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What are cyclodextrins (CDs)?
Cyclodextrins are cyclic oligosaccharides consisting of α-1,4-glucopyranose units. The main representatives are alpha-, beta- and gamma-CDs with 6-8 glucose units, respectively. Due to their relatively lipophilic central cavity, they can physically include other molecules. Typical guest molecules are apolar and fit the cavity, like key and hole.
 
Are cyclodextrins synthetic or natural products?
Cyclodextrins can be found in nature. Some bacteria (e.g. Bacillus macerans) produce CDs from starch by enzymatic process for their energy storage. This process is mimicked by the industry using cyclodextringlycosyltransferase enzyme and starch (corn, potato, manioc, etc) as raw material. The so-called native CDs (alpha-, beta-, gamma-CDs) are considered natural. To change the properties of native CDs, synthetic CD derivatives are also produced from them via chemical modification.
 
Are cyclodextrins toxic?
In general native CDs have favorable toxicological profiles. There are numerous food products on the market containing native CDs, beta-cyclodextrin is even listed as E459 as a common food additive. However, depending on the region and the intended use some restrictions apply. Five CD derivatives (the native alpha-, beta-, gamma-CDs as well as hydroxypropylated-beta-CD and sulfobutylated-beta-CD) are listed in the US, EP and JP Pharmacopoeias and are widely used in pharmaceutical formulations (in over 40 approved drug formulations so far).
 
What is the inclusion complex and what is the driving force of complex formation?
All CDs have a relatively lipophilic cavity. Within the cavity they can entrap other molecules by physical, non-covalent and reversible forces (e.g. van der Waals forces, hydrogen bonds). Typical guest molecules are apolar and fit the cavity, like key and hole. The main driving force of the complex formation in aqueous medium is that the high-enthalpy water molecules in the CD-cavity are replaced with the guest molecule. No covalent bonds are formed between the host and the guest. The complex formation and dissociation are dynamic equilibrium processes. The formed complex dissociates to its original constituents unchanged.
 
What are the advantages of CD complexation?
▲     Improvement of physical and chemical stability (volatile, oxygen-, light- and heat sensitive compounds)
▲     Reduction of undesirable tastes and odors
▲     Increased solubility in water
▲     Stable aqueous solutions of insoluble compounds can be prepared without the use of organic co-solvents or surfactants
▲     Enhanced rate of dissolution
▲      Improved wettability
▲      Liquids can be transformed into solid form
▲      Extended release of compounds
▲      Alleviation of local irritaions (reduced side effects)
▲      Enhanced absorption
▲      Incompatible compounds can be mixed and used together in complexed form
▲      Stabilization of emulsions and suspensions


 
How can the CD complexes be prepared?
There are various ways to prepare the complexes in solid form. Just to name a few: by mechanical activation, kneading, co-crystallization, as well as by making aqueous common solution, or suspension. Usually the final step of the process is the removal of water. Considerable experience and some developmental work is required to find the ideal method for the complexation: the properties of the host and the guest molecule need to be taken into consideration.
 
What are the typical guest compounds?
Numerous organic or inorganic compounds form inclusion complexes with CDs. Guest compounds can be gases, liquids and solids as well. Concerning their application, these can be pharmaceuticals, vitamins, food additives, pesticides, aroma compounds, fragrances, etc. Due to the wide variety of cyclodextrin derivatives (in cavity size, charge and substituents - hundreds of derivatives) the number of guest compounds suitable for complexation is immerse.
 
Why use synthetic CD derivatives instead of native CDs?
Beta-CD has a limited water solubility (1.8% at room temperature). Using proper derivatization, products of highly enhanced solubility can be manufactured. Industrially produced modified CDs are hydroxypropyl-, sulfobutyl- and methyl-beta-CDs (HPBCD, SBECD, RAMEB), which are randomly substituted derivatives. They are mixtures of millions of compounds having similar structure.
Some CD-derivatives are single isomers (may be characterized by an exact formula): per- and monosubstituted CDs.
Regarding the type of substituents, there are ionic (such as SBECD, Quaternary amino CDs, etc.) and non-ionic (TRIMEB, HPBCD, etc) derivatives. Some special derivatives have been developed for biological applications (e.g. fluorescent derivatives). For further examples see our catalog.


 
What are CD polymers?
CDs can be coupled to each other or to a macromolecular scaffold by chemical crosslinking. Different CD polymers (water soluble or swelling) can be produced depending on the manufacturing conditions. The cavity size of CDs are not influenced by the crosslinking process, therefore these remain open for inclusion complex formation. The application of these nanostructures is based on the cooperativity of the adjacent rings. These polymers can be widely used (pharmaceutical industry, environmental biotechnology, etc).

 
Remdesivir lyophilized preparations for injection
The Remdesivir lyophilized preparation for injection is a white-grey or yellow freeze-dried solid without preservatives.In addition to the active ingredients, lyophilized preparations contain the following inactive ingredients: water for injection, Betadex sulfobutyl ether sodium (SBECD) and hydrochloric acid and / or sodium hydroxide.SBECD is an anionic high water soluble clodextrin derivative that can well package with drug molecules to form a non-covalent complex, thus improving the stability, water soluble, safety, reducing nephrotoxicity, etc.

 
What is useful of Hydroxypropyl-beta-cyclodextrin in oral preparations

Hydroxypropyl-beta-cyclodextrin are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: 
1.Can enhancement solubility, dissolution rate, stability, and bioavailability; 
2.Can modify the drug release site and/or time profile; 
3.Can reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug–drug or drug–additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders.

 A more recent trend focuses on the use of Hydroxypropyl-beta-cyclodextrin as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water-soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g., as osmotic pumps) and/or hydrophobic CDs. New controlled delivery systems based on nanotechnology carriers (nanoparticles and conjugates) have also been reviewed.



 
  • What is the difference between the indicators of hydroxypropyl beta cyclodextrin injection grade and oral grade?
    The difference between the oral grade and injection grade of hydroxypropyl beta cyclodextrin is reflected in two points:
    The first is that hydroxypropyl beta cyclodextrin injection grade increases the index control of bacterial endotoxin, requiring bacterial endotoxin to be less than 0.01EU/mg.
    The second is that the  hydroxypropyl beta cyclodextrin injection grade has higher requirements for the residual index of beta-cyclodextrin: <0.1%.
    What are the preparations of hydroxypropyl betacyclodextrin currently being developed or marketed?
    Preparations include Butylphthalide injection, Itraconazole injection, Letermovir injection, Telavancin injection, etc.
    What are the differences between hydroxypropyl beta cyclodextrin, 2-hydroxypropyl beta cyclodextrin and (2-hydroxypropyl) beta cyclodextrin?
    1. The Arabic numerals in the name of hydroxypropyl beta cyclodextrin usually indicate the modification position.
    2. Cyclodextrins can be substituted at positions 2, 3 and 6 in the sugar unit. The 2-position substitution of commercially available hydroxypropyl beta cyclodextrin accounts for about 50-60%. 2-Hydroxypropyl beta cyclodextrin refers to hydroxypropyl beta cyclodextrin substituted by 2-position cyclodextrin, which is difficult to produce and generally only used for scientific research.
    3. Another hydroxypropyl group has two isomers (2-hydroxypropyl) and (3-hydroxypropyl). The commercially available hydroxypropyl beta cyclodextrin is (2-hydroxypropyl) beta-cyclodextrin, where 2 represents the 2-position of the propyl group instead of the 2-position of the cyclodextrin.
    Why does hydroxypropyl beta cyclodextrin have two CAS numbers, 128446-35-5 and 94035-02-6?
    Cas numbers such as ID numbers are unique. However, hydroxypropyl beta cyclodextrin itself is a mixture, and there are many isomers. The official Cas organization Scifinder gave hydroxypropyl beta cyclodextrin two CAS numbers in the early days. At present, the two numbers have been merged and it is recommended to delete 94035 -02-6. 128446-35-5 is used in the Chinese Pharmacopoeia, and 128446-35-5 is also used in the US Pharmacopoeia.
    What is the advantage of shydroxypropyl beta cyclodextrin of Zhiyuan Biotechnology compared with other counterparts?
    First, through the comparative test of UV absorbance, the impurity content of Zhiyuan Biotechnology products is the least, which is obviously due to the level of the same industry at home and abroad.
    Second, through the comparative detection of the inclusion efficiency of 6-methylcoumarin, the products of the Chinese Pharmacopoeia standard of Zhiyuan Biotechnology and the European Pharmacopoeia and American Pharmacopoeia have stronger packaging capacity and higher packaging efficiency than similar products. 
    What is the formula of the corresponding relationship between the molar substitution degree and the hydroxypropyloxy content in the Chinese Pharmacopoeia and the US Pharmacopoeia of hydroxypropyl beta cyclodextrin?
    1. Because a beta cyclodextrin molecule is composed of 7 glucose unit molecules, the relationship between the average substitution degree and the molar substitution degree is 7 times: average substitution degree = molar substitution degree * 7.
    2. The index indicating the degree of substitution in the Chinese Pharmacopoeia is the content of hydroxypropyloxy group, and in the European and American Pharmacopoeia is the degree of molar substitution, and the formula conversion relationship is as follows:
    n=1135A/(75-58A)
    n is the average degree of substitution, A is the hydroxypropoxy content
    Why can't hydroxypropyl beta-cyclodextrin be used in food?
    Answer: 1. It has not entered the catalogue of food additives in China, and cannot be used in food according to regulations (Alpha cyclodextrin, beta cyclodextrin, and gamma cyclodextrin have entered the catalogue of food additives),
    2. In foreign countries, there are only three parent cyclodextrins, alpha, beta and gamma, in the food additives given by the Food and Agriculture Organization of the United Nations.
    What are the degrees of substitution of hydroxypropyl beta cyclodextrin?
    Generally, there are three degrees of substitution. One is 4.5-5.0 (it can also be understood as ≤5.0, and complies with ChP, USP, EP); one is 5.0-6.0 (complies with USP); the other is customized products.
    What is the solubility of hydroxypropyl beta cyclodextrin in water?
    1. When the degree of substitution is 4.2, the solubility in water: >100g/(100g water, 20℃)
    2. When the degree of substitution is 5.3, the solubility in water: >115g/(100g water, 20℃)
    What is the use of technical grade hydroxypropyl beta cyclodextrin?
    1. It belongs to the enterprise standard and is mainly used in veterinary medicine, industry, daily chemical and other industries.
    2. Popular science: The GMP we are talking about refers to "Good Manufacturing Practice for Drugs"; the reference for veterinary drug production is "GMP for Veterinary Drugs > "Good Manufacturing Practice for Veterinary Drugs";
    For industrial use, please refer to the management system of IS09001.
    What is the difference between hydroxypropyl beta cyclodextrin injection grade and other grades?
    1. There are requirements for bacterial endotoxin.
    2. There are requirements for bacterial endotoxin, and the residue of beta-cyclodextrin is less than 0.1%. The conductivity is between 30-50μs/cm. 
    Why is sodium sulfobutyl beta cyclodextrin more expensive than hydroxypropyl beta cyclodextrin?
    SBECD and HPBCD are different due to the production cost. For the types of inclusion drugs, HPBCD is generally positioned as a central nervous system drug; SBECD is generally an antifungal drug. For the types of inclusion drugs, please refer to the following table:
    Hydroxypropyl beta cyclodextrin: as biocompatibility enhancement, complexing agent, solubilizer, osmotic agent, stabilizer, diluent for tablets or capsules, viscosity increasing agent, water reducing activity, etc., used in Injections, oral solid preparations, ophthalmic preparations, intranasal preparations, inhalation preparations and external preparations can also be used as carriers for lipophilic targeted drugs and as protein protectors and stabilizers.
    Sulfobutyl beta cyclodextrin sodium: Increase drug solubility, improve bioavailability; increase drug stability; relieve and improve local irritation; adjust drug release; enhance drug absorption and utilization. It has applications in injection preparations, oral preparations, intranasal preparations and ophthalmic preparations.
    Is there any introduction of heavy metal elements in the production process of cyclodextrin?
    1. No.
    2. For heavy metals in hydroxypropyl beta cyclodextrin and sulfobutyl beta cyclodextrin sodium, we have formulated an elemental analysis report with reference to the guidelines of Q3D in ICH, and the content of each heavy metal element can be effectively controlled. For specific data, please refer to the elemental analysis report.
    3. For the detection of heavy metal content in other products, we refer to the “Chinese Pharmacopoeia” 2020 edition of the four general chapters 0821 for control.
    What guiding principles are used for elemental impurity analysis?
     For the heavy metals in hydroxypropyl beta cyclodextrin and sulfobutyl beta cyclodextrin sodium, we have formulated an elemental analysis report with reference to the Q3D guidelines in ICH, and the content of each heavy metal element can be effectively controlled. For specific data, please refer to the elemental analysis report.
    How to understand the expiration date of the product?
    1. The validity period of cyclodextrin excipients refers to the re-inspection period, and it is not broken when it expires
    2. After the API is made, the cyclodextrin has changed, and it is not possible to simply look at the cyclodextrin. At this time, it is a new substance, which is jointly processed by the cyclodextrin and the API. Its stability cannot be determined solely by the validity period of its constituents.
    For example, the raw and auxiliary materials for the production of API in general factories will have a re-inspection period of about 1 year, but the validity period of the produced API is calculated from the time of production, and the validity period of the preparation should be calculated from the production of the preparation.
    How many years is the product validity period?
    The shelf life of hydroxypropyl beta cyclodextrin is 2 years from the date of production and stored in accordance with the specified storage conditions. Storage past the expiration date on the label does not necessarily mean the product is no longer usable. In this case, however, for quality assurance reasons, the user must check to confirm the performance required for the intended use.
     Why is the test report of hydroxypropyl beta-cyclodextrin not pure?

    All pharmacopoeia, including Chinese Pharmacopoeia and US Pharmacopoeia, do not stipulate the measurement of purity. At present, there is no detection method, and there is no standard substance for liquid phase detection, so purity cannot be detected. Hydroxypropyl beta-cyclodextrin itself is a mixture, the average degree of substitution is 2.8-10.5, and the degree of substitution may be 3 or 5. We can generally calculate it based on other indicators tested?
    (100-burning residue-beta content%-chloride)/(100-moisture%)

    2. In the Chinese Pharmacopoeia, the content of hydroxypropoxy group (19.6%-26.3%) is measured, and the average degree of substitution (3.5-5.0) is calculated by formula.
    Formula: n=1135A/(75-58A)
    n is the average degree of substitution, A is the hydroxypropoxy content
    The hydroxypropoxy content is the mass content of hydroxypropyl in the whole product. It can be calculated by the total substitution degree: hydroxypropoxy content=75n/(58n+1135) n is the average substitution degree

    3. Foreign is the molar degree of substitution, the molar degree of substitution X7 = the average degree of substitution

    The difference between technical grade hydroxypropyl beta cyclodextrin and pharmaceutical grade hydroxypropyl beta cyclodextrin:
    1. Impurity residues are different: there are more technical grade impurities, such as sodium chloride, propylene glycol, etc.
    2. The average degree of substitution is different: the degree of substitution of technical grade is 4-6, and the degree of substitution of pharmaceutical grade is 3.5-5
    3. The control of indicators such as microorganisms is different: the technical level does not control microbial endotoxins, etc.
    4. The effective content is different: the effective content of technical grade is more than 96% lower, and the content of oral grade is more than 98%
    5.CP pharmaceutical grade has no electrical conductivity, no chloride, it is the content of hydroxypropoxy and no substitution index.
     Compared with peers, what are the product advantages of our company?
    1. The output is the largest in the same industry, at 2,000 tons per year
    2. The degree of substitution is in line with the customer's use, mainly used as a dispersant
    3. The best price
    4. Can provide 50% aqueous solution with lower cost
  • What is the advantage of sulfobutyl beta cyclodextrin sodium of Zhiyuan Biotechnology compared with other counterparts?
    1.Hemolysis test and cytotoxicity test proved that there was no statistical difference in all data points between Zhiyuan Biotechnology product and original product.
    2.Through ultraviolet absorbance contrast detection, the impurities of Zhiyuan Biotechnology products reach the international level of original research, obviously better than the domestic industry.
    3.By comparing the inclusion efficiency of Posaconazole and voriconazole, it is found that Zhiyuan Biotechnology product has the same capacity and good stability as the original research.
    What is the progress of the joint application of Zhiyuan Biotechnology sulfobutyl beta cyclodextrin sodium?
    The joint application of sulfobutyl beta cyclodextrin sodium of Zhiyuan Biotechnology and Simcere Pharmaceutical Group has passed the on-site audit.
    CDE Registration Number: F20190000285.
    What preparations are currently being developed or marketed for sulfobutyl beta cyclodextrin sodium?
    Preparations include Posaconazole injection, Voriconazole injection, Radesivir injection, Cafezomib injection, Ziprasidone injection, Aripiprazole injection, Amiodarone injection, etc.
    What are the main injections complexed by sulfobutyl beta cyclodextrin sodium listed by FDA at present?
    Voriconazole injection (Trade name:Vfend),Ziprasidone injection (Trade name:Geodon),Posaconazole injection (Trade name:Noxafil)
    What insoluble drugs is sulfobutyl beta cyclodextrin sodium commonly used for?
    Mainly include: Voriconazole, Cafazomib, Ziprasidone, Malopytan (animal drug), Aripiprazole, Posaconazole, Carbamazepine, Mefaram, Delafloxacin, Mebendazole, Topiramate, Omeprazole, Clopidogrel, Docetaxel, Sofebuvir, Ziprasidone mesylate, Meloxicam, Tetrahydroprogesterone and several other nitrogenous API bases are in various clinical stages.
    The higher the pH, the better. but the quality standard of our products stipulates that it is 4.0-6.8, so it can be guaranteed to be around 6.5.
    PH problem of sulfobutyl beta cyclodextrin sodium aqueous solution:
    1.When pH was less than 5.5, it tended to decrease for a short time (about 48 hours) and then increase.
    2.When pH is greater than 5.5, the pH of the solution increases with the increase of storage time and tends to be neutral.
    How to test the bacterial endotoxin of sulfobutyl beta cyclodextrin sodium?
    For the detection of bacterial endotoxin in any product, refer to General Chapter 1143 of the 2020 edition of the Chinese Pharmacopoeia or USP-NF2021 <85>, first carry out methodological verification, and use the verification method to test the corresponding samples to see if they meet the regulations. The period of verification and testing is about 7-15 days. The inspection method of microbial limit is the same, and the period of verification and testing is about 20-30 days.
    What is the pH requirement of Voriconazole for sulfobutyl beta cyclodextrin sodium?
  •  Is the methyl beta cyclodextrin of Zhiyuan Biotechnology pharmaceutical grade?
     The methyl beta cyclodextrin produced by Zhiyuan has been registered with the China CDE, and the registration number is F20210000272. Since methyl beta cyclodextrin has not entered the pharmacopoeia at home and abroad, the product testing standard is the enterprise standard, but the microbial indicators are controlled during the production process, and relevant enterprises are welcome to make joint declarations.
    What is the basic information of methyl beta cyclodextrin?
    answer:
    A. Calculation of the molecular weight of methyl beta cyclodextrin 1135+14n (n is the degree of substitution)
    B. The solubility of methyl beta-cyclodextrin in water is more than 100g/(100g water, 20℃), that is, the 50% aqueous solution is clear.
    C. 50% aqueous solution is clear and colored.
    D. The conductivity is similar to that of hydroxypropyl beta-cyclodextrin. Theoretically, it can reach 10μs/cm, but the cost will be greatly increased. If the customer service has requirements for it, you can refer to the USP standard of hydroxypropyl beta cyclodextrin ≤ 200μS/cm.
    E. methyl beta cyclodextrin refers to 2, 3, 6 substitutions. If all positions 2, 3 and 6 are substituted, the degree of substitution is 21.
    F. 2,6-dimethyl beta cyclodextrin refers to 2, 6-position substitution, and its substitution degree is 14.
    G. Packaged in medicinal low-density polyethylene bags.
    H. Methyl beta-cyclodextrin has high surface activity, and it belongs to fat-soluble cyclodextrin, which has good skin permeability, which is conducive to bringing active ingredients into the skin. Therefore, it is more effective than hydroxypropyl beta cyclodextrin in cosmetics. For more uses, see the literature.
    I. The existing vaccine pretreatment uses 2,6-dimethyl beta-cyclodextrin.
    Methyl is an oil-soluble cyclodextrin?
    Oil-soluble cyclodextrins include highly substituted methyl cyclodextrins, acetyl cyclodextrins (not yet done), and fatty acyl cyclodextrins (not yet done). Existing cyclodextrins recommend highly substituted methyl cyclodextrins. (Acetylcyclodextrin can be produced if acetic anhydride can be used for the record of the Public Security Bureau.)
    How to apply oil-soluble cyclodextrin?
    The application of methyl cyclodextrin currently available in the market is that one application is used in paint as a control agent for thickeners. That is, when the paint needs to be thickened, the thickener can be released to adjust the viscosity of the paint. Another use is in the production of vaccines to solubilize cholesterol-like substances to help microbial growth. (This paragraph is only methyl, methyl cyclodextrin can be soluble in some organic solvents and water soluble, it is not a typical oil-soluble cyclodextrin)
    Application in the literature: Oil-soluble cyclodextrin is used in combination with other cyclodextrins to control the release of drugs at specified sites.
    Advantages of methyl beta cyclodextrin
    Answer: 1. The domestic exclusive technology is a new product developed by our company relying on Shandong University;
    2. The largest domestic output;
    3. The range of substitution degree is wide, and the application methods are wide. There are products with an average substitution degree of 12 or more, and there are products with a substitution degree of less than 12;
    4. Can control endotoxin and other impurity residues, and meet the strict requirements of drugs, vaccines, cosmetics, etc.;
    5. Priority filing in CDE, filing materials are complete.
    Which organic solvents can oil-soluble cyclodextrin dissolve in?
     Highly substituted methyl cyclodextrin is soluble in chloroform, tetrahydrofuran and other organic solvents, but insoluble in extremely weak polar organic solvents such as petroleum ether, cyclohexane, and benzene.
  • Basic information of hydroxypropyl gamma cyclodextrin:
    1. It is used in the production of eye drops abroad, and there are listed products.
    2. Hydroxypropyl gamma cyclodextrin has a larger cavity, suitable for inclusion of macromolecular substances, with higher solubility and stronger anti-crystallization ability.
    3. Hydroxypropyl gamma cyclodextrin microorganism and endotoxin control: with hydroxypropyl beta cyclodextrin, the existing conditions cannot achieve sterility.
    4. Hydroxypropyl gamma cyclodextrin Calculate the average degree of substitution 75n/(58n+1297)=hydroxypropoxy content
    HPGCD: The molecular weight is 58n+1297, and the calculated average substitution degree is 75n/(58n+1297)=hydroxypropoxy content
     75n=(58n+1297)*25.4%
    75n=58n*25.4%+1297*25.4%
    75n=58n*25.4%+1297*25.4%
    75n=14.73n+329.44
    n=5.47
    The molecular weight of hydroxypropyl gamma cyclodextrin is 58n+1297=58*5.47+1297=1614.26
     Is the hydroxypropyl gamma cyclodextrin of Zhiyuan Biotechnology pharmaceutical grade? What industry is it mainly used in?
    The hydroxypropyl gamma cyclodextrin produced by Zhiyuan Biotechnology is currently the enterprise standard, and both microorganisms and bacterial endotoxins are controlled during the production process. At present, it is widely used in ophthalmic medicine.
    Advantages of hydroxypropyl gamma cyclodextrin
     1. The domestic exclusive technology is a new product developed by our company relying on Shandong University;
    2. The largest domestic output;
    3. Can control endotoxin and other impurity residues, meet the strict requirements of drugs, vaccines, cosmetics, etc.
  • What is the difference between the three basic cyclodextrins?
     Alpha cyclodextrin, beta cyclodextrin, and gamma cyclodextrin are three commonly used basic cyclodextrins, and their raw materials are tapioca starch or corn starch. The difference is reflected in the following two points:
    First, the diameter of the cyclodextrin cavity is different;
    Second, the solubility of cyclodextrin in water is different.