CN116165194A - Method for determining compatibility in spray drying solution production transfer - Google Patents

Abstract

The invention discloses a method for determining the compatibility of a spray-dried solution in the production transfer. The raw material drug solution or the mixed solution of raw and auxiliary materials, the spray-dried wet product and the spray-dried product under different working conditions are investigated. Compatibility of industrial production equipment and production processes. The method provided by the present invention can accurately judge the products produced under different circumstances, thereby ensuring avoidance of most possible risks in the production transfer process, preventing instrument corrosion, precipitation of spray-dried solution, and spray-dried powder crystal form. Transformation, etc., resulting in instrument blockage, foreign impurities, unstable product properties, etc., to ensure the safety of production transfer. This method is convenient to operate, simple in steps and controllable in cost, and can be completed with only conventional laboratory equipment. Has better practicability.

Description

A Compatibility Determination Method in Production Transfer of Spray Dried Solution

technical field

The invention relates to the technical field of biopharmaceuticals, in particular to a method for determining the compatibility of a spray-dried solution in production transfer.

Background technique

In the development process of pharmaceutical preparations, when using spray drying technology to prepare pharmaceutical preparations, the preparation of pharmaceutical preparations is often explored on a laboratory scale, and then scaled up and transferred to GMP-level industrial scale-up production. However, the research conditions such as equipment material and ambient temperature used in the laboratory research are different from those in the subsequent GMP scale-up production. These differences may cause problems such as instrument corrosion during the production process, precipitation of the spray-dried solution, and crystal transformation of the spray-dried powder. , And eventually lead to problems such as unstable product properties, affecting the entire production process and the performance of the final product. Therefore, in order to avoid the risks in the scale-up production, a series of transfer support research work is needed. By exploring the compatibility between the spray-drying solution and the equipment used in the scale-up production, the stability of the spray-drying solution can be adjusted to ensure the safety of the scale-up production. .

Therefore, there is a need in the art for a method for determining the compatibility of spray-drying production transfers. While the operation is simple and cost-effective, it can intuitively and effectively determine the compatibility between the spray-drying solution and the spray-drying powder in the production transfer and the production equipment and production process. Compatibility, so that even if the production transfer method is adjusted, to avoid the risk of enlarged production and ensure the safety of the enlarged production transfer process.

Contents of the invention

In order to solve the above technical problems, the present invention provides the following technical solutions:

A method for determining the compatibility of a spray-dried solution in production transfer, the spray-dried solution includes a raw material drug solution or a mixed solution of raw and auxiliary materials, a spray-dried wet product and spray-dried products under different working conditions, and the method is used to investigate In the production transfer process, the compatibility of the spray-dried solution and the spray-dried powder with industrial production equipment and production technology, the method comprises the following steps:

S1. Take 10-100 mL of the raw material drug solution or the mixed solution of raw and auxiliary materials in a closed container, add stainless steel sheets respectively and fill the closed container with nitrogen, stand or stir at 30 ° C, and investigate the reaction system in 14 Changes in appearance and purity within days;

S2. Take the spray-dried wet product and put it in an airtight container, add a stainless steel sheet and fill the airtight container with nitrogen, and let it stand at 28°C to investigate the appearance change, purity change and crystal form of the reaction system within 14 days Variety;

S3. Take the spray-dried product and place it in an airtight container, add stainless steel sheet and fill the airtight container with nitrogen, let it stand under the condition of too high temperature, and investigate the appearance change and purity change of the reaction system within 1 hour and crystal form changes;

S4. Take the spray-dried product and place it in an open container, add a stainless steel sheet and place the open container in a vacuum oven, and let it stand at a temperature 5°C higher than the secondary drying condition, and investigate the reaction system in Appearance change, purity change and crystal form change within 14 days.

Specifically, the stainless steel sheet is 316L stainless steel sheet.

Specifically, the different working conditions include an overheating working condition and a secondary drying working condition.

Specifically, in said S1, the inspection items of appearance change include color and precipitation, and the specific inspection criteria are:

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 API; if there is no color change, the chemical compatibility is good;

Visually check whether there is precipitation. If there is precipitation, the chemical compatibility is poor. It is necessary to reduce the concentration of the spray drying solution until there is no precipitation; if there is no precipitation, the chemical compatibility is good.

Specifically, in S1, S2, S3 and S4, the change in purity 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 poor. Good sex.

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

Specifically, in the above-mentioned S2, S3 and S4, the inspection items of appearance change all include color and state, and the specific inspection standards are:

Visually check 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;

Visually inspect whether there is agglomeration or serious agglomeration, if there is, the chemical compatibility is poor; if not, the chemical compatibility is good.

Specifically, in S2, S3 and S4, the investigation of crystal form change is to use X-ray diffraction to determine the crystal structure. If it is amorphous, the chemical compatibility is good; if it is not amorphous, the chemical compatibility is poor.

Specifically, the method also includes judging the compatibility between the spray-dried product and the cleaning agent, and the cleaning agent includes methanol, ethanol and acetone, and the method of judging is: adding excessive spray-dried product powder into the cleaning agent, mixing evenly , stand still for 10-20 minutes, take out the suspension and centrifuge at high speed, take the supernatant to measure the concentration of the raw material drug, calculate the solubility of the spray-dried product in the cleaning agent according to the concentration of the raw material drug, and the cleaning agent with the lowest solubility has the best compatibility. By judging the compatibility between the product and the cleaning agent, we can choose the most suitable cleaning agent for the product.

The beneficial effects of the present invention include:

(1) The method provided by the present invention has wide applicability. It can not only judge the chemical compatibility of the raw material drug solution and the raw and auxiliary material solution, but also include the compatibility investigation of products at different stages in the whole production process, such as spray drying wet The inspection of products, the inspection of products produced when the equipment fails during the production process, and the inspection of products obtained by secondary drying can accurately judge the products produced under different circumstances, so as to ensure that most of the production transfer process is avoided. Possible risks, prevent the occurrence of instrument clogging and corrosion caused by the precipitation of the spray drying solution, and ensure the safety of production transfer.

(2) The method provided by the present invention is convenient to operate, simple in steps and controllable in cost, and can be completed with only conventional laboratory utensils, and has good practicability.

Detailed ways

The technical solution of the present invention will be clearly and completely described below, obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

Embodiment one

The instruments and equipment used in GMP production are all made of 316L stainless steel. There are a large number of glass materials in the equipment used in the laboratory and research institutes that are in contact with materials. The chemical compatibility of solid dispersion powder and 316L stainless steel under high temperature and vacuum conditions in the drying process.

The specific implementation method is:

1. Stability investigation of API and API/excipient (excipient required for solid dispersion) solution in spray drying solution

a) Add 316L stainless steel sheet to 10-100mL API and API/excipient solution respectively, fill the container with nitrogen gas, seal the container, let it stand or stir at 30 degrees Celsius, and inspect the appearance and purity within 14 days.

b) Inspection items and standards:

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 drug; if there is no color change, the chemical compatibility is good;

Visually check whether there is precipitation. If there is precipitation, the chemical compatibility is poor. It is necessary to reduce the concentration of the spray drying solution until there is no precipitation; if there is no precipitation, the chemical compatibility is good.

Purity: Use high performance liquid chromatography to determine whether the purity of the reaction system solution is reduced. If the purity is reduced, the chemical compatibility is poor; if the purity is not reduced, the chemical compatibility is good.

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

c) Corresponding measures when the result is abnormal:

If there is precipitation, it is necessary to reduce the concentration of the spray drying solution until there is no precipitation;

If the purity decreases or the color changes, the solvent needs to be replaced to avoid degradation of the API.

2. Investigation on the stability of wet product solid dispersion powder obtained by spray drying

a) The wet product solid dispersion powder is added to a glass container, and then 316L stainless steel sheet is added to fully contact the solid dispersion powder. The container is filled with nitrogen, and the container is sealed and left to stand at 28 degrees Celsius to investigate the appearance, purity and Crystalline changes.

b) Inspection items and standards:

Appearance: The solid dispersion powder has no change in color and state (no agglomeration or severe agglomeration) by visual inspection.

Purity: The purity of the solid dispersion was not reduced as determined by HPLC.

Crystal form: The solid dispersion is amorphous as determined by X-ray diffraction.

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

c) Corresponding measures when the result is abnormal:

If any of the above inspection items does not meet the standard, the composition of the solid dispersion needs to be updated.

3. When the instrument fails during the production process, that is, under the condition of too high temperature, the stability of the solid dispersion powder is investigated

a) The wet product solid dispersion powder is added to a glass container, and then 316L stainless steel sheet is added to fully contact the solid dispersion powder. The container is filled with nitrogen, and the container is sealed, and the temperature is 20 degrees Celsius higher than the production temperature. Appearance, purity and crystal form changes.

b) Inspection items and standards:

Appearance: The solid dispersion powder has no change in color and state (no agglomeration or severe agglomeration) by visual inspection.

Purity: The purity of the solid dispersion was not reduced as determined by high performance liquid chromatography.

Crystal form: The solid dispersion is amorphous as determined by X-ray diffraction.

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

c) Corresponding measures when the result is abnormal:

If any of the above inspection items does not meet the standard, it is necessary to abandon the batch of products or update the composition of the solid dispersion

4. Compatibility between solid dispersion powder and equipment material and product stability in the secondary drying process

a) The solid dispersion powder of the wet product is added to a glass container, and then 316L stainless steel sheet is added to fully contact the solid dispersion powder. The container is opened and placed in a vacuum oven at a temperature 5 degrees Celsius higher than the secondary drying temperature during production. 14 Day-to-day appearance, purity and crystal form variation.

b) Inspection items and standards:

Appearance: The solid dispersion powder has no change in color and state (no agglomeration or severe agglomeration) by visual inspection.

Purity: The purity of the solid dispersion was not reduced as determined by high performance liquid chromatography.

Crystal form: The solid dispersion is amorphous as determined by X-ray diffraction.

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

c) Corresponding measures when the result is abnormal:

If any of the above inspection items does not meet the standard, it is necessary to adjust the drying temperature in actual production and evaluate the drying effect in real time.

Five, the choice of cleaning agent

a) Determination of the solubility of the solid dispersion powder in three commonly used organic solvents, the organic solvent being methanol, ethanol or acetone.

b) Specific operation steps: Add excess solid dispersion powder into the investigation solvent, mix evenly, let stand for 10-20 minutes, take out a certain amount of suspension and centrifuge at high speed, take the supernatant to measure the concentration of the raw material drug, and load the drug according to the solid dispersion Calculate the solubility of the solid dispersion based on the volume ratio, and the obtained solubility is used as a reference for the selection of cleaning agents. The cleaning agent with the smallest solubility has the best compatibility.

6. Determination of viscosity of spray drying solution

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

In summary, the above-mentioned embodiments are only preferred embodiments of the present invention, and are not intended to limit the protection scope of the present invention. Any modifications, equivalent replacements, Improvements and the like should all be included within the protection scope of the present invention.

Claims (9)

1. a determination method of compatibility in the production transfer of spray-dried solution, it is characterized in that, described spray-dried solution comprises bulk drug solution or raw material mixed solution, spray-dried wet product and the spray-dried product under different working conditions, so The method is used to investigate the compatibility of the spray-dried solution and the spray-dried powder with industrial production equipment and production techniques in the production transfer process, and the method comprises the following steps: S1. Take 10-100 mL of the raw material drug solution or the mixed solution of raw and auxiliary materials in a closed container, add stainless steel sheets respectively and fill the closed container with nitrogen, stand or stir at 30 ° C, and investigate the reaction system in 14 Changes in appearance and purity within days; S2. Take the spray-dried wet product and put it in an airtight container, add a stainless steel sheet and fill the airtight container with nitrogen, and let it stand at 28°C to investigate the appearance change, purity change and crystal form of the reaction system within 14 days Variety; S3. Take the spray-dried product and place it in an airtight container, add stainless steel sheet and fill the airtight container with nitrogen, let it stand under the condition of too high temperature, and investigate the appearance change and purity change of the reaction system within 1 hour and crystal form changes; S4. Take the spray-dried product and place it in an open container, add a stainless steel sheet and place the open container in a vacuum oven, and let it stand at a temperature 5°C higher than the secondary drying condition, and investigate the reaction system in Appearance change, purity change and crystal form change within 14 days. 2. the determination method of compatibility in the production transfer of spray drying solution as claimed in claim 1, is characterized in that, described stainless steel sheet is 316L stainless steel sheet. 3. the determination method of compatibility in the production transfer of spray-drying solution as claimed in claim 1, is characterized in that, described different working conditions comprise temperature too high working condition and secondary drying working condition, and described temperature is too high to mean The temperature is 20°C higher than the production temperature. 4. the determination method of compatibility in the production transfer of spray drying solution as claimed in claim 1, is characterized in that, in described S1, the investigation item of appearance change comprises color and precipitation, and concrete investigation standard is: 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 API; if there is no color change, the chemical compatibility is good; Visually check whether there is precipitation. If there is precipitation, the chemical compatibility is poor. It is necessary to reduce the concentration of the spray drying solution until there is no precipitation; if there is no precipitation, the chemical compatibility is good. 5. the determination method of compatibility in the spray drying solution production transfer as claimed in claim 1, is characterized in that, in described S1, S2, S3 and S4, purity change refers to the use of high performance liquid chromatography to measure the reaction system solution Whether the purity is reduced, if the purity is reduced, the chemical compatibility is poor; if the purity is not reduced, the chemical compatibility is good. 6. the determination method of compatibility in the production transfer of spray-dried solution as claimed in claim 1, is characterized in that, described spray-dried wet product is wet product solid dispersion powder, and described spray-dried product is solid dispersion powder. 7. the determination method of compatibility in the production transfer of spray drying solution as claimed in claim 1, it is characterized in that, in described S2, S3 and S4, the investigation item of appearance change all comprises color and state, and concrete investigation standard is: Visually check 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; Visually inspect whether there is agglomeration or serious agglomeration, if there is, the chemical compatibility is poor; if not, the chemical compatibility is good. 8. the determination method of compatibility in the production transfer of spray drying solution as claimed in claim 1, it is characterized in that, in described S2, S3 and S4, the investigation of crystal form change is to use X-ray diffraction to measure crystal structure, if If it is amorphous, the chemical compatibility is good; if it is not amorphous, the chemical compatibility is poor. 9. the determination method of compatibility in the production transfer of spray-dried solution as claimed in claim 1, is characterized in that, described method also comprises the compatibility judgment of spray-dried product and cleaning agent, and described cleaning agent comprises methyl alcohol, ethanol and Acetone, the judgment method is: add excessive spray-dried product powder into the cleaning agent, mix evenly, let it stand for 10-20 minutes, take out the suspension and centrifuge at high speed, take the supernatant to measure the concentration of the raw material medicine, according to the concentration of the raw material medicine Calculate the solubility of the spray-dried product in the cleaning agent, and the cleaning agent with the least solubility has the best compatibility.