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

Abstract

Provided is a method for reducing the generation of nitroso compounds in a drug raw material or a drug. 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.

Description

Method for reducing the formation of nitroso compounds in pharmaceutical raw materials or pharmaceuticals

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

[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).

[0003] Ministry of Health, Labour and Welfare Notification (PSEHB / PDA Notification No. 1008-1, PSEHB / SD Notification No. 1008-1, PSEHB / CNA Notification No. 1008-1) "Voluntary Inspection for the Risk of Nitrosamine Contamination in Pharmaceuticals" October 8, 2021

[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.

[0006] The present invention includes the following aspects: <1> A method for reducing the formation of nitroso compounds in a pharmaceutical raw material or a medicine, comprising the following steps A and / or B: Step A: removing at least a portion of nitrogen oxides in an atmosphere that comes into contact with the pharmaceutical raw material or the medicine; Step B: producing and / or storing the pharmaceutical raw material or the medicine in an atmosphere having a nitrogen oxide content of 50 ppb or less. <2> The method according to <1>, comprising the step of producing and / or storing the pharmaceutical raw material or the medicine in an atmosphere having a nitrogen oxide content of 10 ppb or less. <3> The method according to <1> or <2>, wherein step A and / or step B are achieved by the following steps C and / or D: Step C: introducing second air, from which at least a portion of the nitrogen oxides have been removed from first air, as the atmosphere that comes into contact with the pharmaceutical raw material or the medicine; Step D: capturing at least a portion of the nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the medicine. <4> The method according to <3>, wherein in 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 have been removed. <5> The method according to any of <1> to <4>, wherein the pharmaceutical raw material has an amino group or a substituted amino group. <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 the following steps A and / or B: Step A: removing at least a portion of the nitrogen oxides in an atmosphere in contact with the pharmaceutical raw material or the pharmaceutical; Step B: 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> The production method according to <6>, comprising the 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.<8> The production method according to <6> or <7>, wherein step A and / or step B are achieved by the following step C and / or step D: Step C: introducing second air, from which at least a portion of the nitrogen oxides have been removed from first air, as an atmosphere to be in contact with the pharmaceutical raw material or the pharmaceutical; Step D: capturing at least a portion of the nitrogen oxides in the atmosphere to be in contact with the pharmaceutical raw material or the pharmaceutical. <9> The production method according to <8>, wherein in step C, the second air from which at least a portion of the nitrogen oxides contained in the first air have been removed is obtained by passing the first air through a filter. <10> The production method according to any of <6> to <9>, wherein the pharmaceutical raw material has an amino group or a substituted amino group. <11> A pharmaceutical raw material or a pharmaceutical containing the same that can generate and / or be caused to generate nitroso compounds, which satisfies the following condition A and / or condition B: Condition A: the pharmaceutical raw material is present in an atmosphere from which at least a portion of the nitrogen oxides have been removed; Condition B: the pharmaceutical raw material is present in an atmosphere in which the nitrogen oxide content is 50 ppb or less. <12> The pharmaceutical raw material or drug containing the same according to <11>, which is present in an atmosphere having a nitrogen oxide content of 10 ppb or less. <13> The pharmaceutical raw material or drug containing the same according to <11> or <12>, wherein condition A and / or 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 drug is second air obtained by removing at least a portion of the nitrogen oxides from first air; Condition D: The atmosphere in contact with the pharmaceutical raw material or the drug has at least a portion of the nitrogen oxides captured by a capture unit that captures at least a portion of the nitrogen oxides contained in the atmosphere. <14> The pharmaceutical raw material or drug containing the same according to <13>, wherein under condition C, the second air from which at least a portion of the nitrogen oxides contained in the first air have been removed is obtained by passing the first air through a filter.<15> A pharmaceutical raw material or a medicine containing the same that can generate and / or cause the generation of nitroso compounds, which satisfies the following condition A' and / or condition B': Condition A': the pharmaceutical raw material has been present in an atmosphere from which at least a portion of nitrogen oxides has been removed; Condition B': the pharmaceutical raw material has been present in an atmosphere in which the nitrogen oxide content is 50 ppb or less. <16> The pharmaceutical raw material or the medicine containing the same according to <15>, which has been present in an atmosphere in which the nitrogen oxide content is 10 ppb or less. <17> The pharmaceutical raw material or the medicine containing the same according to <15> or <16>, in which condition A' and / or condition B' are 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 medicine is second air from which at least a portion of nitrogen oxides has been removed from first air; Condition D': the atmosphere that has been in contact with the pharmaceutical raw material or the medicine has at least a portion of the nitrogen oxides captured by a capture unit that captures at least a portion of the nitrogen oxides contained in the atmosphere. <18> The pharmaceutical raw material according to <17>, or a medicine containing the same, wherein under condition C', the second air is obtained by passing the first air through a filter from which at least a portion of the nitrogen oxides contained in the first air has been removed. <19> The pharmaceutical raw material according to any of <11> to <18>, or a medicine containing the same, wherein the pharmaceutical raw material has an amino group or a substituted amino group. <20> A facility or equipment for reducing the generation of nitroso compounds in the production and / or storage of a pharmaceutical raw material capable of generating and / or causing generation of nitroso compounds, or a medicine containing the same, the facility or equipment comprising a removal unit that removes at least a portion of the nitrogen oxides contained in the atmosphere. <21> The facility or equipment according to <20>, wherein the removal unit is the following means C and / or means D: Means C: a removal unit that removes at least a portion of the nitrogen oxides contained in the first air to obtain second air; Means D: a capture unit that captures at least a portion of the nitrogen oxides contained in the atmosphere. <22> The facility or equipment according to <21>, wherein means C is a filter.<23> The facility or equipment according to any one of <20> to <22>, wherein the pharmaceutical raw material has an amino group or a substituted amino group. <24> A package in which a pharmaceutical raw material capable of generating and / or causing generation of a nitroso compound or a medicine containing the same is contained in a packaging container, wherein the package satisfies the following condition A: ＊ and / or condition B ＊ Packages that meet the following criteria: Condition A ＊ Condition B: The device is housed together with a trapping unit that traps at least a portion of the nitrogen oxides contained in the atmosphere. ＊<25> The package according to <24>, wherein the nitrogen oxide content in the atmosphere inside the packaging container is 50 ppb or less. <26> The package according to <24> or <25>, wherein the pharmaceutical raw material has an amino group or a substituted amino group. <27> A pharmaceutical composition containing atomoxetine or a salt thereof, wherein the content of nitroso compounds in the pharmaceutical composition is 1 ppm or less. <28> A method for producing a pharmaceutical composition containing atomoxetine or a salt thereof, comprising the following steps A and / or 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; wherein the content of nitroso compounds in the pharmaceutical composition is 1 ppm or less. <29> The manufacturing method according to <28>, comprising a step of producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 10 ppb or less. <30> A method for reducing the formation of nitroso compounds in a pharmaceutical composition containing atomoxetine or a salt thereof, comprising the following steps A and / or B: Step A: removing at least a portion of nitrogen oxides in an atmosphere in 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, wherein the nitroso compound content in the pharmaceutical composition is 1 ppm or less. <31> The method according to <30>, comprising a step of producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 10 ppb or less. <32> A pharmaceutical composition containing duloxetine or a salt thereof, wherein the nitroso compound content in the pharmaceutical composition is 1 ppm or less.<33> A method for producing a pharmaceutical composition containing duloxetine or a salt thereof, the method comprising the following steps A and / or B: Step A: removing at least a portion of nitrogen oxides in an atmosphere in 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, wherein the content of nitroso compounds in the pharmaceutical composition is 1 ppm or less. <34> The method according to <33>, comprising the step of producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 10 ppb or less. <35> A method for reducing the production of nitroso compounds in a pharmaceutical composition containing duloxetine or a salt thereof, the method comprising the following steps A and / or B: Step A: removing at least a portion of nitrogen oxides in an atmosphere in 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, wherein the nitroso compound content in the pharmaceutical composition is 1 ppm or less. <36> The method according to <35>, comprising the step of producing and / or storing the pharmaceutical composition in an atmosphere having a nitrogen oxide content of 10 ppb or less.

[0007] The present invention also includes the following aspects. <1a> A method for reducing the formation of nitroso compounds in a pharmaceutical raw material or a medicine, comprising the following steps A and / or B: Step A: removing at least a portion of the nitrogen oxides in an atmosphere that comes into contact with the pharmaceutical raw material or the medicine; Step B: producing and / or storing the pharmaceutical raw material or the medicine in an atmosphere having a nitrogen oxide content of 50 ppb or less. <2a> The method according to <1a>, in which steps A and / or B are achieved by the following steps C and / or D: Step C: introducing air from outside air, from which at least a portion of the nitrogen oxides has been removed, into the atmosphere that comes into contact with the pharmaceutical raw material or the medicine; Step D: capturing at least a portion of the nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw material or the medicine. <3a> The method according to <2a>, in step C, removing at least a portion of the nitrogen oxides contained in the outside air by passing the outside air through a filter. <4a> The method according to any one of <1a> to <3a>, wherein the pharmaceutical raw material has an amino group or a substituted amino group. <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 the following steps A and / or B: Step A: removing at least a portion of the nitrogen oxides in an atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical; Step B: 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 method according to <5a>, wherein step A and / or step B are achieved by the following steps C and / or D: Step C: introducing air from outside air, from which at least a portion of the nitrogen oxides has been removed, into the atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical; Step D: 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> The manufacturing method according to <6a>, wherein in the step C, at least a portion of nitrogen oxides contained in the outside air is removed by passing the outside air through a filter.<8a> The manufacturing method according to any one of <5a> to <7a>, wherein the pharmaceutical raw material has an amino group or a substituted amino group. <9a> A pharmaceutical raw material capable of generating and / or causing generation of nitroso compounds, or a medicine containing the same, which satisfies the following condition A and / or condition B: Condition A: The pharmaceutical raw material is present in an atmosphere from which at least a portion of nitrogen oxides has been removed; Condition B: The pharmaceutical raw material 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 condition A and / or 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 medicine is air from which at least a portion of nitrogen oxides has been removed from outside air; Condition D: At least a portion of the nitrogen oxides in the atmosphere in contact with the pharmaceutical raw material or the medicine are captured by a capturer that captures at least a portion of the nitrogen oxides contained in the atmosphere. <11a> The pharmaceutical raw material according to <10a>, wherein condition A and / or condition B are achieved by condition C, and condition C is achieved by outside air passing through a filter, or a medicine containing the same. <12a> The pharmaceutical raw material according to any of <9a> to <11a>, wherein the pharmaceutical raw material has an amino group or a substituted amino group. <13a> A facility or equipment for reducing the generation of nitroso compounds in the production and / or storage of a pharmaceutical raw material capable of generating and / or causing generation of nitroso compounds, or a medicine containing the same, the facility or equipment comprising a removal unit that removes at least a portion of nitrogen oxides contained in the atmosphere. <14a> The facility or equipment according to <13a>, wherein the removal unit 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 capture unit that captures at least a portion of nitrogen oxides contained in the atmosphere. <15a> The facility or equipment according to <14a>, wherein means C is a filter.<16a> The facility or equipment according to any one of <13a> to <15a>, wherein the pharmaceutical raw material has an amino group or a substituted amino group. <17a> A package in which a pharmaceutical raw material that can generate and / or be generated by a nitroso compound, or a medicine containing the same, is contained in a packaging container, the package satisfying the following condition A' and / or condition B': Condition A': the pharmaceutical raw material is contained together with a capture part that captures at least a portion of the nitrogen oxides contained in the atmosphere; Condition B': the content of nitrogen oxides in the atmosphere within the packaging container is 50 ppb or less. <18a> The package according to <17a>, wherein the pharmaceutical raw material has an amino group or a substituted amino group.

[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.

[0009] FIG. 1 is a schematic diagram showing an overview of the experimental system employed in Example 1. FIG. 2 is a graph showing the results of Example 1. FIG. 3 is a graph showing the results of Example 2. FIG. 4 is a graph showing the results of Examples 3-4. Filter unit D was used. FIG. 5 is a graph showing the results of Examples 3-4. Filter unit E was used. FIG. 6 is a graph showing the results of Example 4-1. Nitrogen oxides were removed from supply air. FIG. 7 is a graph showing the results of Example 4-2. Nitrogen oxides were removed from compressed air.

[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 atoms and oxygen atoms. Examples of nitrogen oxides include nitric oxide (NO), nitrogen dioxide (NO ２ ), nitrogen trioxide (NO ３ ), nitrous oxide (N２ O), dinitrogen trioxide (N ２ O ３ ), dinitrogen tetroxide (N ２ O ４ ), dinitrogen pentoxide (N ２ O ５ Nitrogen oxides also include ions composed of nitrogen and oxygen atoms. Examples of such ions include NO ＋ , NO ２ － , NO ３ － 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 HNO ２ , H ２ NO ２ ＋ In one embodiment, the nitrogen oxides contain no atoms other than nitrogen and oxygen atoms.

[0012] In this specification, where specific nitrogen oxides are mentioned, the ions of the nitrogen oxides are also intended unless otherwise specified. For example, the expressions "nitric oxide" and "NO" also include the ions. Similarly, the expressions "nitrogen dioxide" and "NO" also include the ions. ２ " also encompasses ions thereof. 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. Method for Reducing the Formation of Nitroso Compounds According to new findings by the present inventors, nitrogen oxides in the atmosphere are involved in the formation of nitroso compounds in pharmaceutical raw materials or medicines (see the Examples of the present application). Therefore, in order to reduce the formation 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 formation 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 formation of nitroso compounds in pharmaceutical raw materials or medicines can be reduced by a method comprising Step A and / or Step B. Step A: A step of removing at least a portion of the nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw materials or medicines. Step B: A step of producing and / or storing the pharmaceutical raw materials or medicines in an atmosphere with 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, as an application in the "facility or equipment," 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."

[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, a pharmaceutical raw material or a 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, nitrogen oxides (NO, NO) contained in the atmosphere ２ The quantitative determination of nitrogen oxides (and their ions, etc.) 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 are no particular limitations 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 second air, from which at least a portion of the nitrogen oxides have been removed from the first air, as an atmosphere that comes into 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.

[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 to pass first air through a filter to remove at least a portion of the nitrogen oxides contained in the first air and produce second air. Examples of first air include outside air, as well as gases and their raw materials that are introduced into an apparatus or line. An example of gas that is introduced into an apparatus or line 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) into 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 to provide a trapping unit for trapping nitrogen oxides in the same atmosphere as that in which the 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] In this specification, a nitroso compound is a compound having N(R １ ) (R ２ It is a compound having a structure represented by the general formula: R 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. The heteroelement-containing group may consist solely of one or more heteroelement atoms, or may contain one or more heteroelement 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 can be generated by nitroso compounds] Pharmaceutical raw materials that can generate and / or can be generated by nitroso compounds are classified into the following types. However, these types do not cover all pharmaceutical raw materials that can generate and / or can be generated by nitroso compounds. Furthermore, pharmaceutical raw materials that can generate and / or can be generated by nitroso compounds may fall into multiple types.

[0028] ◆ Pharmaceutical raw materials having an amino group or a substituted amino group The first type is a pharmaceutical raw material having an amino group or a substituted amino group. ２A 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 using amines 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 the production of pharmaceutical raw materials. In such pharmaceutical raw materials, nitroso compounds may be generated through 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] The third type is pharmaceutical raw materials whose decomposition products can be nitrosated. The pharmaceutical raw materials before decomposition may or may not have a moiety that can be nitrosated. Examples of such pharmaceutical raw materials (and decomposition products) include 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. This nitrite can itself change to form nitroso compounds, or it can change 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 and further 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 trap. 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 trap is a component that captures 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 trap.

[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 a material that adsorbs 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. Further examples include the zeolites described in WO 2019 / 042884.

[0035] ◆ Use of reducing agents and reduction catalysts When nitrogen oxides are burned 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 (NO ２ ), nitrogen trioxide (NO ３ ) and their ions are acidic when dissolved in water and can be neutralized and / or chemisorbed with 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 hydride salts (lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, etc.).

[0037] In the embodiment using a base, nitric oxide (NO) may be preliminarily converted to nitrogen dioxide (NO ２ It is preferable to oxidize the nitrite to nitrite. By carrying out such a treatment, it becomes possible to 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 ２ , FeBr ２ , FeSO ４ , FeCl ３ , FeBr ３ , Fe ２ (SO ４ ) ３ , Fe(NO ３ ) ３, hydrates thereof, etc.), permanganates (sodium permanganate, potassium permanganate, magnesium permanganate, etc.), dichromates (ammonium dichromate, potassium dichromate, etc.), hydrogen peroxide, etc.

[0038] ◆Replacing the Atmosphere By replacing the atmosphere with a gas that contains little or no nitrogen oxides, the nitrogen oxide content in the atmosphere can be reduced to 50 ppb or less (e.g., 10 ppb or less). 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. Specific examples of combinations include the following filter units: Filter unit A: A filter unit using pelletized activated alumina as a base material and sodium permanganate and / or potassium permanganate as an impregnating agent. Filter unit B: A filter unit using crushed highly purified activated carbon as a base material and potassium carbonate as an impregnating agent. Filter unit C: A filter unit using granular activated carbon woven into nonwoven fabric as a base material and potassium carbonate as an impregnating agent. Filter unit D: A filter unit in which activated carbon is sandwiched between two sheets of nonwoven fabric and formed into a pleated shape. Filter unit E: A filter unit using an anion for adsorbing acidic gases as an impregnating agent.

[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 Examples 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 individually below.

[0042] [2.1. Method for producing a pharmaceutical raw material or a drug] The method described in Section [1] can be applied to a method for producing a pharmaceutical raw material that can generate and / or be made to generate a nitroso compound, or a drug 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 pharmaceutical raw materials or medicines containing them. This pharmaceutical raw material or medicine satisfies the following condition A and / or condition B, which correspond to the above-mentioned step A and / or step B. Condition A: The pharmaceutical raw material or medicine is present in an atmosphere from which at least a portion of nitrogen oxides has been removed. Condition B: The pharmaceutical raw material or medicine is present in an atmosphere in which the nitrogen oxide content is 50 ppb or less (e.g., 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 material or the medicine is second air from which at least a portion of the nitrogen oxides has been removed from first air. Condition D: The atmosphere that comes into contact with the pharmaceutical raw material or the medicine has at least a portion of the nitrogen oxides captured by a capture unit that captures at least a portion of the nitrogen oxides contained in the atmosphere.

[0047] The method described in section [1] can also be applied to pharmaceutical raw materials or pharmaceuticals containing the same in other embodiments. This pharmaceutical raw material or pharmaceutical satisfies the following condition A' and / or condition B', which correspond to the above-mentioned step A and / or step B. Condition A': The pharmaceutical raw material or pharmaceutical has been present in an atmosphere from which at least a portion of nitrogen oxides has been removed. Condition B': The pharmaceutical raw material or pharmaceutical has been present in an atmosphere in which the nitrogen oxide content is 50 ppb or less (e.g., 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 material or the medicine is second air from which at least a portion of the nitrogen oxides has been removed from first air. Condition D': The atmosphere that has been in contact with the pharmaceutical raw material or the medicine has at least a portion of the nitrogen oxides 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 raw materials thereof 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 embodiment or combination of the embodiments 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 medicine containing the same that can generate and / or cause the generation of a nitroso compound is contained in a packaging container. The pharmaceutical raw material or medicine is subjected to the following condition A, which corresponds to the above-mentioned step A and / or step B. ＊ and / or condition B ＊ Condition A is satisfied. ＊Condition B: The device is housed together with a trapping part that traps at least a portion of the nitrogen oxides contained in the atmosphere. ＊ 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 an aluminum pillow. In addition, large containers such as drums and containers may 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 contained in an aluminum pillow, condition A can be satisfied. ＊ 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 containing a small amount of nitrogen oxides, condition A can be satisfied. ＊ 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 facilities or equipment. The facilities or equipment are facilities or equipment for manufacturing and / or storing pharmaceutical raw materials that can generate and / or cause the generation of nitroso compounds or pharmaceuticals containing such raw materials, and are facilities or equipment for reducing the generation of nitroso compounds. The facilities or equipment are equipped with a removal section that removes at least a portion of nitrogen oxides contained in the atmosphere.

[0062] As described in Section [1], the function of the removal unit includes not only 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 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, such as from outside air, 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 corresponding to the above-mentioned step C and / or step D. 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 capture unit that captures at least a portion of the nitrogen oxides contained in the atmosphere.

[0064] In the method C, examples of the first air include outside air, as well as gases and raw materials thereof 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 Comprising Atomoxetine or a Salt Thereof One aspect of the present invention is a pharmaceutical composition comprising atomoxetine or a salt thereof. The pharmaceutical composition has a particularly low content of nitroso compounds, and the content 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:

[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, coating agents, etc. These ingredients may each be contained independently, either alone or in combination of two or more.

[0075] One aspect of the present invention is a method for producing a pharmaceutical composition containing atomoxetine or a salt thereof, which method includes 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 the 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 composition and the related method may employ any of the embodiments described in Section [1] or a combination thereof.

[0079] 2.4. Pharmaceutical Compositions Comprising Duloxetine or a Salt Thereof One aspect of the present invention is a pharmaceutical composition comprising 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.

[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 method includes 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-described 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 composition and the related method may employ any of the embodiments described in Section [1] or a combination thereof.

[0090] Example 1 In this example, we will re-describe an experiment previously reported (Org. Process Res. Dev. 2023, 27, 11, 2123-2133). A model experiment simulating fluidized bed granulation was conducted to confirm the effectiveness of nitrogen oxides (nitrogen dioxide, NO ２ The effect of the presence of NO on the formation of a nitroso compound (N-nitrosodimethylamine, NDMA) was investigated. The nitroso compound in this experimental system is thought to be formed 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 and the following procedure. 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 then forcedly stirred in a flask at 65°C. A mechanical stirrer was used for stirring. 2. Granulation liquid (volume ratio of ethanol:water = 1:5.5) and NO were mixed. ２ The contained gas was sprayed into the reaction system. The spray rate was 0.1 mL / min for the granulation liquid and 0.1 mL / min for NO. ２ The gas content was 4 L / min. ２ NO in the containing gas ２The concentrations were 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. The N-nitrosodimethylamine contained in the drug substance and the water in the trap tube was measured by LC / MS analysis.

[0091] [Results] 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 5,300 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, ２ NO in the containing gas ２ The higher the concentration, the greater the amount of N-nitrosodimethylamine produced. ２ It can be seen that this occurs even at low concentrations on the order of ppb.

[0093] In a preliminary investigation, the inventors investigated the NO in the air near the intake port of a fluidized bed granulator actually used in a manufacturing plant. ２ The concentration is measured. ２ The concentration was approximately 5 to 60 ppb. Considering the results of Figure 2 together, 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, the NO in the air flowing into the fluidized bed granulator ２ If the concentration can be reduced, it is thought that the amount of N-nitrosodimethylamine produced can be reduced.

[0094] Example 2: Under actual production conditions, nitrogen oxides (nitrogen dioxide, NO ２The effect of the presence of NO in the atmosphere on the formation of a nitroso compound (N-nitrosodimethylamine, NDMA) was examined. The specific procedure is as follows: 1. At two factories in different locations (Osaka Prefecture and Yamagata Prefecture), NO was measured. ２ The concentration was tracked and measured. ２ Atmospheric NO measured at measurement points (located within 3 km of each factory) ２ The concentrations were converted to monthly average values ​​and recorded over time. 2. During the same period, the amount of N-nitrosodimethylamine contained in metformin formulations manufactured at the two plants was measured by LC / MS analysis. 3. NO in the atmosphere ２ The concentrations and the amount of N-nitrosodimethylamine contained in the metformin formulation were plotted on the same graph.

[0095] [Results] The results are shown in Figure 3. The figure shows the amount of N-nitrosodimethylamine contained in 741 batches of metformin preparations manufactured at the Osaka and Yamagata plants (Osaka plant: white circle, Yamagata plant: black circle) and the amount of atmospheric NO ２ The concentrations (Osaka Plant: open triangles, Yamagata Plant: closed triangles) are shown.

[0096] Atmospheric NO at the Osaka Plant ２ The concentration was approximately 8 to 24 ppb, and the atmospheric NO ２ The concentration was about 2 to 8 ppb. ２ Seasonal variations were observed in concentrations, with concentrations increasing in winter and decreasing in summer.

[0097] The amount of N-nitrosodimethylamine contained in metformin preparations is ２ The concentration of N-nitrosodimethylamine in the formulations produced at the Osaka plant was higher than that in the formulations produced at the Yamagata plant. ２ Metformin preparations manufactured during the winter, when concentrations are higher, tend to contain higher amounts of N-nitrosodimethylamine. Of the 17 batches that exceeded the provisional standard (43 ppb), 16 were manufactured between October and March.

[0098] This result indicates that atmospheric NO ２ The results show a strong correlation between the concentration of nitrogen oxides and the amount of N-nitrosodimethylamine in metformin formulations, suggesting that, for example, removing at least a portion of the 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 in the atmosphere can be removed by applying a filter. Among these, filter unit A was used to remove NOx from NOx. ２ The filter units B and C have the function of oxidizing NO ２ These filters have the function of physically and chemically adsorbing nitrogen oxides, which are acidic in solutions such as these. Filter units D and E have both oxidation and adsorption functions. Filter unit A: A filter unit using pelletized activated alumina as a base material and potassium permanganate as an adsorbent. Filter unit B: A filter unit using crushed highly refined activated carbon as a base material and potassium carbonate as an adsorbent. Filter unit C: A filter unit using granular activated carbon woven into nonwoven fabric as a base material and potassium carbonate as an adsorbent. Filter unit D: A filter unit in which activated carbon is sandwiched between two sheets of nonwoven fabric and formed into a pleated shape (in this example, PureGate YA (Puretec Co., Ltd.) was used). Filter unit E: A filter unit using an anion for adsorbing acidic gases as an adsorbent (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 filters used were configured as follows (the air passed through the filters in the order listed above). Before and after passing through the filters, NO, NO ２ The total concentration of each filter unit was measured.

[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.

[0103] In Example 3-1, the concentration and removal effect at about 30 minutes after the start of the test are shown in Table 1. In Example 3-2, the concentration and removal effect at about 5 minutes, about 3 hours, and about 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 reduced the concentration and removal effect of nitrogen oxides (particularly NO and NO ２ ) can be removed continuously with high efficiency. Considering the results of Examples 1 and 2 together, it is suggested that the generation of nitroso compounds in pharmaceutical raw materials or pharmaceuticals can be reduced by, for example, passing the air introduced into a factory through a filter.

[0104] [Example 3-3] A number of different types of filters with different combinations of filter units were used and operated for a long period of time (33 hours). This demonstrated that nitrogen oxides in the atmosphere can be continuously removed over a long period of time. The filters used were configured as follows (air passes 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.

[0106] As can be seen from Table 2, application of the filter according to this embodiment reduces the amount of nitrogen oxides (especially NO and NO ２ ) can be removed continuously with high efficiency. ２ When comparing the removal efficiencies of NO, combinations 2 and 4 were the best, combination 3 was next best, and combination 1 was next best. The NO removal efficiency was similar for all combinations. When comparing the filter lifespan, combination 2 was the best, and combinations 1, 3, and 4 were similar.

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

[0108] [Results of Example 3-4] The results when filter unit D was used are shown in Figure 4. The results when filter unit E was used 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 FIG. 4, the filter unit D is ２ As can be seen from FIG. 5, the filter unit E had a high removal efficiency of about 95% for NO, but the removal efficiency of NO was not so high. ２ The removal efficiency of NO was high, remaining at about 90%, but the removal efficiency of NO was not so high. Therefore, these filter units were not able to remove NO like filter unit A. ２ It is estimated that a higher effect can be achieved by combining it with a filter unit that oxidizes the gas.

[0110] Example 4 It was demonstrated that nitrogen oxides contained in the air used in pharmaceutical manufacturing sites can be removed by applying a filter.

[0111] [Example 4-1] It was demonstrated that a filter was applied to the supply air line leading to a manufacturing facility to reduce nitrogen oxides in the supply air that passed through. The filters used were configured as follows (air passed through the filters in the order listed above). The air supply velocity to the filters was 3 m ３ / min and was operated for about 2 hours. ２ The total concentration was measured. ・Filter unit A ・Filter unit B ・Filter unit C ・HEPA filter ・Medium-performance filter ・HEPA filter *HEPA filter and medium-performance filter are for dust removal.

[0112] [Example 4-2] It was demonstrated that a filter was provided in the compressed air line of a device used for coating pharmaceuticals, and that nitrogen oxides in the compressed air that passed through could be reduced. The filters used had the following configuration (atmospheric air passed 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 operation lasted for approximately 2 hours. Before and after passing through the filter, NO, NO ２ The total concentration was measured. First layer: 40 g of the packing material from filter unit A was taken out and packed into a column. Second layer: 60 g of the packing material from filter unit B was taken out and packed into a 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.

[0114] As can be seen from FIG. 6 and Table 3, by applying the filter, the nitrogen oxides (particularly NO and NO) contained in the intake air were reduced. ２Due to fluctuations in the measurement values, 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 FIG. 7 and Table 3, by applying a filter, nitrogen oxides (especially NO ) contained in compressed air were reduced. ２ Because the concentration of NO before passing through the filter was low, the removal efficiency of NO was low, but the NO that accounts for the majority of nitrogen oxides was removed. ２ The removal efficiency of the catalyst was very high, and as a result, nitrogen oxides were removed with very high efficiency.

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

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

[0118] [Preparation Example 1] Film-coated tablets of atomoxetine hydrochloride were prepared 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 charged when producing 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 further mixed. In this manner, a mixed powder for tableting was obtained. (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 obtained solution. 6. Talc was added to the obtained liquid and stirred to prepare a coating liquid. (Preparation of film-coated tablets) 7. The mixed powder for tableting was compressed to obtain plain 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 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.

[0120]

[0121] [Evaluation method] Nitrosoatomoxetine (see below for structure) contained in the atomoxetine hydrochloride drug substance and film-coated tablets was quantified by LC / MS analysis (liquid chromatography mass spectrometry). Specific measurement conditions were as follows: Liquid chromatography: Instrument used: Xevo TQ Absolute (Waters); Stationary phase: Stainless steel tube (inner diameter 3.0 mm, length 15 cm) filled with biphenylated silica gel for liquid chromatography (average particle size: 2.6 μm); Mobile phase: Aqueous ammonium acetate / methanol mixture; Mass spectrometry: Ionization method: ESI; Analysis conditions: MRM (m / z: 302>177)

[0122] [Results] The results are shown in 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 was demonstrated that the production of nitrosoduloxetine can be reduced in pharmaceuticals containing duloxetine hydrochloride.

[0125] [Preparation Example 2] Enteric-coated duloxetine hydrochloride granules were prepared according to the following procedure. The materials and quantities used are as shown in Table 6. The quantities shown in Table 6 are the amounts required to prepare 7,500 30 mg duloxetine hydrochloride capsules. (Preparation of Drug Granules) 1. Hypromellose was dispersed in ethanol, and purified water was added to dissolve. 2. Duloxetine hydrochloride was added to the resulting 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. (Preparation of 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 resulting 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. Hypromellose acetate succinate and talc were added to the resulting solution and stirred to prepare coating solution III. 10. Coating solution III was sprayed onto 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 Example, and in an unfiltered atmosphere in the Comparative Example. Specifically, in the Example, 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 configuration used for the air supply was the same as in Example 4-1, and the filter configuration used for the compressed air was the same as in Example 4-2.

[0127]

[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.

[0129] [Results] The results are shown in 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 could be significantly reduced by producing the granules in a filtered atmosphere. The same tendency was observed in 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.

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

Claims

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

2. The method according to claim 1, comprising the 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.

3. The method according to claim 1 or 2, wherein step A and / or step B are achieved by the following steps C and / or D: Step C: A step of introducing second air, from which at least a portion of the nitrogen oxides have been removed from the first air, as an atmosphere that comes into 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 materials or the pharmaceutical.

4. The method according to claim 3, wherein in step C, the second air is obtained by passing the first air through a filter to remove at least a portion of the nitrogen oxides contained in the first air.

5. The method according to any one of claims 1 to 4, wherein the pharmaceutical raw material has an amino group or a substituted amino group.

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 the following steps A and / or B: Step A: removing at least a portion of the nitrogen oxides in an atmosphere that comes into contact with the pharmaceutical raw material or the pharmaceutical; Step B: producing and / or storing the pharmaceutical raw material or the pharmaceutical in an atmosphere in which the nitrogen oxide content is 50 ppb or less.

7. The method according to claim 6, further comprising the step of producing and / or storing the pharmaceutical raw material or the pharmaceutical in an atmosphere containing 10 ppb or less of nitrogen oxides.

8. The manufacturing method according to claim 6 or 7, wherein step A and / or step B are achieved by the following steps C and / or D: step C: introducing second air, from which at least a portion of the nitrogen oxides have been removed, as the atmosphere that comes into contact with the pharmaceutical raw materials or the pharmaceutical; step D: capturing at least a portion of the nitrogen oxides in the atmosphere that comes into contact with the pharmaceutical raw materials or the pharmaceutical.

9. The manufacturing method according to claim 8, wherein in step C, the second air is obtained by passing the first air through a filter to remove at least a portion of the nitrogen oxides contained in the first air.

10. The method of any one of claims 6 to 9, wherein the pharmaceutical raw material has an amino group or a substituted amino group.

11. A pharmaceutical raw material or a medicine containing the same that can generate and / or cause the generation of nitroso compounds, which satisfies the following condition A and / or condition B: Condition A: The raw material is present in an atmosphere from which at least a portion of nitrogen oxides has been removed; Condition B: The raw material is present in an atmosphere in which the nitrogen oxide content is 50 ppb or less.

12. The pharmaceutical raw material or drug containing the same according to claim 11, which exists in an atmosphere having a nitrogen oxide content of 10 ppb or less.

13. A pharmaceutical raw material or a medicine containing the same according to claim 11 or 12, wherein the above condition A and / or 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 medicine is second air from which at least a portion of the nitrogen oxides has been removed from first air; Condition D: The atmosphere in contact with the pharmaceutical raw material or the medicine has at least a portion of the nitrogen oxides captured by a capture section that captures at least a portion of the nitrogen oxides contained in the atmosphere.

14. The pharmaceutical raw material or pharmaceutical containing the same according to claim 13, wherein under 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.

15. A pharmaceutical raw material or a medicine containing the same that can generate and / or cause the generation of nitroso compounds, which satisfies the following condition A' and / or condition B': Condition A': The raw material has been present in an atmosphere from which at least a portion of nitrogen oxides has been removed; Condition B': The raw material has been present in an atmosphere in which the nitrogen oxide content is 50 ppb or less.

16. The pharmaceutical raw material or pharmaceutical containing the same according to claim 15, which has been present in an atmosphere having a nitrogen oxide content of 10 ppb or less.

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

18. The pharmaceutical raw material or pharmaceutical containing the same according to claim 17, wherein under 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.

19. A pharmaceutical raw material or a medicine containing the same according to any one of claims 11 to 18, wherein the pharmaceutical raw material has an amino group or a substituted amino group.

20. Facilities or equipment for reducing the generation of nitroso compounds in the manufacture and / or storage of pharmaceutical raw materials or pharmaceuticals containing such raw materials that may generate and / or cause the generation of nitroso compounds, the facilities or equipment being equipped with a removal section that removes at least a portion of nitrogen oxides contained in the atmosphere.

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 unit that removes at least a portion of the nitrogen oxides contained in the first air to produce second air; Means D: a capture unit that captures at least a portion of the nitrogen oxides contained in the atmosphere.

22. The facility or equipment according to claim 21, wherein the means C is a filter.

23. The facility or equipment according to any one of claims 20 to 22, wherein the pharmaceutical raw material has an amino group or a substituted amino group.

24. Packages containing pharmaceutical raw materials or pharmaceuticals containing such raw materials that may generate and / or cause the generation of nitroso compounds, and that meet the following condition A: ＊ and / or condition B ＊ Packages that meet the following criteria: Condition A ＊ Condition B: The device is housed together with a trapping unit that traps at least a portion of the nitrogen oxides contained in the atmosphere. ＊ The nitrogen oxide content in the atmosphere inside the packaging container is 50 ppb or less.

25. The package according to claim 24, wherein the nitrogen oxide content in the atmosphere inside the packaging container is 10 ppb or less.

26. The package according to claim 24 or 25, wherein the pharmaceutical ingredient has an amino group or a substituted amino group.

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

28. A method for producing a pharmaceutical composition containing atomoxetine or a salt thereof, comprising the following steps A and / or 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 in which the nitrogen oxide content is 50 ppb or less; wherein the content of nitroso compounds in the pharmaceutical composition is 1 ppm or less.

29. The method of claim 28, further comprising the step of producing and / or storing the pharmaceutical composition in an atmosphere containing no more than 10 ppb of nitrogen oxides.

30. A method for reducing the production of nitroso compounds in a pharmaceutical composition containing atomoxetine or a salt thereof, the method comprising the following steps A and / or 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 in which the nitrogen oxide content is 50 ppb or less; wherein the nitroso compound content in the pharmaceutical composition is 1 ppm or less.

31. The method of claim 30, further comprising the step of producing and / or storing the pharmaceutical composition in an atmosphere containing no more than 10 ppb of nitrogen oxides.

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

33. A method for producing a pharmaceutical composition containing duloxetine or a salt thereof, comprising the following steps A and / or 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 in which the nitrogen oxide content is 50 ppb or less; wherein the content of nitroso compounds in the pharmaceutical composition is 1 ppm or less.

34. The method of claim 33, further comprising the step of producing and / or storing the pharmaceutical composition in an atmosphere containing no more than 10 ppb of nitrogen oxides.

35. A method for reducing the production of nitroso compounds in a pharmaceutical composition containing duloxetine or a salt thereof, the method comprising the following steps A and / or 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 in which the nitrogen oxide content is 50 ppb or less; wherein the nitroso compound content in the pharmaceutical composition is 1 ppm or less.

36. The method of claim 35, further comprising the step of producing and / or storing the pharmaceutical composition in an atmosphere containing no more than 10 ppb of nitrogen oxides.

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