Pinellia Rhizoma (PR) is the dried tuber of Pinellia ternata (Thunb.) Breit. It has the effects of drying dampness and resolving phlegm, subduing rebelliousness, stopping vomiting, eliminating lumps and dispersing knots, and is one of the commonly used traditional Chinese medicines in clinical practice. Pinelliae Rhizoma Praeparatum cum Alumine (PRPA) is a concocted tablet of Pinelliae Rhizoma Praeparatum soaked in alum or boiled, which has the effect of dispelling cold and phlegm compared with raw Pinelliae Rhizoma. The mass-transfer relationship between the two can be summarised as follows: free organic acids increased, total sugars, total alkaloids and some nucleosides and proteins decreased after the raw half-summers were concocted. The changes of single components in organic acids and nucleosides are rarely reported, and there is a lack of systematic analyses of the changing patterns of the main components of hemichrysanthemum and Qing hemichrysanthemum.
The preparation method of Qingdianxia is relatively fixed, and Qingdianxia in the 2015 edition of the Pharmacopoeia of the People’s Republic of China (hereinafter referred to as the Chinese Pharmacopoeia) is made by soaking in 8% alum solution, while the 2020 edition of the Chinese Pharmacopoeia adds boiled Qingdianxia on this basis. However, in addition to the alum soaking and alum boiling methods to make Qingdianxia tablets, there are companies trying to use alum steaming method to improve the production process of Qingdianxia tablets.
High-temperature steaming method is favoured as an emerging concoction process with the advantages of controllable process, time-saving and labour-saving as well as better toxicity-reducing effect on toxic herbs. According to the evidence, there is no record of steaming method in the preparation of Pinellia ternata, but some scholars have studied the steaming preparation of Pinellia ternata, Mo and Li established a stable high-pressure steaming preparation of Pinellia ternata, and Xiao used steaming preparation to obtain Pinellia ternata, which had an increase in the content of total organic acid, a significant decrease in the content of calcium oxalate crystals, and the limit of alum in compliance with the pharmacopoeia standard. The content of calcium oxalate needle crystals was significantly reduced, and the alum limit complied with the pharmacopoeia standard. However, there are still many questions that need to be answered about the steaming method, such as the stability of the quality of Qingdianxia obtained by steaming, the efficacy of Qingdianxia obtained by steaming, the consistency of the quality of Qingdianxia obtained by steaming with that obtained by dipping and boiling.
In the present study, the herbs of Pinellia ternata from different origins were concocted into Pinellia ternata tablets according to the immersion method, boiling method and steaming method respectively, and the content determination methods established by the team in the previous stage were used to analyse the mass transfer relationship between raw Pinellia ternata and Pinellia ternata in terms of leachate, organic acids, polysaccharides, nucleosides and proteins, and to investigate the consistency of quality between Steaming and immersion and boiling Pinellia ternata to lay a foundation for further studies on the pharmacological effect and detoxification mechanism of Pinellia ternata. This will lay the foundation for further research on the pharmacological and detoxification mechanisms of Qingbianxia.

In this study, we compared the differences between three Qingdianxia concoctions from the perspective of mass component transfer and evaluated the steaming method, a new concoction process. Based on the investigation of the influencing factors of mass transfer mentioned above, the key step that makes the steaming method different from the immersion and boiling methods should be steaming, and the high temperature of the steaming step as well as the lack of direct contact with the water body directly led to the retention and increase of leachate, oxalic acid, and polysaccharides. Combining all the test indicators and various analytical methods, it can be seen that the effect of steaming on the intrinsic quality of the artillery products and the traditional Qing half-summer to produce a significant difference in the artillery products, whether the artillery products can be called “Qing half-summer” is debatable.
However, the quality indexes of Bianxia and Qingbianxia have not been determined so far, and the 2020 edition of the Chinese Pharmacopoeia only uses the leachate as the quality index. Citric acid, L-malic acid and adenine, which were positively correlated with the content of leachate, were also basically important positive components of the first and second principal components in the principal component analysis. This result suggests the possibility of applying the components of citric acid, L-malic acid, and adenine in evaluating the quality of raw hemichrysanthemum, and at the same time, according to the currently established quality evaluation methods, the steaming method demonstrated a better quality than that demonstrated by the leaching and boiling methods of the concocted products. Moreover, through the yield of drinking tablets and alum limit, the steaming method has a greater advantage over the boiling method in terms of production efficiency and safety, respectively.
The quality of tablets prepared by immersion method and boiling method was in good consistency, and the quality of tablets prepared by steaming method differed considerably, but the clinical effects of the products obtained by the three methods of preparation have not yet been compared. The boiling method is included in local Chinese medicine tablet concoctions specifications (e.g., Beijing, Inner Mongolia, Jilin, Henan, etc.) and the 1963 edition of the Chinese Pharmacopoeia, but the steaming method has been reported less frequently and has not been included in the pharmacopoeia or the local standards. According to the results of this study, the steaming method is desirable in terms of its compositional content and stability, and whether it can be included as a formal method of concoction requires further in-depth study.
Steaming method can be used to shorten the time of concoction due to high temperature, and it shows a tendency of more stable rate of change of content in this study, which has great potential in saving time and labour. The next step could be to further optimise the steaming process: whether the soaking time can be shortened, and whether the high temperature steam can be used to achieve the effect of heart penetration simultaneously. In addition, the intrinsic content of the steamed artefacts differed from that of the traditional process, and the pharmacological effects and clinical efficacy of the artefacts could be compared with those of the traditional Qingdianxia artefacts on the basis of the differences in content, thus exploring the mechanism of Qingdianxia’s pharmacological efficacy, and providing a basis for elucidating the scientificity of the artefacts.

 

Quaternary carbon cheap iron catalysts: a breakthrough in drug manufacturing

On April 5, 2024, a new discovery in medicinal chemistry was reported in the prestigious journal Science: the study shows that chemists at Scripps Research in La Jolla, California, USA, can convert feedstock chemicals to quaternary carbon using a simple, single, inexpensive iron catalyst.

This may be a small step in the history of chemistry, but it’s a big step in the industrialization of future pharmaceutical chemicals.
Why is this so? This article does a detailed analysis. Small molecule compounds have been the mainstream of drugs, industrial mass production can reduce costs in today’s world, small molecule compounds have been one of the mainstream of drug development. Compared to large biomolecules (such as proteins and antibodies), small molecules have smaller molecular volumes and simpler structures, which makes them easier to synthesize and adapt, and thus more suitable for use as drug candidates. In addition, chemical mass production can significantly reduce the cost of drug production.

 

Through large-scale production, higher yields can be achieved and the unit cost of the production process can be reduced, thus making drugs more economical and affordable. Therefore, chemical mass production is very important for small molecule drugs to make them more accessible to mass production and widespread use, thus providing patients with more choices and more affordable therapeutic options.
The synthesis of small molecules with quaternary carbon structure is one of the difficulties in chemical pharmaceutics. Quaternary carbon structure is a special carbon atom structure in organic compounds, which refers to a structure in which one carbon atom forms four covalent bonds with four other carbon atoms. It usually exhibits a morphology similar to the limbs of a carbon atom, and is therefore also known as a seasonal carbon atom. In organic chemistry, the seasonal carbon structure is one of the important intermediates commonly used in the synthesis of drugs, pesticides, and polymeric materials. Since quaternary carbon structures enhance the stability and biological activity of molecules, they play an important role in organic synthesis and drug discovery.

 

However, some drugs require small molecules containing quaternary carbon structures as one of their active ingredients, which poses a challenge to the manufacturing process in pharmaceutical chemical mass production. Because the quaternary carbon is a carbon atom bonded to four other carbon atoms, it plays a crucial role in many drugs. However, making these small molecules containing quaternary carbon structures has been difficult due to the complexity and high cost of their synthesis.

 

The current, just-published findings offer a new solution to this problem. Scientists at Scripps Research have discovered that inexpensive iron catalysts can be used to convert feedstock chemicals into compounds containing quaternary carbon structures. The most important feature of this method is that it is extremely cost-effective, making it a potentially cost-effective approach. In addition, the introduction of quaternary carbon has the advantage of an exponential increase in chemical space, which is expected to overcome the bottleneck of lack of diversity in the molecular backbone of drugs.

 

Specifically, carboxylic acids and olefins can be converted into compounds containing quaternary carbon structures using iron-based catalysts through simple chemical reaction conditions. Moreover, the abundance and low cost of these feedstock chemicals make this approach not only reduce the production cost but also simplify the production process.

 

 

Which drugs are costly because of their quaternary carbon structure?

 

Quaternary carbon structures are widely found in drug molecules and natural products (e.g. verapamil, etc.). However, building quaternary carbon chiral centers has been a great challenge in organic synthesis due to site-blocking crowding and conformational flexibility. Drugs containing quaternary carbon structures, such as certain anticancer drugs, antibiotics, antivirals and antipsychotics, are expensive to produce due to their complex synthesis process, which requires multi-step reaction synthesis and high cost of raw materials. The synthesis process of these drugs may involve intermediates containing quaternary carbon structures, increasing the difficulty and cost of synthesis. Therefore, scientists have been trying to find new and more cost-effective methods of synthesis to reduce the cost of production of such drugs and make them more affordable and popular.

 

Why are small molecule drugs still the mainstream of pharmaceuticals now or in the future?

 

Small molecule drugs are and will continue to be the mainstay of drug development and therapy due to their chemical versatility, low production costs, ease of oral administration, excellent pharmacokinetic properties, and wide range of applications. Their flexible chemical structures enable them to be adjusted and optimized through synthetic methods to meet the therapeutic needs of different diseases, while having the advantages of broader drug targets and easier mass production, providing patients with more economical, convenient and effective treatment options. Moreover, compared with large molecule drugs (e.g. protein drugs), small molecule drugs can usually be administered by oral route of administration, which is more convenient, easier to accept, and easier to follow the medical advice, with higher compliance.