Cyclic amino acids are a class of amino acids that contain a cyclic structure in their side chain. These amino acids typically have a different structure compared to the standard amino acids found in proteins.

One example of a cyclic amino acid is proline, which has a five-membered ring structure in its side chain. Proline is unique because its cyclic structure limits the flexibility of the polypeptide chain, disrupting protein folding. It is commonly found in turns and loops of proteins. Another example is hydroxyproline, which is a derivative of proline. It contains a hydroxyl group (-OH) attached to the side chain nitrogen, adding a polar character to the amino acid.

Cyclic amino acids can have diverse biological functions. Some can act as neurotransmitters, while others serve as precursors for the synthesis of important biomolecules. Studying and understanding the properties of cyclic amino acids is crucial in various fields, including biochemistry, pharmacology, and medicinal chemistry.

The applications of cyclic amino acids in chemistry are numerous and expansive:

Peptide synthesis: Cyclic amino acids are used in peptide synthesis to incorporate specific structural elements into peptides and proteins.

Drug discovery: Cyclic amino acids can be utilized in the design and development of new drugs with enhanced stability, target specificity, or improved pharmacokinetic properties.

Bioengineering: Cyclic amino acids can be employed in bioengineering to create or modify proteins and peptides for various applications, including drug delivery systems or protein-based biomaterials.

Chemical biology: Cyclic amino acids are widely used in chemical biology research as chemical probes or tools to study protein structure, function, and interactions.

Pharmacological research: Cyclic amino acids are studied for their potential therapeutic applications in various diseases, such as cancer, autoimmune disorders, or neurological disorders, due to their ability to modulate protein-protein interactions or enzyme activities.
Overall, cyclic amino acids play significant roles in protein structure, enzyme function, and protein-protein interactions, and their diverse applications make them important building blocks in many areas of chemistry and biology.

Development of cyclic peptide macrocycles: Researchers have developed methods to synthesize cyclic peptide macrocycles containing multiple cyclic amino acids. These macrocycles can exhibit enhanced stability and binding affinity compared to linear peptides, making them attractive candidates for drug development.

Cyclic amino acids as catalysts: Cyclic amino acids have been explored as catalysts for various chemical reactions. By incorporating catalytic groups onto the cyclic amino acid scaffold, researchers have developed efficient and selective catalysts for organic transformations.

Cyclic amino acids in nanotechnology: Cyclic amino acids have been utilized in the fabrication of nanomaterials and nanodevices. By incorporating functionalized cyclic amino acids into nanostructures, researchers can control their assembly, stability, and properties, enabling applications in areas such as sensors, drug delivery, and imaging.

Cyclic amino acids in materials science: Cyclic amino acids have been incorporated into polymers and materials to improve their mechanical properties, thermal stability, and biocompatibility. These materials find applications in areas such as tissue engineering, coatings, and drug delivery systems.

In summary, cyclic amino acids have diverse functions in chemistry, including enhancing the stability and bioavailability of peptides, mimicking natural products, inhibiting enzymes, and enabling molecular recognition. Their applications span various fields, including drug design, protein engineering, natural product synthesis, and materials science. Ongoing research aims to further exploit the unique properties of cyclic amino acids for developing novel therapeutics, catalysts, and nanomaterials.

In an API, any substance that affects the purity of the API is called an impurity. ICHQ3A defines an impurity in a new API as any component that is present in the new API but whose chemical structure is different from that of the new API. In general, impurities are classified into organic impurities, inorganic impurities and residual solvents according to their physical and chemical properties. According to the source, impurities can be divided into: process impurities (reactants and reagents, intermediates, by-products, etc.), degradation products and various impurities introduced from reactants or reagents, etc.; From the perspective of drug toxicity, impurities can be divided into genotoxic impurities and common impurities. Impurity is a key attribute of drug quality and safety, which runs through the whole drug research and development process. Therefore, it is directly related to the quality and safety of marketed drugs to conduct standardized impurity research and control it within a safe and reasonable limit.

Method for Separation of Impurities from Active Substances

The Crystallization

Crystallization is a method to separate and purify impurities and target compounds by using their solubility in the same solvent or their solubility changing trend with temperature. Due to the convenience of crystallization operation, low requirements for equipment, less investment and high purity of the product, it is the first method to consider in the preparation of laboratory impurities.

Preparative Chromatography

Chromatography uses different distribution ratios of various substances between stationary and mobile phases to achieve the purpose of separation. Depending on the stationary phase and mobile phase, there are many types of chromatography, such as normal phase chromatography, reverse phase chromatography, ion chromatography, gel chromatography, etc. According to the different operating pressure of the system, it can be divided into low pressure chromatography, medium pressure chromatography, high pressure chromatography, etc. Chromatography for biological macromolecules such as protein, nucleic acid and other complex mixtures of organic matter separation analysis has a very high power, after the selection of suitable packing, the success of the chance has reached more than half. At present, when the separation is difficult and the preparation of a small amount of impurities cannot be obtained by crystallization and other processes, most of them consider the use of medium and high pressure preparation liquid to achieve.

The Precipitation

The difference in chemical properties between impurity and target compound is used to make the impurity or target compound react with appropriate reagents to form precipitation, which is separated by filtration and other methods. In the development of the separation and extraction process for API, once this method is found, the improvement of the process is often revolutionary, saving a lot of equipment, shortening the process and improving the quality of the product.

High Speed Countercurrent Chromatography

High-speed-counter-current chromatography (HSCC) is a kind of countercurrent color separation method based on unidirectional fluid dynamic and flat system. Since the composition and ratio of solvent system can be infinite, it can be applied to the separation of samples in any polar range in theory, and has its unique feature in the separation of natural compounds.

Identification of Drug Impurities

UV Identification (HPLC-UV)

Most of the drug impurities can be quantitatively analyzed by the ultraviolet identification (HOLC-UV) technique, but the accurate quantification of very and trace impurities cannot be achieved due to the low sensitivity of the ultraviolet detection. However, mass spectrometry technology has the advantages of high sensitivity and high resolution, and has been rapidly developed in recent years due to its excellent quantitative and qualitative analysis ability. At the same time, reducing sample consumption is also one of the driving forces for the development of NMR technology.

Mass Spectrometry (MS)

Quantitative Analysis

Mass spectrometry can be used as an alternative method for the quantification of UV-insensitive impurities. At the same time, because of its high detection sensitivity, it can accurately determine trace impurities that cannot be quantified by UV single wavelength detection. However, in the determination of some special impurities, it is still necessary to obtain the mass spectral response by derivatization or adding alkali metal ions in the mobile phase due to the weak ionization ability.

Structure Identification

It takes a long time to identify the structure of impurity monomer. Therefore, liquid mass spectrometry can be used to identify the structure of impurity quickly in the impurity spectrum analysis of drugs. In this method, the molecular ion peak determined by the primary mass spectrometry is used for the secondary mass spectrometry fragmentation analysis.

Nuclear Magnetic Resonance (NMR)

The qualitative and quantitative application of NMR technology in impurities mainly depends on the acquisition of impurity monomers. In addition, quantitative NMR can be used for the standardization of impurity reference materials in the establishment of quality standards for special impurities. NMR technology is also a quality-related detection technology. Using NMR technology to calculate correction factors and then calibrate other detectors, the reaction process can be monitored. The sensitivity of NMR is dependent on the performance of the probe.

Therefore, in order to improve the sensitivity of NMR detection, some researchers invented a cooling probe, which can detect compounds with only microgram level of compound monomer, which makes the sample consumption of NMR detection realize a leap from milligram to microgram. Simultaneous on-line liquid phase-nuclear magnetic resonance (LC-NMR) technology can also achieve rapid structure identification of drug impurities.

New Analytical Techniques

With the need of rapid impurity analysis and accurate structure identification, some methods have been used for impurity structure identification, such as direct determination of drug impurities, establishment of database of similar impurity fragments by molecular imprinting (MIP) and single crystal X-ray diffraction.

Control of Impurities in Active Substances
Related laws and regulations related to impurity control of commonly used apis:

ICH Q3A: Guidelines for Impurity Research in new apis
ICH Q3B: Guidelines for the study of impurities in new drug preparations
ICH Q3C: Guidelines for residual solvent research
ICH Q3D: Guiding Principles for elemental impurity research
ICH M7: Guidelines for the study of genotoxic impurities
2020 edition of Chinese Pharmacopoeia IV 9102 Guidelines for drug impurity analysis
Impurity Classification Control Strategy
Starting Material and Introducing Impurities
In API impurity study, need to focus on the potential of part of the reaction can be introduced impurities, because such impurities have similar structure and starting material, may enter the subsequent reaction with the starting material, and the physical and chemical properties of this kind of potential impurities and starting material is relatively close, in the subsequent process steps on its ability to remove co., LTD. The starting material itself is also a process impurity in the finished product, so it is particularly important to control and regulate the impurities that need to be controlled at the source.

Based on the concept of "source-FIRST" impurity research, strict supplier screening and audit should be carried out. Obtain the production process of the supplier's starting material, analyze the key quality attributes of the starting material based on the process characteristics, especially whether the starting material and its impurities are removed or transformed in the subsequent process, so as to establish the internal control quality standard of the starting material.

Intermediates and By-products

For impurities such as intermediates and by-products, the concept of process control should be fully reflected. In the study of API, process control should be carried out at each reaction step to ensure the quality of finished products by controlling the purity of intermediates and the conversion rate of reactants at a reasonable limit level. For the by-products that may be produced in each step, it is necessary to track the whereabouts of impurities in the subsequent process, and according to the accumulated data of multiple batches, reasonable development of in-process control and intermediate standards for each step of the reaction.

Degradation of Impurities

Starting materials, intermediates and final products can produce degradation impurities if stored improperly. We can design different strong degradation tests according to the stability test guidelines, so that a large amount of information about degradation impurities can be obtained in a short time. ICH Q1A clearly points out the content of strong degradation test, including high temperature, oxidation, acid-base destruction, light and other destruction methods. The test sample can be destroyed in the solid state of API itself or in the way of solution. In general, suitable strong degradation conditions were selected through different test conditions, and the degradation of principal components was about 10%. It is not necessary to degrade compounds that are stable under severe test conditions.

Organic Reagents and Their Conversion

A large number of organic reagents will be used in the research of APIs. In the process of research, the whereabouts of these organic reagents and their transformation products should be strictly tracked and analyzed. Data should be accumulated in multiple batches and reasonable internal control standards should be formulated.

Conclusion

Impurity is the key and difficult point in the quality research process of active drug. Whether it is a new drug or a generic drug, impurity research runs through the whole research and development. Our study on impurities should be based on the actual process route, refer to the pharmacopoeia and literature of various countries, and reasonably and fully study all kinds of impurities that affect the quality of API, so as to ensure the source control, process control and end point control, and each step has a targeted target, so as to realize the safety and reliability of drugs.

It is often difficult for a single polymer material to meet the material performance requirements of the production or research, polymer composite materials, therefore, have received extensive attention in both academia and manufacturing industry. Composites not only maintain the main characteristics of raw materials, but often have novel characteristics that raw materials do not have. By preparing composite materials, the following properties can be improved, such as strength, stiffness, toughness, hardness, corrosion resistance, wear resistance, durability, appearance, heat conduction and heat insulation, etc. Since the performance of the composite depends on the type of raw material, shape, proportion and process conditions, it can be easily modulated to obtain composites with different properties.

Characteristics of Polymer in Composites
Good overall performance
In order to make the composites superior in performance, the polymer used should have good comprehensive properties. The polymer should be selected reasonably according to the characteristics of the filler and the practical application of the composites to ensure that the inherent properties of the polymer can be maximized.

Strong adhesion to fillers
An important role of polymer in composites is to act as an adhesive, bonding fillers into a whole, thereby forming a new material with brand-new and improved properties. In addition, the polymer can also play a role in transferring loads in the composite system. For example, fiber fillers cannot withstand bending and compression loads so that they cannot be used as load-bearing materials. However, when they are bonded into a whole by a polymer matrix, their mechanical properties can be improved.

Good processing performance
When manufacturing composites, it is hoped that there are relatively easy processing and molding conditions to reduce equipment investment, simplify operation and make large-scale products. The polymer used should have a suitable viscosity and shrinkage force, especially the thermoset resin should have a suitable curing time.

Commonly Used Polymer Matrix
There are two main types of polymer matrix: thermoplastic and thermoset. So far, ~95% of polymer composites are thermoset, including unsaturated polyester resin, epoxy resin, phenolic resin, vinyl ester resin, polyimide resin, bismaleimide, polyurethane resin, cyanate resin, silicone resin, etc. Among them, unsaturated polyester, epoxy and phenolic resin are the three most widely used thermosetting resins.

Unsaturated Polyester Resin

Unsaturated polyester is mainly obtained by polycondensation reaction of dibasic acid and diol under the action of heat and/or catalyst. In practical applications, the unsaturated double bonds of the polymers and the double bonds of the crosslinking monomer need to undergo a crosslinking reaction to form a three-dimensional network structure. Unsaturated polyester resin is easy to process, not only can be cured under normal temperature and pressure, but also can be reacted under heating and pressure; at the same time, it is relatively cheap, so it is the most widely used polymer matrix.

The cross-linking reaction of unsaturated polyester is a free radical copolymerization of vinyl monomer (mostly is styrene) and the double bond of unsaturated polyesters. Therefore, the choice of suitable polymerization initiator, polymerization inhibitor and crosslinking agents is very important for the control of resin properties.

Phenolic Resin

Phenolic resin is a polymer formed by polycondensation of phenolic compounds and aldehyde compounds. Among them, the phenolic resin obtained by polycondensation of phenol and formaldehyde is the most important.

Because the phenolic hydroxyl group has strong polarity, it is easy to absorb water to deteriorate the electrical properties and mechanical properties of the material; and the phenolic hydroxyl group is easy to change under the action of heat or ultraviolet light, generating chromophores such as quinone and changing the color of the material. Therefore, it is often necessary to add some substance to modify:

Polyvinyl acetal --- increasing the toughness of phenolic resin
Epoxy polymer --- creating resin of excellent adhesion and heat resistance at the same time
Silicone --- improving the heat resistance and water resistance of phenolic resin
Epoxy Resin

Epoxy resin is a kind of polymer with aliphatic, alicyclic or aromatic segments as the main chain and containing two or more epoxy groups. Epoxy resin has strong adhesion, high chemical stability, corrosion resistance, high strength and modulus, and good electrical properties. It is an ideal insulating material with arc resistance and high dielectric strength.

Uncured epoxy polymers are usually thermoplastic and have little practicality. Only by adding some curing agents appropriately, the three-dimensional network structure is formed through the ring-opening reaction of epoxy groups or hydroxyl groups, which can make the whole material insoluble and infusible.

BOC Sciences supplies the necessary raw materials to help you manufacture ideal composites. Our experienced technicians are available to review and discuss your manufacturing requirements to help you select the right material and will ensure the success of your final products. From additives, modifiers to monomers and polymers, we can cover your compounding requirements.