Introduction

Traditional Chinese medicines (TCM) are an important class of natural products mainly derives from animals, plants and minerals, most of which need to be improved and processed before clinical use due to their own hard texture, impurities or toxicity, and the pretreatment process is called Chinese medicine processing. In the process of processing, the active ingredients such as alkaloids, glycosides, volatile oils, tannins, organic acids, proteins, amino acids, sugars and inorganic compounds will be affected. Generally, the processing methods of TCM are mainly divided into cleaning, cutting, heating, and adding excipients. Cleaning is used to remove the impurities and non-medicinal parts. Cutting contributes to the decoction of effective components through changing the shape of medicinal materials. Heating is applied to changing the texture and efficacy, correcting the bias, improving the decoction of effective ingredients as well as reducing toxicity and side effects through the procedures of frying, calcining, steaming, boiling, etc. [1]. Adding excipients could not only change the nature, flavor, action and meridian tropism of crude drugs, but also enhance the efficacy and reduce or diminish the toxicity and side effects. Among which, the application of excipients that possesses a long history has reflected the flexibility of clinical medication. And the role in processing medicinal materials is also variable accompanied by the difference between varieties, properties and functions of excipients.

Overall, processing excipients could be divided into liquid excipients and solid excipients. Yellow rice wine, vinegar, salt-water and refined honey are the commonly used liquid ones. Yellow rice wine could promote the upward direction, enhance the effect of blood-activating and stasis-resolving medicinal in invigorating blood circulation, moderate the cold and cool of some herbs with cold-nature [2].Vinegar could reinforce the effect of liver-soothing, dissipating blood stasis and relieving pain of TCM synergistically. Besides, several TCM processed with salt-water could conduct the drug to the kidney meridian and strengthen the efficacy on lower-jiao diseases. Refined honey could change drugs become sweet and sluggish, enhance the effects of benefiting Qi, moistening lung, relieving a cough and stop** pain and dysentery. In addition, ginger juice, licorice juice, black bean juice, bile, lanolin and sesame oil that are used for specific herbs also belongs to the categories of liquid excipients. As for solid excipients, rice could generally reduce the odor and toxicity of animal drugs and increase the role of some tonic drugs in improving the interior and benefiting Qi. Bran could absorb excessive volatile oil and reduce irritation of herbs. Sand helps the medicine to be friability due to homogeneous heating and reduces the toxicity as well. Except for the above commonly used ones, some mineral excipients that not only acts as medicinal materials but also enhance the therapeutic effect and reduce the toxicity were also applied in the process of TCM.

In the Chinese Pharmacopoeia (ChP, 2020 edition), 4 kinds of TCM that processed with mineral excipients has been included. Pinelliae Rhizoma Praeparatum Cum Alumine (Qingbanxia), Pinelliae Rhizoma praeparatum cum Zingibere et Alumine (Jiangbanxia), and Rhizoma Pinelliae Praeparatum (Fabanxia) that derive from the raw Pinellia ternate (Thunb.) Breit. were processed with alumen, ginger juice and soda lime as adjuvant materials, respectively. Arisaematis rhizoma preparatum (Zhitiannanxing) that derives from the Arisaema erubescens (Wall.) Schott, Arisaema heterophyllum Bl. or Arisaema amurense Maxim. is processed with alumen. Besides, Typhonii Rhizoma (Baifuzi) and Hirudo (Shuizhi) that were separately processed with alumen and talci pulvis has also been included as one of the main processing methods, although relative standards have not formed. Meanwhile, some provinces have promulgated their own standards. For example, Atractylodis Macrocephalae Rhizome (Baizhu) and Paeoniae Radix Alba (Baishao) that stir-fried with soil have been included in the standard for preparation of Chinese herbal pieces in Bei**g (2008 edition). Coicis Semen (Yiyiren) stir-fried with soil has been included in the standard for cut crude drug of TCM in Yunnan Province (2005 edition). Moreover, several processed products including Angelicae Sinensis Radix (Danggui) stir-fried with soil, Ophiopogonis Radix (Maidong) mixed with Cinnabaris had also been included in provincial processing specification, even though there is still no formal standards to follow (Table 1). The aforementioned information suggests the essential role of mineral excipients in the field of TCM processing. However, their research status and processing mechanism has not been systematic summarized, which hinders their application and development.

Table 1 Ancient and modern comparison of processing methods on TCM with mineral excipients
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In this paper, the application of several mineral excipients in the processing of TCM is reviewed by sorting out the existing literature reports (Fig. 1, Table 1). Their processing significance on TCM were revealed from components, pharmacodynamics and mechanism aspects, which provides references for better usage of TCM.

Fig. 1
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Effect of mineral excipients on processing TCM

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Effect of mineral excipients on the processing of TCM

Alumen

Alumen is a kind of sulfate mineral alumen stone, which is processed and refined from alunite. It can be used as an external medicine to exert the effects of detoxification, insecticidal, moisturizing and relieving itching as well as oral administration for diseases such as bleeding and diarrhea. Apart from the above physical and biological actions as a TCM, the alumen itself is often used as a processing excipient to reduce toxicity and increase efficacy. Banxia, Baifuzi and Tiannanxing are typical TCM processed with alumen (Fig. 2).

Fig. 2
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Effect of Alumen on the processing of TCM

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The processing method of Banxia and Tiannanxing with alumen could be traced back to the Song Dynasty. The former has been recorded in many classical medical books in China, such as Tai**huiminhejijufang(《太**惠民和剂局方》), Shengjizonglu(《聖濟總錄》) and Baoqingbencaozhezhong(《宝庆本草折衷》), while the latter was first documented by Shengjizonglu [3,4,5]. Besides, standards for the processed products of Baifuzi with alumen have been included in the ChP and 26 provincial processing specifications, which is gradually developed on the basis of previous licorice and ginger processing. So far, boiling or steaming Baifuzi with alumen or ginger has become the universal processing means [6].

Pinelliae Rhizoma

Pinelliae Rhizoma, commonly known as 'Ban-xia' in Chinese, is botanically from the dried tuber of Pinellia ternata (Thunb.) Breit., which has been used to remove dampness and dissipate phlegm, reduce adverse reactions, stop vomiting as well as eliminate swelling and scattered nodules. Furthermore, it is also a famous poisonous plant, and its toxicity is attributed to alkaloids and toxic proteins. Lectin is the most important toxic component of Banxia. And it has been confirmed to have obvious toxic damage to many organs, such as liver, digestive tract, kidney and heart. Interestingly, when verifying the toxic effect of Banxia on stomach and digestive tract, some researchers found that 50 mg/mL of Banxia could inhibit gastric nerve activity in rats, while it did not show any inhibitory effect when processed with ginger juice. Moreover, it also exhibits obvious reproductive toxicity, which lead to the termination of pregnancy and fetal deformity or death. Animal experiments showed that intragastric administration of Banxia powder (9 g/kg) and Banxia decoction (30 g/kg) could increase early embryo mortality by 85.7% and 50.0%, respectively [7,8,9]. Similarly, Banxia no longer causes vomiting and hoarseness in experimental animals after the processing with alumen [10].

As one of the classic herbs processed by alumen, the contents of alkaloids, organic acids, nucleotides, polysaccharides, proteins, amino acids and inorganic elements in Banxia were mainly changed. Ephedrine, a major alkaloid constituent that relieves cough and asthma, its content increases after processing due to nonvolatile and stabilization of ephedrine salt formed by the action of acidic alumen water [10,11,12]. In addition, there are also cases where the content of alkaloid is lower than that of raw one by different processing technology [10, 13]. For example, a significant decrease in the content was observed in other alkaloids including guanosine, uridine and adenosine compared with the crude product, which may be related to the breaking and decomposition of glycosidic bond by dissolving in water and alumen [10, 11, 13,14,70]. In general, drugs with spleen-tonifying and antidiarrheal effects need to be stir-fried with soil, such as Danggui, Baizhu, Baishao, Yiyiren, Dioscoreae Rhizoma (Shanyao) and so on (Fig. 4).

Fig. 4
figure 4

Effect of Soil on the processing of traditional Chinese Medicine

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Products of Danggui, Baizhu, Baishao, and Yiyiren that stir-fried with soil were recorded in historical document Bencaohaili(《本草害利》), Depeibencao(《得配本草》) [71], Qian**yifang (《千金翼方》) [72], Bencaomengquan(《本草蒙筌》) [73] and Bencaocongxin(《本草从新》) [78].

Paeoniae Radix Alba

Paeoniae Radix Alba, commonly known as ‘Bai-shao’ in Chinese, is botanically from the dried root of ranunculaceae plant Paeonia lactiflora Pall..It could be used to nourish blood and regulate menstruation, astringe Yin and stops weating, soften liver and relieve pain as well as stabilize liver yang. Paeoniflorin and albiflorin, two major ingredients of Baishao recorded in ChP, were slightly increased after being fried in soil [80]. There were other studies, though, which reported the content of paeoniflorin was lower than that of raw products [81, 82]. The phenomenon was caused partly by the decomposition of paeoniflorin into albiflorin under the catalysis of high temperature conditions and auxiliary ingredients [81]. Therefore, different processing conditions lead to the different contents of active ingredients. Recently, some scholars compared the antioxidant capacity of raw and processed products of Baishao. The antioxidant capacity of processed one is stronger in view of the increased gallic acid and benzoic acid after soil processing [82]. Likewise, spleen-strengthening and anti-diarrhea effect of Baishao was also enhanced. This is a result for the one side from the assist of the effective components by the trace elements in soil, and for the other side from the its own hemostasis and anti-vomiting characteristics of soil during cooling and anti-diarrhea process [80].

Others

Process with soil usually changes the active ingredients and enhance the curative effect of some TCM with spleen-strengthening activity. Take Yiyiren as an example, its dissolution of oil components and the content of triglyceride was increased due to the looser texture after the process with soil [80]. Moreover, the relative increased lactones and changed the oil composition was also observed owing to the absorption effect of soil. As for Lablab Semen Album (Baibiandou), the content of protein and free amino acid were increased accompanied by the decrease of total phospholipid and lectin after process [83]. Accordingly, its effect on regulating gastrointestinal hormone level, strengthening spleen and stop** diarrhea was enhanced. There are also some reports of Chenpi that have been processed with soil, whose content of hesperidin was increased [84]. However, content of polysaccharide, allantoin and phospholipid of Shanyao decreased because of the high temperature [80, 85]. Apart from the above cases, trace elements in Atractylodis Rhizoma (Cangzhu) were also changed. The levels of Fe, Cr, Ti, Al and TL increased by 2 ~ 4 times, while that of Cu, Na, Mg, Sr, Ba, Cd and Li decreased by 2–3 times [86]. Besides, the content of aromatic compounds in Roudoukou changed greatly, except for the decreased myristate and increased safrole, a new component α-asarone was produced accordingly [46]. Besides, soil process could make the rubber filament of Eucommiae Cortex (Duzhong) easier to break and improve the peculiar smell of GGEC [87, 88].

Soda lime

Soda lime is a mixture of calcium hydroxide, sodium hydroxide or potassium hydroxide, which could also be used as pharmaceutical excipients that reduces toxic components in the processing of TCM. The medicinal materials processed with soda lime are Guanmutong, Banxia and other araceae plants (Fig. 5). The processing of Banxia with soda lime water can be traced back to the Ming Dynasty, which is recorded for the first time in the Yaoxingcu**(《药性粗评》). In addition, they were also mentioned in Yaoxinghuiyuan(《药性会元》) and Bencaogangmushiyi(《本草纲目拾遗》) [5]. At present, the pharmaceutical standard of soda lime water-processing Banxia has been included in the ChP. The processing method of Tiannanxing with soda lime water can be found in the work **anshoulishangxuduanmifang(《仙授理伤续断秘方》) of the Tang Dynasty[89]. SS processed with soda lime water is a folk method. When used in Yangjiang area, the toxicity of it can be greatly reduced [90].

Fig. 5
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Effect of Soda Lime on the processing of traditional Chinese Medicine

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The detoxification mechanism of processing Banxia by soda lime water was similar to that of processing it with alumen. Moreover, the alkaloids and proteins, two kinds of effective and toxic components in Banxia, were also decreased [10, 91]. The change of trace elements is illustrated by the increase of Zn content and production of new element Ni [10]. Miao medicine Arisaema Rhizomatum (Banjielian), which is the dried tuber of araceae plant Arisaema rhizomatum C.E.C. Fischer. When processed by soaking or steaming in soda lime water, the content of total flavonoids in Banjielian decreased significantly, while that was increased when dry soda lime was used [92].

Dishuizhu has strong irritation to the mucous membrane of eyes, throat, intestines and stomach, so its processed products are used in clinic for its lower toxicity and resistance. After processed with soda lime water, the number and content of the chemical components in Dishuizhu were both affected, and the decreased content of total alkaloids, uridine and adenosine in which is most obviously [39]. The reason for the results may be that toxic components were mainly small molecules of acidic components and could be removed by the neutralization with soda lime water. In alkaline solution, meanwhile, the loss of uridine and adenosine is large [39].

As we mentioned above, aristolochic acid A is the toxic component of Guanmutong, which was usually processed with talci pulvis. Significantly, its toxicity could also be reduced by boiling or steaming with soda lime water in view of the reaction with strong alkali supported by soda lime water [60]. Soda lime water can also reduce the toxicity of other herbs, such as Paridis Rhizoma (Chonglou), Haiyu, and Maqianzi. However, their detoxification mechanism is still unclear, which needs further study [93, 94]. Promoting the formation of active ingredients is another processing mechanism of soda lime water. Indigotin, an active component of Indigo Naturalis (Qingdai) was formed and enriched by the promotion of soda lime water through providing alkaline environment, CO2 and carrier [94].

Some literatures also mentioned the enhanced antidiarrheal and anti-inflammatory effect of guava leaf and holly leaf and reduced toxicity of Huechys (Hongniangzi) by processed with soda lime. Besides, soda lime could also prolong the storage life of Dilong by providing strong alkaline and hygroscopic environment [95].

Halloysitum Rubrum

Halloysitum rubrum is a silicate mineral, which has the effect of astringent intestines, hemostasis, myogenesis and sores, and is often used as a processing excipient for soil frying in the process of TCM processing [96].

Roudoukou could be processed by halloysitum rubrum for both reducing the side effects of diarrhea caused by absorption of oil and increasing the antidiarrheal effect [97]. Likewise, immunity, anti-oxidation, anti-inflammatory and anti-cancer effects of Baizhu were also enhanced by halloysitum rubrum for the increased effective components atractylenolide III and polysaccharide, especially the atractylenolide III, whose content was about 3–4 times higher than the raw product [98].

Cinnabaris

Cinnabaris is a kind of sulfide mineral medicine, which has the effects of clearing the heart, calming the mind, brightening the eyes and deintoxication, but is toxic. Cinnabaris is usually prepared by elutriation to reduce the content of sulfur and calcium, so as to reduce toxicity and improve cleanliness. Although the toxicity of cinnabaris is reduced after processing, it is rarely used as an excipient when processing TCM due to the dosage that need to be controlled. The method of processing Maidong with cinnabaris was recorded in the reading of Bencaobiandu(《本草便读》) in the Qing Dynasty, and the use of cinnabaris mixed Maidong appeared in Wujutongyian(《吴鞠通医案》) and Bencaohaili(《本草害利》) for the first time[99]. There is little discussion on the tracing of ancient books on processing Yuanzhi with cinnabaris, but some documents mention that this processing method has been used since ancient times and is still in use at present [100, 101].

Generally, it could be used to process some TCM with anti-anxiety and psychotherapeutic activity on the premise of paying attention to the usage and dosage. Studies had shown that, after processing, the content of cyclosenegenin in Yuanzhi was 6 times higher than that of the raw product, while that of senegenic acid and senegenin was basically unchanged [102]. Some studies have questioned the method of processing Maidong with cinnabaris [103], mainly because of its toxicity and decreased total flavonoids after process [104]. Overall, the processing technology of cinnabaris used for preparing TCM should be further standardized in order to ensure the efficacy and reduce the side effects, which realize its full synergy potential.

Future perspective

To sum up, mineral excipients play an irreplaceable role in the processing of TCM. Among them, alumen and soda lime mainly work at reducing the toxicity of the main drug, but the effective components will also be affected, and thus bring weaker curative effect than that of raw products. Talci pulvis are usually used for processing some medicinal materials containing volatile oils, which relieve gastrointestinal irritation under the premise of ensuring the efficacy and degrade the toxic components of some toxic medicinal materials under high temperature. In addition, some animal medicinal materials could also be deodorized and flavored after processing with talci pulvis, which make their texture crispy and convenient for dispensing. Soil possessed anti-emetic, astringent and hemostatic effects for gastric. It is generally used as auxiliary materials to process herbs with spleen-strengthening and antidiarrhoeal effects and the mechanism was related to enhancing the efficacy and alleviating the irritation through changing the content and composition of volatile oils in herbs. Halloysitum rubrum, as an alternative to the soil, exhibited astringent intestines and antidiarrheal activity by reducing the oil content of medicinal materials. Cinnabaris is an auxiliary material that enhances the heart-clearing and sedative effect of herbs and should be used cautiously due to its toxicity. However, due to their own particularity and affect by various factors, investigated in many aspects including processing technologies, quality standards of mineral excipients and processing mechanism need further study and discuss.

  1. a.

    Standardization of processing methods

    The processing methods including processing temperature, time, acid–base environment and dosage of excipients need to be standardized, so that the effective components of medicinal materials could be fully retained without increase or decrease inconsistently, which greatly ensures the effectiveness of medicinal materials. Besides, the toxic components of many drugs are also active ingredients. How to retain the maximum effectiveness and reduce the harmfulness as much as possible needs to start from the processing technology for unified specification. Standardization of processing technology can better control the quality standard of processed medicinal materials.

  2. b.

    Quality control of mineral excipients

    Some mineral excipients such as cinnabaris are toxic or harmful to the human body. Hg2+, HgCl, Hg (CH2COOH)2 and other trace elements such as Ba, Sb are the main toxic components of cinnabaris [105]. Their metabolism is slow and easy to cause heavy metal accumulation, resulting in liver and kidney injury. Moreover, aluminum accumulation of alumen will affect the development of bone cells [106] and could even lead to visual, memory and other neurological disorders like Alzheimer's disease [107]. Thus, their content, purity and dosage are necessary to control when used as excipients, which help to reduce the loss of effective ingredients and residues of harmful substances.

  3. c.

    In-depth study on processing mechanism

    For now, the variety in the content and composition of active ingredients from many herbs before and after excipients processing is still unclear with inferred results. Significantly, the mechanism research should be combined with pharmacological research in order to explore which are the active ingredients, how to reduce component loss and toxicity as well as better processing technologies.

  4. d.

    Study on the processing of medicine food homology plants

    Some medicine food homology plants including Shanyao, Yiyiren and Baizhu were usually fried with soil. After processing, their spleen-strengthening and antidiarrhoeal effects on stomach had been increased. When used as food, however, whether their soil fried products with increased efficacy could be used and how to define the quality standards need in-depth discussion.

Conclusion

The processing of TCM has received more and more attention with the development of analytical technology and toxicological research. As an important part of the processing field, the mineral excipients have played an essential and indispensable role in TCMs application. In this review, the significance of mineral excipients including alumen, talci pulvis, soil, soda lime, halloysitum rubrum and cinnabaris on TCMs has been summarized from the insight into the components, pharmacodynamics and mechanism, which not only supply comprehensive information on how to balance the necessity and relative merits and disadvantages of mineral excipients in clinical application, but also provide a reference for exploring better processing excipients and technology so as to reserve the efficacy as well as reduce toxic and side substances to the human body.