According to the work goals and tasks determined by edition outline of the Chinese Pharmacopoeia 2025 Edition, under the guidance of the national drug regulatory authorities, the Chinese Pharmacopoeia Commission organized dozens of Improvement of National Drug Standards undertakers to conduct in-depth study, and after review by all members of the 12th Chinese Pharmacopoeia Commission Specialized Committee of Pharmaceutical Excipients and invited experts, the development and revision of the Chinese Pharmacopoeia 2025 Edition standards of pharmaceutical excipients have been completed. Among them, 52 new pharmaceutical excipients monographs have been added, and the total number has reached 387. 245 pharmaceutical excipients monographs have been revised, of which 109 monographs have only textual revisions and 136 monographs have substantive revisions.

General idea for revision of the Chinese Pharmacopoeia standards of pharmaceutical excipients can be summarized as follows: firstly, highlight the critical quality attributes of pharmaceutical excipients, strengthen the improvement of functionality-related characteristics and safety characteristics of pharmaceutical excipients; secondly, enhance the compatibility and universality of the standards, and guide enterprises to select pharmaceutical excipients suitable for the production of preparations; thirdly, continuously pay attention to the international harmonization of standards of pharmaceutical excipients, especially with ICH Q3C and Q3D; fourthly, comprehensively implement the “green environmental protection standards of pharmaceutical excipients” to improve the efficiency and safety of the test; fifthly, constantly improve the standardization and operability of the standards.

This article outlines the general framework and key characteristics of the revised pharmaceutical excipient standards in the 2025 Edition of the Chinese Pharmacopoeia, in order to facilitate accurate understanding and application of the standards. Relevant situations of 46 revised standards of pharmaceutical excipients included in the first supplement of the Chinese Pharmacopoeia 2020 Edition have been introduced elsewhere. ^[4]

1    Addition of Functionality-related Characteristics

Pharmaceutical excipients used in pharmaceutical preparations usually have specific functions, and it is mentioned in the Chinese Pharmacopoeia 9601 Guideline for Functionality-related Characteristics of Pharmaceutical Excipients that functionality-related characteristics (FRCs) of pharmaceutical excipients are those physicochemical properties which have an important impact on the functionality of excipients and the performance of preparations. The Chinese Pharmacopoeia 2025 Edition continues to expand the inclusion of functionality-related characteristics in the standards of pharmaceutical excipients monographs, and some newly added functionality-related characteristics items are detailed in Table 1. Powdered cellulose, carboxymethylcellulose sodium, sodium lauryl sulfate and other monographs have also been deeply studied for functionality-related characteristics. [6-8] Although it is not included in the Chinese Pharmacopoeia 2025 Edition, it lays the foundation for the improvement of subsequent standards.

Tab. 1    The new FRCs of revised standards of pharmaceutical excipients in the Chinese Pharmacopoeia 2025 Edition

2    Addition of Safety Characteristics

The safety of pharmaceutical excipients is divided into two categories: the inherent safety of excipients themselves and the impact of excipients on the safety of preparations. The Chinese Pharmacopoeia 2025 Edition continues to expand the inclusion of safety characteristics in the standards of pharmaceutical excipients monographs, and some items are detailed in Table 2.

3    Enhance the Universality of Standards

In General Chapter 0251 of the Chinese Pharmacopoeia, the suitability of pharmaceutical excipients is emphasized, that is, the selection of pharmaceutical excipients should ensure that the excipients can meet the requirements of drug safety and efficacy, and strengthen the suitability study of pharmaceutical excipients; at the same time, the suitability of the standards of pharmaceutical excipients is also emphasized, [2] that is, standards of pharmaceutical excipients should meet the requirements of the preparations used and carry out corresponding quality control according to the requirements of the preparations; while the standards of pharmaceutical excipients in the Chinese Pharmacopoeia, as the basic requirements for pharmaceutical excipients at the national level, should also continuously adjust and improve the setting of test and limits of “unsafe bottom line” according to the use of pharmaceutical excipients in the marketed preparations and enhance their universality.

For example, the previous standard of pectin contains assay of methoxy groups and specifies that it contains not less than 6.7% of methoxy groups. However, investigation revealed that there was a large difference in the content of methoxy groups between low-methoxy pectin and high-methoxy pectin, while the content of methoxy groups was correlated with esterification degree. Therefore, in the Chinese Pharmacopoeia 2025 Edition, the fixed content limit of methoxy groups is deleted, and enterprises are required to label its limit under the labeling item, which not only suggests the importance of this item, but also does not cause limitations for enterprises to select appropriate excipients.

Tab. 2 The safety factor of revised standards of pharmaceutical excipients in the Chinese Pharmacopoeia 2025 Edition

For another example, in the Chinese Pharmacopoeia 2025 Edition, based on practical production and use, sodium oleate was classified into two models (60 and 95) with respective content limits; the sucrose stearate classification method was revised to Ia, Ⅰb, II, and III, which maintains overall consistency with foreign mainstream pharmacopoeia classifications, and the Ia subtype can also directly correspond to the previous S-15 in the Chinese Pharmacopoeia. The above adjustments are conducive to international integration and strict quality control of products.

In addition, according to the changes in the global sodium hydroxide production process, the chloride limit of sodium hydroxide is adjusted to ensure the supply chain and accessibility of the relevant preparations.

4    Strengthen International Harmonization of Standards

4.1    Harmonization of the Chinese Pharmacopoeia Standards of Pharmaceutical Excipients with ICH Q3D

ICH Q3D is an internationally recognized guideline for the control of elemental impurities in drugs currently and has been widely adopted by member countries of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), and pharmacopoeias such as EP, USP and JP have been transformed and implemented for many years. China joined ICH in 2017 and has implemented ICH Q3D in newly marketed drugs since July 2020. For a long time, the Chinese Pharmacopoeia has used the limit test for heavy metals of wet chemistry to control the heavy metal impurities in drugs and in their components, but this colorimetric method, which relies on the precipitation of heavy metal sulfides through reaction between heavy metal and sulfide ions, has several limitations. The Chinese Pharmacopoeia 2025 Edition will fully incorporate the ICH Q3D concept for elemental impurities by including the general chapters, but it also needs to be transformed in the specific monographs standards. In pharmacopoeias worldwide, pharmaceutical excipients are often treated individually by specific monographs because they predominantly derive from natural sources, and the Chinese Pharmacopoeia Commission also specially establishes a topic to study the harmonization strategy and pathways between elemental impurities in the Chinese Pharmacopoeia standards of pharmaceutical excipients and ICH Q3D and forms technical documents, such as overall scheme, method validation requirements, evaluation templates, etc. Relevant units have also carried out evaluation studies on specific monographs accordingly, [16-25] and a large amount of beneficial data has been accumulated.

The Chinese Pharmacopoeia 2025 Edition not only removes heavy metal wet chemical test of some monographs (e.g., disodium edetate) due to interference issues inherent in this item in previous standards, but also makes a series of adjustments to the arsenic and specific elemental impurity control items in the standard according to the evaluation results, including removal, addition and adjustment of item setting method, which lays a solid foundation for the comprehensive harmonization of monographs standards in subsequent supplements and Pharmacopoeia 2030 Edition.

4.2    Harmonization of the Chinese Pharmacopoeia Standards of Pharmaceutical Excipients with ICH Q3C

Because residual solvents in drugs often have certain hazards, ICH Q3C proposes guidelines for the control of residual solvents in drugs, and foreign mainstream pharmacopoeias such as EP, USP and JP have been harmonized with these guidelines [26] and applied them to marketed monographs. China has implemented ICH Q3C in newly marketed drugs since July 2020. The Chinese Pharmacopoeia 2025 Edition will comprehensively introduce the overall concept of ICH Q3C by revising the general chapters for residual solvents, but it also needs to be transformed in the specific monographs standards. The Chinese Pharmacopoeia Commission also specially establishes a topic to study the harmonization strategy and pathways between residual solvents in the Chinese Pharmacopoeia standards of pharmaceutical excipients monographs and ICH Q3C and forms a harmonization scheme.

After evaluation according to the harmonization scheme, the Chinese Pharmacopoeia 2025 Edition removed residual solvents of monographs standards, such as pectin , soya lecithin and egg yolk lecithin, added tests of starting materials, degradation products acetone and trichloromethane in chlorobutanol, and unified the principles and scales of items and limit setting in the standards.

5    Highlight the Concept of Green Environmental Protection Standards

In alignment with the CPC Central Committee and the State Council’s strategic decisions on ecological civilization construction, and guided by the standard principles of innovative, coordinated, green, open and shared development, based on the strengthening of scientificity, rigor, and operational practicality of the standards, the standards of pharmaceutical excipients in the Chinese Pharmacopoeia actively implement the “green environmental protection standard” concept to fully play the guiding role of standards system in “green pharmaceutical” and “green tests”.

5.1    Reduce the Use of Toxic and Harmful Reagents

Revised identification method of diammonium hydrogen phosphate: in the previous standard, the ammonium salts identification reaction in General Chapter 0301 of the Chinese Pharmacopoeia was used. The results of method (1) were determined by “ammonia odor” and mercurous nitrate was used; in the preparation of alkaline mercuric potassium iodide test solution of method (2), mercuric chloride was used. The result determination method was modified according to the experimental principle and objectives to avoid the use of the above highly toxic reagents.

Removed Identification (2) in calcium glycerophosphate, zinc salts Identification (2) in zinc oxide, Identification (3) in meglumine, Identification (4) in guar gum, and Identification (1) and (2) in isopropyl alcohol: because toxic and harmful reagents such as potassium hydrogen sulfate reagent, sodium sulfide test solution, nickel sulfate, potassium dichromate or diphenylamine were used in the above items and there were a number of other identification items or related assays in the standard that can meet the quality control requirements, so this item was removed.

Removed Identification (1) in zein, and Identification (3) in acacia and spray-dried acacia. Revised the test of sulfur dioxide in pectin: because it used lead acetate solution or reagent, the item was removed or the test method with different principles was used instead.

Removed cottonseed oil test in soybean oil, peanut oil and olive oil: in order to avoid the use of hazardous chemical carbon disulfide, as well as taking into account the items such as fatty acid composition and sterol composition of these monographs have been controlled by instrument methods with high precision, this item was removed.

Removed the content of non-protein nitrogen under the item of “total protein” in wheat starch: because the trichloroacetic acid reagent was used in the determination of non-protein nitrogen, and the proportion of non-protein nitrogen in total nitrogen of this product was very low, it was changed to control the content of “total protein” nitrogen.

Removed Identification (2) in paraffin: because the previous standard could produce emission of hydrogen sulfide, this item was removed and IR identification with strong specificity was added.

Revised the test of halogenated compounds in glycerol: the dehalogenation method of nickel-aluminum alloy in the previous standard was changed to the direct dehalogenation method of sodium hydroxide solution, avoiding the use of hazardous chemical nickel-aluminum alloy.

5.2    Optimize Item Setting

5.2.1    Streamlined optimization of identification items    The Chinese Pharmacopoeia 2025 Edition has optimized identification items with less specificity and cumbersome procedures excessively retained in certain standards. For example, removed one chemical identification with less specificity from the previous 3 chemical identifications and 1 IR identification in povidone K30; removed Identification (1) with less specificity, and added starch color reaction and microscopical identification with strong specificity in pregelatinized starch test in pregelatinized hydroxypropyl starch; removed double-bond identification and UV spectroscopy identification with less specificity, and added HPLC identification in potassium sorbate; removed chemical identification (1), and retained IR and GC identification in triacetin; removed Identifications (1) and (2), and added HPLC identification in soya lecithin and egg yolk lecithin; removed chemical identification and TLC identification, and added GC and IR identification in cholesterol; removed chemical identification, and added GC and IR identification in polysorbate series; removed previous 3 chemical identifications, and added chemical identification with strong specificity in vacant gelatin capsules and enterosoluble vacant gelatin capsules; [30-31] removed chemical identification (1) with cumbersome procedures, and added IR identification with strong specificity in ethyl hydroxybenzoate sodium and propyl hydroxybenzoate sodium; removed magnesium salts Identification (2) with little significance in magnesium stearate.

5.2.2    Integration of similar items    For example, removed the two items of “water-insoluble substances” and “carbonyl compounds” in isopropyl alcohol, because the test effect of “water-insoluble substances” in it is equivalent to that of “clarity and color of solution” and the procedure of “carbonyl compounds” itself is cumbersome and cannot be accurately quantified but can be controlled with “volatile impurities”. For another example, removed the test of oleic acid in sodium oleate and it is tested together under the item of “other fatty acids”. In addition, removed “ammonia compounds” in benzalkonium chloride, and “ammonia compounds” and “nonquaternary ammonium compounds” in benzalkonium bromide, because these two have low sensitivity, and the control range is limited. The test of “amine and amine salts” was added at the same time, which not only controls inorganic ammonium, but also controls the possible presence of residual dimethyl tertiary amine and amine salts in the starting materials. Removed “congealing point” in polyethylene glycol 1000 and above, because the setting of congealing point is mainly used to control the molecular weight and its distribution, which is overlapped with existing “average molecular weight, molecular weight and molecular weight distribution”, plus the congealing point identification methods across international pharmacopoeias are different. [32] Removed “distilling range” in benzyl alcohol, because the benzyl alcohol standard has purity control item; removed refractive index in white beeswax because it has included “glycerol and other polyols”, “ceresin, paraffin and certain other waxes”, “fats, fatty oils, Japan wax, and rosin” and many other tests of related substances; removed Identification (1) and chelating capacity test in disodium edetate, because disodium edetate is a chelating agent and these two tests are used to identify or examine the ability of disodium edetate to chelate metal ions, while the retained “assay” is complexometric titration.

5.2.3    Simplified procedures    For example, the myristic acid reference standard used for localization in the previous standard of myristic acid also needs to be derivatized synchronously with the test article. In order to simplify the procedure, it was changed to directly use the methyl myristate reference standard. For another example, the previous standard of dextrin was drying at 105°C to constant weight, which took about 7 h. After experimental test, it was changed to drying at 130°C for 90 min, which not only saves time, but also harmonizes with the previous relevant starch standard. In addition, sulfite is designed to control the residue of reducing agent sulfite in the raw material gelatin for capsules and has been controlled in the gelatin for capsules, so the test of sulfite was removed in the vacant gelatin capsules and enterosoluble vacant gelatin capsules; the GC method for the simultaneous detection of chloroethanol and ethylene oxide residues was proposed in the study, avoiding the time-consuming and cumbersome respective detection by the two methods used in the previous standard. [33] TLC identification in the previous standard of tragacanth, the hydrolysate extraction of tragacanth after acid addition at high temperature requires procedures such as “centrifuge, transfer the supernatant to a 50 mL round-bottom flask, add 10 mL of water, evaporate to dryness with the aid of a rotary evaporator under reduced pressure at 60°C”. This process took more than 3 h, and after revision, the test procedures are greatly simplified, making the standard test more convenient and efficient.

6    Strengthen the Standardization of Standards

6.1    Standardized Chinese and English Names

According to the nonproprietary naming principle of pharmaceutical excipients, the Chinese Pharmacopoeia 2025 Edition has standardized the Chinese nonproprietary names for Hydroxypropyl Methylcellulose Phthalate (formerly: Hypromellose Phthalate), Hydroxypropyl Methylcellulose Acetate Succinate (formerly: Hypromellose Acetate Succinate), and Polyoxyethylene (40) Stearate (formerly: Polyoxyl 40 Stearate). Additionally, revisions were made to the English nonproprietary names of such excipients as: Methyl Hydroxybenzoate Sodium, Propyl Hydroxybenzoate Sodium, Soya Lecithin, Calcium Phosphate.

6.2    Standardized Molecular Weight and CAS Number

The Chinese Pharmacopoeia 2025 Edition not only added the molecular weights of butane and sodium oleate and other monographs, and according to the revised atomic weight table, the molecular weights of all included pharmaceutical excipients monographs have been comprehensively revised.

The previous CAS number was removed because polyvinyl alcohol and polyoxyethylene (40) stearate and other monographs have many different average molecular weights, paraffin is a mixture, pectin has different sources and different substituent contents, and the CAS number cited in the previous standard was not universal. According to the official reply, both sorbic acid and potassium sorbate have two CAS numbers, so they are listed at the same time. CAS numbers were added for sodium oleate and other monographs as needed.

6.3    Standardized Sources and Regulations

This item mainly records the main process requirements and quality requirements of pharmaceutical excipients, and the standardization of its expression is very important for the implementation of the standard. A series of revisions have been made in the Chinese Pharmacopoeia 2025 Edition, such as the addition of chemical structure description to sodium alginate, the addition of approximate subordinate sources to tragacanth, the clarification of benzalkonium chloride as a mixture, the clarification of calcium phosphate as a mixture of calcium phosphate salts, and the standardized expression of emulsifier for ethyl acrylate and methyl methacrylate copolymer dispersion.

6.4    Standardized Description Item

On the one hand, the Chinese Pharmacopoeia 2025 Edition has standardized the description of some pharmaceutical excipients (such as calcium hydrogen phosphate dihydrate, polyoxyethylene (40) stearate, magnesium hydroxide, dextrin, benzalkonium chloride, etc.) according to the actual sample situation to avoid misjudgment causing unqualified products. On the other hand, according to the unified revision principle, ^[34,35] the description of solubility under Description has been standardized.

6.5    Standardized Category Item

Category items are essential to reflect the functionality of pharmaceutical excipients, and the words in the previous standards were not uniform enough, and the Chinese Pharmacopoeia 2025 Edition has been standardized systematically based on the function category terms in Annex 3 of Detailed Rules for the Preparation of National Pharmaceutical Excipient Standards 2025 Edition. [36]

6.6    Standardized IR Reference Spectrum

Firstly, according to the Detailed Rules for the Preparation of National Pharmaceutical Excipient Standards 2025 Edition, ^[36] the general principle of Annex 1, that is, “Where it is suitable to establish IR reference spectrum, it is preferred to consider the comparison with reference spectrum”, comprehensively combed the standards of monographs of pharmaceutical excipients to be included in the Chinese Pharmacopoeia 2025 Edition; secondly, the spectra involved in the monographs determined to be compared with IR reference spectrum are all presented after the corresponding monographs in the Chinese Pharmacopoeia, thus saving the test cost and facilitating the implementation of the standards.

6.7    Standardized Text Details

In the Chinese Pharmacopoeia 2025 Edition, according to the preparation and supply of reference standards by the National Institutes for Food and Drug Control, the names of reference standards involved in the standards of pharmaceutical excipients were systematically standardized, for example, methyl myristate was uniformly changed to myristic acid methyl ester, L-phenylalanine was changed to phenylalanine, etc. This time, the calculation formulas in the standard were also systematically standardized to avoid calculation errors caused by non-uniform formats. In addition, some prompt messages have been added in “Note”. For example, vanillin was added with “this product is also called vanilline”, maltose was added with “this standard is not applicable to the types with maltose content less than 98.0%”, avoiding the confusion or misuse of the standard executor.

The Chinese Pharmacopoeia willcontinue aligning with international trends in excipient standards development, combining with the new progress in the industrial development of pharmaceutical excipients in China, and continuously strengthen the scientificity, rigor, universality and innovativeness of standards of pharmaceutical excipients to make it highlight the critical quality attributes of pharmaceutical excipients, better become an important reference and basis for the selection and quality control of pharmaceutical excipients, and help the high-quality development of China’s pharmaceutical industry.

(Chinese Pharmacopoeia Commission)