Selection, evaluation, or manufacturing method of sodium lauryl sulfate or preparations containing it as a raw material for pharmaceutical formulations.
By pretreating sodium lauryl sulfate under accelerated conditions and detecting impurities, the method addresses quality differences in sodium lauryl sulfate, ensuring stable and effective pharmaceutical formulations.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Patents
- Current Assignee / Owner
- CHUGAI PHARMA CO LTD
- Filing Date
- 2020-12-25
- Publication Date
- 2026-06-17
Smart Images
Figure 0007874969000019 
Figure 0007874969000020 
Figure 0007874969000021
Abstract
Description
Technical Field
[0001] The present invention relates to a method for selecting sodium lauryl sulfate as a pharmaceutical preparation raw material, a method for evaluating the quality of a pharmaceutical preparation containing the preparation raw material, and a method for producing a highly stable pharmaceutical preparation using the selected sodium lauryl sulfate in a pharmaceutical preparation containing sodium lauryl sulfate. The present invention also relates to a selected pharmaceutical preparation raw material, and a pharmaceutical composition or pharmaceutical preparation containing a certain amount of the selected pharmaceutical preparation raw material and / or its impurities.
Background Art
[0002] The compound represented by formula (I) (Compound name: 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile, common name: Alecitinib):
Chemical Formula
[0003] [Patent Document 1] Patent No. 4918630 [Patent Document 2] Patent No. 5859712 [Patent Document 3] Patent No. 4902928 [Non-patent literature]
[0004] [Non-Patent Document 1] Alecensa 150mg Capsules Package Insert, Revised December 2018 [Overview of the project] [Problems that the invention aims to solve]
[0005] There is a need for a method to detect slight differences in the quality of sodium lauryl sulfate used as a raw material in the manufacture of pharmaceutical formulations, and to identify sodium lauryl sulfate of desirable quality for use as a raw material in pharmaceutical formulations. [Means for solving the problem]
[0006] In view of the above problems, the present inventors conducted extensive research and discovered that slight differences in the quality of sodium lauryl sulfate contained in formulations containing alectinib or its salts affect the stability and dissolution properties of the formulations. They found that the following method of pre-treating sodium lauryl sulfate under accelerated conditions can solve the above problems, and thus completed the present invention. In other words, the present invention relates to a method for selecting pharmaceutical formulation raw materials consisting of sodium lauryl sulfate as described below. <1> A method for sorting pharmaceutical raw materials comprising sodium lauryl sulfate, characterized in that the pharmaceutical raw materials are pretreated under accelerated conditions, and then impurities are detected. <2> The acceleration condition is characterized by a temperature of 65 to 75°C. <1> The sorting method described below. <3> The acceleration conditions are characterized by a humidity condition of less than 79%RH. <1> or <2> The sorting method described below. <4> The acceleration conditions are characterized by a humidity of approximately 10%RH. <1> ~ <3> The selection method described in any one of the following items. <5> The acceleration conditions are characterized by a temperature of approximately 70°C and a humidity of approximately 10%RH or less. <1> ~ <4> The selection method described in any one of the following items. <6> The impurity is sulfate ions, dodecanol, or a sodium lauryl sulfate-dodecanol complex. <1> ~ <3> A selection method described in any one of the following items. <7> The aforementioned impurities are detected using powder X-ray diffraction, ion exchange chromatography, gas chromatography, or quantitative NMR. <1> ~ <6> The selection method described in any one of the following items. <8> The impurity is sulfate ions, and the impurity is detected using ion exchange chromatography. <1> ~ <7> The selection method described in any one of the following items. <9> Under the aforementioned acceleration conditions, pretreatment is performed for two days or more. <1> ~ <8> The selection method described in any one of the following items. <10> Under the aforementioned acceleration conditions, pretreatment is performed for 4 days. <1> ~ <8> The selection method described in any one of the following items. <10a> Select a pharmaceutical raw material in which the impurity is sulfate ions and the sulfate ion content in the pharmaceutical raw material is 1 mg / L or less. <1> ~ <10> The selection method described in any one of the following items. <10b> Select pharmaceutical raw materials in which the impurity is sulfate ions and the sulfate ion content in the pharmaceutical raw material is 1 mg / L or less in a solution obtained by dissolving approximately 100 mg of the pharmaceutical raw material in 1 L of water. <1> The sorting method described in any one of the items in <10a>.
[0007] Another aspect of the present invention is a method for evaluating the quality of a pharmaceutical product, wherein, in the case of a pharmaceutical product containing alectinib, which is a pharmaceutical product raw material that has been detected and sorted for impurities under accelerated conditions, the measurement of impurities is omitted. <2> A method for evaluating the quality of a pharmaceutical preparation containing a pharmaceutical preparation raw material consisting of a compound represented by formula (I) or a salt thereof and sodium lauryl sulfate, a. A step of selecting a pharmaceutical product using the pharmaceutical product raw material that has been pretreated under accelerated conditions and then sorted for impurities, b. For the pharmaceutical preparation selected in step a, the step of omitting the measurement of impurities in the preparation, The quality evaluation method, including the above. [ka] <2a> The acceleration condition is characterized by a temperature of 65 to 75°C, <2> The quality evaluation method described below. <2b> The acceleration conditions are characterized by a humidity condition of less than 79%RH, <2> Alternatively, the quality evaluation method described in <2a>. <2c> The acceleration conditions are characterized by a humidity of approximately 10%RH, <2> A quality evaluation method described in any one of the items in <2b>. <2d> The acceleration conditions are characterized by a temperature of approximately 70°C and a humidity of approximately 10%RH or less. <2> A quality evaluation method described in any one of the items in <2c>. <2e> The impurity is sulfate ions, dodecanol, or a sodium lauryl sulfate-dodecanol complex. <2> A quality evaluation method described in any one of the items in <2d>. <2f> The impurities are detected using powder X-ray diffraction, ion exchange chromatography, gas chromatography, or quantitative NMR. <2> The quality evaluation method described in any one of the items in <2e>. <2g> The quality evaluation method according to any one of <2> to <2f>, wherein the impurity is sulfate ion and the impurity is detected using ion exchange chromatography. <2h> The quality evaluation method according to any one of <2> to <2g>, wherein pretreatment is performed for 2 days or more under the acceleration conditions. <2i> The quality evaluation method according to any one of <2> to <2h>, wherein pretreatment is performed for 4 days under the acceleration conditions. <2j> The quality evaluation method according to any one of <2> to <2i>, wherein the impurity is sulfate ion, and pharmaceutical raw materials for pharmaceutical preparations in which the content of sulfate ion in the pharmaceutical raw materials is 1 mg / L or less are selected. <2k> The quality evaluation method according to any one of <2> to <2j>, wherein the impurity is sulfate ion, and pharmaceutical raw materials for pharmaceutical preparations in which the content of sulfate ion in the pharmaceutical raw materials is 1 mg / L or less in a solution obtained by dissolving about 100 mg of the pharmaceutical raw materials in 1 L of water are selected.
[0008] Furthermore, another aspect of the present invention is a method for selecting sodium lauryl sulfate, which is a pharmaceutical raw material, according to its storage conditions. <11> A method for selecting a pharmaceutical raw material comprising sodium lauryl sulfate, comprising: a step of selecting a lot or a packaging unit of the pharmaceutical raw material stored under predetermined conditions; b a step of omitting the detection of impurities for the pharmaceutical raw material selected in step a. The selection method comprising the above steps. <12> The selection method according to <11>, wherein the conditions are 30°C to 40°C for 47 days or less. <13> The selection method according to <11>, wherein the conditions are 30°C to 40°C for 47 days or less, and when the temperature exceeds 40°C, the total time at a temperature exceeding 40°C and not exceeding 60°C is within 48 hours. <13a> The selection method according to any one of <11> to <13>, wherein the conditions are 40°C. <13b> The selection method according to any one of <11> to <13a>, wherein the conditions are 45 days. <14> The aforementioned conditions are the storage conditions during transportation. <11> The selection method described in any one of the items in <13b>.
[0009] Another aspect of the present invention relates to a method for evaluating the quality of a pharmaceutical formulation by pre-treating the formulation under accelerated conditions. <16> A method for evaluating the quality of a pharmaceutical preparation containing sodium lauryl sulfate, characterized by pre-treating the preparation under accelerated conditions and then detecting impurities. <17> The aforementioned pharmaceutical preparation contains a compound represented by formula (I) or a salt thereof. <16> The quality evaluation method described below. [ka] <18> The acceleration condition is characterized by a temperature of 55 to 65°C. <16> ~ <17> A quality evaluation method described in any one of the following items. <19> The acceleration condition is characterized by a temperature of approximately 60°C. <16> ~ <18> A quality evaluation method described in any one of the following items. <20> The impurity is sulfate ions, dodecanol, or a sodium lauryl sulfate-dodecanol complex. <16> ~ <19> A quality evaluation method described in any one of the following items. <21> The aforementioned impurities are detected using powder X-ray diffraction, ion exchange chromatography, gas chromatography, or quantitative NMR. <16> ~ <20> A quality evaluation method described in any one of the following items. <22> The impurity is dodecanol, and this impurity is detected using gas chromatography. <16> ~ <21> A quality evaluation method described in any one of the following items. <23> The impurity is sulfate ions, and the impurity is detected using ion exchange chromatography. <16> ~ <22> A quality evaluation method described in any one of the following items. <24> The aforementioned pretreatment is performed under the aforementioned accelerated conditions for two days or more. <16> ~ <23> A quality evaluation method described in any one of the following items. <25> The aforementioned pretreatment is carried out for 7 days under the aforementioned accelerated conditions. <16> ~ <24> A quality evaluation method described in any one of the following items. <26> The pharmaceutical preparations are selected in which the aforementioned impurities are present in the preparation at a concentration of 2% or less, as dodecanol / sodium lauryl sulfate (mol / mol%) or sulfate ions / sodium lauryl sulfate (mol / mol%). <16> ~ <25> A quality evaluation method described in any one of the following items.
[0010] Furthermore, yet another aspect of the present invention is a method for producing a pharmaceutical formulation of alectinib, comprising the step of pre-treating and sorting sodium lauryl sulfate, which is a pharmaceutical formulation raw material, under accelerated conditions. <27> A method for producing a pharmaceutical preparation containing sodium lauryl sulfate, a. A step of pre-treating sodium lauryl sulfate, a pharmaceutical raw material, under accelerated conditions. b. After the pretreatment in step a, a step is performed to detect impurities and select pharmaceutical raw materials in which the content of sulfate ions, which are impurities, is 1 mg / L or less, and c. A step of manufacturing a pharmaceutical product using the pharmaceutical product raw materials selected in step b above. The manufacturing method, including the above. <28> The aforementioned pharmaceutical preparation contains a compound represented by formula (I) or a salt thereof. <27> The manufacturing method described above. [ka] <29> A method for producing a pharmaceutical preparation containing a compound represented by formula (I) or a salt thereof and sodium lauryl sulfate, a. A step of manufacturing the pharmaceutical preparation using a pharmaceutical preparation raw material consisting of sodium lauryl sulfate, b. A step of pre-treating the pharmaceutical preparation manufactured in step a. c. After the pretreatment in step b, the step of detecting impurities and selecting pharmaceutical preparations in which the impurity, dodecanol / sodium lauryl sulfate (mol / mol%) or sulfate ions / sodium lauryl sulfate (mol / mol%), is 2% or less. The manufacturing method, including the above. [ka]
[0011] Furthermore, yet another aspect of the present invention is a pharmaceutical raw material or a pharmaceutical formulation thereof containing a predetermined proportion of impurities measured by pre-treating sodium lauryl sulfate, which is a pharmaceutical raw material, under accelerated conditions, or an alectinib-containing composition or a pharmaceutical formulation thereof. <30> A pharmaceutical composition comprising a compound represented by formula (I) or a salt thereof and sodium lauryl sulfate, wherein, when a pharmaceutical preparation containing the composition is measured after pretreatment under accelerated conditions, the composition contains dodecanol / sodium lauryl sulfate or sulfate ion / sodium lauryl sulfate in a proportion that does not affect the dissolution of the preparation. [ka] <31> The dodecanol / sodium lauryl sulfate (mol / mol%) or sulfate ion / sodium lauryl sulfate (mol / mol%) in the composition is measured by powder X-ray diffraction, ion exchange chromatography, gas chromatography, or quantitative NMR to be 2% or less. <30> The composition described above. <32> A pharmaceutical preparation containing a compound represented by formula (I) or a salt thereof and sodium lauryl sulfate, wherein the preparation contains, in a proportion that does not affect the dissolution properties, the dodecanol / sodium lauryl sulfate or sulfate ion / sodium lauryl sulfate ratio in the preparation, measured after pretreatment under accelerated conditions. [ka] <33> The dodecanol / sodium lauryl sulfate (mol / mol%) or sulfate ion / sodium lauryl sulfate (mol / mol%) in the above-mentioned formulation is measured by powder X-ray diffraction, ion exchange chromatography, gas chromatography, or quantitative NMR to be 2% or less. <32> The preparation described above. <34> A pharmaceutical preparation containing sodium lauryl sulfate, wherein the preparation contains, in a proportion that does not affect the dissolution properties of the pharmaceutical preparation, the dodecanol / sodium lauryl sulfate or sulfate ion / sodium lauryl sulfate ratio in the preparation, as measured after pretreatment under accelerated conditions. <35> A pharmaceutical formulation raw material comprising sodium lauryl sulfate, wherein the sulfate ions in the formulation raw material measured after pretreatment under accelerated conditions are 1 mg / L or less, as measured by ion exchange chromatography.
[0012] The present invention also includes the following embodiments. (1) A method for sorting a pharmaceutical preparation raw material consisting of sodium lauryl sulfate, characterized in that the preparation raw material is pretreated under accelerated conditions and then impurities are detected. (2) The sorting method according to (1), characterized in that the acceleration condition is a temperature condition of 65 to 75°C. (3) The sorting method according to (1) or (2), characterized in that the acceleration condition is a humidity condition below 79%RH. (4) The sorting method according to any one of (1) to (3), characterized in that the acceleration condition is a humidity condition of approximately 10% RH. (5) The sorting method according to any one of (1) to (4), characterized in that the acceleration conditions are a temperature of approximately 70°C and a humidity of approximately 10% RH or less. (6) The sorting method according to any one of (1) to (3), wherein the impurity is sulfate ions, dodecanol, or a sodium lauryl sulfate-dodecanol complex. (7) The sorting method according to any one of (1) to (6), wherein the impurities are detected using powder X-ray diffraction, ion exchange chromatography, gas chromatography, or quantitative NMR. (8) The sorting method according to any one of (1) to (7), wherein the impurity is sulfate ions, and the impurity is detected using ion exchange chromatography. (9) The sorting method according to any one of (1) to (8), wherein the pretreatment is performed for two days or more under the acceleration conditions. (10) The sorting method according to any one of (1) to (8), wherein pretreatment is performed for 4 days under the acceleration conditions. (11) A method for evaluating the quality of a pharmaceutical preparation, characterized by detecting impurities after pretreatment of the pharmaceutical preparation under accelerated conditions. (11a) The quality evaluation method according to (11), wherein the pharmaceutical preparation contains sodium lauryl sulfate. (12) The quality evaluation method according to (11) or (11a), wherein the acceleration condition is a temperature condition of approximately 60°C. (13) The quality evaluation method according to (11), (11a), or (12), wherein the pharmaceutical preparation contains a compound represented by formula (I) or a salt thereof. [ka]
[0013] (14) A method for producing a pharmaceutical preparation containing sodium lauryl sulfate, a. A step of pre-treating sodium lauryl sulfate, a pharmaceutical raw material, under accelerated conditions. b. After the above pretreatment, a step of detecting impurities and selecting the pharmaceutical raw materials in which the sulfate ion content, which is an impurity, is 1 mg / L or less, and c. A step of manufacturing a pharmaceutical product using the pharmaceutical raw materials selected in step b above. The manufacturing method, including the above. (15) The method for producing the pharmaceutical preparation according to (14), wherein the pharmaceutical preparation contains a compound represented by formula (I) or a salt thereof. [ka] [Effects of the Invention]
[0014] According to the method of the present invention, the quality of sodium lauryl sulfate (SLS) as a pharmaceutical raw material can be determined or selected, and pharmaceutical compositions manufactured using SLS pharmaceutical raw materials selected by the method of the present invention have excellent stability and can provide high-quality pharmaceutical formulations. According to the sorting method of the present invention, sodium lauryl sulfate, a pharmaceutical raw material, can be sorted into a pharmaceutical raw material capable of producing a highly stable pharmaceutical formulation by pre-treating it under predetermined accelerated conditions. Alternatively, in the sorting method of the present invention, the detection of impurities can be omitted depending on the storage conditions of the pharmaceutical raw material. Furthermore, according to the quality evaluation method of the present invention, the quality of a pharmaceutical preparation can be evaluated by pre-treating sodium lauryl sulfate, a pharmaceutical preparation raw material, under predetermined accelerated conditions and detecting the amount of impurities. Alternatively, according to the quality evaluation method of the present invention, a pharmaceutical preparation containing sodium lauryl sulfate can be evaluated as having a quality that allows for the omission of measuring impurities in the pharmaceutical preparation, based on whether or not it was manufactured using sodium lauryl sulfate, a pharmaceutical preparation raw material that has been pre-treated under predetermined accelerated conditions and selected according to the amount of impurities. Furthermore, according to the manufacturing method of the present invention, a pharmaceutical formulation raw material containing sodium lauryl sulfate can be selected for low impurity content by pre-treating the sodium lauryl sulfate raw material under predetermined accelerated conditions, and a pharmaceutical formulation can be manufactured using the selected pharmaceutical formulation raw material, thereby producing a pharmaceutical formulation containing sodium lauryl sulfate with excellent stability. Furthermore, according to the present invention, it is possible to provide a pharmaceutical raw material useful for producing pharmaceutical formulations with excellent stability, or an alectinib-containing composition or pharmaceutical formulation containing impurities in a predetermined proportion or less that does not affect solubility. [Brief explanation of the drawing]
[0015] [Figure 1A] This graph shows the results of powder X-ray diffraction measurements when Lot 1 of sodium lauryl sulfate was stored under temperature condition 1A. [Figure 1B]This graph shows the results of powder X-ray diffraction measurements when Lot 2 of sodium lauryl sulfate was stored under temperature condition 1A. [Figure 1C] This graph shows the results of powder X-ray diffraction measurements when Lot 1 of sodium lauryl sulfate was stored under temperature condition 1B. [Figure 1D] This graph shows the results of powder X-ray diffraction measurements when Lot 2 of sodium lauryl sulfate was stored under temperature condition 1B. [Figure 2A] This graph shows the results of powder X-ray diffraction measurements when Lot 1 of sodium lauryl sulfate was stored under humidity condition 2A. [Figure 2B] This graph shows the results of powder X-ray diffraction measurements when Lot 2 of sodium lauryl sulfate was stored under humidity condition 2A. [Figure 2C] This graph shows the results of powder X-ray diffraction measurements when Lot 1 of sodium lauryl sulfate was stored under humidity condition 2B. [Figure 2D] This graph shows the results of powder X-ray diffraction measurements when Lot 2 of sodium lauryl sulfate was stored under humidity condition 2B. [Figure 3] This is a graph showing the results of powder X-ray diffraction measurements of a sodium lauryl sulfate / dodecanol complex. [Figure 4] These are scanning electron microscope images of sodium lauryl sulfate and the sodium lauryl sulfate-dodecanol complex. [Figure 5] This is a chart of the proton nuclear magnetic resonance spectra of sodium lauryl sulfate and the sodium lauryl sulfate-dodecanol complex. [Figure 6A] This graph shows the results of powder X-ray diffraction measurements when Lot 1 of sodium lauryl sulfate was stored at a temperature of 70°C and a relative humidity of approximately 10% (saturated LiCl aqueous solution). [Figure 6B] This graph shows the results of powder X-ray diffraction measurements when Lot 2 of sodium lauryl sulfate was stored at a temperature of 70°C and a relative humidity of approximately 10% (LiCl saturated salt aqueous solution). [Figure 7A] This graph shows the results of powder X-ray diffraction measurements when formulation LotA was stored under temperature condition 5A. [Figure 7B]This graph shows the results of powder X-ray diffraction measurements when formulation LotB was stored under temperature condition 5A. [Figure 7C] This graph shows the results of powder X-ray diffraction measurements when formulation LotA was stored under temperature condition 5B. [Figure 7D] This graph shows the results of powder X-ray diffraction measurements when formulation LotB was stored under temperature condition 5B. [Figure 7E] This graph shows the results of powder X-ray diffraction measurements when formulation LotA was stored at a temperature of 5C. [Figure 7F] This graph shows the results of powder X-ray diffraction measurements when formulation LotB was stored at a temperature of 5C. [Figure 8A] This is the dissolution test profile when formulation LotC was stored at 60°C. [Figure 8B] This is the dissolution test profile when formulation LotD is stored at 60°C. [Figure 9A] This graph shows the results of powder X-ray diffraction measurements when formulation LotC was stored at 60°C. [Figure 9B] This graph shows the results of powder X-ray diffraction measurements when formulation LotD was stored at 60°C. [Figure 10A] This is the dissolution test profile when formulation LotE is stored at 60°C. [Figure 10B] This is the dissolution test profile when formulation LotF is stored at a temperature of 60°C. [Figure 10C] This is the dissolution test profile when formulation LotG is stored at 60°C. [Figure 10D] This is the dissolution test profile when formulation LotH is stored at a temperature of 60°C. [Figure 10E] This is the dissolution test profile when formulation Lot I is stored at a temperature of 60°C. [Figure 10F] This is the dissolution test profile when formulation LotJ is stored at a temperature of 60°C. [Figure 10G] This is the dissolution test profile when formulation LotK is stored at a temperature of 60°C. [Figure 11]This graph shows the GC / MS measurement results for dodecanol when formulations LotA and LotB were stored at 60°C. [Modes for carrying out the invention]
[0016] The present invention will be described below. In the present invention, "sodium lauryl sulfate" is a substance known as an additive in pharmaceutical formulations, and in particular, it is a substance that constitutes the pharmaceutical composition of a pharmaceutical formulation as a solubilizer for alectinib, a poorly soluble drug. Sodium lauryl sulfate is known to exist in monohydrate, 1 / 2 hydrate, 1 / 8 hydrate, and non-solvate forms (Reference: Journal of Crystal Growth 263 (2004) 480-490), and is usually stored at room temperature and preferably used within one year of manufacture. Any form can be used as a raw material for the pharmaceutical formulation of the present invention. "Pharmaceutical formulation raw material" refers to a substantially pure single compound (e.g., sodium lauryl sulfate) used as an additive in pharmaceutical formulations containing active ingredients such as alectinib. Pharmaceutical formulation raw material refers to a material containing the desired compound in an amount of kilograms or more for use in the industrial manufacture of the pharmaceutical formulation. Substantially pure means that while some impurities are tolerable, it contains the desired compound in a manner that makes it generally marketable. In this invention, pharmaceutical formulation raw material may be purchased commercially from a manufacturer, or it may be manufactured by the company itself or by commissioning another company. Furthermore, pharmaceutical formulation raw material may be used immediately after purchase or manufacture, or it may be used after a predetermined period, for example, more than one year, has elapsed since purchase / manufacturing. Furthermore, "a pharmaceutical raw material consisting of sodium lauryl sulfate" means a pharmaceutical raw material containing substantially pure sodium lauryl sulfate, and may contain trace amounts of impurities such as sulfate ions, dodecanol, or sodium lauryl sulfate-dodecanol complex.
[0017] "Selection" means selecting pharmaceutical raw materials or pharmaceutical preparations of higher purity. Specifically, it means selecting lots or packaging units of pharmaceutical raw materials or pharmaceutical preparations with fewer impurities by measuring the impurity content in each lot or packaging unit of pharmaceutical raw materials or pharmaceutical preparations. Preferably, selecting pharmaceutical raw materials means selecting pharmaceutical raw materials of higher purity, and more preferably, lots or packaging units of pharmaceutical raw materials whose impurity content conforms to the purity test described in the Japanese Pharmacopoeia (17th edition). A lot refers to the smallest production and shipment unit of raw materials or products manufactured under the same conditions within a predetermined period. A packaging unit refers to one or more lots of pharmaceutical raw materials or pharmaceutical preparations packaged in predetermined weight or quantity units. More preferably, when the pharmaceutical raw material is sodium lauryl sulfate and the impurity is sulfate ions, the selection of pharmaceutical raw materials is a method of selecting lots or packaging units in which the sulfate ion content, when measured using ion exchange chromatography, is 5 mg / L or less, preferably 3 mg / L or less, and most preferably 1 mg / L or less in a solution of the sample dissolved in water. Alternatively, this method involves selecting lots or packaging units containing 1 mg / L or less in a solution of approximately 100 mg / L obtained by dissolving the sample in water. When selecting pharmaceutical preparations, if the impurities of the pharmaceutical preparation are dodecanol, sulfate ions, or sodium lauryl sulfate / dodecanol complex, this method involves selecting lots or packaging units in which, when measured using powder X-ray diffraction, ion exchange chromatography, gas chromatography, or quantitative NMR, the dodecanol / sodium lauryl sulfate (mol / mol%) or sulfate ions / sodium lauryl sulfate (mol / mol%) is 5% or less, preferably 3% or less, and most preferably 2% or less. Ion chromatography is a type of liquid chromatography that primarily measures ionic species components. It separates and quantifies ionic species components in a sample solution within a packed column using an eluent as the mobile phase and an ion exchanger or similar as the stationary phase. Gas chromatography separates substances through the interaction between the stationary phase and the gas, performing qualitative analysis based on the time it takes to reach the detector and quantitative analysis based on the signal strength from the detector. Powder X-ray diffraction measurements can be performed according to standard methods, such as the "Powder X-ray Diffraction Measurement Method" described in the Japanese Pharmacopoeia (17th Edition). Quantitative NMR is a method of quantification that uses the principle that the area of the signal peak observed on the NMR spectrum is proportional to the number of hydrogen atoms contained in the sample and does not depend on the chemical structure of the substance. Therefore, by using a substance of known purity other than the analyte as a standard substance, absolute quantification of the analyte is possible. Preferably, gas chromatography or ion chromatography using an anion exchange column is used, and the preferred mobile phase, column, and detector for ion chromatography are as follows. Mobile phase (eluent): 5 mM Na2CO3 solution or 20 mM NaOH solution Column: When using a 5mM Na2CO3 solution, Metrosep A Supp 7-250 / 4.0 (Metrohm) can be used, or when using a 20mM NaOH solution, Ion Pac AS11-HC 4mm diameter, 250mm length (Thermo Scientific) can be used. Detector: Electrical conductivity meter The preferred column and measurement conditions for gas chromatography are as follows: Column: HP-5MS UI, 0.25mm ID x 30m, 0.25μm (manufactured by Agilent) Injection volume: 1.0uL Split ratio: 1:10 Column temperature: 40°C (1 min) → (20°C / min) → 180°C → (5°C / min) → 190°C → (50°C / min) → 300°C (4 min) Injector temperature: 300℃ Interface temperature: 30℃ Carrier gas: He Flow rate: 1mL / min Ion voltage: 70 eV Ionization mode: ESI- Measurement mode: SIM Monitoring ion (m / z): 83.0 "Accelerated conditions" refer to conditions that are more severe than normal storage conditions, specifically, conditions such as temperature and humidity that are more severe than normal storage conditions. Specifically, accelerated temperature conditions for pharmaceutical raw materials refer to temperature conditions of 50°C or higher, preferably about 60°C or higher, more preferably about 60°C to 80°C, even more preferably about 65°C to 75°C, and most preferably about 70°C. The humidity conditions used in these accelerated conditions are 80%RH or lower, preferably below 79%RH, and more preferably below about 10%RH. Furthermore, if pharmaceutical raw materials are stored under certain conditions, the proportion of impurities generated can be kept low. Therefore, if a pharmaceutical product containing pharmaceutical raw materials stored under such conditions is selected, the measurement of impurities can be omitted. The temperature acceleration conditions for pharmaceutical formulations refer to temperature conditions of 50°C or higher, preferably about 50°C to 70°C or higher, more preferably about 55°C to 65°C, and most preferably about 60°C. Furthermore, "storage" refers to the storage of pharmaceutical raw materials for a certain period of time from the time of manufacture until use, in a warehouse, storage facility, or cargo area where temperature and humidity can be controlled, and includes transportation that takes more than one day. In the present invention, "predetermined conditions" refer to the temperature and number of days during the storage period. Specifically, the temperature and number of days are preferably 40°C or lower for 47 days or less, more preferably 30°C to 40°C for 47 days or less, and most preferably 30°C to 40°C for 45 days or less. "Exceeding the specified conditions" in the case of temperature conditions means that the product is stored at a temperature higher than 40°C during storage. However, even if the temperature condition is exceeded, if it remains within the specified range, the impact on the formation of impurities is small, and therefore the measurement of impurities can be omitted. Specifically, if the temperature exceeds 40°C, the measurement of impurities can be omitted if the cumulative time between 40°C and 60°C is 48 hours or less. Furthermore, in the case of conditions regarding the number of days, "exceeding the specified conditions" means being stored at a temperature of 40°C or lower for 47 days, preferably for more than 45 days. However, the measurement of impurities can also be omitted for products stored at room temperature to 30°C for a period of one year or less. Thus, even if the storage conditions exceed those that allow for the omission of impurity measurement (additional conditions), this still falls under the category of "exceeding the specified conditions." In this specification, "approximately" means that a tolerance of ±10% is permitted. "Pretreatment" refers to a prescribed treatment applied to pharmaceutical raw materials before they are used in the manufacture of pharmaceutical preparations. Specifically, the prescribed treatment refers to leaving the pharmaceutical raw materials to stand for a prescribed period of time under the aforementioned accelerated conditions. The prescribed period is one day or more for pharmaceutical raw materials, preferably two days or more, more preferably three days or more, and even more preferably four days. For pharmaceutical preparations, it is five days or more, preferably seven days or more, even more preferably seven days or more and within fourteen days, and most preferably within seven days.
[0018] "Impurities" refer to substances other than the raw material contained in each lot or package unit of the raw material for pharmaceutical formulations, such as raw materials for manufacturing the raw material for pharmaceutical formulations, their decomposition products, and complexes. Alternatively, it refers to raw materials for manufacturing the raw material for pharmaceutical formulations, decomposition products, and complexes contained in pharmaceutical formulations. For example, when the raw material for pharmaceutical formulations is sodium lauryl sulfate, or when a pharmaceutical formulation contains sodium lauryl sulfate, the main impurities are sulfate ions, dodecanol, or sodium lauryl sulfate / dodecanol complexes. Sulfate ions as impurities in the raw material for pharmaceutical formulations can be measured using ion exchange chromatography, and the acceptable concentration of sulfate ions is 5 mg / L or less, preferably 3 mg / L or less, and most preferably 1 mg / L or less in a solution of the sample dissolved in water. Dodecanol as an impurity in pharmaceutical formulations can be measured using powder X-ray diffraction, ion exchange chromatography, gas chromatography, or quantitative NMR, similar to the method used in "selection," and its concentration is preferably 2% or less as dodecanol / sodium lauryl sulfate (mol / mol%) or sulfate ions / sodium lauryl sulfate (mol / mol%).
[0019] The "percentage that does not affect dissolution" refers to the percentage of impurities such that the difference between the dissolution of a pharmaceutical preparation containing a predetermined amount of impurities and the dissolution of a pharmaceutical preparation without impurities is 10% or less. For example, for pharmaceutical preparations containing impurities of various concentrations, in a dissolution test using the 16th edition of the Japanese Pharmacopoeia dissolution test paddle method at 37°C at 100 revolutions per minute, with 900 mL of the 16th edition of the Japanese Pharmacopoeia dissolution test solution No. 1 containing 7% polyoxyethylene (10) octylphenyl ether in the test solution, the drug dissolution rate at a predetermined time, preferably 75 minutes, is compared with the drug dissolution rate of a pharmaceutical preparation without impurities, and the amount of impurities in the preparation where the difference is 10% or less is determined. Specifically, for pharmaceutical preparations containing sodium lauryl sulfate, the impurity is preferably 2% or less as dodecanol / sodium lauryl sulfate (mol / mol%) or sulfate ions / sodium lauryl sulfate (mol / mol%). "Detection" refers to the qualitative or quantitative confirmation of substances other than the raw material (impurities) contained in each lot or packaging unit of a pharmaceutical preparation or pharmaceutical raw material. For example, when the pharmaceutical raw material is sodium lauryl sulfate, or when a pharmaceutical preparation contains sodium lauryl sulfate, the presence or absence of impurities such as sulfate ions, dodecanol, or sodium lauryl sulfate-dodecanol complexes is qualitatively or quantitatively confirmed using methods similar to those used in "selection," such as powder X-ray diffraction, ion exchange chromatography, gas chromatography, or quantitative NMR.
[0020] A "pharmaceutical preparation" refers to a pharmaceutical composition containing a physiologically active substance as an active ingredient and further containing pharmaceutically acceptable additives, prepared in a form suitable for administration. In the present invention, oral preparations are preferred. An "oral preparation" is a preparation that can be administered orally, and the active ingredient is mainly absorbed from the intestinal tract. Oral preparations include solid and liquid preparations, but in the present invention, solid preparations are preferred, specifically including solid preparations such as tablets, capsules, powders, lozenges, and chewable preparations, with tablets being particularly preferred. The pharmaceutical preparation of the present invention may contain, as additives, excipients, lubricants, coatings, binders, disintegrants, stabilizers, flavoring agents, and diluents commonly used in pharmaceutical preparations. The pharmaceutical preparation in the present invention is preferably a pharmaceutical preparation containing the compound represented by formula (I) or a salt thereof, more preferably alectinib hydrochloride. [ka] In this invention, the pharmaceutical preparation used for quality evaluation may be a pharmaceutical preparation manufactured in-house or a commercially available pharmaceutical preparation. A "pharmaceutical composition" means a mixture of two or more substances that contains a physiologically active substance as an active ingredient and also contains pharmaceutically acceptable additives, which are used for the treatment or prevention of diseases. In the present invention, the physiologically active substance is preferably a compound represented by formula (I) or a salt thereof. [ka] The additives preferably include sodium lauryl sulfate, and may further include lactose monohydrate, hydroxypropyl cellulose, carmellose calcium, and magnesium stearate.
[0021] "Quality evaluation method" refers to a method for evaluating the quality of a pharmaceutical preparation by qualitatively or quantitatively measuring impurities in the pharmaceutical preparation. Qualitative or quantitative measurement of impurities can be performed using methods such as powder X-ray diffraction, ion exchange chromatography, gas chromatography, or quantitative NMR. Preferably, the quality evaluation method evaluates the quality of the pharmaceutical preparation using the impurity content. Specifically, using the method used in "sorting," pharmaceutical preparations with an impurity content of 5% or less, preferably 3% or less, and more preferably 2% or less of dodecanol / sodium lauryl sulfate (mol / mol%) or sulfate ion / sodium lauryl sulfate (mol / mol%) are evaluated as pharmaceutical preparations of favorable quality.
[0022] "The compound represented by formula (I)" is formula (I) [ka] The compound represented by is 9-ethyl-6,6-dimethyl-8-(4-morpholine-4-ylpiperidine-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile, commonly known as alectinib. The "salt" of the compound represented by formula (I) is preferably a pharmaceutically acceptable salt. Examples of "pharmaceutically acceptable salts" include sulfonates such as hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate, sulfate, methanesulfonate, and p-toluenesulfonate; carboxylates such as acetate, citrate, malate, tartrate, succinate, and salicylate; alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as magnesium and calcium salts; and ammonium salts such as ammonium salts (NH4X: where X is a monovalent acid group), alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts. Preferably, it is a hydrochloride salt, and most preferably, it is a monohydrochloride salt. The compound represented by formula (I) or a salt thereof can be produced by known methods (for example, the method described in Patent Document 2). The monohydrochloride salt of the compound represented by formula (I) may be amorphous or crystalline. In the case of crystals, crystals (Type I crystals) having peaks at diffraction angles (2θ) around 8.4°, 14.0°, 16.7°, 18.8°, and 23.3° in the powder X-ray diffraction pattern are preferred. The monohydrochloride salt of the compound represented by formula (I) may also be a hydrate. The amorphous form of the monohydrochloride salt of the compound represented by formula (I) can be produced by the method described in WO2016 / 021707, and the crystals having these peaks can be produced by the method described in WO2015 / 163447. The compound represented by formula (I) or a salt thereof is contained in the entire composition in an amount of 20 to 70% by weight, preferably 35 to 60% by weight, and more preferably 45 to 50% by weight, on an equivalent basis of the free form. The preparations obtained by the manufacturing method of the present invention contain, per unit preparation, 150 mg to 800 mg, preferably 150 mg to 400 mg, and particularly preferably 150 mg to 300 mg of the compound represented by formula (I) or its salt, converted to the free form. Specifically, these are 150 mg capsule preparations and 150 mg, 300 mg, and 600 mg tablets. [Examples]
[0023] Example 1: Pretreatment condition setting (temperature) for evaluation method of sodium lauryl sulfate Appropriate amounts of sodium lauryl sulfate from different manufacturing lots (Lot 1 (manufacturing date: 2015.12.22) and Lot 2 (manufacturing date: 2017.3.10)) obtained from the same manufacturer were placed in glass vials and stored in a sealed system under two conditions: Condition 1A: temperature 60°C, Condition 1B: temperature 70°C. Powder X-ray diffraction (XRPD) was measured for samples before storage, after 3 days, and after 4 days of storage under the conditions shown below. Method for measuring powder X-ray diffraction: Measurement device: X'Pert-Pro MPD (manufactured by PANalytical) Cathode: Cu Tube voltage: 45kV Tube current: 40mA Step size: 0.02 Scanning axis: 2θ Sampling time per step: 43 seconds Scanning range: 3~40° Figure 1 shows the powder X-ray diffraction patterns of Lot1 and Lot2 under storage conditions 1A and 1B. In Lot2, the XRPD pattern remained unchanged for 4 days after storage under both conditions 1A and 1B. On the other hand, in Lot1, new peaks were observed at diffraction angles (2θ) around 4.9° and 7.4° after 4 days of storage under condition 1A, and after 3 days under condition 1B. The following shows the point at which a new peak was first detected in the XRPD of Lot1 and Lot2 under conditions 1A and 1B.
[0024] Condition 1A Lot 1: After 4 days of storage Lot 2: Not detected after 4 days of storage. Condition 1B Lot 1: After 3 days of storage Lot 2: Not detected after 4 days of storage. Therefore, we determined that the higher temperature condition 1B allowed for faster evaluation of sodium lauryl sulfate Lot1 and Lot2, and proceeded to investigate humidity in Example 2.
[0025] Example 2: Pretreatment condition setting (humidity) for evaluation method of sodium lauryl sulfate Approximately 250 mg each of two different lots (Lot 1 and Lot 2) of sodium lauryl sulfate used in Example 1 were placed in glass vials and stored in an open system under two conditions: Condition 2A: temperature 70°C, relative humidity approximately 79% (NaCl saturated salt aqueous solution), and Condition 2B: temperature 70°C, relative humidity approximately 10% (LiCl saturated salt aqueous solution). Under Condition 2A, measurements were taken before storage, and after 1 day, 2 days, and 3 days of storage. *1 Under condition 2B, powder X-ray diffraction was measured for samples before storage and after 1 day, 2 days, 3 days, and 6 days of storage, using the conditions shown in Example 1. *1: Lot1, after being stored for 2 and 3 days under condition 2A, was in a liquid state, so powder X-ray diffraction measurements were not performed.
[0026] Figure 2 shows the powder X-ray diffraction patterns of Lot1 and Lot2 under storage conditions 2A and 2B. Under condition 2B, the XRPD pattern of Lot2 remained unchanged until 6 days of storage, while in Lot1, new peaks were observed at diffraction angles (2θ) around 4.9° and 7.4° after 3 days. On the other hand, under condition 2A, peaks were observed in Lot1 after 1 day of storage and in Lot2 after 3 days. This indicates the point at which a new peak was first detected in the XRPD of Lot1 and Lot2 under conditions 2A and 2B.
[0027] Condition 2A Lot 1: After 1 day storage Lot 2: After 3 days of storage Condition 2B Lot 1: After 3 days of storage Lot 2: Not detected after 6 days of storage. Based on these results, we determined that condition 2B, with its lower relative humidity, was the most effective condition for distinguishing between sodium lauryl sulfate Lot 1 and Lot 2, and therefore used it for selecting the sodium lauryl sulfate samples.
[0028] Example 3: Identification of impurities in sodium lauryl sulfate during storage. Sodium lauryl sulfate (approximately 85 mg) was added to dodecanol (approximately 2 mL), and the mixture was stirred for approximately 12 hours while maintaining the temperature at 30°C. The precipitated solid was filtered to obtain white crystals. Powder X-ray diffraction analysis was performed on the above crystals (sodium lauryl sulfate-dodecanol complex) under the conditions of Example 1, and the measurement results are shown in Figure 3. The diffraction angle peaks (2θ) around 4.9° and 7.4° observed in the sodium lauryl sulfate-dodecanol complex closely matched the peaks of the unknown substance observed when sodium lauryl sulfate was stored in Examples 1 and 2. Furthermore, sodium lauryl sulfate and the sodium lauryl sulfate-dodecanol complex were observed using a scanning electron microscope under the following conditions. The results are shown in Figure 4. While sodium lauryl sulfate was a thin, plate-like crystal, the sodium lauryl sulfate-dodecanol complex had a different shape.
[0029] Scanning electron microscope measurement conditions: Ion sputtering equipment: JFC-1500 (manufactured by JEOL) Measurement device: SEM VE-9800 (manufactured by Keyence) Acceleration voltage: 2kV Objective lens magnification: 100x
[0030] To determine the molar ratio of sodium lauryl sulfate to dodecanol in the sodium lauryl sulfate-dodecanol complex, approximately 6 mg of the sodium lauryl sulfate-dodecanol complex was dissolved in 1 mL of 99.8% Methanol-d4, and the proton nuclear magnetic resonance spectrum (1H-NMR spectrum) was measured under the conditions shown below. Measuring device: ECP500 (manufactured by JEOL) Solvent: Methanol-d4 X resolution: 0.22673 [Hz] Number of scans: 16 Relaxation delay: 60s The proton nuclear magnetic resonance spectrum chart is shown in Figure 5. Quantitative analysis revealed that the molar ratio of sodium lauryl sulfate to dodecanol in the sodium lauryl sulfate-dodecanol complex was 1.18:1.00. From these results, it was found that sodium lauryl sulfate decomposes during storage and forms a complex with dodecanol, one of its decomposition products.
[0031] Example 4: Investigation of storage period under accelerated conditions (XRPD, ion chromatography) Approximately 250 mg of sodium lauryl sulfate was placed in a glass vial and stored in an open system at a temperature of 70°C and a relative humidity of approximately 10% (LiCl saturated salt aqueous solution). Powder X-ray diffraction was measured for samples before storage and after 1, 2, 3, 4, 7, and 11 days of storage, under the conditions shown in Example 1. Figure 6 shows the XRPD patterns of different lots (Lot 1, Lot 2) of sodium lauryl sulfate used in Example 1 up to 11 days of storage. In Lot 2, no peaks indicating the sodium lauryl sulfate-dodecanol complex were detected up to 11 days of storage, whereas in Lot 1, peaks indicating the sodium lauryl sulfate-dodecanol complex were detected in samples from 3 days of storage onward. Furthermore, the sulfate ions produced by the decomposition of sodium lauryl sulfate in Lot 1 and Lot 2 after 4 days of storage were quantified using the ion chromatography method shown below. As a result, the sulfate ion concentration in the sample solution prepared using sodium lauryl sulfate Lot 2 was 1 mg / L or less, while the sulfate ion concentration in the sample solution prepared using sodium lauryl sulfate Lot 1 was 24.1 mg / L, indicating that sodium lauryl sulfate Lot 1 had decomposed after 4 days of storage.
[0032] Method for measuring sulfate ions by ion chromatography: Approximately 5 mg of sodium lauryl sulfate was weighed out and water was added to make 50 mL. The solution was sonicated for 15 minutes and filtered through a membrane filter (DISMIC-25HP PTFE 0.45 μm HYDROPHILIC, ADVANTEC). The filtrate was passed through a washed solid-phase extraction cartridge (Dionex OnGuard II RP, ThermoFisher Scientific), and the eluate was used as the sample solution. Separately, sulfate ion standard solutions for ion chromatography (1 g / L, Wako Pure Chemical Industries) were used to prepare solutions with sulfate ion concentrations of 1 mg / L, 2 mg / L, 3 mg / L, 4 mg / L, and 5 mg / L, which were used as standard solutions. Ion chromatography was performed using a Compact IC Flex (Metrohm) under the following analytical conditions.
[0033] Column: Metrosep A Supp 7-250 / 4.0 (Made by Metrohm) Guard column: Metrosep A Supp 4 / 5 S-Guard / 4.0 (manufactured by Metrohm) Suppressor: MSM, MCS (Metrohm brand) Eluent: 5mM Na2CO3 solution Washing solution: Purified water Flow rate: 0.8mL / min Sample temperature: 20℃ Column temperature: 45℃ Injection amount: 10ml Measurement time: 24 min The sulfate ion concentration in the sample solution was calculated based on a calibration curve created using standard solutions.
[0034] Example 5: Investigation of pretreatment methods for quality evaluation of pharmaceutical formulations (temperature) From Example 3, it was found that impurities in sodium lauryl sulfate vary depending on the lot. Therefore, we manufactured formulation Lot A of Alecensa capsules (150 mg) using sodium lauryl sulfate Lot 1, and formulation Lot B of Alecensa capsules (150 mg) using sodium lauryl sulfate Lot 3 (manufacturing date: 2015.10.02) from the same manufacturer but with a different manufacturing date, according to Example 1 of Patent 5859712, and investigated the presence of complex impurities under different storage conditions. Formulations Lot A and Lot B were placed in glass vials and stored in a sealed system under the following temperature conditions: 5A: 60°C, 5B: 70°C, and 5C: 80°C. Powder X-ray diffraction was measured for samples taken after 4, 7, 10, and 14 days of storage under condition 5A, 2 and 3 days under condition 5B, and 1 day under condition 5C, using the conditions shown in Example 1. Figure 7 shows the powder X-ray diffraction patterns of LotA and LotB under storage conditions 5A, 5B, and 5C. Under condition 5A, the peak associated with the sodium lauryl sulfate-dodecanol complex was not detected in LotB samples up to 10 days after storage, whereas it was detected in LotA samples after 7 days of storage.
[0035] This shows the point at which the peak of the sodium lauryl sulfate-dodecanol complex was first detected in the XRPD patterns of LotA and LotB under each temperature condition. Condition 5A LotA: After 7 days of storage LotB: After 14 days of storage Condition 5B LotA: After 2 days of storage LotB: After 2 days of storage Condition 5C LotA: After 1 day storage LotB: After 1 day storage Therefore, condition 5A, 60°C, was determined to be a suitable condition for evaluating the stability of formulations Lot A and Lot B, and was used for quality evaluation of the formulations.
[0036] Example 6: Effects of sodium lauryl sulfate impurities on formulations To investigate the effect of sodium lauryl sulfate impurities on the formulation, formulation Lot C was prepared using sodium lauryl sulfate Lot 1, which was used in Example 1, and formulation Lot D was prepared using sodium lauryl sulfate Lot 4 (manufacturing date: 2016.06.28), which was from the same manufacturer but manufactured on a different date. Both formulations of Alecensa capsules (150 mg) were prepared in the same manner as in Example 5, and their dissolution rates were examined. Formulation LotC and Formulation LotD were placed in glass vials and stored in a sealed system at a temperature of 60°C. Dissolution tests were performed on samples before storage and after 7 days of storage under the following conditions. The results showed that the dissolution profile of LotD was the same as before storage, while the dissolution rate of LotC was significantly lower than before storage (Figure 8).
[0037] Method for conducting dissolution tests: The Japanese Pharmacopoeia Dissolution Test Solution 1, containing 7% polyoxyethylene(10) octylphenyl ether, was used to perform the test using the Japanese Pharmacopoeia Dissolution Test paddle method at 37°C and 100 revolutions per minute. Furthermore, powder X-ray diffraction was measured for samples before storage and after storage for 5, 6, 7, 8, 9, 12, and 14 days, under the conditions shown in Example 1. As a result, the peak associated with the sodium lauryl sulfate-dodecanol complex was not detected in LotD until after 14 days of storage, whereas it was detected in LotC after 7 days of storage (Figure 9). Furthermore, dodecanol was quantified by GC / MS in the samples after 7 days of storage using the method described below.
[0038] Method for measuring dodecanol by GC / MS: The contents of three capsules of each formulation were removed and mixed. 50 mg of the capsule contents were weighed out, and hexane was added to make 25 mL. The solution was sonicated for 30 minutes, transferred to a centrifuge tube, and centrifuged. The supernatant was used as the sample solution. Separately, solutions with dodecanol concentrations of 1 g / L, 5 g / L, 10 g / L, 50 g / L, and 100 g / L were prepared using 1-dodecanol (Wako Pure Chemical Industries, Ltd.) and used as standard solutions. GC / MS was performed using a 7850A (Agilent) under the following analytical conditions. Column: HP-5MS UI, 0.25mm ID x 30m, 0.25μm (manufactured by Agilent) Injection volume: 1.0uL Split ratio: 1:10 Column temperature: 40℃ (1 min) -> (20℃ / min) -> 180℃ -> (5℃ / min) -> 190℃ -> (50℃ / min) -> 300℃ (4 min) Injector temperature: 300℃ Interface temperature: 30℃ Carrier gas: He Flow rate: 1mL / min Ion voltage: 70 eV Ionization mode: ESI- Measurement mode: SIM Monitoring ion (m / z): 83.0
[0039] As a result, the dodecanol concentration in LotD was below the limit of quantification, while the dodecanol / sodium lauryl sulfate (mol / mol%) in LotC was 6.2%. From the above, it was found that formulation LotD, manufactured using sodium lauryl sulfate Lot4, showed no degradation of sodium lauryl sulfate and no change in dissolution properties after 7 days of storage at 60°C, whereas formulation LotC, manufactured using sodium lauryl sulfate Lot1, showed degradation of sodium lauryl sulfate after 7 days of storage at 60°C, and the dissolution properties of the formulation also decreased. Therefore, it was found that higher quality formulations can be manufactured by selecting sodium lauryl sulfate of appropriate quality and manufacturing the formulation. In other words, it was found that measuring the sulfate ion concentration detected by ion chromatography after 4 days of storage under accelerated conditions of 70°C and approximately 10% relative humidity is effective in selecting pharmaceutical raw materials to be used in the manufacture of more stable formulations, in order to exclude sodium lauryl sulfate lots that degrade easily, such as Lot1, and select sodium lauryl sulfate that does not degrade easily, such as Lot2. Furthermore, sodium lauryl sulfate with a sulfate ion concentration of 1 mg / L or less measured by this method can be selected as pharmaceutical raw materials that can be used to manufacture pharmaceutical formulations with superior stability.
[0040] Example 7: Setting storage conditions (temperature) for sodium lauryl sulfate Sodium lauryl sulfate is normally stored at room temperature, but storage conditions (temperature) were set considering the possibility of higher temperatures during transport. Sodium lauryl sulfate Lot 5 (manufacturing date: October 13, 2016) was used for primary packaging in a poly bag and secondary packaging in an aluminum bag, and stored under the temperature conditions and for the period shown in Table 1. Subsequently, approximately 250 mg was placed in a glass vial and stored in an open system at a temperature of 70°C and a relative humidity of approximately 10% (LiCl saturated salt aqueous solution) for 4 days. After storage, sulfate ions produced by the decomposition of sodium lauryl sulfate were quantified in the sample using the ion chromatography method shown in Example 4. [Table 1]
[0041] As a result, the sulfate ion concentration detected by ion chromatography was 1 mg / L or less under all of the above conditions. Therefore, the most severe condition 6 (45 days at 40°C and 48 hours at 60°C) was set as the upper limit for storage conditions, and it was determined that lots of sodium lauryl sulfate stored without exceeding this limit should be used in the manufacture of formulations with superior stability.
[0042] Example 8: Relationship between impurities in sodium lauryl sulfate and formulation quality (dissolution) The relationship between the amount of dodecanol, an impurity of sodium lauryl sulfate, detected in the formulation and its dissolution properties was investigated using multiple lots of the formulation. Formulation lots Lot E (manufacturing date: 2016.08.24), Lot F (manufacturing date: 2016.08.29), Lot G (manufacturing date: 2016.08.24), Lot H (manufacturing date: 2016.10.19), Lot I (manufacturing date: 2016.03.29), Lot J (manufacturing date: 2016.03.24), and Lot K (manufacturing date: 2015.07.07) were placed in glass vials and stored at 60°C in a sealed system. Dissolution tests were performed on samples before storage and after 7 days of storage, and dodecanol was quantified by GC / MS on the samples after 7 days of storage. The dissolution tests and quantification of dodecanol by GC / MS were performed using the method shown in Example 6. Dissolution tests revealed that while the dissolution profiles of Lot H, Lot I, Lot J, and Lot K were similar to those before storage, the dissolution rates of Lot E, Lot F, and Lot G were significantly lower than before storage (Figures 10A-G). Furthermore, quantitative analysis of dodecanol in the stored samples showed that the dodecanol / sodium lauryl sulfate (mol / mol%) in Lot H, Lot I, Lot J, and Lot K was 2% or less, while the dodecanol / sodium lauryl sulfate (mol / mol%) in Lot E, Lot F, and Lot G all exceeded 2% (Table 2). [Table 2]
[0043] Based on the decomposition mechanism of sodium lauryl sulfate, it is conceivable that the dodecanol / sodium lauryl sulfate (mol / mol%) produced by decomposition is equal to the sulfate ion / sodium lauryl sulfate (mol / mol%). Therefore, from these results, it was found that if the dodecanol / sodium lauryl sulfate (mol / mol%) or sulfate ion / sodium lauryl sulfate (mol / mol%) is detected at a value exceeding 2% in the formulation after storage in a sealed system at 60°C for 7 days, it leads to a decrease in the dissolution rate of the formulation and affects the quality of the formulation.
[0044] Example 9: Confirmation of the kinetic properties of sodium lauryl sulfate decomposition in the formulation. In Example 6, it was confirmed that the decomposition rate of sodium lauryl sulfate in the formulation differed depending on the formulation lot, and the kinetic characteristics of this decomposition were investigated. Formulations Lot A and Lot B were stored in a sealed system at a temperature of 60°C, and for Lot A, samples were taken before storage and after 4 days, 7 days, 8 days, 9 days, 12 days, and 14 days of storage. For Lot B, samples were taken after 4 days, 7 days, 8 days, 9 days, and 12 days of storage. Dodecanol was quantified using the GC / MS measurement method for dodecanol shown in Example 6. The results are shown in Figure 11. It was confirmed that the time until dodecanol could be detected differed between formulations LotA and LotB, and that the amount increased exponentially after dodecanol was produced. These findings are thought to reflect the fact that sulfuric acid is generated from the decomposition of sodium lauryl sulfate in the formulation, and this sulfuric acid acts as a catalyst to accelerate the decomposition, resulting in the accelerated decomposition of sodium lauryl sulfate. [Industrial applicability]
[0045] This invention is used for sorting sodium lauryl sulfate, a pharmaceutical raw material used in the manufacture of pharmaceuticals, or for sorting, quality evaluation, and manufacturing compositions or pharmaceuticals containing sodium lauryl sulfate.
Claims
1. A method for sorting pharmaceutical formulation raw materials consisting of sodium lauryl sulfate, characterized in that impurities are detected after pre-treatment of the pharmaceutical formulation raw materials under accelerated conditions, wherein the pre-treatment is performed by leaving the pharmaceutical formulation raw materials standing for three days or more under temperature conditions of 65 to 75°C and humidity conditions of less than 79% RH.
2. A method for evaluating the quality of a pharmaceutical product containing a pharmaceutical product raw material comprising a compound represented by formula (I) or a salt thereof and sodium lauryl sulfate, comprising: a step of selecting a pharmaceutical product using a pharmaceutical product raw material that has been pretreated under accelerated conditions and then sorted by detecting impurities; and b step of omitting the measurement of impurities in the pharmaceutical product selected in step a, wherein the pretreatment involves leaving the pharmaceutical product raw material standing for three days or more under temperature conditions of 65 to 75°C and humidity conditions of less than 79% RH. 【Chemistry 1】
3. The method according to claim 1 or 2, characterized in that the acceleration condition is a humidity condition of about 10% RH.
4. The method according to any one of claims 1 to 3, characterized in that the acceleration conditions are a temperature of approximately 70°C and a humidity of approximately 10% RH or less.
5. The method according to any one of claims 1 to 4, wherein the impurity is sulfate ions, dodecanol, or a sodium lauryl sulfate / dodecanol complex.
6. The method according to any one of claims 1 to 5, wherein the impurities are detected using powder X-ray diffraction, ion exchange chromatography, gas chromatography, or quantitative NMR.
7. The method according to any one of claims 1 to 6, wherein the impurity is sulfate ions, and the impurity is detected using ion exchange chromatography.
8. The method according to any one of claims 1 to 7, wherein the pretreatment is performed for four days under the aforementioned acceleration conditions.
9. A method for evaluating the quality of a pharmaceutical preparation containing sodium lauryl sulfate, characterized by pre-treating the preparation under accelerated conditions and then detecting impurities, wherein the pharmaceutical preparation is a capsule containing lactose monohydrate, hydroxypropyl cellulose, carmellose calcium, and magnesium stearate, and the pre-treatment involves standing the pharmaceutical preparation at a temperature of 55 to 65°C for 7 days or more, and the pharmaceutical preparation contains a compound represented by formula (I) or a salt thereof. 【Transformation 3】
10. The quality evaluation method according to claim 9, characterized in that the acceleration condition is a temperature condition of approximately 60°C.
11. The quality evaluation method according to any one of claims 9 to 10, wherein the impurity is sulfate ions, dodecanol, or a sodium lauryl sulfate / dodecanol complex.
12. The quality evaluation method according to any one of claims 9 to 11, wherein the impurities are detected using powder X-ray diffraction, ion exchange chromatography, gas chromatography, or quantitative NMR.
13. The quality evaluation method according to any one of claims 9 to 12, wherein the impurity is dodecanol, and the impurity is detected using gas chromatography.
14. The quality evaluation method according to any one of claims 9 to 13, wherein the impurity is sulfate ions, and the impurity is detected using ion exchange chromatography.
15. A quality evaluation method according to any one of claims 9 to 14, wherein the aforementioned impurity is present in the preparation at a concentration of 2% or less as dodecanol / sodium lauryl sulfate (mol / mol%) or sulfate ion / sodium lauryl sulfate (mol / mol%).
16. A method for producing a pharmaceutical preparation containing sodium lauryl sulfate, a. A step of pre-treating sodium lauryl sulfate, a pharmaceutical raw material, under accelerated conditions. b. After the pretreatment in step a, a step of detecting impurities and selecting pharmaceutical raw materials in which the content of sulfate ions, which are impurities, is 1 mg / L or less, and c. A step of manufacturing a pharmaceutical product using the pharmaceutical product raw materials selected in step b above. A manufacturing method comprising the above, wherein the pretreatment involves standing the pharmaceutical preparation raw material for three days or more under temperature conditions of 65 to 75°C and humidity conditions of less than 79% RH, and the pharmaceutical preparation contains a compound represented by formula (I) or a salt thereof. 【Chemistry 4】
17. A method for producing a pharmaceutical preparation containing a compound represented by formula (I) or a salt thereof and sodium lauryl sulfate, wherein the pharmaceutical preparation is a capsule containing lactose monohydrate, hydroxypropyl cellulose, carmellose calcium, and magnesium stearate. a. A step of manufacturing the pharmaceutical preparation using a pharmaceutical preparation raw material consisting of sodium lauryl sulfate, b. A step of pre-treating the pharmaceutical preparation manufactured in step a. c. After the pretreatment in step b, the step of detecting impurities and selecting pharmaceutical preparations in which the impurities, dodecanol / sodium lauryl sulfate (mol / mol%) or sulfate ions / sodium lauryl sulfate (mol / mol%), are present in a concentration of 2% or less. A manufacturing method comprising the above, wherein the pretreatment involves leaving the pharmaceutical preparation standing for 7 days or more under temperature conditions of 55 to 65°C. 【Transformation 5】