A multi-stage distillation purification method of pharmaceutical-grade glycerol
By employing a synergistic approach of multi-stage distillation and adsorbent treatment, the problem of stable control of high-risk impurities in synthetic glycerol has been solved, enabling the production of pharmaceutical-grade glycerol with high purity, stability, and consistency, suitable for high-end injectable formulations.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGSU BAOYI PHARM CO LTD
- Filing Date
- 2026-04-10
- Publication Date
- 2026-06-30
AI Technical Summary
Existing technologies are insufficient to effectively remove high-risk impurities such as aldehydes and ketones and residual solvents from synthetic glycerin, resulting in product purity and safety failing to meet the stringent requirements for injectables, and significant batch-to-batch variations.
A multi-stage distillation method is employed, including heating and degassing, molecular distillation, adsorbent bed treatment, and sterile filtration, to remove low-boiling-point impurities, aldehydes and ketones, and trace colored substances. By precisely controlling the vacuum and temperature, and combining activated carbon and molecular sieve adsorbents, deep purification is achieved.
It achieves a total aldehyde and ketone impurity content of ≤0.005%, a total residual solvent content of ≤0.001%, a product purity of ≥99.7%, and a batch-to-batch RSD of <1%, meeting the high standards required for injectables, eliminating the risk of biological contamination, and is suitable for large-scale industrial production.
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Figure CN122301650A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of glycerol purification technology, and in particular to a multi-stage distillation purification method for pharmaceutical-grade glycerol. Background Technology
[0002] Glycerin, as an important pharmaceutical excipient, is widely used in injections, oral solutions, and topical preparations. Currently, pharmaceutical glycerin is mainly divided into two categories: plant-derived glycerin and synthetic glycerin. Plant-derived glycerin is usually derived from the saponification or transesterification of natural oils. Its raw materials are affected by factors such as planting environment, climate conditions, and origin, which may lead to the presence of trace amounts of plant proteins, pollen allergens, pesticide residues, and aflatoxins, among other biological impurities. These impurities are difficult to completely remove even with conventional refining processes. For injections, they may trigger immune or pyrogenic reactions in sensitive individuals, failing to meet the stringent safety requirements for pediatric and immunocompromised patients.
[0003] Synthetic glycerol is prepared via a chemical synthesis route using petrochemically derived epichlorohydrin as a raw material, thus avoiding the inherent bio-based contamination risks of plant-derived glycerol at the molecular structure level. However, industrially synthesized crude glycerol still contains impurities such as unreacted epichlorohydrin, aldehydes and ketones produced by side reactions (e.g., formaldehyde, acetaldehyde, pyruvaldehyde), organic solvents (e.g., methanol, ethanol), and low-molecular-weight polymers. Among these, aldehydes and ketones pose a potential genotoxic risk, and pharmacopoeias in various countries impose strict limits on their residual levels in injectable excipients (typically requiring ≤0.05%). Existing conventional distillation techniques struggle to stably control these high-risk impurities at trace levels, and batch-to-batch variations are significant, failing to meet the stringent requirements for purity, safety, and stability in injectable excipients. Summary of the Invention
[0004] The purpose of this invention is to provide a multi-stage distillation purification method for pharmaceutical-grade glycerin, which solves the technical problems of existing plant-derived glycerin having the risk of biological impurities and existing synthetic glycerin purification processes having difficulty in stably controlling high-risk impurities such as aldehydes, ketones, and residual solvents at trace levels, resulting in product purity and safety failing to meet injection standards and large batch-to-batch variations.
[0005] To achieve the above objectives, the present invention provides a multi-stage distillation purification method for pharmaceutical-grade glycerol, comprising the following steps: Using industrially synthesized crude glycerol as raw material, heating and degassing are performed to remove dissolved low-boiling-point gases and volatile components, resulting in pretreated material. The pretreated material is fed into a first-stage molecular distillation apparatus and distilled under a first vacuum and a first temperature to remove residual trace amounts of low-boiling-point impurities, thereby obtaining intermediate material. The intermediate material is fed into a second-stage molecular distillation apparatus for deep purification under second vacuum and second temperature conditions. The gaseous glycerol component is separated and collected to obtain a high-purity glycerol fraction. The high-purity glycerol fraction was passed through an adsorbent bed under nitrogen protection to remove trace amounts of colored substances and residual polar impurities. After cooling, pharmaceutical-grade glycerol was obtained. The obtained pharmaceutical-grade glycerin was filtered and filled into sterile containers.
[0006] The industrially synthesized crude glycerol is obtained by chemical synthesis using epichlorohydrin as a raw material, and its source does not contain plant protein, aflatoxin, or genetically modified components.
[0007] The heating and degassing process specifically includes heating the crude glycerol to 80°C-100°C and stirring continuously for 30-60 minutes under a negative pressure of 1kPa-5kPa to remove dissolved oxygen, carbon dioxide and low-boiling-point impurities.
[0008] Wherein, the first vacuum degree is 0.1Pa-10Pa, the first temperature is 110℃-140℃, and the low-boiling-point impurities include one or more of water, methanol, ethanol, and acetone.
[0009] Wherein, the second vacuum degree is not higher than 0.1 Pa, and the second temperature is 160℃-200℃.
[0010] In the second-stage molecular distillation process, the separated light component impurities are aldehydes and ketones, including one or more of formaldehyde, acetaldehyde, and acetone aldehyde.
[0011] The adsorbent in the adsorbent bed is a mixture of activated carbon and molecular sieve; the adsorption process is maintained at 60℃-80℃ for 1-2 hours, and nitrogen is continuously introduced during the adsorption process to isolate it from air.
[0012] The filtration process is carried out in a sterile environment using a 0.22μm filter membrane.
[0013] This invention discloses a multi-stage distillation purification method for pharmaceutical-grade glycerol. First, a first-stage molecular distillation removes low-boiling-point impurities such as water, methanol, and ethanol. Then, a second-stage molecular distillation precisely separates genotoxic aldehydes and ketones such as formaldehyde, acetaldehyde, and acetone aldehydes under ultra-high vacuum conditions. Finally, a composite adsorbent of activated carbon and molecular sieves is used to further remove trace colored substances and residual polar impurities. The process is then completed under aseptic conditions through filtration and filling. Through the synergistic effect of these processes, this invention can stably control the total amount of aldehydes and ketones in synthetic glycerol to ≤0.005%, the total amount of residual solvent to ≤0.001%, the product purity to ≥99.7%, bacterial endotoxin to <2.5 EU / g, and batch-to-batch RSD <1%. All indicators are significantly superior to the standards of various national pharmacopoeias. The method of this invention not only completely avoids the risk of bio-based contamination of plant-derived glycerin from the source, but also achieves trace control of high-risk impurities through multi-stage refining. The resulting product has high purity, good stability, and strong batch-to-batch consistency, which can meet the stringent requirements of high-end injectables such as human serum albumin injection and vaccine injection for excipients, and is suitable for large-scale industrial production. Attached Figure Description
[0014] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.
[0015] Figure 1 This is a flowchart of the multi-stage distillation purification method for pharmaceutical-grade glycerol according to the present invention. Detailed Implementation
[0016] The embodiments of the present invention are described in detail below. Examples of the embodiments are shown in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and intended to explain the present invention, but should not be construed as limiting the present invention.
[0017] Please see Figure 1 ,in Figure 1 This is a flowchart of a multi-stage distillation purification method for pharmaceutical-grade glycerol.
[0018] This invention provides a multi-stage distillation purification method for pharmaceutical-grade glycerol, comprising the following steps: S1: Using industrially synthesized crude glycerol as raw material, heat and degas it to remove dissolved low-boiling-point gases and volatile components, and obtain pretreated material.
[0019] Specifically, the industrially synthesized crude glycerol is obtained through chemical synthesis using epichlorohydrin as a raw material, and its source does not contain plant protein, aflatoxin, or genetically modified components.
[0020] The heating and degassing treatment specifically includes: heating the crude glycerol to 80℃-100℃ and continuously stirring it for 30-60 minutes under a negative pressure of 1kPa-5kPa to remove dissolved oxygen, carbon dioxide and low-boiling-point impurities.
[0021] In this embodiment, step S1, by subjecting the crude industrial synthetic glycerol to negative pressure heating degassing treatment, can effectively remove dissolved gases such as oxygen and carbon dioxide, as well as some volatile components with low boiling points, from the raw material, creating stable conditions for subsequent high vacuum distillation and avoiding the impact of gas release on the vacuum stability of the distillation process.
[0022] S2: The pretreated material is fed into the first-stage molecular distillation apparatus and distilled under the first vacuum and first temperature conditions to remove residual trace amounts of low-boiling-point impurities and obtain intermediate material.
[0023] Specifically, the first vacuum degree is 0.1 Pa-10 Pa, and the first temperature is 110℃-140℃; the low-boiling-point impurities include one or more of water, methanol, ethanol, and acetone.
[0024] In this embodiment, the pretreated material is purified using first-stage molecular distillation. Molecular distillation utilizes the difference in the mean free path of molecules under high vacuum conditions, allowing low-boiling-point impurities to preferentially escape from the heating surface and condense and separate. By controlling the vacuum level at 0.1 Pa-10 Pa and the temperature at 110℃-140℃, trace amounts of low-boiling-point impurities such as water, methanol, ethanol, and acetone can be selectively removed. The main component, glycerol, has a higher boiling point and does not evaporate significantly under these conditions, thus achieving preliminary enrichment and separation of impurities. This step employs a scraped-film molecular distillation apparatus, where a scraper forms a uniform thin liquid film on the heating surface. This not only significantly shortens the heating time and avoids the decomposition of heat-sensitive substances but also significantly improves heat and mass transfer efficiency, ensuring stable and reliable removal of low-boiling-point impurities. After this step, the content of low-boiling-point impurities in the obtained intermediate material is significantly reduced.
[0025] S3: The intermediate material is fed into a second-stage molecular distillation apparatus for deep purification under second vacuum and second temperature conditions, separating and collecting the gaseous glycerol component to obtain a high-purity glycerol fraction.
[0026] Specifically, the second vacuum degree is no higher than 0.1 Pa, and the second temperature is 160℃-200℃.
[0027] During the second-stage molecular distillation process, the separated light component impurities are aldehydes and ketones, including one or more of formaldehyde, acetaldehyde, and acetone aldehyde.
[0028] In this embodiment, a second-stage molecular distillation is used to deeply purify the intermediate material. By raising the vacuum level to an ultra-high vacuum of no more than 0.1 Pa and using a distillation temperature of 160℃-200℃, the mean free path of glycerol molecules is significantly increased, allowing them to evaporate smoothly from the heating surface and reach the condensing surface for collection. Meanwhile, heavier impurities with higher boiling points and substances with poor thermal stability remain at the bottom of the vessel. This step also uses a scraped-film molecular distillation apparatus to ensure that the material forms a continuously renewing thin liquid film on the heating surface, with an extremely short heating time (typically only a few seconds to tens of seconds), effectively avoiding thermal decomposition or polymerization of glycerol at high temperatures. Under these conditions, aldehydes and ketones (such as formaldehyde, acetaldehyde, and acetone aldehydes) with boiling points between glycerol and the previously low-boiling-point impurities are directionally separated into the lighter components for removal. By precisely controlling the process parameters of the second-stage molecular distillation, the total content of aldehydes and ketones in the product can be stably controlled below ≤0.005%, which is significantly better than the ≤0.05% limit standard stipulated by various pharmacopoeias, eliminating the risk of genotoxicity at the source.
[0029] S4: The high-purity glycerol fraction is passed through an adsorbent bed under nitrogen protection to remove trace amounts of colored substances and residual polar impurities. After cooling, pharmaceutical-grade glycerol is obtained.
[0030] Specifically, the adsorbent in the adsorbent bed is a mixture of activated carbon and molecular sieve; the adsorption process is maintained at 60℃-80℃ for 1-2 hours, and nitrogen is continuously introduced during the adsorption process to isolate air.
[0031] In this embodiment, this step refines the high-purity glycerol fraction obtained from the second-stage molecular distillation using an adsorbent bed. The aim is to remove trace amounts of colored substances and polar impurities that may remain after distillation, further improving the purity and sensory quality of the product. The adsorbent is a mixture of activated carbon and molecular sieves. Activated carbon, with its abundant pore structure and large specific surface area, can effectively adsorb trace amounts of colored substances (such as polycyclic aromatic hydrocarbon pigment precursors produced by thermal degradation) and some non-polar organic impurities in glycerol. Molecular sieves, with their regular pore structure and polar adsorption characteristics, selectively adsorb trace amounts of moisture and residual aldehydes and ketones. The synergistic effect of both allows for the simultaneous removal of impurities of different properties. The adsorption process is controlled at a temperature of 60℃-80℃ to ensure that the glycerol has suitable fluidity for sufficient contact with the adsorbent while avoiding excessive temperature that could lead to glycerol oxidation or adsorbent desorption. The adsorption time is maintained for 1-2 hours to ensure that adsorption reaches equilibrium, maximizing the removal of trace impurities. Nitrogen gas is continuously purged throughout the adsorption process for protection, isolating the glycerol from oxygen and moisture in the air and preventing oxidation reactions that could produce new colored substances or degradation impurities under heating. After this step, the resulting pharmaceutical-grade glycerol is colorless and transparent, with a color change ΔE < 0.5, significantly superior to products from traditional processes. Furthermore, residual aldehydes, ketones, and moisture are further removed.
[0032] S5: Filter the obtained pharmaceutical-grade glycerin and fill it into a sterile container.
[0033] Specifically, the filtration is performed using a 0.22μm filter membrane in a sterile environment.
[0034] In this embodiment, a 0.22μm filter membrane is used for filtration in this step. This pore size can effectively trap microorganisms, particles, and any residual adsorbent powder, ensuring the clarity and sterility of the filtered glycerol. The filtration operation is carried out in a Class 100 clean area or isolator, with the ambient temperature controlled at room temperature to avoid excessively high glycerol viscosity due to low temperatures affecting filtration efficiency or the risk of introducing new pyrogens due to high temperatures. The filtered glycerol is directly filled into pre-sterilized borosilicate glass bottles or stainless steel containers using aseptic filling equipment. The filling process involves online monitoring of particulate matter and microbial load throughout to ensure a sterile filling environment. The filling containers must have good sealing properties to prevent secondary contamination during storage and transportation.
[0035] This invention discloses a multi-stage distillation purification method for pharmaceutical-grade glycerol. This method fully leverages the selective separation advantages of each stage of molecular distillation and the deep purification capabilities of adsorption refining. Through precise and coordinated control of process parameters, it achieves the step-by-step targeted removal of various impurities from synthetic glycerol: First, in step S2, low-boiling-point impurities such as water and alcohols are removed, creating stable conditions for subsequent high-vacuum distillation. Then, in step S3, under ultra-high vacuum conditions, genotoxic aldehydes and ketones such as formaldehyde, acetaldehyde, and acetone aldehydes are selectively separated into lighter components, ensuring their total content is stably controlled below ≤0.005%, significantly superior to pharmacopoeia standards in various countries. Finally, in step S4, through the combined adsorption of activated carbon and molecular sieves, trace colored substances and residual polar impurities are further removed, resulting in a colorless and transparent high-purity product. The entire process is carried out under nitrogen protection, effectively preventing glycerol oxidation and ensuring product stability. The pharmaceutical-grade glycerin obtained by the method of this invention has a purity ≥99.7%, total impurities ≤0.3%, residual solvent ≤0.001%, bacterial endotoxin <2.5 EU / g, and batch-to-batch RSD <1%. All key quality indicators meet or even exceed the stringent requirements for injectable excipients. Furthermore, the product is completely free of plant proteins, aflatoxin, and other biological contaminants, eliminating the risk of allergens at the source. The method of this invention features a clear process route, simple operation and control, and good batch-to-batch reproducibility, making it suitable for large-scale industrial production. The resulting product can be widely used in high-end formulations such as human serum albumin injections, vaccine injections, and chemical drug injections, providing high-quality excipient support for ensuring the safety, efficacy, and stability of injectable drugs.
[0036] The above-disclosed embodiments are merely one or more preferred embodiments of this application and should not be construed as limiting the scope of this application. Those skilled in the art can understand that all or part of the processes for implementing the above embodiments and equivalent changes made in accordance with the claims of this application still fall within the scope of this application.
Claims
1. A multi-stage distillation purification method for pharmaceutical-grade glycerin, characterized in that, Includes the following steps: Using industrially synthesized crude glycerol as raw material, heating and degassing are performed to remove dissolved low-boiling-point gases and volatile components, resulting in pretreated material. The pretreated material is fed into a first-stage molecular distillation apparatus and distilled under a first vacuum and a first temperature to remove residual trace amounts of low-boiling-point impurities, thereby obtaining intermediate material. The intermediate material is fed into a second-stage molecular distillation apparatus for deep purification under second vacuum and second temperature conditions. The gaseous glycerol component is separated and collected to obtain a high-purity glycerol fraction. The high-purity glycerol fraction was passed through an adsorbent bed under nitrogen protection to remove trace amounts of colored substances and residual polar impurities. After cooling, pharmaceutical-grade glycerol was obtained. The obtained pharmaceutical-grade glycerin was filtered and filled into sterile containers.
2. The multi-stage distillation purification method for pharmaceutical-grade glycerin as described in claim 1, characterized in that, The industrially synthesized crude glycerol is obtained through chemical synthesis using epichlorohydrin as a raw material, and its source does not contain plant protein, aflatoxin, or genetically modified components.
3. The multi-stage distillation purification method for pharmaceutical-grade glycerin as described in claim 1, characterized in that, The heating and degassing treatment specifically includes: heating the crude glycerol to 80℃-100℃ and continuously stirring it for 30-60 minutes under a negative pressure of 1kPa-5kPa to remove dissolved oxygen, carbon dioxide and low-boiling-point impurities.
4. The multi-stage distillation purification method for pharmaceutical-grade glycerin as described in claim 1, characterized in that, The first vacuum degree is 0.1 Pa-10 Pa, and the first temperature is 110℃-140℃; the low-boiling-point impurities include one or more of water, methanol, ethanol and acetone.
5. The multi-stage distillation purification method for pharmaceutical-grade glycerin as described in claim 1, characterized in that, The second vacuum degree is no higher than 0.1 Pa, and the second temperature is 160℃-200℃.
6. The multi-stage distillation purification method for pharmaceutical-grade glycerin as described in claim 5, characterized in that, During the second-stage molecular distillation process, the separated light component impurities are aldehydes and ketones, including one or more of formaldehyde, acetaldehyde, and acetone aldehyde.
7. The multi-stage distillation purification method for pharmaceutical-grade glycerin as described in claim 1, characterized in that, The adsorbent in the adsorbent bed is a mixture of activated carbon and molecular sieve; the adsorption process is maintained at 60℃-80℃ for 1-2 hours, and nitrogen is continuously introduced during the adsorption process to isolate air.
8. The multi-stage distillation purification method for pharmaceutical-grade glycerin as described in claim 1, characterized in that, The filtration was performed using a 0.22μm filter membrane in a sterile environment.