Method for reducing generation of nitroso compounds in drug raw material or drug

Abstract

To provide a method for reducing the generation of nitroso compounds in a drug raw material or a drug.SOLUTION: This method includes the following step A and / or B. Step A: a step for removing at least a portion of nitrogen oxides in an atmosphere that comes into contact with the drug raw material or the drug. Step B: a step for producing and / or storing the drug raw material or the drug under an atmosphere where the content of the nitrogen oxides is 50 ppb or less.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] The present invention relates to a method for reducing the formation of nitroso compounds in pharmaceutical raw materials or pharmaceuticals. [Background technology]

[0002] Nitroso compounds are a general term for compounds in which a nitroso group is bonded to the nitrogen atom of an amine. Their general structure is N(R 1 )(R 2 )-N=O. Some nitroso compounds are suspected of being carcinogenic, and there have been cases where pharmaceuticals containing nitroso compounds have been voluntarily recalled (see, for example, Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Ministry of Health, Labour and Welfare Notification (PSEHB / PDA Notification No. 1008-1, PSEHB / SD Notification No. 1008-1, PSEHB / SD Notification No. 1008-1) "Voluntary Inspection for the Risk of Nitrosamine Contamination in Pharmaceuticals" October 8, 2021 Summary of the Invention [Problem to be solved by the invention]

[0004] As mentioned above, nitroso compounds are suspected of being carcinogenic, and therefore it has been desirable to develop a method for reducing the formation of nitroso compounds in pharmaceutical raw materials and medicines.

[0005] One aspect of the present invention aims to provide a method for reducing the formation of nitroso compounds in pharmaceutical raw materials or pharmaceuticals. [Means for solving the problem]

[0006] The present invention includes the following aspects. <1> 1. A method for reducing the formation of nitroso compounds in a pharmaceutical raw material or pharmaceutical, comprising: A method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical; Step B: A step of producing and / or storing the pharmaceutical raw material or the pharmaceutical in an atmosphere having a nitrogen oxide content of 50 ppb or less. <2> a step of producing and / or storing the pharmaceutical raw material or the pharmaceutical in an atmosphere having a nitrogen oxide content of 10 ppb or less; <1> The method described below. <3> The above step A and / or step B are achieved by the following step C and / or step D. <1> or <2> Method to do this: Step C: introducing second air obtained by removing at least a portion of nitrogen oxides from the first air as an atmosphere to be in contact with the pharmaceutical raw materials or the pharmaceutical; Step D: A step of capturing at least a portion of the nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical. <4> In the step C, the first air is passed through a filter to obtain the second air from which at least a portion of the nitrogen oxides contained in the first air has been removed. <3> The method described below. <5> The pharmaceutical raw material has an amino group or a substituted amino group. <1> ~ <4> A method according to any one of the preceding claims. <6> A method for producing a pharmaceutical raw material capable of generating and / or causing generation of a nitroso compound, or a pharmaceutical containing the same, comprising: A manufacturing method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical; Step B: A step of producing and / or storing the pharmaceutical raw material or the pharmaceutical in an atmosphere having a nitrogen oxide content of 50 ppb or less. <7> a step of producing and / or storing the pharmaceutical raw material or the pharmaceutical in an atmosphere having a nitrogen oxide content of 10 ppb or less; <6> The manufacturing method described in <8> The above step A and / or step B are achieved by the following step C and / or step D. <6> or <7> The manufacturing method described in Step C: introducing second air obtained by removing at least a portion of nitrogen oxides from the first air as an atmosphere to be in contact with the pharmaceutical raw materials or the pharmaceutical; Step D: A step of capturing at least a portion of the nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical. <9> In the step C, the first air is passed through a filter to obtain the second air from which at least a portion of the nitrogen oxides contained in the first air has been removed. <8> The manufacturing method described in <10> The pharmaceutical raw material has an amino group or a substituted amino group. <6> ~ <9> 1. The manufacturing method according to any one of the preceding claims. <11> A pharmaceutical raw material capable of generating and / or causing generation of a nitroso compound, or a pharmaceutical containing the same, Pharmaceutical raw materials or medicines containing them that meet the following conditions A and / or B: Condition A: The atmosphere is one in which at least a portion of nitrogen oxides has been removed; Condition B: The substance is present in an atmosphere in which the nitrogen oxide content is 50 ppb or less. <12> It exists in an atmosphere where the nitrogen oxide content is 10 ppb or less, <11> 1. A pharmaceutical raw material according to claim 1, or a medicine containing the same. <13> The above condition A and / or the above condition B are achieved by the following condition C and / or condition D: <11> or <12> Pharmaceutical raw materials or medicines containing the same according to Condition C: The atmosphere in contact with the pharmaceutical raw material or the pharmaceutical is second air obtained by removing at least a portion of nitrogen oxides from the first air; Condition D: In the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical, at least a portion of the nitrogen oxides contained in the atmosphere is captured by a capture unit that captures at least a portion of the nitrogen oxides. <14> Under the condition C, the first air is passed through a filter to obtain the second air from which at least a portion of the nitrogen oxides contained in the first air has been removed. <13> 1. A pharmaceutical raw material according to claim 1, or a medicine containing the same. <15> A pharmaceutical raw material capable of generating and / or causing generation of a nitroso compound, or a pharmaceutical containing the same, Pharmaceutical raw materials or medicines containing them that meet the following conditions A' and / or B': Condition A': The material was in an atmosphere from which at least a portion of nitrogen oxides had been removed; Condition B': The sample was in an atmosphere with a nitrogen oxide content of 50 ppb or less. <16> The substance was in an atmosphere with a nitrogen oxide content of 10 ppb or less. <15> 1. A pharmaceutical raw material according to claim 1, or a medicine containing the same. <17> The above condition A' and / or the above condition B' are achieved by the following condition C' and / or condition D'. <15> or <16> Pharmaceutical raw materials or medicines containing the same according to Condition C': The atmosphere that has been in contact with the pharmaceutical raw material or the pharmaceutical is second air from which at least a portion of nitrogen oxides has been removed from the first air; Condition D': At least a portion of the nitrogen oxides contained in the atmosphere that has been in contact with the pharmaceutical raw material or the pharmaceutical has been captured by a capture unit that captures at least a portion of the nitrogen oxides contained in the atmosphere. <18> Under the condition C', the first air is passed through a filter to obtain the second air from which at least a portion of the nitrogen oxides contained in the first air has been removed. <17> 1. A pharmaceutical raw material according to claim 1, or a medicine containing the same. <19> The pharmaceutical raw material has an amino group or a substituted amino group. <11> ~ <18> 1. A pharmaceutical raw material according to any one of the preceding items or a medicine containing the same. <20> A facility or equipment for reducing the generation of nitroso compounds in the production and / or storage of pharmaceutical raw materials that may generate and / or cause the generation of nitroso compounds or pharmaceuticals containing the same, A removal unit is provided which removes at least a portion of nitrogen oxides contained in the atmosphere. Facilities or equipment. <21> The removal unit is the following means C and / or means D: <20> The facilities or equipment listed in: Means C: a removal unit that removes at least a portion of the nitrogen oxides contained in the first air to produce second air; Means D: A trapping section that traps at least a portion of the nitrogen oxides contained in the atmosphere. <22> The means C is a filter. <21> The facilities or equipment described in. <23> The pharmaceutical raw material has an amino group or a substituted amino group. <20> ~ <22> Any facility or equipment described in any of the above. <24> A package in which a pharmaceutical raw material capable of generating and / or causing the generation of a nitroso compound or a pharmaceutical containing the same is contained in a packaging container, Condition A below *and / or Condition B * The packaging meets: Condition A * : housed with a trapping portion that traps at least a portion of the nitrogen oxides contained in the atmosphere; Condition B * The nitrogen oxide content in the atmosphere inside the packaging container is 50 ppb or less. <25> The nitrogen oxide content in the atmosphere inside the packaging container is 10 ppb or less. <24> The package described in <26> The pharmaceutical raw material has an amino group or a substituted amino group. <24> or <25> The package described in <27> A pharmaceutical composition comprising atomoxetine or a salt thereof, The content of nitroso compounds in the pharmaceutical composition is 1 ppm or less. Pharmaceutical compositions. <28> 1. A method for producing a pharmaceutical composition comprising atomoxetine or a salt thereof, comprising: A manufacturing method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in an atmosphere that comes into contact with atomoxetine or a salt thereof, or the pharmaceutical composition; Step B: producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 50 ppb or less; Here, the content of nitroso compounds in the pharmaceutical composition is 1 ppm or less. <29> and producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 10 ppb or less. <28> The manufacturing method described in <30> 1. A method for reducing the formation of nitroso compounds in a pharmaceutical composition containing atomoxetine or a salt thereof, comprising: A method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in an atmosphere that comes into contact with atomoxetine or a salt thereof, or the pharmaceutical composition; Step B: producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 50 ppb or less; Here, the content of nitroso compounds in the pharmaceutical composition is 1 ppm or less. <31> and producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 10 ppb or less. <30> The method described below. <32> A pharmaceutical composition comprising duloxetine or a salt thereof, The content of nitroso compounds in the pharmaceutical composition is 1 ppm or less. Pharmaceutical compositions. <33> 1. A method for preparing a pharmaceutical composition comprising duloxetine or a salt thereof, comprising: A manufacturing method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in an atmosphere that comes into contact with duloxetine or a salt thereof, or the pharmaceutical composition; Step B: producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 50 ppb or less; Here, the content of nitroso compounds in the pharmaceutical composition is 1 ppm or less. <34> and producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 10 ppb or less. <33> The manufacturing method described in <35> 1. A method for reducing the formation of nitroso compounds in a pharmaceutical composition containing duloxetine or a salt thereof, comprising: A method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in an atmosphere that comes into contact with duloxetine or a salt thereof, or the pharmaceutical composition; Step B: producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 50 ppb or less; Here, the content of nitroso compounds in the pharmaceutical composition is 1 ppm or less. <36> and producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 10 ppb or less. <35> The method described below.

[0007] The present invention also includes the following aspects. <1a> 1. A method for reducing the formation of nitroso compounds in a pharmaceutical raw material or pharmaceutical, comprising: A method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical; Step B: A step of producing and / or storing the pharmaceutical raw material or the pharmaceutical in an atmosphere having a nitrogen oxide content of 50 ppb or less. <2a> The method according to <1a>, wherein the step A and / or the step B is achieved by the following step C and / or step D: Step C: introducing air from which at least a portion of nitrogen oxides has been removed from the outside air as an atmosphere to be in contact with the pharmaceutical raw materials or the pharmaceutical; Step D: A step of capturing at least a portion of the nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical. <3a> In the step C, the outside air is passed through a filter to remove at least a portion of the nitrogen oxides contained in the outside air. The method described in <2a>. <4a> The pharmaceutical raw material has an amino group or a substituted amino group. The method according to any one of <1a> to <3a>. <5a> A method for producing a pharmaceutical raw material capable of generating and / or causing generation of a nitroso compound, or a pharmaceutical containing the same, comprising: A manufacturing method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical; Step B: A step of producing and / or storing the pharmaceutical raw material or the pharmaceutical in an atmosphere having a nitrogen oxide content of 50 ppb or less. <6a> The manufacturing method according to <5a>, wherein the step A and / or the step B is achieved by the following step C and / or step D: Step C: introducing air from which at least a portion of nitrogen oxides has been removed from the outside air as an atmosphere to be in contact with the pharmaceutical raw materials or the pharmaceutical; Step D: A step of capturing at least a portion of the nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical. <7a> In the step C, the outside air is passed through a filter to remove at least a portion of the nitrogen oxides contained in the outside air. The manufacturing method described in <6a>. <8a> The pharmaceutical raw material has an amino group or a substituted amino group. The method according to any one of <5a> to <7a>. <9a> A pharmaceutical raw material capable of generating and / or causing generation of a nitroso compound, or a pharmaceutical containing the same, Pharmaceutical raw materials or medicines containing them that meet the following conditions A and / or B: Condition A: The atmosphere is one in which at least a portion of nitrogen oxides has been removed; Condition B: The substance is present in an atmosphere in which the nitrogen oxide content is 50 ppb or less. <10a> A pharmaceutical raw material or a medicine containing the same according to <9a>, wherein the above condition A and / or the above condition B are achieved by the following condition C and / or condition D: Condition C: The atmosphere in contact with the pharmaceutical raw material or the pharmaceutical is air from which at least a portion of nitrogen oxides has been removed; Condition D: In the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical, at least a portion of the nitrogen oxides contained in the atmosphere is captured by a capture unit that captures at least a portion of the nitrogen oxides. <11a> Condition A and / or Condition B are achieved by Condition C, Condition C above is achieved by the outside air passing through the filter. <10a> A pharmaceutical raw material or a medicine containing the same. <12a> The pharmaceutical raw material has an amino group or a substituted amino group. A pharmaceutical raw material according to any one of <9a> to <11a> or a medicine containing the same. <13a> A facility or equipment for reducing the generation of nitroso compounds in the production and / or storage of pharmaceutical raw materials that may generate and / or cause the generation of nitroso compounds or pharmaceuticals containing the same, A removal unit is provided which removes at least a portion of nitrogen oxides contained in the atmosphere. Facilities or equipment. <14a> The removal unit is the facility or equipment according to <13a>, which is the following means C and / or means D: Means C: a removal unit that removes at least a portion of nitrogen oxides contained in the outside air; Means D: A trapping section that traps at least a portion of the nitrogen oxides contained in the atmosphere. <15a> The means C is a filter. Facilities or equipment described in <14a>. <16a> The pharmaceutical raw material has an amino group or a substituted amino group. Facilities or equipment described in any of <13a> to <15a>. <17a> A package in which a pharmaceutical raw material capable of generating and / or causing the generation of a nitroso compound or a pharmaceutical containing the same is contained in a packaging container, Packages that meet condition A' and / or condition B' below: Condition A': The device is housed with a capture unit that captures at least a portion of the nitrogen oxides contained in the atmosphere; Condition B': The nitrogen oxide content in the atmosphere inside the packaging container is 50 ppb or less. <18a> The pharmaceutical raw material has an amino group or a substituted amino group. Packages as described in <17a>. [Effects of the Invention]

[0008] According to one aspect of the present invention, there is provided a method for reducing the formation of nitroso compounds in a pharmaceutical raw material or pharmaceutical. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 is a schematic diagram showing an outline of the experimental system employed in Example 1. [Figure 2] 1 is a graph showing the results of Example 1. [Figure 3] 1 is a graph showing the results of Example 2. [Figure 4] 1 is a graph showing the results of Example 3-4, in which filter unit D was used. [Figure 5] 1 is a graph showing the results of Example 3-4, in which filter unit E was used. [Figure 6] 4 is a graph showing the results of Example 4-1, in which nitrogen oxides were removed from the intake air. [Figure 7] 4 is a graph showing the results of Example 4-2, in which nitrogen oxides were removed from compressed air. DETAILED DESCRIPTION OF THE INVENTION

[0010] An embodiment of the present invention will be described below, but the present invention is not limited thereto. The present invention is not limited to the configurations described below, and various modifications are possible within the scope of 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. In this specification, unless otherwise specified, "A to B" representing a numerical range means "greater than or equal to A and less than or equal to B."

[0011] In this specification, nitrogen oxides is a general term for compounds mainly composed of nitrogen and oxygen atoms. Examples of nitrogen oxides include nitric oxide (NO), nitrogen dioxide (NO2), nitrogen trioxide (NO3), dinitrogen monoxide (NO), dinitrogen trioxide (NO3), dinitrogen tetroxide (NO4), and dinitrogen pentoxide (NO5). Substances such as ions composed of nitrogen and oxygen atoms are also included in nitrogen oxides. Examples of such ions include NO + , NO2 - , NO3 - In one embodiment, the nitrogen oxide may contain atoms other than nitrogen and oxygen atoms (such as hydrogen atoms). The number of atoms other than nitrogen and oxygen atoms may be 5 or less, 4 or less, 3 or less, or 2 or less. Examples of nitrogen oxides having such heteroatoms include HNO2, H2NO2 + In one embodiment, the nitrogen oxides contain no atoms other than nitrogen and oxygen atoms.

[0012] In this specification, where a specific nitrogen oxide is mentioned, the ion of that nitrogen oxide is also intended unless otherwise specified. For example, the expressions "nitric oxide" and "NO" also include the ion. Similarly, the expressions "nitric dioxide" and "NO2" also include 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.

[0013] As used herein, pharmaceutical raw materials include components that serve as raw materials for pharmaceuticals, such as active pharmaceutical ingredients and pharmaceutical additives, as well as starting materials, intermediates, and impurities in the manufacturing process of such components. Impurities in the manufacturing process include impurities that cannot be removed due to technical issues as well as impurities that cannot be removed due to cost issues. In one embodiment, pharmaceutical raw materials are components 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 components that serve as raw materials for pharmaceuticals. As used herein, a pharmaceutical refers to a composition obtained by combining pharmaceutical raw materials. A pharmaceutical may contain starting materials, intermediates, and / or impurities in the manufacturing process of the pharmaceutical raw materials.

[0014] 1. Methods for reducing the formation of nitroso compounds According to new findings by the present inventors, nitrogen oxides in the atmosphere are involved in the generation of nitroso compounds in pharmaceutical raw materials or medicines (see the Examples of the present application). Therefore, in order to reduce the generation of nitroso compounds, it is essential to use pharmaceutical raw materials or pharmaceutical ingredients with a low content of nitrite, and to handle the pharmaceutical raw materials or medicines in an environment that does not adsorb nitrogen oxides contained in the air. Therefore, the generation of nitroso compounds can be reduced by handling pharmaceutical raw materials or medicines containing them in an atmosphere with low levels of nitrogen oxides. Specifically, the generation of nitroso compounds in pharmaceutical raw materials or medicines can be reduced by a method including Step A and / or Step B. Step A: A step of removing at least a portion of nitrogen oxides in the atmosphere that comes into contact with pharmaceutical raw materials or pharmaceuticals. Step B: A step of producing and / or storing pharmaceutical raw materials or pharmaceuticals in an atmosphere having a nitrogen oxide content of 50 ppb or less.

[0015] In step A, the atmosphere is appropriately treated to remove at least a portion of the nitrogen oxides in the atmosphere. Step A encompasses not only the removal of at least a portion of the nitrogen oxides contained in the "atmosphere currently in contact with the pharmaceutical raw materials or the pharmaceutical," but also the removal of at least a portion of the nitrogen oxides contained in the "air that will become the atmosphere that will come into contact with the pharmaceutical raw materials or the pharmaceutical in a later step." For example, step A also anticipates supplying air from which at least a portion of the nitrogen oxides has been removed, as the atmosphere that will come into contact with the pharmaceutical raw materials or the pharmaceutical. This is evident from the fact that Section [2.3] of this specification lists a removal unit (such as a filter, as described in Section [1.3]) that removes at least a portion of the nitrogen oxides "contained in the ambient air" as an application in the "facility or equipment."

[0016] The reduction rate of nitrogen oxides in the air (e.g., atmosphere) before and after step A 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, based on the concentration of nitrogen oxides in the air (e.g., atmosphere) before step A. The reduction rate of nitric oxide and / or nitrogen dioxide in the air (e.g., atmosphere) before and after step A 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, based on the content of the same gases in the air (e.g., atmosphere) before step A.

[0017] In step B, the pharmaceutical raw material or the pharmaceutical containing the same is produced, stored, or produced and stored in an atmosphere with a low nitrogen oxide content. The nitrogen oxide content in the atmosphere in step B may be 40 ppb or less, 30 ppb or less, 20 ppb or less, 10 ppb or less, or 5 ppb or less. The nitric oxide and / or nitrogen dioxide content in the atmosphere in step B may be 40 ppb or less, 30 ppb or less, 20 ppb or less, 10 ppb or less, or 5 ppb or less.

[0018] By applying this method, the amount of nitroso compounds contained in the pharmaceutical raw material or the pharmaceutical containing it may be reduced by 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.

[0019] In this specification, the quantitative determination of nitrogen oxides (NO, NO, and their ions, etc.) contained in the atmosphere is based on JIS B 7953. Examples of nitrogen oxide measuring instruments based on this principle include the NA-721 (Kimoto Electronics Co., Ltd.) and the APNA-380 (Horiba, Ltd.).

[0020] In this specification, the quantification of nitroso compounds contained in pharmaceutical raw materials or pharmaceuticals containing them is carried out by LC / MS analysis, GC / MS analysis, or HPLC analysis depending on the type of nitroso compound to be measured. When multiple measurement methods are available, LC / MS analysis is given the highest priority, followed by GC / MS analysis.

[0021] There is no particular limitation on the means for achieving step A and / or step B. In one embodiment, step A and / or step B are achieved by step C and / or step D. Step C: A step of introducing the second air obtained by removing at least a portion of the nitrogen oxides from the first air as an atmosphere to be contacted with the pharmaceutical raw materials or the pharmaceutical. Step D: A step of capturing at least a portion of the nitrogen oxides in the atmosphere in contact with the pharmaceutical raw material or pharmaceutical.

[0022] Process C is relatively easy to apply to large-scale targets such as facilities, equipment, and devices. A specific example of process C is passing first air through a filter to remove at least a portion of the nitrogen oxides contained in the first air to produce second air. Examples of first air include outside air, as well as gases and their raw materials that are introduced into equipment or lines. An example of gas that is introduced into equipment or lines is compressed air. The first air may be second air in an upstream process. For example, some nitrogen oxides may be removed from outside air (first air) to supply air (second air) to a facility, and then some nitrogen oxides may be further removed from the air (first air) inside the facility to produce compressed air (second air). The filter is, for example, a filter that can oxidize, adsorb, or decompose nitrogen oxides. In one embodiment, the filter oxidizes and further adsorbs or decomposes nitrogen oxides. For example, the outside air, which is the first air, may be pretreated before passing through the filter. Examples of pretreatment include air compression and adjustment of the components contained in the air.

[0023] Step D is easily applicable to both large and small targets. A specific example of Step D is providing a trapping unit for trapping nitrogen oxides in the same atmosphere as that in which a pharmaceutical raw material or a pharmaceutical containing the same comes into contact. The trapping unit contains, for example, a substance capable of adsorbing or decomposing nitrogen oxides. Examples of such substances include the substances described below as substances that adsorb nitrogen oxides.

[0024] [1.1. Nitroso compounds] As used herein, a nitroso compound is defined as a compound represented by N(R 1 )(R 2 R is a compound having a structure represented by the general formula: -N=O. 1 and R 2 The structures of R are independent of each other and are, for example, hydrocarbon groups which may have a heteroatom-containing group. 1 and R 2may be bonded to form a ring. Examples of hydrocarbon groups include alkyl groups, cycloalkyl groups, and aryl groups. A heteroatom-containing group may consist solely of one or more heteroatom atoms, or may contain one or more heteroatom atoms and both carbon and / or hydrogen atoms.

[0025] 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), N-nitrosomorpholine (NMOR), etc. These nitroso compounds are generally present as impurities in pharmaceutical raw materials or pharmaceuticals.

[0026] Other examples of nitroso compounds include compounds in which the pharmaceutical raw material itself is nitrosated, such as nitrosoorphenadrine, nitrosoquinapril, nitrosorasagiline, nitrosopropranolol, nitrosoamoxapine, nitrosovarenicline, nitrosoduloxetine, and nitrosoatomoxetine.

[0027] [1.2. Pharmaceutical raw materials that can generate and / or cause the generation of nitroso compounds] Pharmaceutical raw materials that may and / or can generate nitroso compounds are classified into the following types. However, these types do not cover all pharmaceutical raw materials that may and / or can generate nitroso compounds. Furthermore, pharmaceutical raw materials that may and / or can generate nitroso compounds may fall into multiple types.

[0028] Pharmaceutical raw materials containing amino groups or substituted amino groups The first type is a pharmaceutical raw material having an amino group or a substituted amino group. An amino group is a functional group represented by -NH2. A substituted amino group is a functional group in which one or two hydrogen atoms contained in an amino group are substituted with other groups. 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.

[0029] Pharmaceutical raw materials in which amines are used as starting materials, intermediates and / or catalysts The second type is pharmaceutical raw materials that use amines as starting materials, intermediates, and / or catalysts in their production. These pharmaceutical raw materials may produce nitroso compounds due to nitrosation of the remaining starting materials, intermediates, and / or catalysts. The amines may be primary, secondary, or tertiary amines. 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. Metformin hydrochloride, as discussed in Examples 1 and 2 of the present application, falls into this category because it is synthesized using dimethylamine hydrochloride as a starting material.

[0030] Pharmaceutical raw materials whose decomposition products may be nitrosated The third type is a pharmaceutical raw material whose decomposition products can be nitrosated. The pharmaceutical raw material before decomposition may or may not have a moiety 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.

[0031] Pharmaceutical raw materials whose impurities cause nitroso compounds Talc, which is widely used as a pharmaceutical raw material, contains nitrite as an impurity, which can either be converted to form nitroso compounds or can convert other substances to form nitroso compounds.

[0032] [1.3. Means for removing or capturing nitrogen oxides] The means for removing or capturing nitrogen oxides is a means capable of oxidizing, adsorbing, and / or decomposing nitrogen oxides. In one embodiment, the means oxidizes, adsorbs, and / or decomposes nitrogen oxides. By using this means, at least a portion of the nitrogen oxides in the atmosphere can be removed. Alternatively, by using this means, the nitrogen oxide content in the atmosphere can be reduced to 50 ppb or less (e.g., 10 ppb or less). This means can function as a remover and / or a trapper. The remover is a component that removes at least a portion of the nitrogen oxides in the air (e.g., in the atmosphere) to provide an atmosphere with a reduced nitrogen oxide content. The trapper is a component that traps at least a portion of the nitrogen oxides in the atmosphere to provide an atmosphere with a reduced nitrogen oxide content. A component may function as both a remover and a trapper.

[0033] Examples of means for removing or capturing nitrogen oxides include the following types. However, these types do not cover all means for removing or capturing nitrogen oxides. Furthermore, some means for removing or capturing nitrogen oxides may fall into multiple types.

[0034] ◆ Use of substances that adsorb nitrogen oxides Examples include activated carbon, alumina, zeolite, calcium hydroxide, metal oxides (such as oxides of alkaline earth metals, alkali metals, rare earth metals, and combinations thereof), silica gel, etc. Examples of zeolites include molecular sieve 3A, molecular sieve 13X, mordenite zeolite, etc., and further examples include the zeolites described in WO 2019 / 042884.

[0035] ◆ Use of reducing agents and reduction catalysts When nitrogen oxides are combusted in contact with a reducing agent and a reduction catalyst, the nitrogen oxides are decomposed into water and nitrogen. Examples of reducing agents include hydrogen, ammonia, and hydrocarbons. Examples of reduction catalysts include vanadium-titania supports, precious metal-based catalysts, precious metal-hydrophobic supports, zeolite-based catalysts, alumina-based catalysts, iron ore catalysts, and activated coke catalysts.

[0036] Use of bases Among nitrogen oxides, nitrogen dioxide (NO2), nitrogen trioxide (NO3), and their ions are acidic when dissolved in water and can be neutralized and / or chemically adsorbed by a base. Examples of bases include hydroxide salts (lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, cesium hydroxide, etc.), carbonate salts (lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate, cesium carbonate, etc.), bicarbonate salts (lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), hydride salts (sodium hydride, potassium hydride, etc.), phosphate salts (lithium phosphate, sodium phosphate, potassium phosphate, calcium phosphate, barium phosphate, cesium phosphate, etc.), and phosphate bihydrogen salts (lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, etc.).

[0037] In embodiments using a base, it is preferable to oxidize nitric oxide (NO) to nitrogen dioxide (NO) beforehand, if necessary. Such a treatment can also remove nitric oxide contained in the atmosphere. Examples of oxidizing agents that can be used for oxidation include persulfuric acid or its salts (persulfuric acid, ammonium persulfate, sodium persulfate, potassium persulfate, etc.), divalent or trivalent iron salts (FeCl, FeBr, FeSO, FeCl, FeBr, Fe(SO), Fe(NO), hydrates thereof, etc.), permanganates (sodium permanganate, potassium permanganate, magnesium permanganate, etc.), dichromates (ammonium dichromate, potassium dichromate, etc.), and hydrogen peroxide.

[0038] ◆Replacement of atmosphere The nitrogen oxide content in the atmosphere can be reduced to 50 ppb or less (e.g., 10 ppb or less) by replacing the atmosphere with a gas containing little or no nitrogen oxides. The replacing gas can be, for example, an inert gas (nitrogen, rare gas, etc.).

[0039] The above-mentioned means may be used alone or in combination. A specific example of a combination is the following filter unit. Filter unit A: A filter unit with pellet-shaped activated alumina as the base material and sodium permanganate and / or potassium permanganate as the additive. Filter unit B: A filter unit that uses crushed highly refined activated carbon as a base material and potassium carbonate as an additive. Filter unit C: A filter unit with granular activated carbon woven into nonwoven fabric as the base material and potassium carbonate as an additive. Filter unit D: A filter unit made by sandwiching activated carbon between two sheets of nonwoven fabric and forming them into pleats. Filter unit E: A filter unit with an anion as an adsorbent for acid gas adsorption.

[0040] The above-mentioned filter units can be further combined for use. Examples of combinations include the following (listed in the order in which the first air, such as outside air, passes through): Filter unit A → Filter unit B Filter unit A → Filter unit B → Filter unit C Filter unit A → Filter unit C Filter unit A → Filter unit C → Filter unit C

[0041] [2. Application of the method] The method described in Section [1] can be applied to manufacturing methods, pharmaceutical raw materials, pharmaceuticals, packaging, facilities, equipment, etc. Each application aspect will be explained separately below.

[0042] [2.1. Pharmaceutical raw materials or pharmaceutical manufacturing methods] The method described in Section [1] can be applied to a method for producing a pharmaceutical raw material capable of generating and / or causing generation of a nitroso compound, or a pharmaceutical containing the same. This production method includes the above-mentioned step A and / or step B. Step A and / or step B may be achieved by the above-mentioned step C and / or step D. This production method can employ any embodiment described in Section [1] or a combination thereof.

[0043] In the manufacturing method, examples of locations where an atmosphere low in nitrogen oxides is introduced include manufacturing plants, manufacturing rooms, manufacturing equipment, storage warehouses, storage rooms, storage facilities, laboratory rooms, laboratory 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.

[0044] Examples of manufacturing processes that are carried out in an atmosphere with low levels of nitrogen oxides include synthesis, purification, pulverization, dissolution, mixing, granulation, drying, tableting, coating, filling into capsules, packaging in packaging materials, and storage.

[0045] [2.2. Pharmaceutical raw materials, medicines and their packaging] The method described in Section [1] can be applied to a pharmaceutical raw material or a medicine containing the same, which satisfies the following conditions A and / or B corresponding to the above-mentioned step A and / or step B. Condition A: The atmosphere is one from which at least a portion of nitrogen oxides has been removed. Condition B: The substance is present in an atmosphere in which the nitrogen oxide content is 50 ppb or less (for example, 10 ppb or less).

[0046] Condition A and / or Condition B may be achieved by the following Condition C and / or Condition D, which correspond to the above-mentioned Step C and / or Step D. Condition C: The atmosphere that comes into contact with the pharmaceutical raw materials or pharmaceuticals is the second air from which at least a portion of the nitrogen oxides has been removed from the first air. Condition D: In the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical, at least a portion of the nitrogen oxides contained in the atmosphere are captured by a capture unit that captures at least a portion of the nitrogen oxides.

[0047] The method described in Section [1] can also be applied in other embodiments to a pharmaceutical raw material or a medicine containing the same, which satisfies the following conditions A' and / or B' corresponding to the above-mentioned step A and / or step B. Condition A': The sample was in an atmosphere from which at least a portion of the nitrogen oxides had been removed. Condition B': The sample was in an atmosphere in which the nitrogen oxide content was 50 ppb or less (for example, 10 ppb or less).

[0048] Condition A' and / or Condition B' may be achieved by the following Condition C' and / or Condition D', which correspond to the above-mentioned Step C and / or Step D. Condition C': The atmosphere that has been in contact with the pharmaceutical raw materials or pharmaceuticals is the second air from which at least a portion of the nitrogen oxides has been removed from the first air. Condition D': At least a portion of the nitrogen oxides contained in the atmosphere that has been in contact with the pharmaceutical raw material or the pharmaceutical has been captured by a capture unit that captures at least a portion of the nitrogen oxides contained in the atmosphere.

[0049] Under condition A, for example, the nitrogen oxides in the atmosphere can be reduced by removing at least a portion of the nitrogen oxides in the atmosphere or by introducing air from which at least a portion of the nitrogen oxides contained therein have been removed as the atmosphere.

[0050] Under condition C, examples of the first air include outside air, as well as gases and their raw materials that are introduced into the equipment or lines. An example of the gas that is introduced into the equipment or lines is compressed air. Under condition C, the second air may be obtained by passing the first air through a filter.

[0051] In condition D, the trapping section may include a means for removing or trapping nitrogen oxides as described in section [1.3].

[0052] Under conditions A and B, the pharmaceutical raw material or pharmaceutical is currently placed in a reduced nitrogen oxide atmosphere. Under conditions A' and B', the pharmaceutical raw material or pharmaceutical has previously been placed in a reduced nitrogen oxide atmosphere. Under conditions A, B, A', and B', the period of time that the pharmaceutical raw material or pharmaceutical is (or was) placed in a reduced nitrogen oxide atmosphere can 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. Under conditions A' and B', the time that has elapsed since the last time the pharmaceutical raw material or pharmaceutical was placed in a reduced nitrogen oxide atmosphere can 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.

[0053] Under conditions C and D, the pharmaceutical raw material or pharmaceutical is currently in contact with a nitrogen oxide-reduced atmosphere. Under conditions C' and D', the pharmaceutical raw material or pharmaceutical has previously been in contact with a nitrogen oxide-reduced atmosphere. Under conditions C, D, C', and D', the period of time that the pharmaceutical raw material or pharmaceutical is (or was) in contact with a nitrogen oxide-reduced atmosphere can 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. Under conditions C' and D', the time that has elapsed since the last time the pharmaceutical raw material or pharmaceutical was in contact with a nitrogen oxide-reduced atmosphere can 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.

[0054] The pharmaceutical raw material or pharmaceutical may adopt any of the embodiments or combinations thereof described in Section [1].

[0055] The method described in Section [1] can be applied to a package in which a pharmaceutical raw material or a drug containing the same that can generate and / or cause the generation of nitroso compounds is contained in a packaging container. The pharmaceutical raw material or drug is subjected to the following condition A, which corresponds to the above-mentioned step A and / or step B. * and / or Condition B * It meets the following criteria. Condition A * : The device is housed together with a trapping part that traps at least a portion of the nitrogen oxides contained in the atmosphere. Condition B * The nitrogen oxide content in the atmosphere inside the packaging container is 50 ppb or less (for example, 10 ppb or less).

[0056] In the embodiment of the package, the package container may be a primary package or a secondary package. Therefore, the package container may contain unpackaged pharmaceutical raw materials or medicines, or may contain packaged pharmaceutical raw materials or medicines. In one embodiment, the package container further contains a desiccant.

[0057] Specific examples of packaging include PTP packaging, strip packaging, aluminum packaging, and bottle filling. PTP packaging, strip packaging, aluminum packaging, etc. may be secondary packaged in aluminum pillows. In addition, large containers such as drums and containers can also be packaging containers for packaging pharmaceutical raw materials or pharmaceuticals.

[0058] For example, if the primary packaged pharmaceutical raw materials or pharmaceuticals and the capture part are placed in an aluminum pillow, condition A can be met. * and / or Condition B * As another example, if a pharmaceutical raw material or a pharmaceutical and a capture part are contained in a bottle, condition A can be satisfied. * and / or Condition B * As another example, if the atmosphere inside the packaging container is replaced with a gas that contains a small amount of nitrogen oxides, condition A can be met. * and / or Condition B * can be satisfied.

[0059] In condition B', the trapping section may include the means for removing or trapping nitrogen oxides described in section [1.3].

[0060] The package may employ any of the embodiments described in section [1] or a combination thereof.

[0061] 2.3 Facilities and Equipment The method described in Section [1] can be applied to a facility or equipment. The facility or equipment is a facility or equipment for manufacturing and / or storing pharmaceutical raw materials or pharmaceuticals containing such raw materials that may generate and / or cause the generation of nitroso compounds, and is a facility or equipment for reducing the generation of nitroso compounds. The facility or equipment is equipped with a removal section that removes at least a portion of nitrogen oxides contained in the atmosphere.

[0062] As mentioned in Section [1], the function of the removal unit is not limited to removing at least a portion of the nitrogen oxides contained in the "atmosphere currently in contact with the pharmaceutical raw materials or the pharmaceutical," but also includes removing at least a portion of the nitrogen oxides contained in the "air that will become the atmosphere that will come into contact with the pharmaceutical raw materials or the pharmaceutical in a later step." For example, the removal unit is also expected to include a component that supplies air, from which at least a portion of the nitrogen oxides has been removed, as the atmosphere that will come into contact with the pharmaceutical raw materials or the pharmaceutical.

[0063] In one embodiment, the removal unit is means C and / or means D, which correspond to step C and / or step D described above. Means C: A removal section for removing at least a portion of the nitrogen oxides contained in the first air to produce second air. Means D: A trapping unit that traps at least a portion of nitrogen oxides contained in the atmosphere

[0064] In the method C, examples of the first air include outside air, as well as gases and their raw materials that are introduced into the equipment or lines. An example of the gas that is introduced into the equipment or lines is compressed air.

[0065] The removal section and trapping section in this embodiment may include the means for removing or trapping nitrogen oxides described in Section [1.3].

[0066] Examples of facilities include manufacturing plants, manufacturing rooms, storage warehouses, storage rooms, laboratory facilities, laboratories, medical facilities, medical rooms, packaging facilities, packaging rooms, shipping facilities, shipping rooms, and portions thereof. Examples of equipment include manufacturing equipment, storage rooms, laboratory equipment, medical equipment, packaging equipment, shipping equipment, and portions thereof.

[0067] The facility or equipment may employ any of the embodiments described in Section [1] or a combination thereof.

[0068] 2.4. Pharmaceutical Compositions Containing Atomoxetine or a Salt Thereof One aspect of the present invention is a pharmaceutical composition containing atomoxetine or a salt thereof. The pharmaceutical composition has a particularly low content of nitroso compounds, which may be 1 ppm or less, and may be 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 0.1 ppm or less. In one embodiment, the above numerical ranges refer to the content of nitrosoatomoxetine. In one embodiment, the structure of nitrosoatomoxetine is as shown below. [ka]

[0069] Examples of salts of atomoxetine include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, maleate, fumarate, citrate, benzoate, methanesulfonate, etc. In one embodiment, the pharmaceutical composition comprises atomoxetine hydrochloride.

[0070] Atomoxetine or a salt thereof may be crystalline or amorphous. When atomoxetine is crystalline, the crystalline form is not particularly limited.

[0071] Atomoxetine or a salt thereof may be an anhydrous form or a hydrate. When atomoxetine is a hydrate, the number of waters of hydration is not particularly limited.

[0072] In one embodiment, atomoxetine or a salt thereof is an anhydrous form of the free form, a hydrate of the free form, an anhydrous salt, a hydrate of the salt, or any combination thereof.

[0073] The pharmaceutical composition may contain adherent water. The presence or absence of adherent water in the pharmaceutical composition and the amount of adherent water are not particularly limited.

[0074] The pharmaceutical composition may contain ingredients other than atomoxetine or a salt thereof. Examples of such ingredients include active ingredients other than atomoxetine or a salt thereof, and pharmaceutical additives. Examples of pharmaceutical additives include excipients, disintegrants, binders, lubricants or flow agents (anti-adherents), colorants, flavorings, sweeteners, preservatives or antiseptics, and coating agents. These ingredients may each be contained independently, either alone or in combination.

[0075] One aspect of the present invention is a method for producing a pharmaceutical composition containing atomoxetine or a salt thereof, which comprises the above-mentioned step A and / or step B.

[0076] One aspect of the present invention is a method for reducing the formation of nitroso compounds in a pharmaceutical composition containing atomoxetine or a salt thereof, which comprises the above-described step A and / or step B.

[0077] In a pharmaceutical composition containing atomoxetine or a salt thereof, atomoxetine or a salt thereof is a pharmaceutical raw material, and therefore, the above-mentioned step A may include a step of removing at least a portion of nitrogen oxides in the atmosphere that comes into contact with atomoxetine or a salt thereof.

[0078] The pharmaceutical compositions and related methods may employ any of the embodiments described in Section [1] or a combination thereof.

[0079] 2.4. Pharmaceutical Compositions Containing Duloxetine or a Salt Thereof One aspect of the present invention is a pharmaceutical composition containing duloxetine or a salt thereof. The pharmaceutical composition has a particularly low content of nitroso compounds, which may be 1 ppm or less, 0.9 ppm or less, 0.85 ppm or less, 0.83 ppm or less, 0.8 ppm or less, 0.7 ppm or less, 0.6 ppm or less, or 0.5 ppm or less. In one embodiment, the above-mentioned numerical ranges refer to the content of nitroso duloxetine. In one embodiment, the structure of nitroso duloxetine is shown below. In one embodiment, the above-mentioned numerical ranges refer to the content of nitroso compounds (e.g., nitroso duloxetine) in the granules, excluding the capsule. [ka]

[0080] Examples of salts of duloxetine include hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, maleate, fumarate, citrate, benzoate, methanesulfonate, etc. In one embodiment, the pharmaceutical composition comprises duloxetine hydrochloride.

[0081] Duloxetine or a salt thereof may be crystalline or amorphous. When duloxetine or a salt thereof is crystalline, the crystalline form is not particularly limited.

[0082] Duloxetine or a salt thereof may be anhydrous or a hydrate. When duloxetine or a salt thereof is a hydrate, the number of waters of hydration is not particularly limited.

[0083] In one embodiment, duloxetine or a salt thereof is an anhydrous form of the free form, a hydrate of the free form, an anhydrous salt, a hydrate of the salt, or any combination thereof.

[0084] The pharmaceutical composition may contain adherent water. The presence or absence of adherent water in the pharmaceutical composition and the amount of adherent water are not particularly limited.

[0085] The pharmaceutical composition may contain ingredients other than duloxetine or its salt. Examples of such ingredients include active ingredients other than duloxetine or its salt, and pharmaceutical additives. Examples of pharmaceutical additives include excipients, disintegrants, binders, lubricants or flow agents (anti-adherents), colorants, flavorings, sweeteners, preservatives or antiseptics, coating agents, etc. These ingredients may be contained independently, either alone or in combination of two or more.

[0086] One aspect of the present invention is a method for producing a pharmaceutical composition containing duloxetine or a salt thereof, which comprises the above-mentioned step A and / or step B.

[0087] One aspect of the present invention is a method for reducing the formation of nitroso compounds in a pharmaceutical composition containing duloxetine or a salt thereof, which comprises the above-mentioned step A and / or step B.

[0088] In the pharmaceutical composition containing duloxetine or a salt thereof, duloxetine or a salt thereof is a pharmaceutical raw material, and therefore, the above-mentioned step A may include a step of removing at least a portion of nitrogen oxides in the atmosphere that comes into contact with duloxetine or a salt thereof.

[0089] The pharmaceutical compositions and related methods may employ any of the embodiments described in Section [1] or a combination thereof. [Example]

[0090] Example 1 This example revisits an experiment previously reported (Org. Process Res. Dev. 2023, 27, 11, 2123-2133). A model experiment simulating fluidized bed granulation was conducted to examine the effect of nitrogen oxides (nitrogen dioxide, NO2) on the production of a nitroso compound (N-nitrosodimethylamine, NDMA). The nitroso compound in this experimental system is believed to have been produced by nitrosation of the raw material (dimethylamine) remaining in the metformin drug substance. Specifically, the experiment was conducted using the experimental apparatus shown in Figure 1, following the procedure below. 1. 10.0 g of metformin drug substance and 0.06 g of light anhydrous silicic acid were mixed and ground in a mortar and pestle, and then vigorously stirred in a flask at 65° C. A mechanical stirrer was used for stirring. 2. The granulation liquid (volume ratio of ethanol to water = 1:5.5) and NO2-containing gas were sprayed into the reaction system. The spray rates were 0.1 mL / min for the granulation liquid and 4 L / min for the NO2-containing gas. The NO2 concentration in the NO2-containing gas was 0 ppb, 25 ppb, 50 ppb, or 100 ppb. 3. The gas effluent from the reaction system was passed twice through a trap tube containing 100 mL of water. 4. After the reaction was completed, the gas in the flask was vented with air for 5 minutes, and the remaining drug substance was allowed to dry naturally. 5. N-nitrosodimethylamine contained in the drug substance and the water in the trap tube was measured by LC / MS analysis.

[0091] [result] Under all reaction conditions, N-nitrosodimethylamine was not detected in the drug substance remaining after the reaction, but was detected in the water in the trap tube. This suggests that N-nitrosodimethylamine in the reaction system was evaporated by heating and airflow and discharged from the reaction vessel (N-nitrosodimethylamine has a vapor pressure of approximately 5300 Pa at 65°C and a boiling point of 152°C).

[0092] The amount of N-nitrosodimethylamine detected in the water in the trap tube is shown in Figure 2. As can be seen from the figure, the amount of N-nitrosodimethylamine produced tended to increase as the NO2 concentration in the NO2-containing gas increased. It also shows that nitrosation of dimethylamine contained in metformin active ingredient occurs even at low NO2 concentrations on the order of ppb.

[0093] In a preliminary study, the inventors measured the NO2 concentration in the air near the intake port of a fluidized bed granulator actually used in a manufacturing plant. The NO2 concentration was found to be approximately 5 to 60 ppb. Considering this together with the results of Figure 2, it is highly likely that N-nitrosodimethylamine is generated when metformin drug substance is granulated in a fluidized bed granulator in the actual manufacturing process. Therefore, if the NO2 concentration of the air flowing into the fluidized bed granulator can be reduced, it is thought that the amount of N-nitrosodimethylamine generated can be reduced.

[0094] Example 2 Under actual manufacturing conditions, we investigated the effect of nitrogen oxides (nitrogen dioxide, NO2) on the production of nitroso compounds (N-nitrosodimethylamine, NDMA). The specific procedure is as follows: 1. Atmospheric NO2 concentrations were tracked and measured at two factories in different locations (Osaka and Yamagata prefectures). Specifically, the atmospheric NO2 concentrations measured at the NO2 measurement points closest to the factories (located within 3 km of each factory) were converted to monthly average values ​​and recorded. 2. During the same period, the amount of N-nitrosodimethylamine contained in metformin formulations manufactured at two factories was measured by LC / MS analysis. 3. The atmospheric NO2 concentration and the amount of N-nitrosodimethylamine contained in metformin formulations were plotted on the same graph.

[0095] [result] The results are shown in Figure 3. The figure shows the amount of N-nitrosodimethylamine contained in 741 batches of metformin formulations manufactured at the Osaka and Yamagata plants (Osaka plant: open circles, Yamagata plant: closed circles) and the atmospheric NO2 concentration (Osaka plant: open triangles, Yamagata plant: closed triangles).

[0096] Atmospheric NO2 concentrations at the Osaka Plant were approximately 8-24 ppb, and at the Yamagata Plant they were approximately 2-8 ppb. In both areas, atmospheric NO2 concentrations showed seasonal variations, with concentrations rising in winter and falling in summer.

[0097] The amount of N-nitrosodimethylamine contained in metformin formulations showed a tendency to follow the NO2 concentration in the atmosphere. Specifically, formulations manufactured at the Osaka plant contained more N-nitrosodimethylamine than formulations manufactured at the Yamagata plant. Furthermore, metformin formulations manufactured in winter, when atmospheric NO2 concentrations are high, tended to contain higher amounts of N-nitrosodimethylamine. Of the 17 batches that exceeded the provisional standard (43 ppb), 16 batches were manufactured between October and March.

[0098] These results indicate a strong correlation between atmospheric NO2 concentrations and the amount of N-nitrosodimethylamine in metformin formulations, suggesting that, for example, removing at least a portion of nitrogen oxides from the air entering a factory could reduce the formation of nitroso compounds in pharmaceutical raw materials or pharmaceuticals.

[0099] Example 3 It was demonstrated that nitrogen oxides can be removed from the atmosphere by applying filters. Of these, filter unit A has the function of oxidizing NO to NO2, while filter units B and C have the function of physically and chemically adsorbing nitrogen oxides such as NO2, whose solutions are acidic. Filter units D and E have both oxidation and adsorption functions. Filter unit A: A filter unit with pellet-shaped activated alumina as the base material and potassium permanganate as the additive. Filter unit B: A filter unit that uses crushed highly refined activated carbon as a base material and potassium carbonate as an additive. Filter unit C: A filter unit with granular activated carbon woven into nonwoven fabric as the base material and potassium carbonate as an additive. Filter unit D: A filter unit formed into a pleated shape by sandwiching activated carbon between two sheets of nonwoven fabric (in this example, PureGate YA (Puretec Co., Ltd.) was used). Filter unit E: A filter unit containing an anion for adsorbing acidic gases as an impregnating agent (in this example, SC-SA (Oshitari Laboratory Co., Ltd.) was used).

[0100] [Example 3-1] It was demonstrated that nitrogen oxides in the atmosphere can be removed by combining filter units. The filter configurations used were as follows (the air passed through the filters in the order listed above). The concentrations of NO, NO2, and their total were measured before and after passing through the filters. Filter unit A Filter unit B Filter unit C

[0101] [Example 3-2] A filter having the same configuration as in Example 3-1 was used and operated for an even longer period (approximately 7 hours), demonstrating that nitrogen oxides in the atmosphere can be removed continuously for an extended period of time.

[0102] [Results of Examples 3-1 and 3-2] The results of Examples 3-1 and 3-2 are shown in Table 1. [Table 1]

[0103] In Example 3-1, the concentration and removal effect approximately 30 minutes after the start of the test are shown in Table 1. In Example 3-2, the concentration and removal effect approximately 5 minutes, approximately 3 hours, and approximately 7 hours after the start of the test are shown in Table 1. As can be seen from the table, application of the filter according to this example enables continuous removal of nitrogen oxides (particularly NO and NO2) with high efficiency. Considering the results of Examples 1 and 2 together, it is suggested that, for example, by passing the air introduced into a factory through a filter, the generation of nitroso compounds in pharmaceutical raw materials or pharmaceuticals can be reduced.

[0104] [Example 3-3] The system was operated for a long period of time (33 hours) using several types of filters with different combinations of filter units. This demonstrated that nitrogen oxides in the atmosphere can be removed continuously over a long period of time. The filter configurations used were as follows (the air passed through them in the order listed above): Combination 1 Filter unit A Filter unit B Combination 2 Filter unit A Filter unit B Filter unit C Combination 3 Filter unit A Filter unit C Combination 4 Filter unit A Filter unit C Filter unit C

[0105] [Results of Example 3-3] The results of Example 3-3 are shown in Table 2. Note that the measured values ​​may fluctuate, and therefore the concentration may be a negative value. [Table 2] TIFF2025168321000006.tif125169TIFF2025168321000007.tif122170TIFF2025168321000008.tif124170

[0106] As can be seen from Table 2, application of the filter according to this example allows for continuous removal of nitrogen oxides (especially NO and NO2) with high efficiency. When comparing the NO2 removal efficiencies, combinations 2 and 4 were the best, followed by combination 3 and combination 1. The NO removal efficiencies were comparable for all combinations. When comparing the filter lifespans, combination 2 was the best, and combinations 1, 3, and 4 were comparable.

[0107] [Example 3-4] A filter unit different from that used in the above-mentioned example was used and operated for a long period of time (approximately 8 hours). This demonstrated that nitrogen oxides in the atmosphere can be continuously removed over a long period of time. The filter units used were as follows: Filter unit D Filter unit E

[0108] [Results of Examples 3-4] The results for filter unit D are shown in Figure 4. The results for filter unit E are shown in Figure 5. In both figures, the upper part shows the change in nitrogen oxide concentration over time, and the lower part shows the change in nitrogen oxide removal efficiency over time.

[0109] As can be seen from Figure 4, filter unit D maintained a high NO2 removal efficiency of approximately 95%, but its NO removal efficiency was not as high. As can be seen from Figure 5, filter unit E maintained a high NO2 removal efficiency of approximately 90%, but its NO removal efficiency was not as high. Therefore, it is estimated that these filter units can be more effective when combined with a filter unit that oxidizes NO to NO2, such as filter unit A.

[0110] Example 4 It was demonstrated that the application of filters can remove nitrogen oxides from the air used in pharmaceutical manufacturing sites.

[0111] [Example 4-1] It was demonstrated that nitrogen oxides in the air that passes through a filter can be reduced by applying a filter to the air supply line leading to a manufacturing facility. The filters used were configured as follows (air passes through the filters in the order listed above). The air supply velocity to the filters was 3 m 3 The NO, NO2 and total concentrations were measured before and after passing through the filter. Filter unit A Filter unit B Filter unit C HEPA filter Medium performance filter HEPA filter *HEPA filters and medium-performance filters are used to remove dust.

[0112] [Example 4-2] It was demonstrated that nitrogen oxides in the compressed air passing through a filter installed in the compressed air line of a pharmaceutical coating device can be reduced. The filters used were configured as follows (atmospheric air passes through the filters in the order listed above). The feed air supply rate to the filter was 100 L / min, the feed air pressure was 0.5 MPa, and the device was operated for approximately 2 hours. The NO, NO2, and total concentrations were measured before and after passing through the filter. First layer: 40 g of the packing material from filter unit A was taken out and packed into the column. Second layer: 60 g of the packing material from filter unit B was taken out and packed into the column.

[0113] [Results of Examples 4-1 and 4-2] The results of removing nitrogen oxides from intake air are shown in Figure 6. The results of removing nitrogen oxides from compressed air are shown in Figure 7. In both figures, the upper part shows the change in nitrogen oxide concentration over time, and the lower part shows the change in nitrogen oxide removal efficiency over time. Table 3 also shows the average nitrogen oxide concentration and average removal efficiency before and after passing through the filter. [Table 3]

[0114] As can be seen from Figure 6 and Table 3, applying the filter successfully removed most of the nitrogen oxides (especially NO and NO2) contained in the intake air. Due to fluctuations in the measurements, the average concentration after passing through the filter was a negative value, and the removal efficiency exceeded 100%, but it is clear that nitrogen oxides were removed with extremely high efficiency.

[0115] As can be seen from Figure 7 and Table 3, applying the filter made it possible to remove most of the nitrogen oxides (especially NO2) contained in the compressed air. Because the concentration of NO before passing through the filter was low, the removal efficiency of NO was low, but the removal efficiency of NO2, which makes up the majority of nitrogen oxides, was very high, so as a result, nitrogen oxides were removed with extremely high efficiency.

[0116] Example 5 It has been demonstrated that the use of air from which at least a portion of nitrogen oxides has been removed in the production of pharmaceuticals can reduce the content of nitroso compounds in the formulation.

[0117] [Example 5-1] It has been demonstrated that the production of nitrosoatomoxetine can be reduced in pharmaceuticals containing atomoxetine hydrochloride.

[0118] [Manufacturing Example 1] Film-coated atomoxetine hydrochloride tablets were produced according to the following procedure. The materials and amounts used are as shown in Table 4. The amounts shown in Table 4 are the amounts required to produce 75,000 5 mg atomoxetine hydrochloride tablets. (Manufacturing 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 further mixed to obtain a mixed powder for tableting. (Preparation of coating liquid) 4. Hypromellose and hydroxypropyl cellulose were added to purified water and dissolved. 5. Titanium oxide dispersed in purified water was added to the resulting solution. 6. Talc was added to the obtained liquid and stirred to prepare a coating liquid. (Manufacturing of film-coated tablets) 7. The mixed powder for tableting was compressed to obtain uncoated tablets. 8. The coating solution was sprayed onto the plain tablets and dried to obtain film-coated tablets.

[0119] In Production Example 1, steps 1 to 8 were carried out in a filtered atmosphere in the example, and in an unfiltered atmosphere in the comparative example. Specifically, in the example, the air supplied to the production room, the air supplied to the coating device, and the compressed air supplied to the coating device were all air from which at least some of the nitrogen oxides had been removed through a filter. The filter used for the air supply was the same in construction as in Example 4-1, and the filter used for the compressed air was the same in construction as in Example 4-2.

[0120] [Table 4]

[0121] [Evaluation method] Nitrosoatomoxetine (see below for the structure) contained in the atomoxetine hydrochloride drug substance and 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 ·Analysis conditions: MRM (m / z:302>177) [ka]

[0122] [result] The results are shown in Table 5. [Table 5]

[0123] As can be seen from Table 5, the content of nitroso forms increases during the production of film-coated tablets. However, the rate of increase can be significantly reduced by producing the tablets in a filtered atmosphere. As a result, the production method according to one embodiment of the present invention yielded a pharmaceutical containing atomoxetine hydrochloride with a particularly low content of nitroso forms.

[0124] [Example 5-2] It has been demonstrated that the production of nitrosoduloxetine can be reduced in pharmaceuticals containing duloxetine hydrochloride.

[0125] [Manufacturing Example 2] Enteric-coated granules of duloxetine hydrochloride were produced according to the following procedure. The materials and amounts used are as shown in Table 6. The amounts shown in Table 6 are the amounts required to produce 7,500 30 mg capsules of duloxetine hydrochloride. (Manufacturing of drug granules) 1. Hypromellose was dispersed in ethanol and dissolved by adding 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 intermediate granules) 4. Hypromellose was added to purified water and dissolved. 5. Talc was added to the resulting solution and stirred. 6. Titanium oxide dispersed in purified water was added to the obtained liquid and stirred to prepare coating liquid II. 7. Coating solution II was sprayed onto the drug granules and dried to obtain intermediate granules. (Manufacturing of enteric coated granules) 8. Triethyl citrate was added to purified water and dissolved. 9. Hypromellose acetate succinate and talc were added to the obtained solution and stirred to prepare coating solution III. 10. Coating solution III was sprayed onto the intermediate granules and dried to obtain enteric-coated granules.

[0126] In Production Example 2, steps 1 to 10 were carried out in a filtered atmosphere in the Examples, and in an unfiltered atmosphere in the Comparative Examples. Specifically, in the Examples, the air supplied to the rooms in which drug granules, intermediate granules, and enteric-coated granules were produced, the air supplied to the coating apparatus, and the compressed air supplied to the coating apparatus were all air from which at least some of the nitrogen oxides had been removed through a filter. The filter used for the air supply was the same in construction as in Example 4-1, and the filter used for the compressed air was the same in construction as in Example 4-2.

[0127] [Table 6]

[0128] [Evaluation method] The amounts of nitrosoduloxetine (see below for the structure) contained in the duloxetine hydrochloride drug substance and the enteric-coated granules were quantified by liquid chromatography-mass spectrometry, specifically according to the method described in ACS Omega 2024, 9, 11, 13440-13446. [ka]

[0129] [result] The results are shown in Table 7. [Table 7]

[0130] As can be seen from Table 7, the content of nitroso compounds increases during the production of enteric coated granules. However, the rate of increase can be significantly reduced by producing the granules in a filtered atmosphere. The same trend was observed across different lots, demonstrating reproducibility of the effect of reducing the production of nitroso compounds. As a result, the production method according to one embodiment of the present invention yielded a duloxetine hydrochloride-containing pharmaceutical product with a particularly low content of nitroso compounds. [Industrial Applicability]

[0131] The present invention can be used for the production of pharmaceutical raw materials or pharmaceuticals.

Claims

1. 1. A method for reducing the formation of nitroso compounds in a pharmaceutical raw material or pharmaceutical, comprising: A method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical; Step B: A step of producing and / or storing the pharmaceutical raw material or the pharmaceutical in an atmosphere having a nitrogen oxide content of 50 ppb or less.

2. a step of producing and / or storing the pharmaceutical raw material or the pharmaceutical in an atmosphere having a nitrogen oxide content of 10 ppb or less; The method of claim 1.

3. The method according to claim 1, wherein step A and / or step B is achieved by step C and / or step D below: Step C: introducing second air obtained by removing at least a portion of nitrogen oxides from the first air as an atmosphere to be in contact with the pharmaceutical raw material or the pharmaceutical; Step D: A step of capturing at least a portion of the nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical.

4. In the step C, the first air is passed through a filter to obtain the second air from which at least a portion of the nitrogen oxides contained in the first air has been removed. The method of claim 3.

5. The pharmaceutical raw material has an amino group or a substituted amino group. The method of claim 1.

6. A method for producing a pharmaceutical raw material capable of generating and / or causing generation of a nitroso compound, or a pharmaceutical containing the same, comprising: A production method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical; Step B: A step of producing and / or storing the pharmaceutical raw material or the pharmaceutical in an atmosphere having a nitrogen oxide content of 50 ppb or less.

7. a step of producing and / or storing the pharmaceutical raw material or the pharmaceutical in an atmosphere having a nitrogen oxide content of 10 ppb or less; The method of claim 6.

8. The method according to claim 6, wherein the step A and / or the step B is achieved by the following step C and / or step D: Step C: introducing second air obtained by removing at least a portion of nitrogen oxides from the first air as an atmosphere to be in contact with the pharmaceutical raw material or the pharmaceutical; Step D: A step of capturing at least a portion of the nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical.

9. In the step C, the first air is passed through a filter to obtain the second air from which at least a portion of the nitrogen oxides contained in the first air has been removed. The method of claim 8.

10. The pharmaceutical raw material has an amino group or a substituted amino group. The method of claim 6.

11. A pharmaceutical raw material capable of generating and / or causing generation of a nitroso compound, or a pharmaceutical containing the same, A pharmaceutical raw material or a medicine containing the same, which satisfies the following condition A and / or condition B: Condition A: The atmosphere is one in which at least a portion of nitrogen oxides has been removed; Condition B: The material is present in an atmosphere having a nitrogen oxide content of 50 ppb or less.

12. It is present in an atmosphere in which the nitrogen oxide content is 10 ppb or less, A pharmaceutical raw material according to claim 11 or a medicine containing the same.

13. 12. The pharmaceutical raw material or the medicine containing the same according to claim 11, wherein the condition A and / or the condition B is achieved by the following condition C and / or condition D: Condition C: The atmosphere in contact with the pharmaceutical raw materials or the pharmaceutical is a second air obtained by removing at least a portion of nitrogen oxides from the first air; Condition D: In the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical, at least a portion of the nitrogen oxides contained in the atmosphere is captured by a capture unit that captures at least a portion of the nitrogen oxides.

14. Under the condition C, the first air is passed through a filter to obtain the second air from which at least a portion of the nitrogen oxides contained in the first air has been removed. A pharmaceutical raw material according to claim 13 or a medicine containing the same.

15. A pharmaceutical raw material capable of generating and / or causing generation of a nitroso compound, or a pharmaceutical containing the same, A pharmaceutical raw material or a medicine containing the same, which satisfies the following condition A' and / or condition B': Condition A': The sample was in an atmosphere from which at least a portion of nitrogen oxides had been removed; Condition B': The sample was in an atmosphere with a nitrogen oxide content of 50 ppb or less.

16. The product was in an atmosphere with a nitrogen oxide content of 10 ppb or less. A pharmaceutical raw material according to claim 15 or a medicine containing the same.

17. 16. The pharmaceutical raw material or the medicine containing the same according to claim 15, wherein the condition A' and / or the condition B' is achieved by the following condition C' and / or condition D': Condition C': The atmosphere that has been in contact with the pharmaceutical raw material or the pharmaceutical is a second air obtained by removing at least a portion of nitrogen oxides from the first air; Condition D': At least a portion of the nitrogen oxides contained in the atmosphere that has been in contact with the pharmaceutical raw material or the pharmaceutical has been captured by a capture unit that captures at least a portion of the nitrogen oxides contained in the atmosphere.

18. Under the condition C', the first air is passed through a filter to obtain the second air from which at least a portion of the nitrogen oxides contained in the first air has been removed.

18. The pharmaceutical raw material according to claim 17 or a medicine containing the same.

19. The pharmaceutical raw material has an amino group or a substituted amino group. A pharmaceutical raw material according to claim 11 or 15, or a medicine containing the same.

20. A facility or equipment for reducing the generation of nitroso compounds in the production and / or storage of pharmaceutical raw materials that may generate and / or cause the generation of nitroso compounds or pharmaceuticals containing the same, A removal unit is provided which removes at least a portion of nitrogen oxides contained in the atmosphere. Facilities or equipment.

21. The facility or equipment according to claim 20, wherein the removal unit is the following means C and / or means D: Means C: a removal section for removing at least a portion of the nitrogen oxides contained in the first air to obtain second air; Means D: A trapping section for trapping at least a portion of the nitrogen oxides contained in the atmosphere.

22. The means C is a filter.

22. The facility or equipment of claim 21.

23. The pharmaceutical raw material has an amino group or a substituted amino group.

21. The facility or equipment according to claim 20.

24. A package in which a pharmaceutical raw material capable of generating and / or causing generation of a nitroso compound or a pharmaceutical containing the same is contained in a packaging container, The following condition A ＊ and / or condition B ＊ The packaging meets the following requirements: Condition A ＊ : housed with a trapping part that traps at least a portion of the nitrogen oxides contained in the atmosphere; Condition B ＊ The nitrogen oxide content in the atmosphere inside the packaging container is 50 ppb or less.

25. The nitrogen oxide content in the atmosphere inside the packaging container is 10 ppb or less.

25. The package of claim 24.

26. The pharmaceutical raw material has an amino group or a substituted amino group.

25. The package of claim 24.

27. A pharmaceutical composition comprising atomoxetine or a salt thereof, The content of nitroso compounds in the pharmaceutical composition is 1 ppm or less. Pharmaceutical compositions.

28. 1. A method for producing a pharmaceutical composition comprising atomoxetine or a salt thereof, comprising: A production method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in an atmosphere that comes into contact with atomoxetine or a salt thereof, or the pharmaceutical composition; Step B: producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 50 ppb or less; Here, the content of the nitroso compound in the pharmaceutical composition is 1 ppm or less.

29. producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 10 ppb or less; The method of claim 28.

30. 1. A method for reducing the formation of nitroso compounds in a pharmaceutical composition containing atomoxetine or a salt thereof, comprising: A method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in an atmosphere that comes into contact with atomoxetine or a salt thereof, or the pharmaceutical composition; Step B: producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 50 ppb or less; Here, the content of the nitroso compound in the pharmaceutical composition is 1 ppm or less.

31. producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 10 ppb or less; 31. The method of claim 30.

32. A pharmaceutical composition comprising duloxetine or a salt thereof, The content of nitroso compounds in the pharmaceutical composition is 1 ppm or less. Pharmaceutical compositions.

33. 1. A method for preparing a pharmaceutical composition comprising duloxetine or a salt thereof, comprising: A production method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in an atmosphere that comes into contact with duloxetine or a salt thereof or the pharmaceutical composition; Step B: producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 50 ppb or less; Here, the content of the nitroso compound in the pharmaceutical composition is 1 ppm or less.

34. producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 10 ppb or less; The method of claim 33.

35. 1. A method for reducing the formation of nitroso compounds in a pharmaceutical composition containing duloxetine or a salt thereof, comprising: A method comprising the following step A and / or step B: Step A: removing at least a portion of nitrogen oxides in an atmosphere that comes into contact with duloxetine or a salt thereof or the pharmaceutical composition; Step B: producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 50 ppb or less; Here, the content of the nitroso compound in the pharmaceutical composition is 1 ppm or less.

36. producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 10 ppb or less; 36. The method of claim 35.

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