Method for evaluating the stability of liquid dosage form drugs packaged in a vial and application thereof

Abstract

The application discloses a method for evaluating the stability of a liquid dosage form medicine packaged in a vial and application thereof. Compared with a traditional filling process, the application controls the mass-volume ratio of oxygen in the injection liquid, reduces the difference in the residual oxygen amount in the headspace between batches of products, is highly repeatable and controllable. The application provides a reliable basis for parameter setting in the production and processing process of oxygen-sensitive injection liquid, helps to promote the product quality improvement of the injection liquid medicine, reduces quality problems caused by oxygen, maintains the long-term stability of the injection liquid medicine in the storage and transportation process, and saves production cost.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical process technology, and more specifically, to a method for evaluating the stability of vial-packaged liquid dosage forms and its application. Background Technology

[0002] In the pharmaceutical industry, the level of headspace residual oxygen has a significant impact on the stability and safety of drugs, especially oxygen-sensitive drugs. Contact with oxygen can lead to drug decomposition and deterioration, affecting the quality and efficacy of the drug. For oxygen-sensitive liquid dosage forms, inert gas is introduced into the packaging container before and after filling to replace the air. The final oxygen concentration remaining in the headspace inside the packaging container is called headspace residual oxygen, usually expressed as a volume percentage (%), and its calculation formula is: .

[0003] Generally speaking, the lower the headspace residual oxygen content, the higher the product quality. However, in practical applications, it has been found that relying solely on headspace residual oxygen content as an indicator to assess the stability of liquid dosage forms has many limitations. Currently, in order to improve the stability of liquid dosage forms, pharmaceutical companies often pursue the lowest possible headspace residual oxygen content during the production and processing process, while neglecting the necessity of finely controlling headspace residual oxygen content based on the characteristics of the injectable drug itself.

[0004] In the filling process of liquid dosage forms, batch-to-batch variations in headspace residual oxygen significantly affect product quality. Common packaging containers for liquid dosage forms include ampoules and vials. Ampoule production lines typically control the average headspace residual oxygen level below 3%, with industry-leading levels below 1%. However, filling-sealing production lines often fill and seal dozens of liquid dosage forms simultaneously, leading to fluctuations in headspace residual oxygen levels within the same batch. For vials, pre-filling nitrogen purging involves inserting a nitrogen purging tube into the vial and blowing in nitrogen gas to replace residual oxygen. Post-filling nitrogen purging occurs after filling, where a horizontal air curtain is blown towards the vial opening to replace any remaining oxygen. The residual oxygen level in sealed vials is generally between 3% and 5%. Both of these packaging methods require experienced technicians to adjust the headspace residual oxygen level for each batch, which is time-consuming, labor-intensive, and difficult to guarantee consistently effective control.

[0005] More importantly, actual production and quality testing revealed significant differences in the quality of final products for different types of injectable drugs, even with the same filling volume and headspace residual oxygen control. This clearly demonstrates that relying solely on headspace residual oxygen is insufficient to accurately assess the stability of filled liquid dosage forms and to effectively control and eliminate the potential impact of oxygen on drug quality. Therefore, there is an urgent need to develop more direct and effective evaluation indicators and methods to more precisely control the oxygen content within packaging containers and to establish a corresponding standardized production system, thereby providing a more reliable guarantee for the quality and stability of oxygen-sensitive liquid dosage forms. Summary of the Invention

[0006] To address the aforementioned problems in the prior art, this invention provides a method for evaluating the stability of liquid dosage forms packaged in vials and its application.

[0007] One object of the present invention is to provide a method for evaluating the stability of liquid dosage forms packaged in vials.

[0008] Another object of the present invention is to provide the application of the method in the quality control of the preparation of vial-packaged liquid dosage forms of medicine.

[0009] Another object of the present invention is to provide a method for filling a vial-packaged liquid dosage form of medicine.

[0010] To achieve the above objectives, the present invention is implemented through the following solution: During its preliminary work, the applicant discovered that, although the headspace oxygen levels of sampled products were the same when filling vials of liquid dosage forms, there were still significant differences in product quality (such as storage stability). Further investigation revealed that this was due to the different mass of oxygen in the empty space above the liquid in the vial, resulting in a different ratio of oxygen mass to the volume of the filled medication. For the same type of vial, even with identical headspace oxygen levels, the actual total amount of residual oxygen within the packaging container differs due to variations in the volume of the filled medication; furthermore, different volumes of medication consume different amounts of oxygen.

[0011] Based on this, the applicant hypothesizes that the ratio of oxygen mass to drug volume has a more accurate impact on the quality of the injection solution than the headspace residual oxygen content. In other words, different ratios of oxygen mass to drug volume (which can be understood as how much oxygen affects each unit volume of drug solution) will result in different product quality. Therefore, detecting the oxygen mass to drug volume ratio is beneficial for quality control of liquid dosage forms, especially oxygen-sensitive liquid dosage forms, providing a more accurate and reliable basis for controlling headspace residual oxygen content parameters and setting process parameters for subsequent product manufacturing.

[0012] Therefore, this invention seeks protection for the following: A method for evaluating the stability of liquid dosage forms packaged in vials includes the following steps: The filling parameters of the vial-packaged liquid dosage form drug are collected, the index value z is calculated, and the stability of the vial-packaged liquid dosage form drug is determined based on z. The filling parameters include: vacuum degree x, oxygen density ρ, and vial volume V. 瓶 The filling volume V of liquid dosage form drugs 液 Where x is the vacuum level inside the vial after evacuation, and ρ is the density of oxygen at the filling temperature; The formula for calculating z is: z = {Ax} 2 +Bx+C]×(V 瓶 -V 液 )×ρ} / V 液 Where z>0, the unit is mg / mL; x>0, the unit is Torr; V 瓶 >0, unit is mL; 1<ρ<1.5, unit is mg / mL; 0≤V 液 <V 瓶 The unit is mL; A, B and C are the coefficients of the corresponding terms obtained by polynomial fitting with x as the independent variable and y as the dependent variable in the headspace residual oxygen in the vial after filling. The liquid dosage form of the drug is an oxygen-sensitive drug; The criteria for determining the stability of the vial-packaged liquid dosage form drug are as follows: if z ≤ threshold, the vial-packaged liquid dosage form drug has good stability; if z > threshold, the vial-packaged liquid dosage form drug has poor stability.

[0013] In this invention, the method for obtaining A, B, and C in the calculation formula of z includes the following steps: taking x as the independent variable and the headspace residual oxygen y in the vial after filling as the dependent variable, different x are preset, and the value of y of the finished product after filling is measured and subjected to polynomial fitting to obtain the coefficients A, B, and C corresponding to the polynomial.

[0014] In some specific embodiments, the formula for calculating z is: z = {[1 × 10 -5 x 2 +0.0208x-0.6445]×(V 瓶 -V 液 )×ρ} / V 液 In this invention, the method for obtaining the threshold includes the following steps: pre-setting different x and V values. 瓶 and V 液, a plurality of corresponding samples are obtained by filling the liquid dosage form drug with vials, the headspace residual oxygen content y of the samples is determined, and the mass O and z of oxygen in the samples are calculated; an accelerated test is performed on each sample, the impurity generation of each sample is detected, and whether each sample is qualified is determined in combination with the quality evaluation standard of the liquid dosage form drug; at the end of the accelerated test, for the sample closest to the critical value of the quality evaluation standard, the corresponding z thereof is taken as the threshold value of the liquid dosage form drug; wherein, the calculation formula of O is: O=y×(V 瓶 -V 液 )×ρ; the calculation formula of z is: z=O / V 液 .

[0015] Those skilled in the art usually use accelerated tests to evaluate drug stability, and conventional accelerated tests generally require the drug to be placed for 6 months at 40°C±2°C and a relative humidity of 75%±5%. In the present invention, in order to evaluate the stability of the liquid dosage form drug packaged in vials and obtain the threshold value, the accelerated test is carried out under the conditions of a temperature of 40±2°C and a relative humidity (RH) of 75%±5%. Samples are taken before the start of the accelerated test (0 months of acceleration), at 3 months of acceleration and 6 months of acceleration respectively, and whether each sample is qualified is determined in combination with the quality evaluation standard of the liquid dosage form drug.

[0016] In some specific embodiments, the threshold value is less than 0.080 mg / mL.

[0017] Preferably, the liquid dosage form drug is an injection drug.

[0018] In the present invention, the injection drug refers to an injection drug whose active ingredient is prone to oxidative degradation when exposed to oxygen, including but not limited to clodronate disodium injection, compound diclofenac sodium injection, nicotinamide injection, oxytocin injection, nitroglycerin injection, vitamin C injection, adenosine disodium triphosphate injection, noradrenaline bitartrate injection, dopamine hydrochloride injection or adrenaline hydrochloride injection.

[0019] Preferably, the liquid dosage form drug comprises any one or more of clodronate disodium injection, compound diclofenac sodium injection, nicotinamide injection, oxytocin injection, nitroglycerin injection, vitamin C injection, adenosine disodium triphosphate injection, noradrenaline bitartrate injection, dopamine hydrochloride injection or adrenaline hydrochloride injection.

[0020] More preferably, the liquid dosage form drug comprises any one or more of noradrenaline bitartrate injection, dopamine hydrochloride injection or adrenaline hydrochloride injection.

[0021] More preferably, if the liquid dosage form is norepinephrine bitartrate injection, then the threshold is less than or equal to 0.013 mg / mL; if the liquid dosage form is dopamine hydrochloride injection, then the threshold is 0.013 mg / mL to 0.017 mg / mL; if the liquid dosage form is epinephrine hydrochloride injection, then the threshold is less than 0.080 mg / mL.

[0022] More preferably, if the liquid dosage form is norepinephrine bitartrate injection, the threshold is 0.010 mg / mL; if the liquid dosage form is dopamine hydrochloride injection, the threshold is 0.015 mg / mL; if the liquid dosage form is epinephrine hydrochloride injection, the threshold is 0.070 mg / mL.

[0023] In this invention, the filling temperature is the set temperature of the filling instrument, used to control the temperature of the packaging container and maintain it constant throughout the entire process, from filling the liquid dosage form drug, to vacuuming, filling with protective gas, and finally sealing. In some specific embodiments, a freeze dryer is used for filling, in which case the filling temperature is the set temperature of the freeze dryer shelf.

[0024] Preferably, the filling parameters further include filling temperature T, and ρ is calculated from T using the formula: ρ=P×M / (R×T); where P represents standard atmospheric pressure; M represents the molar mass of oxygen; R represents the gas constant; and T≥0, with the unit being Kelvin.

[0025] More preferably, P is 1 atm.

[0026] More preferably, M is 32 g / mol.

[0027] More preferably, R is 0.0821 Latm / (molK).

[0028] More preferably, if the unit of the collected T is Celsius (°C), it is first converted to Kelvin (K), i.e., T+273.15, and then substituted into the formula to calculate ρ.

[0029] In some specific implementations, the filling temperature is 0°C, then ρ is 1.429 mg / mL.

[0030] In some specific implementations, the filling temperature is 20°C, then ρ is 1.331 mg / mL.

[0031] In some specific implementations, the filling temperature is 25°C, then ρ is 1.309 mg / mL.

[0032] In some specific implementations, the filling temperature is 30°C, then ρ is 1.287 mg / mL.

[0033] In some specific embodiments, the filling temperature is 35°C, and ρ is 1.266 mg / mL.

[0034] In some specific embodiments, the filling temperature is 40°C, and ρ is 1.246 mg / mL.

[0035] Use of said method in quality control of liquid dosage form drugs packaged in vials.

[0036] Use of said method in preparation of liquid dosage form drugs packaged in vials.

[0037] A filling method for a liquid dosage form drug packaged in a vial, combining said method for evaluating the stability of a liquid dosage form drug packaged in a vial and the expectation for the stability of the liquid dosage form drug, presetting z, and calculating x; filling the liquid dosage form drug into the vial, vacuumizing until the vacuum degree is x, filling with protective gas to atmospheric pressure, and sealing.

[0038] Preferably, the protective gas is nitrogen.

[0039] In some specific embodiments, when the liquid dosage form drug is norepinephrine bitartrate injection, the preset z is: 0 mg / mL < z < 0.013 mg / mL; when the liquid dosage form drug is dopamine hydrochloride injection, the preset z is: 0 mg / mL < z ≤ 0.017 mg / mL; when the liquid dosage form drug is epinephrine hydrochloride injection, the preset z is: 0 mg / mL < z < 0.080 mg / mL.

[0040] In some specific embodiments, when the liquid dosage form drug is norepinephrine bitartrate injection, the preset z is: 0 mg / mL < z ≤ 0.010 mg / mL; when the liquid dosage form drug is dopamine hydrochloride injection, the preset z is: 0 mg / mL < z ≤ 0.015 mg / mL; when the liquid dosage form drug is epinephrine hydrochloride injection, the preset z is: 0 mg / mL < z ≤ 0.070 mg / mL.

[0041] Preferably, the filling temperature is 0°C to 40°C.

[0042] More preferably, the filling temperature is 20°C to 40°C.

[0043] In some specific embodiments, when the oxygen-sensitive injection drug is norepinephrine bitartrate injection, the filling temperature is 20°C.

[0044] In some specific implementations, the oxygen-sensitive injectable drug is dopamine hydrochloride injection, and the filling temperature is 40°C.

[0045] In some specific implementations, if the oxygen-sensitive injectable drug is epinephrine hydrochloride injection, then the filling temperature is 30°C.

[0046] Products prepared by any of the filling methods described herein should also be within the scope of protection of this invention.

[0047] Compared with the prior art, the present invention has the following beneficial effects: Compared to traditional filling processes, this invention reduces batch-to-batch variations in headspace residual oxygen by controlling the ratio of oxygen mass to drug volume in the injection solution, resulting in high repeatability and good controllability. It provides a reliable basis for parameter settings in the production and processing of oxygen-sensitive injectable solutions, helping to improve product quality, reduce production costs, minimize quality problems caused by oxygen, and maintain long-term stability of injectable drugs during storage and transportation. Attached Figure Description

[0048] Figure 1 The formula is fitted to the vacuum degree and the measured headspace residual oxygen. Detailed Implementation

[0049] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods; the materials and reagents used, unless otherwise specified, are commercially available.

[0050] Example 1: Establishment of a quality control formula for injectable drugs 1. Filling of water for injection Using a pipette, 6 mL of water for injection (25°C, nitrogen gas was introduced below the liquid surface until the dissolved oxygen content was below 2 mg / L) was filled into an 8 mL vial. The vial was partially stoppered and transferred to a lyophilizer. The shelf temperature of the lyophilizer was set to 25°C (oxygen density was 1.309 mg / mL), and the nitrogen pressure was adjusted to 0.04 MPa. The lyophilizer was used to evacuate the vial to a vacuum level (i.e., the vacuum level in the lyophilizer settings interface) of 50 Torr. Then, the vacuuming was stopped, and nitrogen gas was introduced into the vial to atmospheric pressure (760 Torr). The vial was allowed to equilibrate for 3 minutes, then the vial was stoppered, removed from the lyophilizer, and the filling process was completed, thus obtaining sample 1.

[0051] Sample 2 was prepared using the same method, with the only difference being that a freeze dryer was used to evacuate the sample to a vacuum of 100 Torr.

[0052] Sample 3 was prepared using the same method, with the only difference being that the sample was evacuated to a vacuum of 180 Torr using a freeze dryer.

[0053] Sample 4 was prepared by using the same method, with the only difference being that the vacuum degree was 250 Torr using a freeze dryer.

[0054] Sample 5 was prepared using the same method, with the only difference being that it was prepared by maintaining a constant pressure of 760 Torr using a freeze dryer (without the need for vacuuming or nitrogen filling).

[0055] 2. Numerical measurement and formula fitting The measured values ​​(%) of headspace residual oxygen for samples 1–5 were determined using an oxygen concentration analyzer, with each sample at each vacuum level measured in parallel four times. The specific results are shown in Table 1.

[0056] Table 1. Measurement results of samples evacuated to different vacuum levels.

[0057] Based on the results of the previous step, the measured values ​​of vacuum degree and headspace residual oxygen of samples 1-5 were used as key variables for polynomial fitting, and the resulting curves are shown below. Figure 1 As shown, the obtained fitting formula is as shown in formula (1), R 2 =0.9996.

[0058] Formula (1): y=1×10 -5 x 2 +0.0208x -0.6445; Where y represents the headspace residual oxygen content, in percentage (y>0); and x represents the vacuum degree, in Torr (x>0).

[0059] Substituting the vacuum degree of samples 1-5 into formula (1) yields the calculated headspace residual oxygen content. The specific results are shown in Table 2. It can be seen that the vacuum degree of each sample is basically consistent with its corresponding target value, and the deviation between the measured and calculated headspace residual oxygen content is less than 0.2%, indicating high consistency. This shows that there is a significant correlation between vacuum degree and headspace residual oxygen content during the perfusion process of the injection solution.

[0060] Table 2. Comparison and analysis results of actual and calculated values ​​of headspace residual oxygen content for samples at different vacuum levels.

[0061] 3. Formula optimization By combining the volume of the vial and the volume of the filled medicine, the mass of oxygen can be obtained using formula (2).

[0062] Formula (2): O = y × (V 瓶 -V液 )×ρ; Where O represents the mass of oxygen, in mg, O>0 because filling cannot completely remove oxygen from the container; y represents the headspace residual oxygen, in %, y>0; V 瓶 V represents the volume of a vial, expressed in mL. 瓶 >0;V 液 This indicates the volume of the infused drug solution, expressed in mL, where 0 ≤ V. 液 <V 瓶 ρ represents the density of oxygen, with units of mg / mL, and 1 < ρ < 1.5.

[0063] The ratio of the mass of oxygen to the volume of the infused drug solution is calculated by formula (3) and denoted as z, z>0, with the unit being mg / mL.

[0064] Formula (3): z = O / V 液 ; Where O represents the mass of oxygen, measured in mg, and O > 0; V 液 This indicates the volume of the injected drug solution, expressed in mL.

[0065] Based on formula (2), a new parameter z from formula (3) is introduced to obtain formula (4).

[0066] Formula (4): z = {[1×10 -5 x 2 +0.0208x-0.6445]×(V 瓶 -V 液 )×ρ} / V 液 .

[0067] The density (ρ) of oxygen can be calculated using the ideal gas law as shown in formula (5).

[0068] Formula (5): ρ = P × M / (R × T); Where P represents standard atmospheric pressure, 1 atm; M represents the molar mass of oxygen, 32 g / mol; R represents the gas constant, R = 0.0821 Latm / (mol K); and T represents the temperature of oxygen, in K (Kelvin K = °C + 273.15).

[0069] According to formula (5), the oxygen density corresponding to the commonly used temperature for preparing injectable drugs is obtained as shown in Table 3.

[0070] Table 3 Oxygen density at various temperatures

[0071] Based on the results in Table 1, the measured values ​​of headspace residual oxygen for samples 1-5 were substituted into formulas (2), (3), and (5) to calculate the measured values ​​of oxygen mass (O) and the ratio of oxygen mass to the volume of liquid infusion solution (z). The vacuum degree of samples 1-5 was substituted into formulas (4) and (5) to calculate the calculated value of z. The specific results are shown in Table 4. It can be seen that the deviation between the measured and calculated values ​​of the ratio of oxygen mass to the volume of liquid infusion solution (z) for each sample is less than 0.001 (mg / mL), indicating high consistency. This shows that during the infusion process, the vacuum degree is significantly correlated with the ratio of oxygen mass to the volume of liquid infusion solution.

[0072] Table 4. Comparison and analysis results of measured and calculated values ​​of oxygen mass and the ratio of oxygen mass to the volume of liquid medicine injected into the bottle for samples at different vacuum levels.

[0073] Application Example 1: Filling and Quality Control of Different Oxygen-Sensitive Injectable Drugs 1. Norepinephrine Bitartrate Injection (1) Filling method The target value of headspace residual oxygen is set in advance, and the vacuum degree is calculated by substituting this value into formula (1).

[0074] Next, using a pipette, different volumes of norepinephrine ditartrate injection were filled into vials of different capacities, partially stoppered, and transferred to a lyophilizer. The shelf temperature of the lyophilizer was set to 20°C (the oxygen density was calculated to be 1.331 mg / mL using formula (5)). The nitrogen pressure was adjusted to 0.04 MPa. The lyophilizer was used to evacuate to the vacuum level calculated in the previous step, and then the evacuation was stopped. Nitrogen gas was then introduced into the vials to atmospheric pressure (760 Torr) using the lyophilizer. After equilibration for 3 minutes, the vials were stoppered, removed from the lyophilizer, and the filling process was completed. The sample series A shown in Table 5 was thus obtained.

[0075] Record the volume (V) of the vials used for filling each sample. 瓶 ) and the volume of the infused drug solution (V) 液 The measured values ​​(%) of headspace residual oxygen for each sample were determined using an oxygen concentration meter, and the measured values ​​of oxygen mass (O) and its relationship with the volume of the infused drug solution (V) for each sample were calculated according to formula (3). 液 The measured values ​​of the ratio (z) of ) are shown in Table 5.

[0076] Table 5 Process parameters of norepinephrine bitartrate injection

[0077] (2) Stability evaluation The samples A-1 to A-4, A-5-1 to A-5-3 and A-6-1 to A-6-3 prepared as shown in Table 6 were placed under accelerated test conditions (temperature 40±2℃, relative humidity (RH) 75%±5%) for 6 months. Samples were taken before the start of the accelerated test (0 months of acceleration), 3 months of acceleration and 6 months of acceleration, and the relevant substances were determined according to the Chinese Pharmacopoeia (ChP2020) Norepinephrine Bitartrate Injection.

[0078] Table 6. Stability evaluation results of norepinephrine bitartrate injection

[0079] Note: The acceptable standard is: total impurities ≤ 0.5% and maximum single impurity ≤ 0.2%.

[0080] The stability evaluation results of the 10 samples are shown in Table 6. All samples were qualified before the accelerated test began. After 3 months of acceleration, samples A-1, A-2, A-5-3, A-6-2 and A-6-3 were unqualified, while the other 5 samples were still qualified. After 6 months of acceleration, samples A-5-1 and A-6-1 were qualified, while the other 8 samples were unqualified.

[0081] Compare the acceleration of samples A-5-1, A-5-2, and A-5-3, as well as the acceleration of samples A-6-1, A-6-2, and A-6-3, to illustrate the effect of different volume values ​​(V) of the vial. 瓶 When the target values ​​for headspace residual oxygen are the same, the volume of the infused drug solution (V) is... 液 The larger the ratio of oxygen mass (O) to the volume of infused solution (V), the greater the ratio of oxygen mass (O) to the volume of infused solution (V). 液 The smaller the ratio (z) of the filling solution, the better the stability of the filling solution.

[0082] Comparing the acceleration of samples A-5-1 to A-5-3 and samples A-6-1 to A-6-3, even with the same vacuum level (x), it was impossible to control the stability of the filled drug solution consistently. Furthermore, under the same vacuum level (x), the mass of oxygen (O) and the volume of the filled drug solution (V) were different. 液 The smaller the ratio (z) of oxygen mass (O) to the volume (V) of the injected solution, the better the stability of the injected solution. This also indicates that the ratio of oxygen mass (O) to the volume of injected solution (V) is... 液 The ratio (z) of ) is more conducive to controlling the stability of the filled medicine solution.

[0083] Comparing the acceleration of samples A-4, A-5-2, and A-6-1, the trends of total impurities and maximum single impurities were basically consistent during the acceleration period. This indicates that although the headspace residual oxygen content was different, the mass of oxygen (O) and the volume of the perfused drug solution (V) remained relatively constant.液 The ratio (z) of oxygen mass (O) to drug volume (V) in norepinephrine bitartrate injection can more accurately and objectively reflect the quality changes of the filled drug solution, and is more conducive to controlling the stability of the filled drug solution. Moreover, when z is 0.013 mg / mL, all three samples are near the critical value of the qualified standard after 6 months of accelerated treatment. Therefore, the ratio of oxygen mass (O) to drug volume (V) in norepinephrine bitartrate injection is a more accurate and objective indicator of the quality changes of the filled drug solution. 液 The threshold for the ratio (z) of ) should be less than or equal to 0.013 mg / mL.

[0084] (3) Optimization of filling method Preset the mass of oxygen (O) and the volume of the drug solution (V) 液 The ratio (z) of ) is 0.005 mg / mL. Substituting into formula (4), the vacuum degree is calculated to be 54 Torr when z is 0.005 mg / mL. 2 mL of norepinephrine bitartrate injection solution was filled into a 3.5 mL vial. The shelf temperature of the freeze dryer was set to 20℃ (the oxygen density was calculated to be 1.331 mg / mL using formula (5)). Samples A-7 and A-8 as shown in Table 7 were prepared according to the filling method of this application example.

[0085] Preset the mass of oxygen (O) and the volume of the drug solution (V) 液 The ratio (z) of ) is 0.010 mg / mL. Substituting into formula (4), the vacuum degree is calculated to be 77 Torr when z is 0.010 mg / mL. 2 mL of norepinephrine bitartrate injection solution was filled into a 3.5 mL vial. The shelf temperature of the freeze dryer was set to 20℃ (the oxygen density was calculated to be 1.331 mg / mL using formula (5)). Sample A-9 as shown in Table 7 was prepared according to the filling method of this application example.

[0086] Table 7 Optimization of process parameters for norepinephrine bitartrate injection

[0087] The samples A-7 to A-9 prepared above, as shown in Table 7, were placed under accelerated test conditions (temperature 40±2℃, relative humidity (RH) 75%±5%) for 6 months. Samples were taken before the start of the accelerated test (0 months of acceleration), 3 months of acceleration, and 6 months of acceleration, and the relevant substances were determined according to the Chinese Pharmacopoeia (ChP2020) Norepinephrine Bitartrate Injection.

[0088] Table 8. Stability evaluation results of norepinephrine bitartrate injection

[0089] Note: The acceptable standard is: total impurities ≤ 0.5% and maximum single impurity ≤ 0.2%.

[0090] As shown in Table 8, samples A-7 to A-9 were all qualified before the accelerated test, after 3 months of acceleration, and after 6 months of acceleration. Furthermore, compared to sample A-5-1, samples A-7 to A-8 showed only slight fluctuations in total impurity and maximum single impurity content during the 6-month accelerated test, and the product stability was comparable to A-5-1. This indicates that the ratio (z) of the preset oxygen mass (O) to the drug solution volume (Vliquid) can effectively control the stability of norepinephrine bitartrate injection. Among these, samples A-7 and A-8 showed better stability than sample A-9. Therefore, the optimal ratio of oxygen mass (O) to drug solution volume (Vliquid) for filling norepinephrine bitartrate injection is... 液 The threshold for the ratio (z) of ) is 0.010 mg / mL.

[0091] (4) Evaluation of batch-to-batch variability in headspace residual oxygen Following the filling method of this application example, three batches of samples A-5-1 as shown in Table 5 and samples A-7 to A-8 as shown in Table 7 were prepared in parallel. After filling, the headspace residual oxygen content of each sample was measured using an oxygen concentration meter.

[0092] The results showed that although the volume of the vial (V) 瓶 The volume of the infused drug solution (V) is different from that of the other two methods. 液 If the oxygen content (O) differs, but the control z is consistent, then there is no significant difference in the actual headspace residual oxygen content affected by different batches of samples. This indicates that the control of oxygen mass (O) and perfusion solution volume (V) is related to the control of the oxygen mass (O) and the perfusion solution volume (V). 液 The ratio (z) of ) can effectively reduce the batch-to-batch variation of norepinephrine bitartrate injection and is easier to control in actual production.

[0093] 2. Dopamine Hydrochloride Injection (1) Filling method The target value of headspace residual oxygen is set in advance, and the vacuum degree is calculated by substituting this value into formula (1).

[0094] Next, different volumes of dopamine hydrochloride injection solution were filled into vials of different capacities using a pipette, partially stoppered, and transferred to a lyophilizer. The shelf temperature of the lyophilizer was set to 40℃ (the oxygen density was calculated to be 1.246 mg / mL using formula (5)). The nitrogen pressure was adjusted to 0.04 MPa. The lyophilizer was used to evacuate to the vacuum level calculated in the previous step, and then the evacuation was stopped. The actual value of the vacuum level was recorded. Nitrogen gas was then introduced into the vials to atmospheric pressure (760 Torr) using the lyophilizer. After equilibration for 3 minutes, the vials were stoppered, removed from the lyophilizer, and the filling was completed. Samples B-1 to B-3 as shown in Table 9 were thus obtained.

[0095] Record the volume of the vial used for filling each sample (V 瓶 ) and the volume of the infused drug solution (V 液 ), use an oxygen concentration analyzer to measure the actual measured value (%) of the residual oxygen in the headspace of each sample separately, calculate the mass of oxygen (O) in each sample according to formula (1), and calculate the actual measured value of the mass of oxygen (O) in each sample and the actual measured value of the ratio (z) of the mass of oxygen (O) to the volume of the infused drug solution (V 液 ) according to formula (3).

[0096] Table 9 Process parameters of dopamine hydrochloride injection

[0097] (2) Stability evaluation Place the samples B-1 to B-3 prepared as shown in Table 9 obtained above under accelerated test conditions (temperature 40±2°C, relative humidity (RH) 75%±5%) for 6 months, take samples at the beginning of the accelerated test (0 month of acceleration), 3 months of acceleration and 6 months of acceleration respectively, determine the content of dopamine hydrochloride according to the dopamine hydrochloride monograph in Chinese Pharmacopoeia (ChP2020), on this basis, the applicant uses the optimized registration standard for the approved dopamine hydrochloride injection product (standard number: YBH13272024) to determine the content of sodium metabisulfite.

[0098] Table 10 Stability evaluation results of dopamine hydrochloride injection

[0099] Note: The qualification standard is: the content of dopamine hydrochloride is 95%~105% and the content of sodium metabisulfite is 0.30~0.55mg / mL.

[0100] The stability evaluation results of samples B-1 to B-3 are shown in Table 10. At the beginning of the accelerated test, 3 months of acceleration and 6 months of acceleration, all samples are qualified. In comparison, the quality stability of samples B-1 and B-3 is significantly better than that of product B-2, and sample B-1 has the smallest fluctuation in content and sodium metabisulfite content during 6 months of acceleration, and the product has the best stability, which indicates that when the volume of the vial (V 瓶 ), the volume of the infused drug solution (V 液 ) and the residual oxygen in the headspace are different, the smaller the ratio (z) of the mass of oxygen (O) to the volume of the infused drug solution (V 液 ), the better the product quality. The threshold of the ratio (z) of the mass of oxygen (O) to the volume of the drug solution (V 液 ) for filling dopamine hydrochloride injection should be 0.013mg / mL~0.017mg / mL.

[0101] (3) Optimization of filling method Preset the mass of oxygen (O) and the volume of the drug solution (V) 液 The ratio (z) of ) is 0.015 mg / mL. When z is 0.015 mg / mL, the vacuum degree is 120 Torr, which is used as the vacuum degree. 13 mL of norepinephrine bitartrate injection solution was filled into a 21 mL vial. The shelf temperature of the freeze dryer was set to 40 °C (the oxygen density was calculated to be 1.246 mg / mL using formula (5)). Sample B-4 as shown in Table 11 was prepared according to the filling method of this application example.

[0102] Preset the mass of oxygen (O) and the volume of the drug solution (V) 液 The ratio (z) of ) is 0.015 mg / mL. When z is 0.015 mg / mL, the vacuum degree is 103 Torr, which is used as the vacuum degree. 2 mL of norepinephrine bitartrate injection solution was filled into a 3.5 mL vial. The shelf temperature of the freeze dryer was set to 40 °C (the oxygen density was calculated to be 1.246 mg / mL using formula (5)). Sample B-5 as shown in Table 11 was prepared according to the filling method of this application example.

[0103] Preset the mass of oxygen (O) and the volume of the drug solution (V) 液 The ratio (z) of ) is 0.015 mg / mL. The vacuum degree is 188 Torr when z is 0.015 mg / mL, calculated using formula (4). 6 mL of norepinephrine bitartrate injection solution was filled into 8 mL vials. The shelf temperature of the freeze dryer was set to 40 °C (the oxygen density was calculated to be 1.246 mg / mL using formula (5)). Sample B-6 as shown in Table 11 was prepared according to the filling method of this application example.

[0104] Table 11 Optimization of process parameters for dopamine hydrochloride injection

[0105] The samples B-4 to B-6 prepared above were placed under accelerated testing conditions (temperature 40±2℃, relative humidity (RH) 75%±5%) for 6 months. Samples were taken before the start of the accelerated test (0 months of acceleration), 3 months of acceleration, and 6 months of acceleration. The content of dopamine hydrochloride was determined according to the Chinese Pharmacopoeia (ChP2020) for dopamine hydrochloride injection. Based on this, the applicant used the optimized registration standard for dopamine hydrochloride injection (standard number: YBH13272024) for the approved product to determine the sodium metabisulfite content.

[0106] Table 12 Stability evaluation results of dopamine hydrochloride injection

[0107] Note: The qualified standard is: the dopamine hydrochloride content is 95% to 105% and the sodium metabisulfite content is 0.30 to 0.55 mg / mL.

[0108] As shown in Table 12, samples B-4 to B-6 were all qualified before the accelerated test, after 3 months of acceleration, and after 6 months of acceleration. Furthermore, compared to samples B-1 to B-3, the dopamine hydrochloride and sodium metabisulfite content in samples B-4 to B-6 only fluctuated slightly during the 6-month accelerated test, and the product stability was comparable to that of sample B-1. This indicates that the preset ratio (z) of oxygen mass (O) to drug volume (Vliquid) can effectively control the stability of dopamine hydrochloride injection. The optimal ratio of oxygen mass (O) to drug volume (Vliquid) for filling dopamine hydrochloride injection is [not specified in the original text]. 液 The threshold for the ratio (z) of ) is 0.015 mg / mL.

[0109] (4) Evaluation of batch-to-batch variability in headspace residual oxygen Following the filling method of this application example, three batches of samples B-4 to B-6 as shown in Table 11 were prepared in parallel. After filling, the headspace residual oxygen content of each sample was measured using an oxygen concentration meter.

[0110] The results showed that although the volume of the vial (V) 瓶 The volume of the infused drug solution (V) is different from that of the other two methods. 液 If the oxygen content (O) differs, but the control z is consistent, then there is no significant difference in the actual headspace residual oxygen content affected by different batches of samples. This indicates that the control of oxygen mass (O) and perfusion solution volume (V) is related to the control of the oxygen mass (O) and the perfusion solution volume (V). 液 The ratio (z) can effectively reduce batch-to-batch variability in dopamine hydrochloride injection and is easier to control in actual production.

[0111] 3. Epinephrine hydrochloride injection (1) Filling method The target value of headspace residual oxygen is set in advance, and the vacuum degree is calculated by substituting this value into formula (1).

[0112] Next, using a pipette, different volumes of epinephrine hydrochloride injection solution were filled into vials of different capacities, partially stoppered, and transferred to a lyophilizer. The shelf temperature of the lyophilizer was set to 30℃ (the oxygen density was calculated to be 1.287 mg / mL using formula (5)). The nitrogen pressure was adjusted to 0.04 MPa. The lyophilizer was used to evacuate to the vacuum level calculated in the previous step, and then the evacuation was stopped. The actual value of the vacuum level was recorded. Nitrogen gas was then introduced into the vials to atmospheric pressure (760 Torr) using the lyophilizer. After equilibration for 3 minutes, the vials were stoppered, removed from the lyophilizer, and the filling was completed. Samples C-1 to C-3 as shown in Table 13 were thus obtained.

[0113] Record the volume of the vial used for filling each sample (V 瓶 ) and the volume of the filled medicinal solution (V 液 ), measure the actually measured value (%) of the residual oxygen in the headspace of each sample separately using an oxygen concentration analyzer, calculate the mass of oxygen (O) in each sample according to formula (1), and calculate the actually measured value of the mass of oxygen (O) in each sample and its ratio (z) to the volume of the filled medicinal solution (V 液 ) according to formula (3).

[0114] Table 13 Process parameters of Epinephrine Hydrochloride Injection

[0115] (2) Stability evaluation Samples C-1 to C-3 prepared as listed in the above Table 13 were placed for 6 months under accelerated test conditions (temperature 40±2°C, relative humidity (RH) 75%±5%). Samples were taken before the start of the accelerated test (0 month of acceleration), at 3 months of acceleration and 6 months of acceleration respectively, and determination was carried out for the related substances item in accordance with the specification for Epinephrine Hydrochloride Injection in Chinese Pharmacopoeia (ChP2020).

[0116] Table 14 Stability evaluation results of Epinephrine Hydrochloride Injection

[0117] Note: The qualification standard is: total impurities ≤1.0%.

[0118] The stability evaluation results of samples C-1 to C-3 are shown in Table 14. Before the start of the accelerated test and at 3 months of acceleration, all samples were qualified; at 6 months of acceleration, sample C-1 and sample C-2 were qualified, and sample C-3 was unqualified. When the volume of the vial (V 瓶 ) is the same and the volume of the filled medicinal solution (V 液 ) is the same, the smaller the target value of residual oxygen in the headspace, the better the stability of Epinephrine Hydrochloride Injection. Furthermore, the threshold value of the ratio (z) of the mass of oxygen (O) to the volume of medicinal solution (V 液 ) for filling Epinephrine Hydrochloride Injection shall be less than 0.080 mg / mL.

[0119] (4) Optimization of filling method Preset the mass of oxygen (O) and the volume of medicinal solution (V 液The ratio (z) of ) is 0.050 mg / mL. When z is 0.050 mg / mL, the vacuum degree is 199 Torr, which is used as the vacuum degree. 4 mL of epinephrine hydrochloride injection solution is filled into a vial with a volume of 8 mL. The shelf temperature of the freeze dryer is set to 30 °C (the oxygen density is calculated to be 1.287 mg / mL using formula (5)). Sample C-4 as shown in Table 15 is prepared according to the filling method of this application example.

[0120] Preset the mass of oxygen (O) and the volume of the drug solution (V) 液 The ratio (z) of ) is 0.060 mg / mL. When z is 0.060 mg / mL, the vacuum degree is 230 Torr, which is used as the vacuum degree. 4 mL of epinephrine hydrochloride injection solution is filled into a vial with a volume of 8 mL. The shelf temperature of the freeze dryer is set to 30 °C (the oxygen density is calculated to be 1.287 mg / mL using formula (5)). Sample C-5 as shown in Table 15 is prepared according to the filling method of this application example.

[0121] Preset the mass of oxygen (O) and the volume of the drug solution (V) 液 The ratio (z) of ) is 0.070 mg / mL. When z is 0.070 mg / mL, the vacuum degree is 260 Torr, which is used as the vacuum degree. 4 mL of epinephrine hydrochloride injection solution is filled into a vial with a volume of 8 mL. The shelf temperature of the freeze dryer is set to 30 °C (the oxygen density is calculated to be 1.287 mg / mL using formula (5)). Sample C-6 as shown in Table 15 is prepared according to the filling method of this application example.

[0122] Table 15 Optimization of process parameters for epinephrine hydrochloride injection

[0123] The samples C-4 to C-6 prepared above, as shown in Table 15, were placed under accelerated test conditions (temperature 40±2℃, relative humidity (RH) 75%±5%) for 6 months. Samples were taken before the start of the accelerated test (0 months of acceleration), 3 months of acceleration, and 6 months of acceleration, and the related substances were determined according to the Chinese Pharmacopoeia (ChP2020) for epinephrine hydrochloride injection.

[0124] Table 16 Stability evaluation results of epinephrine hydrochloride injection

[0125] Note: The acceptable standard is: total impurities ≤ 1.0%.

[0126] As shown in Table 16, samples C-4 to C-6 all passed the accelerated testing before the start of the experiment, after 3 months of acceleration, and after 6 months of acceleration. Furthermore, the stability of sample C-4 was comparable to that of sample C-2, indicating that the preset ratio (z) of oxygen mass (O) to drug volume (Vliquid) can effectively control the stability of epinephrine hydrochloride injection. The optimal ratio of oxygen mass (O) to drug volume (Vliquid) for filling epinephrine hydrochloride injection is... 液 The threshold for the ratio (z) of ) is 0.070 mg / mL.

[0127] (4) Evaluation of batch-to-batch variability in headspace residual oxygen Following the filling method of this application example, three batches of samples C-4 to C-6 as shown in Table 15 were prepared in parallel. After filling, the headspace residual oxygen content of each sample was measured using an oxygen concentration analyzer. The results showed that the volume (V) of the vial... 瓶 The same applies to the volume of the infused solution (V). 液 If the control z is the same, then there is no significant difference in the influence of the actual headspace residual oxygen content on samples prepared in different batches. This indicates that the filling method has high repeatability and is easier to control in actual production.

[0128] In summary, the filling method provided by this invention can be used to study the filling process of different types of injection solutions. It proposes a ratio of oxygen mass to drug volume that is suitable for setting and optimizing process parameters for different bottle volumes or different drug volumes, which facilitates product quality control in actual operation and can guide the subsequent large-scale production of the product.

[0129] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description and ideas, and it is neither necessary nor possible to exhaustively describe all implementation methods here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for evaluating the stability of liquid dosage forms packaged in vials, characterized in that, Includes the following steps: The filling parameters of the vial-packaged liquid dosage form drug are collected, the index value z is calculated, and the stability of the vial-packaged liquid dosage form drug is determined based on z. The filling parameters include: vacuum degree x, oxygen density ρ, and vial volume V. 瓶 The filling volume V of liquid dosage form drugs 液 Where x is the vacuum level inside the vial after evacuation, and ρ is the density of oxygen at the filling temperature; The formula for calculating z is: z = {Ax} 2 +Bx+C]×(V 瓶 -V 液 )×ρ} / V 液 Where z>0, the unit is mg / mL; x>0, the unit is Torr; V 瓶 >0, unit is mL; 1<ρ<1.5, unit is mg / mL; 0≤V 液 <V 瓶 The unit is mL; A, B and C are the coefficients of the corresponding terms obtained by polynomial fitting with x as the independent variable and y as the dependent variable in the headspace residual oxygen in the vial after filling. The liquid dosage form of the drug is an oxygen-sensitive drug; The criteria for determining the stability of the vial-packaged liquid dosage form drug are as follows: if z ≤ threshold, the vial-packaged liquid dosage form drug has good stability; if z > threshold, the vial-packaged liquid dosage form drug has poor stability. The method for obtaining the threshold includes the following steps: pre-setting different x and V values. 瓶 and V 液 The liquid dosage form drug was filled into vials to obtain several corresponding samples. The headspace residual oxygen content y of the samples was measured, and the oxygen mass O and z of the samples were calculated. An acceleration test is performed on each sample, the impurity generation of each sample is detected, and whether each sample is qualified is determined in combination with the quality evaluation standard of the liquid dosage form drug; at the end of the acceleration test, for the sample closest to the critical value of the quality evaluation standard, the corresponding z thereof is used as the threshold value of the liquid dosage form drug; wherein, the calculation formula of O is: O=y×(V 瓶 -V 液 )×ρ; the calculation formula of z is: z=O / V 液 .

2. The method according to claim 1, characterized in that, The liquid dosage form drug is an injectable drug.

3. The method according to claim 2, characterized in that, The liquid dosage form includes any one or more of the following: clodronate disodium injection, compound diclofenac sodium injection, nicotinamide injection, oxytocin injection, nitroglycerin injection, vitamin C injection, adenosine triphosphate disodium injection, norepinephrine bitartrate injection, dopamine hydrochloride injection, or epinephrine hydrochloride injection.

4. The method according to claim 3, characterized in that, The liquid dosage form drug is any one or more of norepinephrine bitartrate injection, dopamine hydrochloride injection, or epinephrine hydrochloride injection.

5. The method according to claim 4, characterized in that, If the liquid dosage form drug is norepinephrine bitartrate injection, then the threshold is less than or equal to 0.013 mg / mL; If the liquid dosage form of the drug is dopamine hydrochloride injection, then the threshold is between 0.013 mg / mL and 0.017 mg / mL; If the liquid dosage form of the drug is epinephrine hydrochloride injection, then the threshold is less than 0.080 mg / mL.

6. The method according to claim 5, characterized in that, If the liquid dosage form of the drug is norepinephrine bitartrate injection, then the threshold is 0.010 mg / mL; If the liquid dosage form of the drug is dopamine hydrochloride injection, then the threshold is 0.015 mg / mL; If the liquid dosage form of the drug is epinephrine hydrochloride injection, then the threshold is 0.070 mg / mL.

7. The method according to claim 1, characterized in that, The filling parameters also include the filling temperature T, and the ρ is calculated from T. The calculation formula is: ρ=P×M / (R×T); where P represents standard atmospheric pressure; M represents the molar mass of oxygen; R represents the gas constant; T≥0, and the unit is Kelvin.

8. The application of the method according to any one of claims 1 to 7 in the quality control of vial-packaged liquid dosage form drugs.

9. A method for filling vials of liquid dosage form drugs, characterized in that, Combining the method described in claim 1 with the desired stability of the liquid dosage form drug, z is predetermined, and x is calculated; The liquid dosage form drug is filled into vials, evacuated to a vacuum level of x, filled with protective gas to atmospheric pressure, and then sealed.

10. The filling method according to claim 9, characterized in that, The protective gas is nitrogen.

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