β-Cyclodextrin

1. Chemical structure and nomenclature

β-Cyclodextrin (Beta-cyclodextrin, abbreviated as β-CD in English), the nomenclature of the International Union of Pure and Applied Chemistry (IUPAC) system is Cycloheptakis-(1 → 4)-α-D-glucopyranosyl, and its Chinese nicknames include betacyclodextrin, β-cyclodextrin, etc. Its IUPAC English name is Cyclomaltoheptaose, and other common names include Cycloheptaamylose (cycloheptyl starch), Cycloheptadextrin, Cyclomaltoheptose, β-Cycloamylose, Schardinger β-Dextrin, and Betadex.

From the viewpoint of molecular structure, β-cyclodextrin is composed of seven α-D-glucopyranose units linked by α-1,4 glycosidic bonds to form a closed-loop structure. This unique ring structure gives it a truncated cone (cylindrical) morphology, with 7 primary hydroxyl groups (C6 position) at one end of the molecule and 14 secondary hydroxyl groups (C2 and C3 positions) at the other end. This structural feature determines the special physical and chemical properties of beta-cyclodextrin, which is hydrophilic and hydrophobic.

The hydroxyl groups on the outside of the molecule give it good water-soluble surface properties, while the cavities inside the molecule create a hydrophobic environment. This unique structure enables β-cyclodextrin to act as a "molecular capsule", wrapping hydrophobic small molecular compounds inside its hydrophobic cavity through host-guest interactions to form stable inclusion complexes (Inclusion Complex).

2. Physical and chemical properties

Basic physical properties of 2.1

| Items | Indicators |
| ------ | ------ |
| Appearance | White or nearly white crystalline powder/crystalline solid |
| Formula | C42H70O35 |
| Relative Molecular Mass | 1134.987 by International Relative Atomic Mass 2018 |
| specific rotation | +160 ° ~ +164 ° |
| Melting point | About 300 ℃ (decomposition) |
| Cavity diameter | 0.60-0.80 nm |
| Cavity depth | About 0.79 nm |

2.2 solubility

The solubility of β-cyclodextrin in water is about 18.5g/L(25 ℃), which belongs to medium solubility. This property allows for both adequate solubility in food and pharmaceutical applications and, in some cases, retention of clathrate stability. Solubility characteristics in the following solvents:

-Soluble: glycerol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), pyridine, hexafluoroisopropanol (HFIP), ethylene glycol
-Medium soluble: water, glycerin
-Insoluble: Ethanol, acetone

Notably, the lower water solubility of β-cyclodextrin (about 1.85g/100mL) is both an advantage and a limitation. In some applications requiring high solubility (such as injections), it is usually necessary to use chemically modified derivatives thereof, such as hydroxypropyl-β-cyclodextrin (HP-β-CD) or sulfobutyl-β-cyclodextrin (SBE-β-CD), and the water solubility of these derivatives can be increased to more than 50g/100mL.

2.3 inclusion characteristics

β-Cyclodextrin's internal cavity diameter (0.60-0.80nm) allows it to form inclusion complexes with a wide range of small molecular compounds, including:

-Most small molecule drugs
-Food flavors and flavor compounds
-Vitamins
-Cosmetic active ingredients
-Certain metal ions

The stability of the inclusion process depends on the following factors:

1. Substrate molecular size matching degree: when the molecular diameter is close to the cavity size, the inclusion rate can reach more than 90%
2. Purity: high purity β-cyclodextrin inclusion effect is more stable
3. pH value: pH 5.0-7.0 neutral environment inclusion stability is the best
4. Temperature: When the temperature exceeds 80 ℃, some clathrates may dissociate

3. Cyclodextrin Family Comparison

The cyclodextrin family mainly includes three natural cyclodextrins, α-(α-CD), β-(β-CD) and γ-(γ-CD), as well as a variety of chemically modified derivatives.

| Type | Number of Glucose Units | Cavity Diameter (nm) | Cavity Depth (nm) | Key Features |
| ------ | ------------- | -------------- | -------------- | ---------- |
| α-Cyclodextrin | 6 | 0.45-0.60 | 0.79 | The smallest cavity, can only contain very small molecules |
| β-cyclodextrin | 7 | 0.60-0.80 | 0.79 | moderate cavity, the most widely used |
| γ-Cyclodextrin | 8 | 0.80-1.00 | 0.79 | Largest cavity for inclusion of macromolecules |

The cavity size of β-cyclodextrin just covers more than 80% of the molecular diameter of common substrates in the fields of medicine and food, which explains why it is the most widely used natural cyclodextrin variety at present.

4. Historical development

The discovery and development of β-cyclodextrin are as follows:

-1891: French chemist Villiers first isolated β-cyclodextrin from the enzymatic hydrolysate of starch, which was then named "cellulosine" (cellulose)
-1904: Austrian chemists Schardinger determine its structure, calling it "Schardinger sugars"(Schardinger sugars)
-1953: The first cyclodextrin-related patent was officially published, marking the beginning of the industrial application of cyclodextrins.
-Since the 1970 s: In order to overcome the shortcomings of natural cyclodextrins (such as low water solubility), a series of β-cyclodextrin derivatives have been developed and synthesized.
-1995: JECFA established the ADI of β-cyclodextrin as 0-5 mg/kg body weight
-1996: The Scientific Committee for Food (SCF) of the European Union also determined the ADI to be 5 mg/kg body weight/day
-2016: EFSA completes re-evaluation of beta-cyclodextrin as a food additive and confirms that ADI remains unchanged

5. Production process

The industrial production of β-cyclodextrin is made from starch as the starting material by enzymatic conversion. The main production processes include:

1. Raw material processing: add alpha-amylase to starch slurry for partial hydrolysis to obtain maltodextrin
2. Enzyme-catalyzed conversion: cyclodextrin glycosyltransferase (CGTase) is added to catalyze the formation of cyclodextrin under specific temperature and pH conditions
3. Separation and purification: the use of beta-cyclodextrin solubility in water is relatively low characteristics, by cooling crystallization or organic solvent precipitation separation
4. Refining and drying: the crude product is recrystallized and refined to obtain high-purity products

In industrial production, the conversion rate can usually reach more than 80%. Pharmaceutical grade β-cyclodextrin requires additional heavy metal removal and microbial inactivation to meet pharmacopoeia standards.

1. Global Market Size and Growth

According to market research data, the global beta-cyclodextrin market has reached a considerable scale in 2024 and has shown a steady growth trend.

1.1 Market Size Data

| Indicator | Data |
| ------ | ------ |
| Global Market Size in 2024 | Approximately $0.355 billion (Total Cyclodextrin Market) |
| β-Cyclodextrin Market Share | Approximately 67.2%(2024) |
| Projected Market Size in 2032 | About $0.453 billion |
| Forecast period compound growth rate (CAGR) | 3.1-6% (slightly different reports) |

1.2 Market Segmentation

Breakdown by product type:

-Food grade beta-cyclodextrin
-Pharmaceutical grade beta-cyclodextrin
-Cosmetic grade beta-cyclodextrin
-Industrial grade beta-cyclodextrin

Breakdown by application area:

-Pharmaceutical industry (the largest application area, accounting for more than 55% of the market share)
-Food and beverage industry (fastest growing sector)
-Cosmetics and personal care
-Chemical and other

Distribution by region:

-North America: about 32.5 percent market share (2024), benefiting from advanced pharmaceutical industry and strong R & D capabilities
-Europe: Mature markets, with Germany, UK, France as major consumers
-Asia-Pacific: Expected to be the fastest growing region, driven by expanded pharmaceutical production and increased R & D investment
-Other regions: Gradual growth in emerging markets such as Latin America, the Middle East and Africa

2. Market drivers

2.1 the needs of the pharmaceutical industry

The pharmaceutical industry is the largest consumer of beta-cyclodextrin, mainly due:

-Insoluble drug problem: According to statistics, about 40% of new drug candidate compounds have the problem of poor water solubility
-Increased bioavailability: β-cyclodextrin as a drug excipient can increase drug solubility by 5-10 times
-Novel drug delivery systems: growing demand for applications in biologics and oncology drugs

2.2 food industry needs

The food and beverage industry is the fastest growing application area, driven:

Clean Label Trends: Increasing Consumer Demand for Natural, Functional Food Additives
-Product stability: β-cyclodextrin can improve the stability and retention of food flavors
-Taste improvement: effectively mask bitter taste and bad flavor, improve product palatability
-Extended shelf life: protection of easily oxidized ingredients by inclusion technology

2.3 cosmetics industry demand

-Growing demand for natural ingredient skin care products
-Active ingredient stability protection
-Extend product shelf life

3. Major market participants

Major players in the global beta-cyclodextrin market include:

| Company Name | Headquarters | Main Products/Features |
| ---------- | ------ | --------------- |
| Wacker Chemie AG | Germany | Pharmaceutical and Food Grade Cyclodextrins, Cavasol Series |
| Roquette | France | Pharmaceutical Grade Cyclodextrins, HPBCD-FD |
| CycloLab | Hungary | R & D-oriented, multiple cyclodextrin derivatives |
| NIHON SHOKUHIN KAKO | Japan | Key Asia Pacific Suppliers |
| Shandong Shengzhi Pharmaceutical | China | Major Domestic Manufacturers |
| Zibo Qianhui Biotechnology | China | Pharmaceutical Excipients and Cyclodextrin Derivatives |

The market concentration is high, and the top three companies (Wacker, Roquette, Ashland) account for more than 60% of the market share.

4. Market Challenges and Constraints

4.1 production costs

The production of β-cyclodextrin involves a complex enzymatic conversion process, resulting in relatively high costs, limiting its widespread use in some price-sensitive applications.

4.2 Regulatory Complexity

The regulatory requirements of food additives and pharmaceutical excipients in different countries and regions are different, which increases the complexity of market access.

4.3 Substitute Competition

In some applications, β-cyclodextrin faces competitive pressure from other inclusion technologies (e. g., liposomes, microencapsulation, etc.).

5. Industry development trend

Rapid Development of 5.1 Cyclodextrin Derivatives

Due to the low water solubility of natural beta-cyclodextrin, the market for its chemically modified derivatives is growing rapidly:

-Hydroxypropyl-β-cyclodextrin (HP-β-CD): greatly improved water solubility for oral and injectable preparations
-Sulfobutyl-β-cyclodextrin (SBE-β-CD): Trade name Captisol®, used in a variety of marketed injectables
-Methyl-β-cyclodextrin: used as a cholesterol extraction tool in cell biology research

5.2 new application expansion

-Nano Drug Delivery System
-Gene therapy vector
-Environmental remediation (heavy metal adsorption)
-Textile printing and dyeing

5.3 regional market changes

-Increased capacity investment in the Asia-Pacific region
-Rapid expansion of the Chinese market
-Consumption growth in emerging markets

1. China's national standard system

1.1GB 1886.352-2021

National Food Safety Standard Food Additive β-cyclodextrin

Published: September 7, 2021

Implementation time: March 7, 2022

Issued by: the People's Republic of China National Health Commission, State Administration of Market Supervision and Administration

Scope of application: suitable for starch by enzymatic hydrolysis, purification of food additives beta-cyclodextrin

Main technical requirements:

Sensory requirements:

| Items | Requirements | Inspection Methods |
| ------ | ------ | ---------- | ------ |
| Color | White or near-white | Viewing under natural light |
| state | crystalline solid or powder | - |

Physical and chemical indicators:

| Items | Indicators | Inspection methods |
| ------ | ------ | ---------- | ------ |
| β-cyclodextrin content (based on dry basis) | 98.0%~ 101.0% | A.3 in Annex A |
| Moisture | ≤ 14.0g/100g | GB 5009.3 direct drying method or Karl Fischer method |
| Residue on ignition | ≤ 0.1% | GB/T 9741 |
| Reducing sugar | ≤ 1.0% | A.4 in Appendix A |
| Lead (Pb) | ≤ 0.5 mg/kg | GB 5009.75 or GB 5009.12 |

Microbial limit:

| Items | Indicators | Inspection methods |
| ------ | ------ | ---------- | ------ |
| Total number of colonies | ≤ 1000 cfu/g | GB 4789.2 |
| Coliform | ≤ 3.0 MPN/g | GB 4789.3 |
| Mold | ≤ 25 cfu/g | GB 4789.15 |
| Yeast | ≤ 25 cfu/g | GB 4789.15 |
| Salmonella | Not detectable/25g | GB 4789.4 |
| Staphylococcus aureus | Not detectable/25g | GB 4789.10 |
| Shigella | Not detectable/25g | GB 4789.5 |
| Hemolytic Streptococcus | Not detectable/25g | GB 4789.11 |

Identification test:

-specific rotation: weigh 1.00g of the sample and dissolve it in 100mL of water, and measure it according to GB/T 613. the specific rotation should be +160 ~ +164
-Chromatographic test: the retention time of the main peak of the sample solution chromatogram should be consistent with the standard solution

1.2GB 2760-2024

Standard full name: "national food safety standards for the use of food additives"

Published: February 8, 2024

Implementation time: February 8, 2025

Alternative standard: GB 2760-2014

Basic information:

| Project | Content |
| ------ | ------ |
| CNS# | 20.024 |
| INS No. | 459 |
| Functional Classification | Thickener, Other |
| Quality Specification | GB 1886.352-2021 |

Regulations for the use of beta-cyclodextrin (partial excerpt):

| Food Classification Number | Food Name | Maximum Usage (g/kg) | Remarks |
| ------------ | ---------- | -------------- | ---------- | ------ |
| 04.02.02.03 | Pickled Vegetables | 0.5 | - |
| 05.02.01 | Gumbase candy | 20.0 | - |
| 05.02.02 | Confectionery other than gum base confectionery (tableted confectionery only) | 15.0 | tableted confectionery only |
| 06.07 | Instant Rice Noodle Products | 1.0 | - |
| 08.02 | Premade Meat Products | 1.0 | - |
| 08.02.01 | Conditioned meat products (raw meat with conditioning) | 1.0 | - |
| 08.02.02 | cured meat products (such as bacon, bacon, salted duck, Chinese ham, sausage) | 1.0 | - |
| 08.02.03 | Meatballs | 1.0 | - |
| 08.02.04 | Other Prepared Meat Products | 1.0 | - |
| 08.03 | Cooked Meat Products | 1.0 | - |
| 08.03.01 | Sauce and Marinated Meat Products | 1.0 | - |
| 08.03.02 | smoked, roasted and roasted meat | 1.0 | - |
| 08.03.03 | Fried Meat | 1.0 | - |
| 08.03.04 | Western-style ham (smoked, smoked, cooked ham) | 1.0 | - |
| 08.03.05 | Meat Enema | 1.0 | - |
| 08.03.06 | Fermented Meat Products | 1.0 | - |
| 08.03.07 | Cooked Dried Meat Products | 1.0 | - |
| 08.03.08 | Meat cans | 1.0 | - |
| 08.03.09 | Other Cooked Meat Products | 1.0 | - |
| 14.02.03 | Fruit and vegetable juice (pulp) beverage | 0.5 | in ready-to-drink state |
| 14.03.02 | Vegetable Protein Drink | 0.5 | On a ready-to-drink basis |
| 14.03.03 | Compound Protein Beverage | 0.5 | On a ready-to-drink basis |
| 14.03.04 | Other Protein Beverages | 0.5 | In Ready-to-Drink Status |

2. International standards and norms

2.1 JECFA Assessment

The Joint FAO/WHO Expert Committee on Food Additives (JECFA) conducted a safety assessment of beta-cyclodextrin in 1995:

-ADI setting: 0-5 mg/kg body weight/day
-Rationale: Based on 1-year dog feeding study NOEL 470 mg/kg bw/d, applying 100-fold safety factor
-Conclusion: No evidence of genotoxicity and carcinogenicity

2.2 EFSA Assessment

The European Food Safety Authority's (EFSA) Scientific Committee on Food Additives and Nutritional Sources (ANS) completed its re-evaluation of beta-cyclodextrin as a food additive in 2016:

-Confirm ADI:5 mg/kg body weight/day
-Assessment conclusion: Based on the existing toxicology database, there is no reason to revise the current ADI.
-Exposure assessment: In the brand loyal consumer scenario, the exposure of the majority group exceeds ADI at the 95th percentile
-Safety confirmation: No evidence of genotoxicity, NOAEL 654-864 mg/kg bw/day in chronic toxicity study (rat)

2.3 EU regulations

In the EU, beta-cyclodextrin is used as a food additive (E 459) and must comply:

-Main legislation: Regulation (EC) No 1333/2008
-Purity standard: Commission Regulation (EU) No 231/2012
-Approved for use: Annex II and Annex III

2.4 US regulations

In the United States:

-FDA approves beta-cyclodextrin as a food additive
-Hydroxypropyl-β-cyclodextrin (HP-β-CD) approved as an orphan drug for the treatment of Niemann-Pick type C disease
-Sulfobutyl-β-cyclodextrin (SBE-β-CD, trade name Captisol®) for a variety of marketed injections

2.5 Pharmacopoeia Standard

Pharmaceutical grade beta-cyclodextrin must meet the main pharmacopoeia standards:

-Chinese Pharmacopoeia (ChP)
-United States Pharmacopeia (USP)
-European Pharmacopoeia (EP)
-Japanese Pharmacopoeia (JP)

3. Test method standard

determination of 3.1 content

high performance liquid chromatography (HPLC-RI):

-Column: octadecylsilane bonded silica gel (φ4.6mm × 25cm,10μm)
-Mobile phase: water: methanol = 85:15
-Column temperature: 30 ℃
-Detector temperature: 35°C
-Flow rate: 1.5 mL/min
-Injection volume: 10μL

3.2 identification method

-Specific rotation method: determination of specific rotation in the range of +160 ° ~ +164 °
-Chromatography: retention time consistent with standard
-Infrared spectroscopy (FTIR): absorption peaks of characteristic functional groups
-Nuclear magnetic resonance (NMR): characteristic signal of glucose unit

Key Indicators of 3.3 Quality Control

-Purity ≥ 98% (on dry basis)
-Heavy metal content ≤ 10ppm (pharmaceutical grade)
-Microbial limits in accordance with regulations
-Moisture ≤ 14%
-Ignition residue ≤ 0.1%