A method for determining compatibility in a spray-dried solution production transfer

Abstract

The application discloses a kind of determination methods for compatibility in spray drying solution production transfer, investigate the raw drug solution or raw material solution, spray drying wet product and spray drying product under different conditions, with the compatibility of industrial production equipment and production process in the production transfer process.The method provided by the application can accurately judge the products produced under different conditions, thereby ensuring to avoid most of the risks that may occur during production transfer, preventing instrument corrosion, precipitation of spray drying solution, crystal transformation of spray drying powder and other problems, thereby causing instrument blockage, foreign impurities, unstable product properties and other problems, ensuring the safety of production transfer.The method is convenient to operate, simple in steps and controllable in cost, can be completed using only conventional laboratory equipment, and has good practicability.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biopharmaceuticals, in particular to a method for determining compatibility in spray drying solution production transfer. BACKGROUND

[0002] In the development process of pharmaceutical preparations, when using spray drying technology to prepare pharmaceutical preparations, the preparation of pharmaceutical preparations is often first explored in the laboratory scale, and then scaled up for production and transferred to GMP-level industrial scale production. However, the research conditions such as equipment material and environmental temperature used in laboratory research are different from subsequent GMP scale production, and these differences may cause problems such as corrosion of instruments, precipitation of spray drying solution, and crystal transformation of spray drying powder during production, and ultimately lead to unstable product properties, affecting the entire production process and the performance of the final product. Therefore, in order to avoid the risks in scale-up production, a series of transfer support research work needs to be carried out, and the compatibility between the spray drying solution and the equipment used in scale-up production is explored to adjust the stability of the spray drying solution and ensure the safety of scale-up production.

[0003] Therefore, there is a need in the art for a method for determining compatibility in spray drying production transfer, which is simple and low in cost, and can directly and effectively determine the compatibility of spray drying solution and spray drying powder with production equipment and production process during production transfer, so as to adjust the production transfer mode to avoid the risks of scale-up production and ensure the safety of scale-up production. SUMMARY

[0004] To solve the above technical problems, the present application provides the following technical solutions:

[0005] A method for determining compatibility in spray drying solution production transfer, the spray drying solution comprising a raw drug solution or a raw material and auxiliary material mixed solution, a spray drying wet product and a spray drying product under different working conditions, the method being used to investigate the compatibility of the spray drying solution and the spray drying powder with industrial production equipment and production process during production transfer, and the method comprising the following steps:

[0006] S1, taking 10-100 mL of the raw drug solution or the raw material and auxiliary material mixed solution in a sealed container, respectively adding a stainless steel sheet and filling the sealed container with nitrogen, and standing or stirring at 30℃, investigating the appearance change and purity change of the reaction system within 14 days;

[0007] S2, taking the spray drying wet product and placing it in a sealed container, adding a stainless steel sheet and filling the sealed container with nitrogen, and standing at 28℃, investigating the appearance change, purity change and crystal form change of the reaction system within 14 days;

[0008] S3, taking the spray-dried product into a closed container, adding stainless steel pieces and filling the closed container with nitrogen, standing under a temperature too high condition, and observing the appearance change, purity change and crystal form change of the reaction system within 1 hour;

[0009] S4, taking the spray-dried product into an open container, adding stainless steel pieces and placing the open container in a vacuum oven, standing under a condition 5°C higher than the temperature of the secondary drying condition, and observing the appearance change, purity change and crystal form change of the reaction system within 14 days.

[0010] Specifically, the stainless steel pieces are 316L stainless steel pieces.

[0011] Specifically, the different conditions include a temperature too high condition and a secondary drying condition.

[0012] Specifically, in S1, the observation items of the appearance change include color and precipitation, and the specific observation standards are:

[0013] visually observing whether there is a color change, if there is a color change, the chemical compatibility is poor, and the solvent needs to be replaced to avoid the active pharmaceutical ingredient from being dissolved; if there is no color change, the chemical compatibility is good;

[0014] visually observing whether there is precipitation, if there is precipitation, the chemical compatibility is poor, and the spray-drying solution concentration needs to be reduced until there is no precipitation; if there is no precipitation, the chemical compatibility is good.

[0015] Specifically, in S1, S2, S3 and S4, the purity change refers to whether the purity of the reaction system solution is reduced by using high performance liquid chromatography, if the purity is reduced, the chemical compatibility is poor; if the purity is not reduced, the chemical compatibility is good.

[0016] Specifically, the spray-dried wet product is a wet solid dispersion powder, and the spray-dried product is a solid dispersion powder.

[0017] Specifically, in S2, S3 and S4, the observation items of the appearance change all include color and state, and the specific observation standards are:

[0018] visually observing whether there is a color change, if there is a color change, the chemical compatibility is poor; if there is no color change, the chemical compatibility is poor;

[0019] visually observing whether there is caking or serious agglomeration, if there is, the chemical compatibility is poor; if there is not, the chemical compatibility is good.

[0020] Specifically, in S2, S3 and S4, the observation of the crystal form change is to determine the crystal structure by using X-ray diffraction, if it is amorphous, the chemical compatibility is good; if it is not amorphous, the chemical compatibility is poor.

[0021] Specifically, the method further comprises judging the compatibility of the spray-dried product with the cleaning agent, wherein the cleaning agent comprises methanol, ethanol and acetone, and the judging method is as follows: adding excessive spray-dried product powder into the cleaning agent, uniformly mixing, standing for 10-20 minutes, taking the supernatant after high-speed centrifugation of the suspension, determining the concentration of the raw material medicine, calculating the solubility of the spray-dried product in the cleaning agent according to the concentration of the raw material medicine, and the cleaning agent with the minimum solubility has the best compatibility. By judging the compatibility of the product with the cleaning agent, the most suitable cleaning agent for the product can be selected.

[0022] The beneficial effects of the present application include:

[0023] (1) The method provided by the present application has wide applicability, which can not only judge the chemical compatibility of raw material medicine solution and raw material solution, but also investigate the compatibility of products at different stages in the whole production process, such as the investigation of spray-dried wet product, the investigation of product generated when the instrument fails in the production process, and the investigation of product obtained by secondary drying. The product generated under different conditions can be accurately judged, thereby avoiding most of the risks that may occur during production transfer, preventing the phenomenon of instrument blockage and corrosion caused by precipitation of spray-dried solution, and ensuring the safety of production transfer.

[0024] (2) The method provided by the present application is convenient to operate, simple in steps and controllable in cost, and can be completed only with conventional laboratory instruments, and has good practicability. DETAILED DESCRIPTION

[0025] The technical solutions of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor belong to the scope of protection of the present application.

[0026] Example 1

[0027] The instruments and equipment used in GMP production are all made of 316L stainless steel, and a large number of glass materials are used in the contact parts of the instruments and equipment used in the laboratory. Therefore, it is necessary to investigate the chemical compatibility of raw material medicine solution or raw material / auxiliary material (auxiliary material required for solid dispersion) mixed solution, spray-dried wet product solid dispersion powder and 316L stainless steel material under high-temperature vacuum conditions in the drying process.

[0028] The specific implementation is as follows:

[0029] I. Investigation of the stability of raw material medicine and raw material medicine / auxiliary material (auxiliary material required for solid dispersion) solution in spray-dried solution

[0030] a) 10-100 mL of the raw material and the raw material / excipient solution are added to a 316L stainless steel sheet, the container is filled with nitrogen, the container is closed, and the appearance and purity are observed at 30 degrees Celsius for 14 days with or without stirring.

[0031] b) Items and standards:

[0032] Appearance: visually check whether there is a color change. If there is a color change, the chemical compatibility is poor, and the solvent needs to be replaced to avoid the dissolution of the raw material. If there is no color change, the chemical compatibility is good.

[0033] Visually check whether there is precipitation. If there is precipitation, the chemical compatibility is poor, and the concentration of the spray drying solution needs to be reduced until there is no precipitation. If there is no precipitation, the chemical compatibility is good.

[0034] Purity: use high performance liquid chromatography to determine whether the purity of the reaction system solution decreases. If the purity decreases, the chemical compatibility is poor. If the purity does not decrease, the chemical compatibility is good.

[0035] When the above standards are met, it is confirmed that the transfer conditions for scale-up production are met.

[0036] c) Corresponding measures when the results are abnormal:

[0037] If there is precipitation, the concentration of the spray drying solution needs to be reduced until there is no precipitation.

[0038] If the purity decreases or the color changes, the solvent needs to be replaced to avoid the degradation of the raw material.

[0039] II. Stability investigation of the wet solid dispersion powder obtained by spray drying

[0040] a) The wet solid dispersion powder is added to a glass container, 316L stainless steel sheets are added to fully contact the solid dispersion powder, the container is filled with nitrogen, the container is closed, and the appearance, purity, and crystal form are observed at 28 degrees Celsius for 14 days.

[0041] b) Items and standards:

[0042] Appearance: visually check whether there is a color change. If there is a color change, the chemical compatibility is poor, and the solvent needs to be replaced to avoid the dissolution of the raw material. If there is no color change, the chemical compatibility is good.

[0043] Purity: high performance liquid chromatography is used to determine whether the purity of the solid dispersion decreases.

[0044] Crystal form: X-ray diffraction is used to determine whether the solid dispersion is amorphous.

[0045] When the above standards are met, it is confirmed that the production conditions are met.

[0046] c) Corresponding measures when the results are abnormal:

[0047] If any of the above items do not meet the criteria, the solid dispersion composition needs to be updated.

[0048] III. Stability of the solid dispersion powder during production process in case of equipment failure, i.e. high temperature conditions

[0049] a) The wet solid dispersion powder is added to a glass container, 316L stainless steel pieces are added and the container is closed and placed in a vacuum oven at a temperature of 5 degrees Celsius above the production temperature. The appearance, purity and crystal form are investigated for 14 days.

[0050] b) Items and criteria:

[0051] Appearance: The solid dispersion powder is visually inspected for changes in color and state (no caking or severe agglomeration).

[0052] Purity: The purity of the solid dispersion is determined by HPLC and no decrease is observed.

[0053] Crystal form: The solid dispersion is determined by X-ray diffraction to be amorphous.

[0054] If the above criteria are met, the production conditions are considered to be met.

[0055] c) Measures in case of abnormal results:

[0056] If any of the above items do not meet the criteria, the batch is rejected or the solid dispersion composition needs to be updated.

[0057] IV. Compatibility of the solid dispersion powder with the equipment material and stability of the product during secondary drying

[0058] a) The wet solid dispersion powder is added to a glass container, 316L stainless steel pieces are added and the container is placed in a vacuum oven at a temperature of 5 degrees Celsius above the production temperature. The appearance, purity and crystal form are investigated for 14 days.

[0059] b) Items and criteria:

[0060] Appearance: The solid dispersion powder is visually inspected for changes in color and state (no caking or severe agglomeration).

[0061] Purity: The purity of the solid dispersion is determined by HPLC and no decrease is observed.

[0062] Crystal form: The solid dispersion is determined by X-ray diffraction to be amorphous.

[0063] If the above criteria are met, the production conditions are considered to be met.

[0064] c) When the result is abnormal, take corresponding measures:

[0065] If any of the above items does not meet the standard, the drying temperature in actual production needs to be adjusted and the drying effect needs to be evaluated in real time.

[0066] V. Selection of cleaning agent

[0067] a) Determine the solubility of the solid dispersion powder in three commonly used organic solvents, namely methanol, ethanol or acetone.

[0068] b) Specific operation steps: add excess solid dispersion powder to the solvent under test, mix well, stand for 10-20 minutes, take a certain amount of suspension, centrifuge at high speed, then take the supernatant to determine the concentration of the API, calculate the solubility of the solid dispersion according to the proportion of the drug loading of the solid dispersion, and take the obtained solubility as the reference for the selection of the cleaning agent. The cleaning agent with the smallest solubility has the best compatibility.

[0069] VI. Determination of viscosity of spray drying solution

[0070] Set the water bath temperature to 25 degrees. After reaching the temperature, add the spray drying solution to be tested into the cylinder jacket. Set the rotor to No. 18 rotor, set the rotation speed parameter to 5 rpm, and the test time to 60 S. Start measuring and record the viscosity, torque, shear stress, shear rate and other data. For Newtonian fluid, the viscosity is equal to the shear stress divided by the shear rate.

[0071] In summary, the above embodiments are only preferred embodiments of the present application and do not limit the protection scope of the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method of determining spray-dried solution production transfer compatibility, characterized by, The spray drying solution includes a raw material solution or a raw material and auxiliary material mixed solution, a spray drying wet product, and a spray drying product under different working conditions, the method is used for investigating the compatibility of the spray drying solution and the spray drying powder with industrial production equipment and production process in the production transfer process, and the method comprises the following steps: S1, 10-100 mL of the raw material solution or the raw material and auxiliary material mixed solution is taken in a sealed container, a stainless steel sheet is added, and the sealed container is filled with nitrogen, and the reaction system is placed at 30 DEG C under static or stirring, and the appearance change and purity change of the reaction system within 14 days are investigated; wherein the investigation items of appearance change include color and precipitation, and the specific investigation standards are: visually observing whether there is color change, if there is color change, the chemical compatibility is poor, and the solvent needs to be replaced to avoid the dissolution of the raw material; if there is no color change, the chemical compatibility is good; visually observing whether there is precipitation, if there is precipitation, the chemical compatibility is poor, and the concentration of the spray drying solution needs to be reduced until there is no precipitation; if there is no precipitation, the chemical compatibility is good; the purity change refers to whether the purity of the solution of the reaction system is reduced by using high performance liquid chromatography, if the purity is reduced, the chemical compatibility is poor; if the purity is not reduced, the chemical compatibility is good; S2, the spray drying wet product is taken in a sealed container, a stainless steel sheet is added, and the sealed container is filled with nitrogen, and the reaction system is placed at 28 DEG C under static, and the appearance change, purity change and crystal form change of the reaction system within 14 days are investigated; S3, the spray drying product is taken in a sealed container, a stainless steel sheet is added, and the sealed container is filled with nitrogen, and the reaction system is placed at a temperature too high working condition, and the appearance change, purity change and crystal form change of the reaction system within 1 hour are investigated; S4, the spray drying product is taken in an open container, a stainless steel sheet is added, and the open container is placed in a vacuum oven, and the reaction system is placed at a temperature 5 DEG C higher than the secondary drying working condition, and the appearance change, purity change and crystal form change of the reaction system within 14 days are investigated; in S2, S3 and S4, the investigation items of appearance change include color and state, and the specific investigation standards are: visually observing whether there is color change, if there is color change, the chemical compatibility is poor; if there is no color change, the chemical compatibility is good; visually observing whether there is caking or serious agglomeration, if there is, the chemical compatibility is poor; if not, the chemical compatibility is good; the purity change refers to whether the purity of the solution of the reaction system is reduced by using high performance liquid chromatography, if the purity is reduced, the chemical compatibility is poor; if the purity is not reduced, the chemical compatibility is good; the investigation of crystal form change is to determine the crystal structure by using X-ray diffraction, if it is amorphous, the chemical compatibility is good; if it is not amorphous, the chemical compatibility is poor.

2. The method of claim 1, wherein the spray-dried solution production transfer compatibility determination is determined by, The stainless steel sheet is a 316L stainless steel sheet.

3. The method of claim 1, wherein the spray-dried solution production transfer compatibility determination is determined by, The different working conditions include a temperature too high working condition and a secondary drying working condition, and the temperature too high refers to a temperature 20 DEG C higher than the production temperature.

4. The method for determining compatibility during the production and transfer of spray-dried solutions as described in claim 1, characterized in that, The spray drying wet product is a wet solid dispersion powder, and the spray drying product is a solid dispersion powder.

5. The method of claim 1, wherein the spray-dried solution production transfer compatibility determination is determined by, The method further comprises judging the compatibility of the spray-dried product with the washing agent, wherein the washing agent comprises methanol, ethanol and acetone, and the judging method is as follows: adding excessive spray-dried product powder into the washing agent, mixing uniformly, standing for 10-20 minutes, taking the supernatant after high-speed centrifugation of the suspension, determining the concentration of the raw material medicine, calculating the solubility of the spray-dried product in the washing agent according to the concentration of the raw material medicine, and the washing agent with the minimum solubility has the best compatibility.