Method for evaluating stability of liquid dosage form medicine packaged in penicillin bottle and application of method

Abstract

The invention discloses a method for evaluating the stability of a penicillin bottle packaged liquid dosage form medicine and application of the method. Compared with a traditional filling and sealing process, the method has the advantages that the difference of headspace residual oxygen among batches of products is reduced by controlling the ratio of the mass of oxygen in the injection to the volume of the liquid medicine, the repeatability is high, and the controllability is good. Reliable basis is provided for parameter setting in the production and processing process of oxygen-sensitive injection liquid medicine, product quality improvement of injection medicine is promoted, quality problems caused by oxygen are reduced, long-term stability of the injection medicine in the storage and transportation process is kept, and production cost is saved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical process, in particular, to a method for evaluating the stability of liquid dosage form drugs packaged in a vial and application thereof. BACKGROUND

[0002] In the pharmaceutical industry, the level of headspace residual oxygen has a significant impact on the stability and safety of drugs, especially for oxygen-sensitive drugs. The contact of oxygen with the drugs can cause decomposition and deterioration of the drugs, affecting the quality and efficacy of the drugs. For oxygen-sensitive liquid dosage form drugs, inert gas is filled into the container before and after the drug liquid is filled into the packaging container to displace the air in the container. The residual oxygen concentration in the headspace of the packaging container is called headspace residual oxygen, which is usually expressed in volume percentage (%) and calculated by the following formula: .

[0003] Generally speaking, the lower the headspace residual oxygen, the higher the product quality. However, in practical applications, it is found that there are many limitations in evaluating the stability of liquid dosage form drugs by only using the headspace residual oxygen indicator. Currently, in order to improve the stability of liquid dosage form drugs, pharmaceutical companies often blindly pursue the headspace residual oxygen of the filled liquid dosage form drugs to be as low as possible, while ignoring the necessity of fine control of the headspace residual oxygen according to the characteristics of the injection drug itself.

[0004] During the filling process of liquid dosage form drugs, the batch-to-batch variation of headspace residual oxygen significantly affects the product quality. The commonly used packaging containers for liquid dosage form drugs include ampoule bottles and vials. The average headspace residual oxygen of the ampoule bottle production line is controlled within 3%, and the advanced level in the industry is controlled within 1%. However, the filling and sealing integrated production line often fills and seals dozens of liquid dosage form drugs at the same time, and the headspace residual oxygen of the same batch of products will fluctuate. The nitrogen filling before filling of the vial generally involves inserting a nitrogen filling tube into the vial and blowing nitrogen gas to replace the residual oxygen in the bottle. The nitrogen filling after filling mainly involves blowing horizontal air curtain towards the bottle opening after filling the vial to replace the residual oxygen, and the residual oxygen of the sealed vial is generally within 3% to 5%. The production and processing of the above two types of packaging need to rely on experienced technical personnel to adjust the headspace residual oxygen of the batch, which is time-consuming and labor-intensive, and it is difficult to ensure stable control effect.

[0005] More importantly, in the actual production and quality detection process, it is found that for different types of injections, even if the same filling volume and residual oxygen content in headspace are used, the quality of the final product still has obvious differences. This fully shows that simply relying on the residual oxygen content in headspace cannot accurately evaluate the stability of the liquid dosage form medicine, and it is difficult to effectively control and eliminate the potential impact of oxygen on the quality of the liquid medicine. Therefore, it is urgent to develop more direct and effective evaluation indexes and methods to more accurately control the oxygen content in the packaging container and establish a supporting standardized production system, thereby providing more reliable protection for the quality and stability of oxygen-sensitive liquid dosage form medicines. SUMMARY

[0006] In order to solve the above problems existing in the prior art, the present application provides a method for evaluating the stability of a liquid dosage form medicine packaged in a vial and an application thereof.

[0007] An object of the present application is to provide a method for evaluating the stability of a liquid dosage form medicine packaged in a vial.

[0008] Another object of the present application is to provide an application of the method in quality control of a liquid dosage form medicine packaged in a vial.

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

[0010] In order to achieve the above object, the present application is implemented by the following scheme: The applicant found in the previous work that when filling a liquid dosage form medicine packaged in a vial, although the residual oxygen content in headspace of the sampled product is the same, the quality (such as storage stability) of the product still has obvious differences. After research, the applicant found that this is due to the different mass of oxygen in the empty part above the liquid in the vial, which leads to different mass ratio of oxygen to the volume of the filled liquid. For the same specification of the medicine bottle, even if the residual oxygen content in headspace is controlled to be the same, the total amount of the actual residual oxygen in the packaging container is different due to the different volume of the filled liquid. On the other hand, the consumption of oxygen by the liquid of different volumes is also different.

[0011] The applicant speculates that, compared with the residual oxygen content in headspace, the mass ratio of oxygen to the volume of the liquid has a more accurate impact on the quality of the injection, that is, the mass ratio of oxygen to the volume of the liquid (which can be understood as how much oxygen will affect each unit volume of liquid) is different, and the quality of the product will also be different. Therefore, detecting the mass ratio of oxygen to the volume of the liquid is beneficial to the quality control of liquid dosage form medicines, especially oxygen-sensitive liquid dosage form medicines, and provides more accurate and reliable basis for the control parameters of the residual oxygen content in headspace of the medicine and the setting of the process parameters for subsequent product production.

[0012] Therefore, the present application claims the following: A method for evaluating the stability of a liquid dosage form medicine packaged in a vial, comprising the following steps: Collecting a filling parameter of the liquid dosage form medicine packaged in the vial, calculating an index value z, and determining the stability of the liquid dosage form medicine packaged in the vial according to the z; The filling parameter comprises a vacuum degree x, a density p of oxygen, and a volume V of the vial 瓶 and a filling volume V of the liquid dosage form medicine 液 ; wherein x is the vacuum degree in the vial after vacuumizing, p is the density of oxygen at the filling temperature, and V The calculation formula of z is: z={[Ax 2 +Bx+C]×(V 瓶 -V 液 )×p} / V 液 ; wherein z>0, the unit is mg / mL; x>0, the unit is Torr; V 瓶 >0, the unit is mL; 1 液 <ρ<1.5, the unit is mg / mL; 0 瓶 ≤V -5 2 < 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 the residual oxygen amount y in the headspace in the vial after the filling is completed as the dependent variable; The liquid dosage form medicine is an oxygen-sensitive medicine; The determination standard of the stability of the liquid dosage form medicine packaged in the vial is that if z≤threshold value, the stability of the liquid dosage form medicine packaged in the vial is good; and if z>threshold value, the stability of the liquid dosage form medicine packaged in the vial is not good.

[0013] In the present application, the method for obtaining A, B and C in the calculation formula of z comprises the following steps: taking x as the independent variable and the residual oxygen amount y in the headspace in the vial after the filling is completed as the dependent variable, presetting different x, and measuring the value of y of the finished product after the filling to obtain A, B and C by polynomial fitting.

[0014] In some specific embodiments, the calculation formula of z is: z={[1×10 -5 x 2 +0.0208x-0.6445]×(V 瓶 -V 液 )×p} / V 液 . In the present application, the method for obtaining the threshold value comprises the following steps: presetting different x, V 瓶 and V 液a number of corresponding samples are obtained by filling the liquid dosage form drug into a number of vials, the headspace residual oxygen amount y of the samples is determined, and the mass O and z of oxygen of the samples are calculated; The accelerated experiment is performed on each sample, and the impurity production 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 experiment, for the sample closest to the critical value of the quality evaluation standard, the corresponding z of the sample is taken as the threshold value of the liquid dosage form drug; wherein the calculation formula of O is: O = y x (V 瓶 -V 液 ) x p; and the calculation formula of z is: z = O / V 液 .

[0015] The skilled in the art generally evaluates the stability of a drug by accelerated experiment, and the conventional accelerated experiment generally requires that the drug is placed at 40℃±2℃ and relative humidity of 75%±5% for 6 months. In the present application, in order to evaluate the stability of the liquid dosage form drug packaged in the vial and obtain the threshold value, the accelerated experiment is performed at a temperature of 40±2℃ and relative humidity (RH) of 75%±5%, and the samples are taken before the accelerated experiment starts (0 month of acceleration), at 3 months of acceleration and at 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 application, the injection drug refers to an injection drug in which the active ingredient is prone to oxidative degradation when in contact with oxygen, including but not limited to disodium clodronate 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 adrenaline hydrochloride injection.

[0019] Preferably, the liquid dosage form drug includes any one or several of disodium clodronate 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 adrenaline hydrochloride injection.

[0020] More preferably, the liquid dosage form drug is any one or several of norepinephrine bitartrate injection, dopamine hydrochloride injection or adrenaline hydrochloride injection.

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

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

[0023] In the present application, the filling temperature is the set temperature of the filling instrument, which is used to control the temperature of the packaging container and keep constant during the whole process from filling the liquid dosage form medicine, vacuumizing, filling the protective gas, to the end of sealing.

[0024] Preferably, the filling parameter further comprises a filling temperature T, and the ρ is calculated from T, and the calculation formula is: ρ = P × M / (R × T); wherein P represents the standard atmospheric pressure; M represents the molar mass of oxygen; R represents the gas constant; T ≥ 0, and the unit is 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, the collected T is in Celsius ℃, which is first converted into Kelvin K, that is, T + 273.15, and then substituted into the formula to calculate ρ.

[0029] In some embodiments, the filling temperature is 0℃, and ρ is 1.429 mg / mL.

[0030] In some embodiments, the filling temperature is 20℃, and ρ is 1.331 mg / mL.

[0031] In some embodiments, the filling temperature is 25℃, and ρ is 1.309 mg / mL.

[0032] In some embodiments, the filling temperature is 30℃, and ρ is 1.287 mg / mL.

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

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

[0035] The method is applied in the quality control of liquid dosage form drugs packaged in a vial.

[0036] The method is applied in the preparation of liquid dosage form drugs packaged in a vial.

[0037] A filling method of liquid dosage form drugs packaged in a vial, in combination with the method for evaluating the stability of liquid dosage form drugs packaged in a vial and the expectation of the stability of liquid dosage form drugs, z is preset, and x is calculated; the liquid dosage form drugs are filled into a vial, vacuumed until the vacuum degree is x, filled with protective gas to normal pressure, and sealed.

[0038] Preferably, the protective gas is nitrogen.

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

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

[0041] Preferably, the filling temperature is 0℃-40℃.

[0042] More preferably, the filling temperature is 20℃-40℃.

[0043] In some specific embodiments, the oxygen-sensitive injection drug is norepinephrine bitartrate injection, and the temperature of the filling is 20℃.

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

[0045] In some specific embodiments, the oxygen-sensitive injection drug is epinephrine hydrochloride injection, and the filling temperature is 30°C.

[0046] The product prepared by any of the filling methods described above should also be within the scope of protection of the present invention.

[0047] Compared with the prior art, the present invention has the following beneficial effects: Compared to traditional potting processes, this method reduces inter-batch variability in headspace residual oxygen levels by controlling the ratio of oxygen mass to liquid volume in the injection, resulting in high repeatability and excellent controllability. This method provides a reliable basis for parameter setting during the production and processing of oxygen-sensitive injections, helping to improve the quality of injections and reduce production costs for manufacturers. It also mitigates oxygen-related quality issues and maintains the long-term stability of injections during storage and transportation. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 It is a formula fitting based on the vacuum degree and the measured residual oxygen content in the headspace. DETAILED DESCRIPTION

[0049] The present invention is further described in detail below with reference to the accompanying drawings and specific examples. The examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used are commercially available unless otherwise specified.

[0050] Example 1 Establishment of a Quality Control Formula for Injection Drugs 1. Filling of water for injection Use a pipette to fill 6 mL of water for injection (25°C, nitrogen is introduced below the liquid surface until the dissolved oxygen content is less than 2 mg / L) into an 8 mL vial, half-stopper it, and transfer it to a freeze dryer. The shelf temperature of the freeze dryer is set to 25°C (oxygen density is 1.309 mg / mL), the nitrogen pressure is adjusted to 0.04 MPa, and the freeze dryer is used to evacuate the vial to a vacuum degree (i.e., the vacuum degree in the freeze dryer parameter setting interface) of 50 Torr. Then, the vacuum is stopped, and nitrogen is filled into the vial to normal pressure (760 Torr) using the freeze dryer. The vial is equilibrated for 3 minutes, stoppered, and taken out of the cabinet to complete the filling. Sample 1 is thus prepared.

[0051] Sample 2 was prepared by the same method except that the vacuum degree was 100 Torr using a freeze dryer.

[0052] According to the same method, the difference is that the vacuum degree of 180 Torr is obtained by using the freeze dryer, and sample 3 is prepared.

[0053] According to the same method, the difference is that the vacuum degree of 250 Torr is obtained by using the freeze dryer, and sample 4 is prepared.

[0054] According to the same method, the difference is that the normal pressure of 760 Torr is maintained by using the freeze dryer (without vacuum and nitrogen filling), and sample 5 is prepared.

[0055] 2. Numerical determination and formula fitting The measured value (%) of the headspace residual oxygen content of samples 1-5 was determined by using an oxygen concentration detector, and each vacuum degree sample was determined in parallel for 4 times. The specific results are shown in Table 1.

[0056] Table 1 Determination results of samples under different vacuum degrees

[0057] According to the determination results of the previous step, the vacuum degree and the measured value of the headspace residual oxygen content of samples 1-5 were used as key variables for polynomial fitting, and the obtained curve is shown in Figure 1 The obtained fitting formula is shown in formula (1), and R 2 =0.9996.

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

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

[0060] Table 2 Comparison analysis results of the actual value and the calculated value of the headspace residual oxygen content of samples under different vacuum degrees

[0061] 3. Formula optimization Combined with the volume of the penicillin bottle and the volume of the perfusion liquid, the mass of oxygen can be obtained by formula (2).

[0062] Formula (2): O=y×(V 瓶 -V液 ) x p; wherein O represents the mass of oxygen, in mg, O > 0 because the filling cannot completely exclude the oxygen in the container; y represents the residual oxygen amount in the headspace, in %, y > 0; V 瓶 represents the volume of the vial, in mL, V 瓶 > 0; V 液 represents the volume of the perfusion liquid, in mL, 0 < V 液 < V 瓶 ; p represents the density of oxygen, in mg / mL, 1 < p < 1.5.

[0063] The ratio of the mass of oxygen to the volume of the perfusion liquid calculated from formula (3) is denoted as z, z > 0, in mg / mL.

[0064] Formula (3): z = O / V 液 ; wherein O represents the mass of oxygen, in mg, O > 0; V 液 represents the volume of the perfusion liquid, in mL.

[0065] The new parameter z of formula (3) is introduced on the basis of formula (2) to obtain formula (4).

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

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

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

[0069] According to formula (5), the corresponding oxygen densities of the injection liquid medicines at the common temperatures of preparation are obtained as shown in Table 3.

[0070] Table 3 Oxygen densities at various temperatures

[0071] According to the results in Table 1, the measured values ​​of the residual oxygen content in the headspace of samples 1 to 5 were substituted into formulas (2), (3), and (5) to calculate the measured values ​​of the mass of oxygen (O) and the measured values ​​of the ratio of the mass of oxygen to the volume of the liquid perfusion solution in the bottle (z); the vacuum degrees of samples 1 to 5 were substituted into formulas (4) and (5) to calculate the calculated values ​​of z. The specific results are shown in Table 4. It can be seen that the deviation between the measured values ​​and the calculated values ​​of the ratio of the mass of oxygen to the volume of the liquid perfusion solution in the bottle (z) for each sample is less than 0.001 (mg / mL), with high consistency. This indicates that during the perfusion process of the injection solution, there is a significant correlation between the vacuum degree and the ratio of the mass of oxygen to the volume of the liquid perfusion solution in the bottle.

[0072] Table 4 Comparative analysis results of the measured values ​​of the mass of oxygen in samples with different vacuum degrees and the ratio of the mass of oxygen to the volume of the liquid in the bottle and the calculated values

[0073] Application Example 1: Filling and Quality Control of Different Oxygen-Sensitive Injection Drugs 1. Norepinephrine bitartrate injection (1) Filling method The target value of the residual oxygen content in the headspace is set in advance, and the value is substituted into formula (1) to calculate the vacuum degree.

[0074] Afterwards, different volumes of norepinephrine bitartrate injection were filled into vials of different capacities using a pipette, half-stoppered, and transferred to a freeze dryer. The freeze dryer shelf temperature was set to 20°C (the oxygen density calculated using formula (5) was 1.331 mg / mL), the nitrogen pressure was adjusted to 0.04 MPa, and the freeze dryer was used to evacuate to the vacuum degree calculated in the previous step. The vacuum was then stopped, and nitrogen was filled into the vials using the freeze dryer to atmospheric pressure (760 Torr). The vials were equilibrated for 3 minutes, stoppered, and removed from the cabinet to complete the filling. The sample A series shown in Table 5 was thus obtained.

[0075] Record the volume of the vial used to fill each sample (V 瓶 ) and the volume of the perfusion solution (V 液 ), use an oxygen concentration meter to measure the actual value (%) of the residual oxygen content in the headspace of each sample, and calculate the actual value of the mass of oxygen (O) of each sample and its relationship with the volume of the perfusion solution (V 液 The specific results are shown in Table 5.

[0076] Table 5 Processing parameters of norepinephrine bitartrate injection

[0077] (2) Stability evaluation The samples A-1 to A-4, samples A-5-1 to A-5-3 and samples A-6-1 to A-6-3 prepared above were placed under accelerated test conditions (temperature 40±2℃, relative humidity (RH) 75%±5%) for 6 months, and samples were taken before the start of the accelerated experiment (acceleration 0 months), at 3 months of acceleration and at 6 months of acceleration, respectively, and the relevant substance items were determined according to the Chinese Pharmacopoeia (ChP 2020) for norepinephrine bitartrate injection.

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

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

[0080] The stability evaluation results of 10 samples are shown in Table 6. Before the start of the accelerated experiment, all samples were qualified; after 3 months of acceleration, samples A-1, A-2, A-5-3, A-6-2 and A-6-3 were unqualified, and the remaining 5 samples were still qualified; after 6 months of acceleration, samples A-5-1 and A-6-1 were qualified, and the remaining 8 samples were unqualified.

[0081] Comparing the acceleration of samples A-5-1, A-5-2 and A-5-3, and the acceleration of samples A-6-1, A-6-2 and A-6-3, it is shown that when the volume (V 瓶 ) of the vial is the same and the target value of the residual oxygen amount in the headspace is the same, the larger the volume (V 液 ) of the perfusion liquid, the smaller the ratio (z) of the mass (O) of oxygen to the volume (V 液 ) of the perfusion liquid, and the better the stability of the filled liquid.

[0082] Comparing the acceleration of samples A-5-1 to A-5-3, and samples A-6-1 to A-6-3, even if the same vacuum degree (x) is controlled, the stability of the filled liquid cannot be controlled consistently, and under the same vacuum degree (x), the smaller the ratio (z) of the mass (O) of oxygen to the volume (V 液 ) of the perfusion liquid, the better the stability of the filled liquid, which also shows that the ratio (z) of the mass (O) of oxygen to the volume (V 液 ) of the perfusion liquid is more conducive to controlling the stability of the filled liquid.

[0083] Comparing the acceleration of samples A-4, A-5-2 and A-6-1, the change trends of total impurities and maximum single impurity of these three samples are basically the same during the acceleration period, which shows that although the residual oxygen amounts in the headspace are different, the ratio (z) of the mass (O) of oxygen to the volume (V液 ) (z) can more accurately and objectively reflect the quality change of the filled liquid medicine, and is more conducive to controlling the stability of the filled liquid medicine. Moreover, when z is 0.013 mg / mL, the three samples are all near the critical value of the qualified standard after being accelerated for 6 months. Therefore, the threshold of the ratio (z) of the mass of oxygen (O) to the volume (V 液 ) of the liquid medicine of the filled levarterenol bitartrate injection should be less than or equal to 0.013 mg / mL.

[0084] (3) Optimization of the filling method The ratio (z) of the mass of oxygen (O) to the volume (V 液 ) of the liquid medicine was set to 0.005 mg / mL. When z is 0.005 mg / mL, the vacuum degree calculated by substituting z into formula (4) is 54 Torr, which is used as the vacuum degree. 2 mL of levarterenol bitartrate injection was filled into a vial with a volume of 3.5 mL, and the shelf temperature of the freeze dryer was set to 20°C (the oxygen density calculated by using formula (5) is 1.331 mg / mL). According to the filling method of this application example, samples A-7 and A-8 shown in Table 7 were prepared.

[0085] The ratio (z) of the mass of oxygen (O) to the volume (V 液 ) of the liquid medicine was set to 0.010 mg / mL. When z is 0.010 mg / mL, the vacuum degree calculated by substituting z into formula (4) is 77 Torr, which is used as the vacuum degree. 2 mL of levarterenol bitartrate injection was filled into a vial with a volume of 3.5 mL, and the shelf temperature of the freeze dryer was set to 20°C (the oxygen density calculated by using formula (5) is 1.331 mg / mL). According to the filling method of this application example, sample A-9 shown in Table 7 was prepared.

[0086] Table 7 Optimization of process parameters of levarterenol bitartrate injection

[0087] The samples A-7 to A-9 prepared above shown in Table 7 were placed under accelerated test conditions (temperature 40±2°C, relative humidity (RH) 75%±5%) for 6 months, and samples were taken before the start of the accelerated experiment (acceleration for 0 months), after 3 months of acceleration, and after 6 months of acceleration, respectively. The related substances of levarterenol bitartrate injection were determined according to the Chinese Pharmacopoeia (ChP 2020).

[0088] Table 8 Results of stability evaluation of levarterenol bitartrate injection

[0089] Note: The acceptance criteria are: total impurities ≤ 0.5% and the maximum single impurity ≤ 0.2%.

[0090] As shown in Table 8, samples A-7 to A-9 passed the accelerated test before the start of the test, after 3 months of acceleration, and after 6 months of acceleration. In addition, compared with sample A-5-1, the total impurity and maximum single impurity content of samples A-7 to A-8 fluctuated only slightly during the 6-month accelerated test, and the stability of the products was comparable to that of A-5-1, indicating that the ratio (z) of the preset oxygen mass (O) to the volume of the drug solution (Vliquid) can effectively control the stability of the norepinephrine bitartrate injection. Among them, compared with sample A-9, samples A-7 and A-8 have better stability, so the optimal oxygen mass (O) to the volume of the drug solution (Vliquid) for filling norepinephrine bitartrate injection is 液 The threshold value of the ratio (z) was 0.010 mg / mL.

[0091] (4) Evaluation of inter-batch variability of headspace residual oxygen According to the filling method of this application example, three batches of sample A-5-1 shown in Table 5 and samples A-7 to A-8 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 ) is different, the volume of the perfusion solution (V 液 ) are different, but the control z is the same, then the samples prepared from different batches are affected by the actual headspace residual oxygen content. This shows that the quality of the controlled oxygen (O) and the volume of the perfused solution (V 液 ) 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 the residual oxygen content in the headspace is set in advance, and the value is substituted into formula (1) to calculate the vacuum degree.

[0094] Afterwards, different volumes of dopamine hydrochloride injection were filled into vials of different capacities using a pipette, half-stoppered, and transferred to a freeze dryer. The freeze dryer shelf temperature was set to 40°C (the oxygen density calculated using formula (5) was 1.246 mg / mL). The nitrogen pressure was adjusted to 0.04 MPa. The freeze dryer was evacuated to the vacuum degree calculated in the previous step, and then the vacuum was stopped. The actual vacuum value was recorded. Nitrogen was then filled into the vials using the freeze dryer to atmospheric pressure (760 Torr). The vials were equilibrated for 3 minutes, stoppered, and removed from the cabinet to complete the filling. Samples B-1 to B-3 as shown in Table 9 were thus obtained.

[0095] The volume (V 瓶 ) of the vial used for filling each sample and the volume (V 液 ) of the drug solution filled were recorded, the measured value of the residual oxygen content in the headspace of each sample was determined using an oxygen concentration meter, the mass of oxygen (O) of each sample was calculated according to formula (1), and the measured value of the mass of oxygen (O) of each sample and the measured value of the ratio (z) of the mass of oxygen (O) to the volume (V 液 ) of the drug solution filled were calculated according to formula (3).

[0096] Table 9 Process parameters of dopamine hydrochloride injection

[0097] (2) Stability evaluation The samples B-1 to B-3 prepared according to Table 9 were placed under accelerated test conditions (temperature 40±2℃, relative humidity (RH) 75%±5%) for 6 months, and samples were taken before the start of the accelerated experiment (0 months of acceleration), 3 months of acceleration and 6 months of acceleration, respectively. The content of dopamine hydrochloride was determined according to the Chinese Pharmacopoeia (ChP2020) for dopamine hydrochloride injection. On this basis, the applicant used the optimized product registration standard for dopamine hydrochloride injection (standard number: YBH13272024) to determine the content of sodium metabisulfite.

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

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

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

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

[0102] Preset the oxygen mass (O) and liquid volume (V 液 ) ratio (z) was 0.015 mg / mL. Formula (4) was used to calculate the vacuum degree to be 103 Torr when z was 0.015 mg / mL, which was used as the vacuum degree. 2 mL of norepinephrine bitartrate injection was filled into a 3.5 mL vial. The freeze dryer shelf temperature was set to 40°C (the oxygen density was calculated to be 1.246 mg / mL using Formula (5)). Sample B-5, shown in Table 11, was prepared according to the filling method of this application example.

[0103] Preset the oxygen mass (O) and liquid volume (V 液 ) ratio (z) was 0.015 mg / mL. Formula (4) was used to calculate the vacuum degree to be 188 Torr when z was 0.015 mg / mL, which was used as the vacuum degree. 6 mL of norepinephrine bitartrate injection was filled into an 8 mL vial. The freeze dryer shelf temperature was set to 40°C (the oxygen density was calculated to be 1.246 mg / mL using Formula (5)). Sample B-6, 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 test conditions (temperature 40±2°C, relative humidity (RH) 75%±5%) for 6 months, and samples were taken before the start of the accelerated experiment (0 months), 3 months and 6 months of acceleration, respectively. The dopamine hydrochloride content was determined according to the Chinese Pharmacopoeia (ChP2020) Dopamine Hydrochloride Injection. On this basis, the applicant adopted the optimized registration standard for the approved product dopamine hydrochloride injection (standard number: YBH13272024) to determine the sodium metabisulfite item.

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

[0107] Note: The acceptance criteria are: dopamine hydrochloride content of 95% to 105% and sodium metabisulfite content of 0.30 to 0.55 mg / mL.

[0108] As shown in Table 12, samples B-4 to B-6 passed the test before the start of the accelerated test, after 3 months of acceleration, and after 6 months of acceleration. Moreover, compared with samples B-1 to B-3, the dopamine hydrochloride content and sodium metabisulfite content of samples B-4 to B-6 fluctuated only slightly during the 6-month accelerated test. The product stability was comparable to that of sample B-1, indicating that the ratio (z) of the preset oxygen mass (O) to the liquid volume (Vliquid) can effectively control the stability of dopamine hydrochloride injection. The optimal ratio of oxygen mass (O) to liquid volume (Vliquid) for filling dopamine hydrochloride injection is 液 The threshold value of the ratio (z) was 0.015 mg / mL.

[0109] (4) Evaluation of inter-batch variability of headspace residual oxygen According to 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 ) is different, the volume of the perfusion solution (V 液 ) are different, but the control z is the same, then the samples prepared from different batches are affected by the actual headspace residual oxygen content. This shows that the quality of the controlled oxygen (O) and the volume of the perfused solution (V 液 ) can effectively reduce the batch-to-batch variation of dopamine hydrochloride injection and is easier to control in actual production.

[0111] 3. Epinephrine hydrochloride injection (1) Filling method The target value of the residual oxygen content in the headspace is set in advance, and the value is substituted into formula (1) to calculate the vacuum degree.

[0112] Afterwards, different volumes of epinephrine hydrochloride injection were filled into vials of different capacities using a pipette, half-stoppered, and transferred to a freeze dryer. The freeze dryer shelf temperature was set to 30°C (the oxygen density calculated using formula (5) was 1.287 mg / mL). The nitrogen pressure was adjusted to 0.04 MPa. The freeze dryer was evacuated to the vacuum degree calculated in the previous step, and then the vacuum was stopped. The actual vacuum value was recorded. Nitrogen was then filled into the vials using the freeze dryer to atmospheric pressure (760 Torr). The vials were equilibrated for 3 minutes, stoppered, and removed from the cabinet to complete the filling. Samples C-1 to C-3 were thus prepared as shown in Table 13.

[0113] The volume (V 瓶 ) of the vial used for filling each sample and the volume (V 液 ) of the drug solution filled were recorded, the measured value (%) of the residual oxygen content in the headspace of each sample was determined using an oxygen concentration meter, the mass (O) of oxygen in each sample was calculated according to formula (1), and the measured value of the mass (O) of oxygen in each sample and the ratio (z) of the mass (O) of oxygen to the volume (V 液 ) of the drug solution were calculated according to formula (3).

[0114] Table 13 Process parameters of adrenaline hydrochloride injection

[0115] (2) Stability evaluation The samples C-1 to C-3 prepared in Table 13 above were placed under accelerated test conditions (temperature 40±2℃, relative humidity (RH) 75%±5%) for 6 months, and samples were taken before the start of the accelerated experiment (acceleration 0 months), at 3 months of acceleration and at 6 months of acceleration, and the related substances of adrenaline hydrochloride injection were determined according to the Chinese Pharmacopoeia (ChP2020).

[0116] Table 14 Stability evaluation results of adrenaline hydrochloride injection

[0117] Note: The pass 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 experiment and at 3 months of acceleration, all samples were qualified; at 6 months of acceleration, samples C-1 and C-2 were qualified, and sample C-3 was unqualified. When the volume (V 瓶 ) of the vial and the volume (V 液 ) of the drug solution were the same, the smaller the target value of the residual oxygen content in the headspace, the better the stability of adrenaline hydrochloride injection. Moreover, the threshold value of the ratio (z) of the mass (O) of oxygen to the volume (V 液 ) of the drug solution for filling adrenaline hydrochloride injection should be less than 0.080 mg / mL.

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

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

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

[0122] Table 15 Process parameter optimization of epinephrine hydrochloride injection

[0123] The samples C-4 to C-6 prepared above shown in Table 15 were placed under accelerated test conditions (temperature 40 ± 2°C, relative humidity (RH) 75% ± 5%) for 6 months. Samples were taken before the start of the accelerated test (0 months of acceleration), at 3 months of acceleration, and at 6 months of acceleration, respectively, and the related substances of the epinephrine hydrochloride injection were determined according to the Chinese Pharmacopoeia (ChP 2020).

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

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

[0126] As shown in Table 16, samples C-4 to C-6 all passed the accelerated test before, after 3 months of accelerated testing, and after 6 months of accelerated testing. 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 liquid volume (Vliquid) can effectively control the stability of epinephrine hydrochloride injection. 液 The threshold value of the ratio (z) of 2 to 3 mmol / L was 0.070 mg / mL.

[0127] (4) Evaluation of inter-batch variability of headspace residual oxygen According to 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 meter. The results showed that the volume of the vial (V 瓶 ) are the same, the volume of the perfusion solution (V 液 ) and consistent control z, there was no significant difference in the actual headspace residual oxygen content among samples prepared from different batches. This indicates that this filling method is highly reproducible and easier to control in actual production.

[0128] In summary, the filling method provided by the present invention can be used to study the filling process of different types of injections. The ratio of oxygen mass to liquid medicine volume proposed is suitable for setting and optimizing process parameters for different bottle volumes or different liquid medicine volumes, which facilitates product quality control in actual operations and can guide subsequent large-scale production of the product.

[0129] Finally, it should be noted that the above embodiments are intended only to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Those skilled in the art will readily appreciate that other variations or modifications may be made based on the above descriptions and concepts. It is not necessary and impossible to provide an exhaustive list of all possible implementations. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention shall 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: The following steps are involved: collecting filling parameters of the liquid dosage form drug packaged in the vial, calculating an index value z, and determining the stability of the liquid dosage form drug packaged in the vial based on z; The filling parameters include: vacuum degree x, oxygen density ρ, volume of the vial V 瓶 and the filling volume V for liquid dosage forms 液 ; Where x is the vacuum degree in the vial after evacuation, and ρ is the density of oxygen at the filling temperature; The calculation formula of 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 , 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 residual oxygen content in the headspace of the vial after filling; The liquid dosage form drug is an oxygen-sensitive drug; The criterion for determining the stability of the liquid dosage form drug packaged in the vial is: if z ≤ threshold value, the stability of the liquid dosage form drug packaged in the vial is good; if z > threshold value, the stability of the liquid dosage form drug packaged in the vial is poor.

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

3. The method according to claim 2, characterized in that The liquid dosage form medicine includes any one or more of 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 medicine 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, the threshold value is less than or equal to 0.013 mg / mL; If the liquid dosage form drug is dopamine hydrochloride injection, the threshold value is between 0.013 mg / mL and 0.017 mg / mL; If the liquid dosage form drug is epinephrine hydrochloride injection, the threshold value is less than 0.080 mg / mL.

6. The method according to claim 5, characterized in that If the liquid dosage form drug is norepinephrine bitartrate injection, the threshold value is 0.010 mg / mL; If the liquid dosage form drug is dopamine hydrochloride injection, the threshold value is 0.015 mg / mL; If the liquid dosage form drug is epinephrine hydrochloride injection, the threshold value 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 ρ is calculated from T using the following formula: ρ=P×M / (R×T); wherein P represents standard atmospheric pressure; M represents the molar mass of oxygen; R represents the gas constant; and T≥0, expressed in degrees Kelvin.

8. Use of the method according to any one of claims 1 to 7 in the quality control of liquid dosage forms packaged in vials.

9. A filling method for packaging liquid dosage forms of drugs in vials, characterized in that: In combination with the method of claim 1 and the expectation of the stability of the liquid dosage form drug, z is preset and x is calculated; The liquid dosage form drug is filled into a vial, evacuated to a vacuum degree of x, filled with protective gas to normal pressure, and sealed.

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

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