Method for reducing dimethylamine impurity present inside metformin hydrochloride

Abstract

Disclosed is a method for reducing dimethylamine, which is an impurity present inside metformin hydrochloride.

Description

A method for reducing dimethylamine, an impurity present in metformin hydrochloride.

[0001] The present invention relates to a method for reducing dimethylamine (hereinafter referred to as 'DMA'), an impurity present in metformin hydrochloride, and more specifically, to a method for reducing dimethylamine (DMA), which is a cause of N-nitrosodimethylamine (NDMA) detected in a finished pharmaceutical product using metformin hydrochloride, during the manufacturing process of the finished pharmaceutical product using metformin hydrochloride, thereby suppressing the occurrence of N-nitrosodimethylamine (NDMA) in the finished pharmaceutical product.

[0002] The detection of N-nitrosodimethylamine (NDMA) in finished pharmaceutical products using metformin hydrochloride has become a significant issue in the pharmaceutical industry.

[0003] Due to these issues, regulations and management plans for genotoxic substances have been continuously developed, and this trend is still continuing.

[0004] Accordingly, the occurrence of N-nitrosodimethylamine (NDMA) has become a major obstacle in the development of finished pharmaceutical products using metformin hydrochloride.

[0005] Several multinational pharmaceutical companies, including Merck, the original pharmaceutical company that produces and sells Glucophage XR extended-release tablets, a finished metformin hydrochloride drug, are conducting extensive research to analyze the cause of N-nitrosodimethylamine (NDMA) and reduce it.

[0006] These studies have elucidated the mechanism by which N-nitrosodimethylamine (NDMA) occurs. It is now generally accepted that NDMA is generated when dimethylamine (DMA) remaining in finished pharmaceutical products reacts with nitric acid or nitrous acid introduced through additives, binding solvents, or other contaminants.

[0007] Accordingly, most research on reducing N-nitrosodimethylamine (NDMA) focuses on reducing nitric acid and nitrite. The mainstream approach is to quantify the amount of nitric acid and nitrite by additive type and manufacturer, identify the correlation between this and NDMA emissions, and then use this data to reduce the levels.

[0008] However, despite these efforts, there is an urgent need for research and development in this area as N-nitrosodimethylamine (NDMA) detected in metformin hydrochloride finished pharmaceutical products is not effectively reduced.

[0009] [Prior Art Literature]

[0010] [Non-patent literature]

[0011] (Non-patent literature 1) International Journal of Pharmaceutics 620 (2022) 121740

[0012] The purpose of the present invention is to provide a method for reducing dimethylamine (DMA), an impurity present in metformin hydrochloride, during the manufacturing process of a finished pharmaceutical product, thereby suppressing the occurrence of N-nitrosodimethylamine (NDMA) in the finished pharmaceutical product.

[0013] Specifically, the technical task is to provide a method for efficiently reducing dimethylamine (DMA), an impurity present in metformin hydrochloride, by mixing metformin hydrochloride, the main ingredient, with an additive and drying the fluidized bed.

[0014] More specifically, the specific task to be solved is to provide a method for efficiently reducing dimethylamine (DMA) by mixing a pharmaceutical additive with the main ingredient, metformin hydrochloride.

[0015] Furthermore, a specific solution is to dry the fluidized bed by mixing the main ingredient, metformin hydrochloride, with pharmaceutical additives to reduce dimethylamine (DMA), an impurity present in metformin hydrochloride.

[0016] In order to solve the above problem, the present invention discloses the following means.

[0017] In one aspect, the present invention discloses a method for reducing dimethylamine, an impurity present in metformin hydrochloride, comprising the steps of mixing metformin hydrochloride and a pharmaceutical additive; and drying the mixed metformin hydrochloride and pharmaceutical additive.

[0018] In another aspect, the present invention discloses a method for producing a pharmaceutical composition comprising metformin hydrochloride with reduced N-nitrosodimethylamine as an active ingredient, the method comprising the steps of: (S1) mixing metformin hydrochloride and a pharmaceutical additive and drying the mixture to reduce and recover dimethylamine, which is an impurity present in metformin hydrochloride; (S2) combining the recovered mixture of metformin hydrochloride and a pharmaceutical additive into a binding solution; (S3) drying and sizing the combined mixture; and (S4) adding a release agent and a lubricant to the sizing mixture and mixing them.

[0019] The reduction method according to the present invention has the advantage of efficiently reducing dimethylamine (DMA) remaining in metformin hydrochloride by mixing metformin hydrochloride, which is the main ingredient, and a pharmaceutical additive when manufacturing a finished pharmaceutical product of metformin hydrochloride, and drying the fluidized bed.

[0020] Therefore, the present invention has the effect of effectively suppressing the occurrence of N-nitrosodimethylamine (NDMA) in a finished pharmaceutical product of metformin hydrochloride by reducing dimethylamine (DMA) in metformin hydrochloride through the reduction method according to the present invention.

[0021] In addition, since the reduction method according to the present invention enables reduction of dimethylamine (DMA) in the raw pharmaceutical material during the manufacturing process of the finished pharmaceutical product of metformin hydrochloride, the possibility of occurrence of N-nitrosodimethylamine (NDMA) due to a change in the manufacturer in the future can be fundamentally blocked through process optimization, and thus there is an advantage of no restrictions in selecting the manufacturer of the raw pharmaceutical material.

[0022] The effects of the present invention are not limited to the effects mentioned above, and various effects may be included within a range apparent to those skilled in the art from the contents described below.

[0023] Figure 1 is a drawing showing a method for manufacturing a metformin hydrochloride wet granule preparation according to the present invention (here, the metformin hydrochloride wet granule preparation refers to a sustained-release layer in a metformin hydrochloride complex preparation).

[0024] Figure 2 compares the effects of drying the main ingredient metformin hydrochloride and using a dimethylamine (DMA)-reducing raw material on the increase of N-nitrosodimethylamine (NDMA) (in Figure 2, wet granules refer to a wet granule preparation according to Comparative Example 1, drying the main ingredient refer to a wet granule preparation according to Example 1, and changing the main ingredient manufacturer refer to a wet granule preparation according to Comparative Example 2).

[0025] Figure 3 shows the drying method of the main ingredient, metformin hydrochloride, and the change in the content of dimethylamine (DMA) over time (in Figure 3, API represents Example 3, which includes a process of drying the main ingredient, metformin hydrochloride, alone, and API + CMC represents Example 4, which includes a process of mixing sodium carboxymethylcellulose into metformin hydrochloride and then drying it).

[0026] Figure 4 compares the trend of increase in N-nitrosodimethylamine (NDMA) between Example 2 manufactured through a dimethylamine (DMA) reduction process and a control drug (Glucophage XR) (in Figure 4, Glucophage XR means the control drug, and the scale-up reagent means the wet granule reagent according to Example 2).

[0027] Hereinafter, the present specification will be described in more detail.

[0028] To explain this more specifically, the terms used in this specification are selected from widely used, general terms, taking into account the functions of the present invention. However, these terms may vary depending on the intentions of engineers working in the field, precedents, the emergence of new technologies, etc. Furthermore, in certain cases, terms may be arbitrarily selected by the applicant, and in such cases, their meanings will be described in detail in the description of the relevant invention. Therefore, the terms used in the present invention should not be defined simply as names of terms, but rather based on the meanings of the terms and the overall content of the present invention.

[0029] Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Terms defined in commonly used dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology, and shall not be interpreted in an idealized or overly formal sense unless explicitly defined herein.

[0030] Numerical ranges are inclusive of the numbers defined in the ranges above. Every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if that lower numerical limitation were explicitly stated. Every minimum numerical limitation given throughout this specification includes every higher numerical limitation, as if that higher numerical limitation were explicitly stated. Every numerical limitation given throughout this specification will include every better numerical range within that broader numerical range, as if that narrower numerical limitation were explicitly stated.

[0031] The following descriptions and embodiments disclosed in the present invention may also be applied to other descriptions and embodiments. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0032] Expressions such as “comprising” as used herein should be understood as open-ended terms implying the possibility of including other embodiments, unless specifically stated otherwise in the phrase or sentence in which the expression is included.

[0033] The circumstances that led to the completion of the present invention are described in detail below.

[0034] Metformin hydrochloride contains trace amounts of dimethylamine (DMA) due to the decomposition of residual dimethylformamide (DMF) solvent used in the synthesis process or other unknown reasons. Dimethylamine (DMA) has a boiling point of only 7°C, so it is a substance that evaporates at room temperature (20-25°C) and has a foul odor similar to ammonia or fishy odor. However, when dimethylamine (DMA) combines with hydrochloride (HCl) to form dimethylamine hydrochloride (hereinafter referred to as 'DMA-HCl'), the boiling point becomes 170-173°C, so it does not evaporate at room temperature (20-25°C). In fact, the Impurity F of metformin hydrochloride listed in the European Pharmacopoeia (EP) is known as dimethylamine hydrochloride (DMA-HCl), and a high proportion of dimethylamine (DMA) exists in the form of hydrochloride, dimethylamine hydrochloride (DMA-HCl), in the main ingredient of metformin hydrochloride, which appears to be the main cause of the occurrence of N-nitrosodimethylamine (NDMA). Therefore, the inventors of the present invention thought that reducing dimethylamine (DMA) in the main ingredient of metformin hydrochloride might suppress the occurrence of N-nitrosodimethylamine (NDMA), and checked by changing to a manufacturer that specifically manages the Impurity F of dimethylamine hydrochloride (DMA-HCl). As a result, it was confirmed that the occurrence of N-nitrosodimethylamine (NDMA) was significantly reduced in the test product using metformin hydrochloride from a manufacturer that clearly managed the Impurity F well.

[0035] Accordingly, the inventors of the present invention, taking note of the fact that dimethylamine (DMA) is volatile, conducted research to suppress the generation of N-nitrosodimethylamine (NDMA) by volatilizing and reducing dimethylamine (DMA) within metformin hydrochloride. They determined that volatilizing freely existing dimethylamine (DMA) is not difficult, and that it can be removed simply by drying in a fluidized bed. However, they determined that a solution was needed to address the issue of how to volatilize dimethylamine (DMA) bound to hydrochloride. They determined that in order to volatilize dimethylamine hydrochloride (DMA-HCl), it is necessary to first remove the hydrochloride to create free dimethylamine (DMA), and that if dimethylamine (DMA) is continuously volatilized and removed, the amount of dimethylamine hydrochloride (DMA-HCl) required to maintain a constant ratio will change into free dimethylamine (DMA). This is because dimethylamine (DMA) and dimethylamine hydrochloride (DMA-HCl) will exist in a constant ratio depending on environmental factors such as the pH within metformin hydrochloride. While it will take time and the reduction efficiency will gradually decrease, and eventually a certain amount of dimethylamine (DMA) will remain and not be completely removed, it will certainly show a reduction effect compared to not going through this reduction process. However, it was determined that a more active method was needed to maximize the dimethylamine (DMA) reduction efficiency.

[0036] As a more proactive method, we conceived the idea of ​​mixing pharmaceutical excipients with metformin hydrochloride. Specifically, when metformin hydrochloride and pharmaceutical excipients were mixed, dimethylamine (DMA) and a characteristic fishy odor were more strongly generated. This can be interpreted as an increase in the amount of volatilized dimethylamine (DMA). It is presumed that the mixing of carboxymethylcellulose sodium, among the pharmaceutical excipients, reduces dimethylamine hydrochloride (DMA-HCl) to a free dimethylamine (DMA) state, resulting in further volatilization. The reasons supporting this assumption are as follows: First, the sodium cation contained in carboxymethylcellulose sodium is highly reactive, so it is believed that a mechanism has occurred where it competes with dimethylamine (DMA) to remove hydrochloride. Another possibility is that the mechanism of reduction and volatilization of dimethylamine hydrochloride (DMA-HCl) occurred due to a local decrease in pH caused by mixing with sodium carboxymethylcellulose, which has a slightly acidic pH. Regardless of the mechanism, it can be seen that the reduction of dimethylamine hydrochloride (DMA-HCl) ultimately increases the probability of returning to free dimethylamine (DMA). Therefore, by mixing metformin hydrochloride and sodium carboxymethylcellulose and applying heat in a fluidized bed dryer to volatilize dimethylamine (DMA), it was confirmed that almost all of the dimethylamine (DMA) remaining in metformin hydrochloride could be removed, thereby completing the present invention.

[0037] Hereinafter, the present invention will be described in detail.

[0038] A method for reducing dimethylamine, an impurity present in metformin hydrochloride.

[0039] To achieve the above purpose, the present invention provides the following.

[0040] In one aspect, the present invention provides a method for reducing dimethylamine, an impurity present in metformin hydrochloride, comprising the steps of mixing metformin hydrochloride and a pharmaceutical additive; and drying the mixed metformin hydrochloride and pharmaceutical additive.

[0041] In the present invention, the step of mixing the metformin hydrochloride and the pharmaceutical additive may be mixed at a weight ratio (w / w) of 15 to 25:1, specifically, at a weight ratio (w / w) of 18 to 20:1, but is not limited thereto.

[0042] In the present invention, the step of drying the mixed metformin hydrochloride and pharmaceutical additive may be performed by drying the mixed metformin hydrochloride and pharmaceutical additive at 50 to 90°C for 10 to 120 minutes, specifically, by drying at 60 to 80°C for 30 to 90 minutes using a fluidized bed dryer, but is not limited thereto.

[0043] In the present invention, the pharmaceutical additive may be sodium carboxymethylcellulose, but is not limited thereto.

[0044] Specifically, when dimethylamine, an impurity present in metformin hydrochloride, is reduced by mixing metformin hydrochloride and carboxymethylcellulose sodium, the reduction rate of dimethylamine (DMA) exceeds 80% even after drying for 30 minutes, and when drying for 60 minutes and 90 minutes, the content of dimethylamine (DMA) is detected to be less than the quantitative limit of 20 ppm.

[0045] Method for manufacturing a pharmaceutical composition comprising metformin hydrochloride with reduced N-nitrosodimethylamine as an active ingredient

[0046] To achieve the above purpose, the present invention provides the following.

[0047] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising metformin hydrochloride with reduced N-nitrosodimethylamine as an active ingredient, the method comprising the steps of: (S1) mixing metformin hydrochloride and a pharmaceutical additive and then drying the mixture to reduce and recover dimethylamine, which is an impurity present in metformin hydrochloride; (S2) combining the recovered mixture of metformin hydrochloride and the pharmaceutical additive into a binding solution; (S3) drying and sizing the combined mixture; and (S4) adding a release agent and a lubricant to the sizing mixture and mixing them.

[0048] In the present invention, in the step (S1), metformin hydrochloride and the pharmaceutical additive may be mixed at a weight ratio (w / w) of 15 to 25:1, specifically, at a weight ratio (w / w) of 18 to 20:1, but is not limited thereto.

[0049] In the present invention, in the step (S1), the mixed metformin hydrochloride and pharmaceutical additives can be dried at 50 to 90°C for 10 to 120 minutes, specifically, they can be dried at 60 to 80°C for 30 to 90 minutes using a fluidized bed dryer, but are not limited thereto.

[0050] In the present invention, the pharmaceutical additive may be sodium carboxymethylcellulose, but is not limited thereto.

[0051] In the present invention, in the step (S2), the binding solution may be purified water, but is not limited thereto.

[0052] In the present invention, in the step (S3), drying may be performed under conditions of 5 to 80°C, but is not limited thereto.

[0053] In the present invention, in the step (S4), the release agent may be hypromellose, but is not limited thereto.

[0054] In the present invention, in the step (S4), the lubricant may be magnesium stearate, but is not limited thereto.

[0055] The method for reducing dimethylamine, an impurity present in metformin hydrochloride described above, can be applied to all methods for producing a pharmaceutical composition containing metformin hydrochloride with reduced N-nitrosodimethylamine as an active ingredient, unless they are contradictory.

[0056] Hereinafter, the present invention will be described in detail based on examples. However, the following examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0057] [Examples and Comparative Examples]

[0058] The purpose of mixing, ingredient names and amounts of the metformin hydrochloride wet granule preparation (sustained-release tablet) manufactured in Examples 1 and 2 and Comparative Examples 1 and 2 below are as shown in Table 1 below, and the basic manufacturing method is as shown in Figure 1.

[0059] Ingredients for formulation purpose, name of ingredient, content (mg / tablet), weight %, main ingredient, metformin hydrochloride 1,000 69.4%, excipient, sodium carboxymethyl cellulose 50 3.5%, sustained-release agent, hypromellose 380 26.4%, lubricant, magnesium stearate 100.7%, bound liquid, purified water 0.22 mL - Total 1440 100%

[0060] Example 1. Wet granule preparation in which DMA reduction process was performed solely with metformin hydrochloride.

[0061] First, metformin hydrochloride (manufacturer: Granules India Ltd. (India), dimethylamine (DMA) content: approximately 110 ppm) was placed in a fluidized bed dryer and dried at 70℃ for 30 minutes to reduce dimethylamine (DMA), an impurity present in metformin hydrochloride, the raw material pharmaceutical. The metformin hydrochloride that went through the dimethylamine (DMA) reduction process was recovered and used. After weighing the raw materials as shown in Table 1, the metformin hydrochloride that went through the dimethylamine (DMA) reduction process and sodium carboxymethylcellulose were mixed and kneaded using purified water as a binder. Then, the kneaded product was dried in dry heat at 50℃ and sieved to have a consistent particle size. After adding hypromellose as a sustained-release agent and performing post-mixing, magnesium stearate was additionally added and finally mixed to manufacture a metformin hydrochloride wet granule prototype (sustained-release tablet).

[0062] Example 2. Wet granule preparation using a DMA reduction process by mixing metformin hydrochloride and sodium carboxymethyl cellulose.

[0063] After weighing the raw materials as shown in Table 1 above, metformin hydrochloride (manufacturer: Sohan Healthcare Pvt. Ltd. (India), dimethylamine (DMA) content: approximately 20 ppm) and carboxymethylcellulose sodium were mixed and placed in a fluidized bed dryer and dried at 70°C for 30 minutes to reduce dimethylamine (DMA), an impurity present in metformin hydrochloride, the raw pharmaceutical material. The mixture that went through the dimethylamine (DMA) reduction process was recovered and used. Thereafter, after weighing the raw materials as shown in Table 1 above, the mixture of the recovered metformin hydrochloride and carboxymethylcellulose sodium was combined with purified water as a binding solution. Then, the mixture was dried under dry heat at 50°C and then sieved to show a certain particle size. After adding hypromellose as a sustained-release agent and performing post-mixing, magnesium stearate was additionally added and finally mixed to manufacture a metformin hydrochloride wet granule preparation (sustained-release tablet).

[0064] Example 3. Confirmation of DMA reduction efficiency with metformin hydrochloride alone.

[0065] Metformin hydrochloride (manufacturer: Granules India Ltd. (India), dimethylamine (DMA) content: approximately 110 ppm) (1 kg, equivalent to 1,000 tablets) was placed in a fluidized bed dryer and dried at 70°C. Sampling was performed at 30, 60, and 90 minutes to confirm the dimethylamine (DMA) reduction efficiency.

[0066] Example 4. Confirmation of DMA reduction efficiency by mixing metformin hydrochloride and carboxymethylcellulose sodium.

[0067] Metformin hydrochloride (manufacturer: Granules India Ltd. (India), dimethylamine (DMA) content: approximately 110 ppm) (1 kg for 1000 tablets) and sodium carboxymethylcellulose were mixed (50 g of sodium carboxymethylcellulose was added so that the weight ratio of metformin hydrochloride and sodium carboxymethylcellulose was 20:1 (w / w)) and placed in a fluidized bed dryer and dried at 70°C. Sampling was performed to confirm the dimethylamine (DMA) reduction efficiency at 30, 60, and 90 minutes over time.

[0068] Comparative Example 1. Preparation of metformin hydrochloride wet granule preparation (sustained-release tablet) without dimethylamine (DMA) reduction process

[0069] After weighing the raw materials as shown in Table 1 above, metformin hydrochloride (manufacturer: Granules India Ltd. (India), dimethylamine (DMA) content: approximately 110 ppm) and sodium carboxymethylcellulose were mixed and kneaded using purified water as a binder. Then, the kneaded product was dried under dry heat at 50°C and sieved to show a certain particle size. After adding hypromellose as a sustained-release agent and performing post-mixing, magnesium stearate was additionally added and finally mixed to manufacture a metformin hydrochloride wet granule test product (sustained-release tablet).

[0070] Comparative Example 2. Preparation of wet granule preparation using metformin hydrochloride from a manufacturer with a low dimethylamine (DMA) content.

[0071] Wet granule preparation (sustained-release tablet) using metformin hydrochloride was manufactured using metformin hydrochloride with a low dimethylamine (DMA) content (manufacturer: Sohan Healthcare Pvt. Ltd. (India), dimethylamine (DMA) content: approximately 20 ppm). Specifically, after weighing the raw materials as shown in Table 1 above, the metformin hydrochloride and sodium carboxymethylcellulose were mixed and kneaded using purified water as a binder. Then, the kneaded product was dried in dry heat at 50°C and sieved to exhibit a certain particle size. After adding hypromellose as a sustained-release agent and performing post-mixing, magnesium stearate was additionally added and then finally mixed to manufacture a metformin hydrochloride wet granule preparation (sustained-release tablet).

[0072] Hereinafter, the present invention will be described in detail based on experimental examples. However, the following experimental examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention.

[0073] [Experimental Example]

[0074] Experimental Example 1. Confirmation of the degree of increase in N-nitrosodimethylamine (NDMA) under harsh conditions (60℃ / 75%RH)

[0075] Experimental method

[0076] Comparative Example 1, in which wet granulation was performed without performing a dimethylamine (DMA) reduction process, and Example 1, in which metformin hydrochloride alone was dried in a fluidized bed dryer at 70°C for 30 minutes and then wet granulation was performed, and Comparative Example 2, in which dimethylamine (DMA) reduction raw material was used, were stored under the same harsh conditions [60°C / 75%RH], and the increase in N-nitrosodimethylamine (NDMA) over time was compared, and the results are shown in Figure 2.

[0077] Experimental results

[0078] Referring to Figure 2, it was clearly confirmed that reducing dimethylamine (DMA) partially suppressed the generation of N-nitrosodimethylamine (NDMA). However, when the reduction process was performed simply with metformin hydrochloride, the generation of N-nitrosodimethylamine (NDMA) was not suppressed to the desired extent. It was confirmed that using raw materials from manufacturers with low dimethylamine (DMA) content was effective in reducing N-nitrosodimethylamine (NDMA) in finished pharmaceutical products and slowing the increase trend, but did not completely suppress the generation.

[0079] Experimental Example 2. Confirmation of dimethylamine (DMA) reduction efficiency

[0080] Experimental method

[0081] In Example 3 using a metformin hydrochloride raw material with a high dimethylamine (DMA) content and Example 4 using a mixture of a metformin hydrochloride raw material with a high dimethylamine (DMA) content and sodium carboxymethylcellulose, the reduction efficiency was confirmed by confirming the content of dimethylamine (DMA) in the metformin raw material through HPLC analysis using samples collected at 30-minute intervals in a fluidized bed dryer at 70°C, and the results are shown in Fig. 3.

[0082] Experimental results

[0083] Referring to Fig. 3, when drying for the first 30 minutes, both the processes of Examples 3 and 4 showed a reduction efficiency of more than 50%, but it was confirmed that the reduction efficiency gradually decreased as 60 and 90 minutes passed. In particular, in the case of Example 4, which includes a process of mixing sodium carboxymethylcellulose with the main ingredient metformin hydrochloride and then drying, it was confirmed that the reduction rate of dimethylamine (DMA) exceeded 80% when drying was performed for 30 minutes under the same conditions. However, in the case of Example 3, which includes a process of drying the main ingredient metformin hydrochloride alone, the reduction rate of dimethylamine (DMA) reached 80% only after 90 minutes or more. In particular, in the 60-minute and 90-minute samples sampled in Example 4, the content of dimethylamine (DMA) was detected to be less than 20 ppm, which is the quantitative limit, and therefore was not shown in the graph of Fig. 3. 20 ppm is a value that exceeds the quantitative limit of the dimethylamine (DMA) quantitative test, so it was difficult to confirm how much more it could be reduced. However, it was confirmed that the dimethylamine (DMA) reduction efficiency could be increased when Example 4, which includes a process of mixing sodium carboxymethylcellulose with the main ingredient, metformin hydrochloride, and then drying it, was applied.

[0084] Experimental Example 3. Confirmation of the occurrence and increase pattern of N-nitrosodimethylamine (NDMA) in the wet granule preparation (sustained-release tablet) according to Example 2 and the control drug.

[0085] Experimental method

[0086] In the above Experimental Example 2, the process according to Example 4 (mixing sodium carboxymethylcellulose into metformin hydrochloride and then drying) was confirmed to have excellent dimethylamine (DMA) reduction efficiency, and the generation and increase patterns of N-nitrosodimethylamine (NDMA) were compared and observed with the commercially available control drug (Glucophage XR extended-release tablet). Specifically, the wet granule preparation (extended-release tablet) according to Example 2 and the commercially available control drug (Glucophage XR extended-release tablet) were stored under harsh conditions [60℃ / 75%RH], and the generation and increase patterns of N-nitrosodimethylamine (NDMA) over time were compared and observed, and the results are shown in Fig. 4.

[0087] Experimental results

[0088] Referring to Fig. 4, in the commercially available control drug (Glucophage XR extended-release tablet), N-nitrosodimethylamine (NDMA) was observed from the beginning because some time had passed since it was manufactured. However, when the N-nitrosodimethylamine (NDMA) increase trend was observed over time while stored under harsh conditions [60℃ / 75%RH], it did not increase significantly and was well managed below a certain level. In the case of the wet granule preparation (extended-release tablet) manufactured through the process of mixing sodium carboxymethylcellulose into metformin hydrochloride according to Example 2 and then drying it, it was confirmed that N-nitrosodimethylamine (NDMA) was not generated at all even after 10 days or more when stored under harsh conditions [60℃ / 75%RH]. In fact, in the stability test results of the finished drug product, N-nitrosodimethylamine (NDMA) was not generated at all even after 6 months of storage under accelerated conditions [40℃ / 75%RH], and N-nitrosodimethylamine (NDMA) was not detected at all even under long-term storage conditions [25℃ / 60%RH].

[0089] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the relevant technical field that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

1. A step of mixing metformin hydrochloride and pharmaceutical additives; and A method for reducing dimethylamine, an impurity present in metformin hydrochloride, comprising a step of drying the above-mentioned mixed metformin hydrochloride and pharmaceutical additives.

2. In the first paragraph, the step of mixing metformin hydrochloride and the pharmaceutical additive is characterized in that the metformin hydrochloride and the pharmaceutical additive are mixed in a weight ratio (w / w) of 15 to 25:1, a method for reducing dimethylamine, which is an impurity present in metformin hydrochloride.

3. A method for reducing dimethylamine, an impurity present in metformin hydrochloride, characterized in that in the step of drying the mixed metformin hydrochloride and pharmaceutical additive in the first paragraph, the mixed metformin hydrochloride and pharmaceutical additive are dried at 50 to 90°C for 10 to 120 minutes.

4. A method for reducing dimethylamine, an impurity present in metformin hydrochloride, characterized in that the pharmaceutical additive in paragraph 1 is sodium carboxymethylcellulose.

5. (S1) A step of mixing metformin hydrochloride and a pharmaceutical additive, drying the mixture, and reducing and recovering dimethylamine, an impurity present in metformin hydrochloride; (S2) A step of combining the mixture of the recovered metformin hydrochloride and pharmaceutical additives into a binding solution; (S3) A step of drying and establishing the combined compound; and (S4) A method for producing a pharmaceutical composition comprising metformin hydrochloride with reduced N-nitrosodimethylamine as an active ingredient, comprising a step of adding a release agent and a lubricant to the established composition and mixing them.

6. A method for producing a pharmaceutical composition, characterized in that in the step (S1) of paragraph 5, metformin hydrochloride and a pharmaceutical additive are mixed at a weight ratio (w / w) of 15 to 25:

1.

7. A method for producing a pharmaceutical composition, characterized in that in the step (S1), the mixed metformin hydrochloride and pharmaceutical additive are dried at 50 to 90°C for 10 to 120 minutes.

8. A method for producing a pharmaceutical composition, characterized in that in paragraph 5, the pharmaceutical additive is sodium carboxymethylcellulose.

9. A method for producing a pharmaceutical composition, characterized in that in the step (S2) of paragraph 5, the binding solution is purified water.

10. A method for producing a pharmaceutical composition, characterized in that in the step (S3) of paragraph 5, drying is performed under conditions of 5 to 80°C.

11. A method for producing a pharmaceutical composition, characterized in that in the step (S4), the release agent is hypromellose.

12. A method for producing a pharmaceutical composition, characterized in that in the step (S4) of paragraph 5, the lubricant is magnesium stearate.

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