

[0080] Duloxetine or its salts may be anhydrous or hydrated. If duloxetine or its salts are hydrated, the number of waters of hydration is not particularly limited.

[0081] In one embodiment, duloxetine or a salt thereof may be a free anhydrous form, a free hydrate, a salt anhydrous form, a salt hydrate, or any combination thereof.

[0082] Pharmaceutical raw materials or pharmaceuticals may contain adhering water. The presence or content of adhering water in pharmaceutical raw materials or pharmaceuticals is not particularly limited.

[0083] Pharmaceuticals may contain ingredients other than duloxetine or its salts. Examples of such ingredients include active ingredients other than duloxetine or its salts, and pharmaceutical additives. Examples of pharmaceutical additives include excipients, disintegrants, binders, lubricants or fluidizers (anti-adhesion agents), colorants, fragrances, sweeteners, preservatives or antiseptics, and coatings. Each of these ingredients may be present individually or in combination of two or more types.

[0084] [Measurement and Evaluation] The methods for measuring the physical properties of the activated carbon and filter used in the examples, and the methods for evaluating the performance of the filters manufactured in the examples are shown below.

[0085] [Shape of activated carbon] The activated carbon was observed visually, and its shape was measured.

[0086] [Filter packing density] The weight of the activated carbon was measured using a weighing scale.

[0087] In the examples and reference examples, the volume of the metal column used as the outer casing of the filter was 40 mL, which was used as the volume of the filter. The ratio of the measured weight of activated carbon to the volume of the filter was calculated and used as the packing density of the filter (unit: g / mL).

[0088] [Average particle size of activated carbon] The value provided by the manufacturer was used as the average particle size.

[0089] [BET specific surface area of ​​activated carbon] The value provided by the manufacturer was used as the BET specific surface area.

[0090] [Filter Performance Evaluation A] The performance of the filters manufactured in Examples 1-1 to 1-8 was measured using the apparatus shown in Figure 1. The specific evaluation procedure is as follows: 1. Air taken in from the atmosphere through the air filter was passed through the compressor and mass flow controller 1 at a flow rate of 2.6 L / min. 2. NO ２ NO taken in from the cylinder ２ This was then passed through the mass flow controller 2 to flow at a rate of 1 mL / min. 3. Air and NO ２The gas was mixed with a static mixer. 4. The mixed gas was passed through a prefilter made by packing approximately 30 g of alumina into a metal column to remove mainly moisture. In this way, the sample air was obtained. Nitrogen oxides (NOx) in the sample air ｘ The concentration of NO was approximately 80 ppb, the pressure was 0.1 MPa, and the flow rate was 1.6 L / min. Almost all of the NO contained in the sample air originated from NO in the atmosphere. 5. The sample air was passed through the filter to be evaluated. At this time, NO ｘ Measuring instrument 1 (Kimoto Electronics Industry Co., Ltd., NA-721) measures NO before it passes through the filter. ｘ Concentration, NO concentration and NO ２ The concentration was measured. Also, NO ｘ Measuring instrument 2 (Kimoto Electronics Industry Co., Ltd., NA-721) measures the NO after it has passed through the filter. ｘ Concentration, NO concentration and NO ２ The concentration was measured. 6. Based on the following formula, NO ｘ Removal efficiency, NO removal efficiency, and NO ２ The removal efficiency was calculated. • NO ｘ Removal efficiency (unit: %) = 100 - {(NOx concentration after passing through the filter / NOx concentration before passing through the filter) × 100} • NO removal efficiency (unit: %) = 100 - {(NO concentration after passing through the filter / NO concentration before passing through the filter) × 100} • NO ２ Removal efficiency (unit: %) = 100 - {(NOx after passing through the filter) ２ Concentration / NO before passing through the filter ２ concentration)×100}

[0091] In evaluating the filter's performance, the sample air was passed through the filter continuously for a predetermined period of time. NO levels were measured throughout the evaluation period. ｘ Removal efficiency, NO removal efficiency, and NO ２ The average removal efficiency is NO in each example. ｘ Removal efficiency, NO removal efficiency, and NO ２ This was defined as the removal efficiency. The performance of the filter was evaluated based on these removal efficiencies.

[0092] [Filter Performance Evaluation B] The performance of the filters manufactured in Examples 1-9 to 1-11 was measured using a modified apparatus of the apparatus shown in Figure 1. That is, an apparatus without a pre-filter downstream of the static mixer was used. The specific evaluation procedure is as follows: 1. Air taken in from the atmosphere through the air filter was passed through the compressor and mass flow controller 1 at a flow rate of 2.6 L / min. 2. NO ２ NO taken in from the cylinder ２ This was then passed through the mass flow controller 2 to flow at a rate of 1 mL / min. 3. Air and NO ２ The gas was mixed with a static mixer. In this way, the sample air was obtained. NO in the sample air. ｘ The concentration was approximately 100 ppb, the pressure was 0.1 MPa, and the flow rate was 1.6 L / min. Almost all of the NO contained in the sample air originated from NO in the atmosphere. 4. The sample air was passed through the filter to be evaluated. At this time, NO ｘ Measuring instrument 1 (Kimoto Electronics Industry Co., Ltd., NA-721) measures NO before it passes through the filter. ｘ Concentration, NO concentration and NO ２ The concentration was measured. Also, NO ｘ Measuring instrument 2 (Kimoto Electronics Industry Co., Ltd., NA-721) measures the NO after it has passed through the filter. ｘ Concentration, NO concentration and NO ２ The concentration was measured. 5. Based on the above formula, NO ｘ Removal efficiency, NO removal efficiency, and NO ２ The removal efficiency was calculated.

[0093] [Example 1] Performance evaluation A (NO ｘ Concentration: approximately 80 ppb) or performance evaluation B (NO ｘ The nitrogen oxide removal capacity of the filter according to one embodiment of the present invention was investigated by applying a concentration of approximately 100 ppb.

[0094] [Example 1-1] A stainless steel pipe (SUS304 TP-A 15A 4M, Nippon Steel Stainless Steel Pipe Co., Ltd.) was cut, and threads were cut into the outer surface so that it could be connected to the threads on the inner surface of a reducer. This was used as a metal column with a volume of 40 mL.

[0095] Activated carbon 1 in a metal column (average particle size: 285 μm, BET specific surface area: 1071 m²) ２ Filter 1 was manufactured by filling it with 26.8 g of activated carbon (spherical). Activated carbon 1 was unmodified activated carbon. The packing density of activated carbon 1 was 0.67 g / mL.

[0096] [Example 1-2] Instead of activated carbon 1, activated carbon 2 (average particle size: 289 μm, BET specific surface area: 1348 m²) ２ Filter 2 was manufactured using the same procedure as in Example 1-1, except that 22.8 g of activated carbon (spherical) was used. Activated carbon 2 was unmodified activated carbon. The packing density of activated carbon 2 was 0.57 g / mL.

[0097] [Examples 1-3] Instead of activated carbon 1, activated carbon 3 (average particle size: 220 μm, BET specific surface area: 1320 m²) ２ Filter 3 was manufactured using the same procedure as in Example 1-1, except that 20.8 g of activated carbon (spherical) was used. Activated carbon 3 was unmodified activated carbon. The packing density of activated carbon 3 was 0.52 g / mL.

[0098] [Example 1-4] Filter 4 was manufactured by performing the same procedure as in Example 1-1, except that 19.2 g of activated carbon 4 (CG48B, Futamura Chemical Co., Ltd., particle size distribution: 96.2% of particles between 2.36 and 5.6 mm, crushed carbon) was used instead of activated carbon 1. Activated carbon 4 was unmodified activated carbon. The packing density of activated carbon 4 was 0.48 g / mL.

[0099] [Example 1-5] Filter 5 was manufactured by performing the same procedure as in Example 1-1, except that 16.0 g of activated carbon 5 (CG48BZ, Futamura Chemical Co., Ltd., particle size distribution: 90.7% of particles between 2.36 and 5.6 mm, crushed carbon) was used instead of activated carbon 1. Activated carbon 5 was unmodified activated carbon. The packing density of activated carbon 5 was 0.40 g / mL.

[0100] [Example 1-6] Filter 6 was manufactured by performing the same procedure as in Example 1-1, except that 22.4 g of activated carbon 6 (CN820B, Futamura Chemical Co., Ltd., particle size distribution: 98.8% of particles between 0.71 and 2.36 mm, crushed carbon) was used instead of activated carbon 1. Activated carbon 6 was unmodified activated carbon. The packing density of activated carbon 6 was 0.56 g / mL.

[0101] [Example 1-7] Filter 7 was manufactured by performing the same procedure as in Example 1-1, except that 21.2 g of activated carbon 7 (GL820B2, Futamura Chemical Co., Ltd., particle size distribution: 98.0% of particles between 0.71 and 2.36 mm, crushed carbon) was used instead of activated carbon 1. Activated carbon 7 was unmodified activated carbon. The packing density of activated carbon 7 was 0.53 g / mL.

[0102] [Example 1-8] Filter 8 was manufactured by performing the same procedure as in Example 1-1, except that 19.2 g of activated carbon 8 (GM820B, Futamura Chemical Co., Ltd., particle size distribution: 94.4% of particles between 0.71 and 2.36 mm, crushed carbon) was used instead of activated carbon 1. Activated carbon 8 was unmodified activated carbon. The packing density of activated carbon 8 was 0.48 g / mL.

[0103] [Examples 1-9] A filter 9 was manufactured by packing 10.0 g of activated carbon 9 (XKC-B, MC Evatec Co., Ltd., pellet form) into a metal column. The activated carbon 9 was activated carbon modified with an impurity agent for acidic gases.

[0104] [Example 1-10] Filter 10 was manufactured by performing the same procedure as in Example 1-9, except that 10.0 g of activated carbon 4 (CG48B, Futamura Chemical Co., Ltd., particle size distribution: 96.2% of particles between 2.36 and 5.6 mm, crushed carbon) was used instead of activated carbon 9. Activated carbon 4 was unmodified activated carbon.

[0105] [Example 1-11] Filter 11 was manufactured by performing the same procedure as in Example 1-9, except that 10.0 g of activated carbon 5 (CG48BZ, Futamura Chemical Co., Ltd., particle size distribution: 90.7% of particles between 2.36 and 5.6 mm, crushed carbon) was used instead of activated carbon 9. Activated carbon 5 was unmodified activated carbon. [Results] The results are shown in Table 1.

[0106] As shown in Table 1, filters 1 to 11 were demonstrated to be able to sufficiently remove nitrogen oxides from air with a nitrogen oxide concentration of 300 ppb or less, and to provide a low nitrogen oxide concentration atmosphere. Furthermore, all filters except filter 9 contain unmodified activated carbon, and these filters have low manufacturing costs.

[0107] It is understood that by utilizing the low nitrogen oxide concentration atmosphere obtained in this way, pharmaceutical raw materials or pharmaceuticals with reduced nitroso compound content can be obtained at low cost.

[0108] [Reference Example 1] We investigated whether high concentrations of nitrogen oxides could be removed using unmodified activated carbon. Specifically, in the experimental system of filter performance evaluation B, NO ２ The flow rate was adjusted to set the nitrogen oxide concentration in the sample air to approximately 5000 ppb. In this experimental setup, the filter to be evaluated was designated as filter 10, and the sample air was passed through it for approximately 4 hours.

[0109] The results are shown in Figure 2. As can be seen from the figure, when sample air containing a high concentration of nitrogen oxides was passed through unmodified activated carbon, the removal of nitrogen oxides was insufficient, and a low nitrogen oxide concentration atmosphere could not be provided. The concentration after passing through the filter at the end of the measurement was NO ２ : 44.3ppb, NO: 179.5ppb, NO ｘ The concentration was 223.8 ppb. The NO concentration is higher than the concentration in typical air, which is due to the reduction reaction of NO ２ This is thought to be because NO was produced from that.

[0110] [Reference Examples 2-4] We investigated whether high concentrations of nitrogen oxides could be removed using the same activated carbon used in the examples. Specifically, we manufactured filters by filling the metal column used in the examples with 3 mL each of the following activated carbons: • Reference Example 2: Activated carbon 4 (same as in Examples 1-4 and 1-10) • Reference Example 3: Activated carbon 5 (same as in Examples 1-5 and 1-11) • Reference Example 4: Activated carbon 9 (same as in Example 1-9)

[0111] In the experimental system for filter performance evaluation B, NO ２ The flow rate was adjusted to achieve a nitrogen oxide concentration of approximately 247 ppm in the sample air. In this experimental setup, the sample air was passed through the fabricated filter for approximately two hours.

[0112] The results are shown in Figure 3. As can be seen from the figure, when sample air containing a high concentration of nitrogen oxides is passed through activated carbon, NO ２ The removal rate of NO decreased sharply, making it impossible to provide a low nitrogen oxide concentration atmosphere. ２ The removal rate decreased to 50% within as little as one hour, and at most within two hours. From this, it can be seen that the filter according to one embodiment of the present invention is effective in removing high concentrations of NO. ２ It can be seen that this cannot be applied to the removal of [the substance].

[0113] [Example 2] An atomoxetine hydrochloride-containing pharmaceutical was manufactured using air that had passed through a filter according to one embodiment of the present invention as both the supply air and compressed air.

[0114] [Manufacturing Example 1] Film-coated tablets of atomoxetine hydrochloride were manufactured according to the following procedure. The materials and quantities used are as shown in Table 2. Note that the quantities listed in Table 2 are the amounts used to manufacture 75,000 5 mg atomoxetine hydrochloride tablets. (Preparation of mixed powder for tableting) 1. Atomoxetine hydrochloride, D-mannitol, and light anhydrous silicic acid were mixed. 2. Partially pregelatinized starch and crystalline cellulose were further added and mixed. 3. Magnesium stearate was added and mixed further. In this way, a mixed powder for tableting was obtained. (Preparation of coating solution) 4. Hypromellose and hydroxypropyl cellulose were added to purified water and dissolved. 5. Titanium dioxide dispersed in purified water was added to the obtained solution. 6. Talc was added to the obtained liquid and stirred to prepare the coating solution. (Manufacturing of film-coated tablets) 7. The mixed powder for tableting was compressed to obtain uncoated tablets. 8. A coating solution was sprayed onto the uncoated tablet and dried to obtain a film-coated tablet.

[0115] In the manufacturing example, the supply air and compressed air used in steps 1 to 8 were filtered air according to one embodiment of the present invention in the example, and unfiltered air in the comparative example. Specifically, in the example, the supply air to the coating apparatus and the compressed air supplied to the coating apparatus were air from which at least a portion of nitrogen oxides had been removed by passing it through a filter. The configuration of the filter used in the example was as follows: ・Supply air filter: From upstream, in order, filter filled with activated carbon 4 → HEPA filter → medium-efficiency filter → HEPA filter (HEPA filter and medium-efficiency filter are for dust removal) ・Compressed air filter: Filter with 100g of activated carbon 4 packed in the column

[0116]

[0117] [Evaluation Method] Nitrosoatomoxetine (structure shown below) contained in the active pharmaceutical ingredient of atomoxetine hydrochloride and in film-coated tablets was quantified by LC / MS analysis (liquid chromatography-mass spectrometry). The specific measurement conditions were as follows: ● Liquid Chromatography - Equipment used: Xevo TQ Absolute (Waters) - Stationary phase: Stainless steel tube (inner diameter 3.0 mm, length 15 cm) packed with biphenylated silica gel for liquid chromatography (average particle size: 2.6 μm) - Mobile phase: Ammonium acetate aqueous solution / methanol mixture ● Mass Spectrometry - Ionization method: ESI - Analytical conditions: MRM (m / z: 302 > 177)

[0118] [Results] The results are shown in Table 3.

[0119] As can be seen from Table 3, the nitroso content increases during the manufacture of film-coated tablets. However, this increase could be significantly reduced by using a filter according to one embodiment of the present invention. As a result, according to the manufacturing method of one embodiment of the present invention, an atomoxetine hydrochloride-containing pharmaceutical with a particularly low nitroso content was obtained.

[0120] [Example 3] A drug containing duloxetine hydrochloride was manufactured using air that had passed through a filter according to one embodiment of the present invention as both the supply air and compressed air.

[0121] [Manufacturing Example 2] Enteric-coated granules of duloxetine hydrochloride were manufactured according to the following procedure. The materials and quantities used are as shown in Table 4. Note that the quantities listed in the total weight column of Table 4 are the amounts used to manufacture 7,500 capsules of 30 mg duloxetine hydrochloride. (Manufacturing of drug granules) 1. Hypromellose was dispersed in ethanol and dissolved in purified water. 2. Duloxetine hydrochloride was added to the obtained solution and stirred to prepare coating solution I. 3. Coating solution I was sprayed onto sucrose / starch spherical granules and dried to obtain drug granules. (Manufacturing of intermediate granules) 4. Hypromellose was added to purified water and dissolved. 5. Talc was added to the obtained solution and stirred. 6. Titanium dioxide dispersed in purified water was added to the obtained liquid and stirred to prepare coating solution II. 7. Coating solution II was sprayed onto drug granules and dried to obtain intermediate granules. (Preparation of enteric-coated granules) 8. Triethyl citrate was added to purified water and dissolved. 9. While cooling the resulting solution to below 10°C in a low-temperature constant-temperature water bath, hypromellose acetate succinate and talc were added and stirred to prepare coating solution III. 10. Coating solution III was sprayed onto the intermediate granules and dried to obtain enteric-coated granules.

[0122] In the manufacturing example 2, the supply air and compressed air used in steps 1 to 10 were filtered air according to one embodiment of the present invention in the example, and unfiltered air in the comparative example. Specifically, in the example, the supply air to the coating apparatus and the compressed air supplied to the coating apparatus were air from which at least a portion of nitrogen oxides had been removed by passing it through a filter. The configuration of the filter used in the example was as follows: ・Supply air filter: From upstream, in order, filter filled with activated carbon 4 → HEPA filter → medium-efficiency filter → HEPA filter (HEPA filter and medium-efficiency filter are for dust removal) ・Compressed air filter: Filter with 60g of activated carbon 4 packed in the column

[0123]

[0124] [Evaluation Method] Nitrosoduloxetine (structure shown below) contained in the active pharmaceutical ingredient and enteric-coated granules of duloxetine hydrochloride was quantified by liquid chromatography-mass spectrometry. Specifically, the method described in ACS Omega 2024, 9, 11, 13440-13446 was followed.

[0125] [Results] The results are shown in Table 5.

[0126] As can be seen from Table 5, the nitroso content increases during the production of enteric-coated granules. However, this increase could be reduced by manufacturing under a filtered atmosphere. As a result, according to the manufacturing method of one embodiment of the present invention, a duloxetine hydrochloride-containing pharmaceutical product with a reduced nitroso content was obtained.

[0127] This invention can be used in the manufacture of pharmaceutical raw materials or pharmaceuticals.

Claims

1. A filter for removing nitrogen oxides from air having a nitrogen oxide concentration of 300 ppb or less, wherein the filter contains activated carbon or an equivalent material.

2. The filter according to claim 1, wherein the activated carbon or equivalent material is substantially unmodified.

3. A manufacturing facility for pharmaceutical raw materials or pharmaceuticals, comprising the filter described in claim 1 or 2.

4. A manufacturing apparatus for pharmaceutical raw materials or pharmaceuticals, comprising the filter described in claim 1 or 2.

5. An air production apparatus or supply apparatus comprising the filter described in claim 1 or 2.

6. A compressed air production apparatus or supply apparatus comprising the filter described in claim 1 or 2.

7. A method for producing pharmaceutical raw materials or pharmaceuticals, comprising the step of removing nitrogen oxides from air having a nitrogen oxide concentration of 300 ppb or less using the filter described in claim 1 or 2, thereby providing a low nitrogen oxide concentration atmosphere.

8. The manufacturing method according to claim 7, comprising the step of manufacturing and / or storing pharmaceutical raw materials or pharmaceuticals under the low nitrogen oxide concentration atmosphere described above.

9. The manufacturing method according to claim 7, wherein the above-mentioned pharmaceutical raw material is atomoxetine or a salt thereof, and the above-mentioned pharmaceutical is a pharmaceutical containing atomoxetine or a salt thereof.

10. The manufacturing method according to claim 7, wherein the above-mentioned pharmaceutical raw material is duloxetine or a salt thereof, and the above-mentioned pharmaceutical is a pharmaceutical containing duloxetine or a salt thereof.

11. A method for reducing the generation of nitroso compounds in pharmaceutical raw materials or pharmaceuticals, comprising the step of removing nitrogen oxides from air having a nitrogen oxide concentration of 300 ppb or less using the filter described in claim 1 or 2 to provide a low nitrogen oxide concentration atmosphere.

12. The method according to claim 11, further comprising the step of manufacturing and / or storing pharmaceutical raw materials or pharmaceuticals under the low nitrogen oxide concentration atmosphere described above.

13. The method according to claim 11, wherein the above-mentioned pharmaceutical raw material is atomoxetine or a salt thereof, and the above-mentioned pharmaceutical is a pharmaceutical containing atomoxetine or a salt thereof.

14. The method according to claim 11, wherein the above-mentioned pharmaceutical raw material is duloxetine or a salt thereof, and the above-mentioned pharmaceutical is a pharmaceutical containing duloxetine or a salt thereof.

15. A method for producing pharmaceutical raw materials or pharmaceuticals, comprising the step of producing and / or storing pharmaceutical raw materials or pharmaceuticals in a low nitrogen oxide concentration atmosphere in which the nitrogen oxide concentration is adjusted to 10 ppb or less by a filter according to claim 1 or 2.

16. The manufacturing method according to claim 15, wherein the above-mentioned pharmaceutical raw material is atomoxetine or a salt thereof, and the above-mentioned pharmaceutical is a pharmaceutical containing atomoxetine or a salt thereof.

17. The manufacturing method according to claim 15, wherein the above-mentioned pharmaceutical raw material is duloxetine or a salt thereof, and the above-mentioned pharmaceutical is a pharmaceutical containing duloxetine or a salt thereof.

18. A method for reducing the generation of nitroso compounds in pharmaceutical raw materials or pharmaceuticals, comprising the step of manufacturing and / or storing pharmaceutical raw materials or pharmaceuticals in a low nitrogen oxide concentration atmosphere in which the nitrogen oxide concentration is adjusted to 10 ppb or less by the filter described in claim 1 or 2.

19. The method according to claim 18, wherein the above-mentioned pharmaceutical raw material is atomoxetine or a salt thereof, and the above-mentioned pharmaceutical is a pharmaceutical containing atomoxetine or a salt thereof.

20. The method according to claim 18, wherein the above-mentioned pharmaceutical raw material is duloxetine or a salt thereof, and the above-mentioned pharmaceutical is a pharmaceutical containing duloxetine or a salt thereof.

21. A pharmaceutical raw material or pharmaceutical containing a nitroso compound that is capable of generating and / or causing the generation of a nitroso compound, and which is present in or has been present in a low nitrogen oxide atmosphere in which the nitrogen oxide concentration is adjusted to 10 ppb or less.

22. The pharmaceutical raw material according to claim 21 or a pharmaceutical containing the same, wherein the above-mentioned pharmaceutical raw material is atomoxetine or a salt thereof.

23. The pharmaceutical raw material according to claim 21 or a pharmaceutical containing the same, wherein the above-mentioned pharmaceutical raw material is duloxetine or a salt thereof.

Images