Study on the Forming Process of Yi Medicine Tongfeng Granules

Xuelian ZHAO, Yisong LI, Ling TAN, Hongna SU, Junzhang QUBIE, Wenbing LI, Yuan LIU

1. Pharmacy College, Southwest Minzu University, Chengdu 610041, China; 2. Sichuan Provincial Qiang-Yi Medicinal Resources Protection and Utilization Technology Engineering Laboratory, Chengdu 610225, China; 3. Key Laboratory of Tibetan Plateau Ethnic Medicinal Resources Protection and Utilization of National Ethnic Affairs Commission of the People’s Republic of China, Chengdu 610225, China; 4. Institute of Qinghai-tibetan Plateau, Southwest Minzu University, Chengdu 610041, China; 5. Ethnic Medicine Institute, Southwest Minzu University, Chengdu 610041, China

Abstract [Objectives] To optimize the forming process of Yi medicine Tongfeng Granules. [Methods] The forming process of Yi medicine Tongfeng Granules was optimized, with paste density, ethanol volume fraction, and type and proportion of excipient as influencing factors, and granule formability, solubility, moisture absorption, and angle of repose as evaluation indicators. Critical relative humidity (CRH) was investigated to select optimal storage conditions. [Results] Maltodextrin was selected as the excipient, and the best process parameters was the ratio of drug to excipient at 1∶2 (g/g), under which the forming rate, solubility, moisture absorption rate, and angle of repose were 81.38%, 98.90%, 8.81%, and 27.5°, respectively. The critical relative humidity was 72%. [Conclusions] The forming process adopted is reasonable and feasible, and can provide a reference for large-scale production of Yi medicine Tongfeng Granules.

Key words Yi medicine, Tongfeng Granules, Excipient, Forming process, Critical relative humidity

1 Introduction

Gout is a recurrent acute joint and soft tissue inflammation, tophi deposits, chronic arthritis and joint damage due to long-term active purine metabolism, excessive purine intake or uric acid excretion disorder[1]. It is a lifelong metabolic disease, with an incidence rate second only to diabetes[2]. Commonly used drugs in its modern clinical treatment include colchicine, non-steroidal anti-inflammatory drugs or glucocorticoids,etc., which can relieve pain in a short term, but will cause relapse after stopping taking the drugs, as well as serious gastrointestinal adverse reactions and severe liver and kidney damage[3-4].

This Yi medicine gout prescription is composed of 18 medicinal materials such asAchyranthesbidentataBl. andReynoutriajaponicaHoutt. It has the effects of clearing away heat and removing dampness, eliminating stagnation, relieving swelling and pain, and reducing blood uric acid concentration. It has been used clinically by Yi doctors for 30 years, with definite curative effect and no side effects. In thus study, sugar-free granules were selected, and the forming process of Yi medicine Tongfeng Granules was studied on the basis of following traditional extraction processes.

2 Materials

2.1 Main instrumentsMultifunctional decocting pot (purchased from Zhushuixi); HTP-312 electronic balance (purchased from Shanghai Huachao Industrial Co., Ltd.); intelligent electric heating constant temperature blast drying oven (purchased from Shanghai Langgan Shiyan Shebei Co., Ltd.); molecular lab water purifier (purchased from Chongqing Molecular Water Treatment Equipment Company).

2.2 Main reagentsMannitol (No.21010102, purchased from Hunan Xinlvfang Pharmaceutical Co., Ltd.); dextrin (No.200907, purchased from Hanzhong Qinfa Hujing Co., Ltd.); corn starch (No.200902, purchased from Hanzhong Qinfa Hujing Co., Ltd.); lactose (No.20200303, purchased from Zhenjiang Shi Kangfu Bioengineering Co., Ltd.); ethanol, water and reagents, all of which were analytically pure.

3 Methods and results

3.1 Preparation of thick pasteTraditional Chinese medicinal materials were weighed according to the prescription, and added with water, which was 12 times the amount of the medicinal materials. The materials were soaked for 60 min, then decocted for 80 min and filtered with gauze. Extraction was performed for three times, and the filtrates were merged, and concentrated by evaporation to a relative density of 1.36 (at 60 ℃). The obtained thick paste was cooled for later use.

3.2 Preliminary selection of excipientsThe thick paste used in the experiment was relatively viscous, and the granules made are sugar-free granules, so it is necessary to initially select suitable auxiliary materials. Currently widely used sugar-free excipients are mannitol, dextrin, soluble starch, lactose, microcrystalline cellulose (MCC), sodium carboxymethyl cellulose (CMC-Na),etc.[5-6]. Appropriate amounts of the above-mentioned excipients were, respectively, weighed and put into a weighing bottle that had been dried to a constant weight. The weighing bottles were then uncovered and put in a desiccator containing a saturated sodium chloride solution with relative humidity of 75%. After equilibrating for 72 h, the moisture absorption conditions were observed. Considering the experimental requirements, dextrin, mannitol, starch and lactose were selected as the screening objects finally.

3.3 Investigation on the relative density of thick pasteThe relative density of the thick paste was selected based on formability. The relative density of the thick paste was generally 1.25-1.36 at 60 ℃[7]. During the experiment, thick pastes with relative density of 1.26 at 60 ℃ and 1.36 at 60 ℃ were selected for investigation. The water contents of the thick pastes were determined, and they were formed to granules after adding different proportions of dextrin and different volume fractions of ethanol. The forming rate was determined, and the density of the thick paste and the proportion of excipient most suitable for granulation were selected. The results are shown in Tables 1 and 2.

3.3.1Determination of forming rate. According to the fourth part of the 2020 edition ofChinesePharmacopoeia(General Rule 0104), the granules were sieved through the No.1 and No.5 screens in sequence, and those that passed the No.1 screen but failed to pass the No.5 screen were collected and weighed, for the calculation of the forming rate[8].

Calculation formula: Forming rate (%)=(Weight of granules passing through the No.1 screen but retained by the No.5 screen/Total weight of granules)×100%

It can be seen from the granulation table that when the density of the thick paste was 1.36 (at 60 ℃), the granules made by adding the excipient 2 times the weight of the thick paste met the requirements.

Table 1 Test of granulation with relative density of 1.26

Table 2 Test of granulation of Yi medicine Tongfeng Granules with relative density of 1.36

3.4 Examination of the types of excipientsAccording to the preliminary determined types of excipients, each excipient was weighed and added into the thick paste according to thick paste∶excipient = 1∶2 (g/g), respectively. The materials were mixed well, and the soft material production conditions were recorded. Granulation was performed with a 14-mesh granulating screen. The granules were dried in an oven at 65 ℃, taken out, and shaped. Comprehensive evaluation was made based on the conditions of the soft material and forming rate, solubility, moisture absorption, and angle of repose, and the most suitable granulating excipient was selected. The results are shown in Table 3.

Table 3 Test of granulation of Yi medicine Tongfeng Granules with various excipients

3.4.1Determination of solubility. According to the requirements of the 2020 edition ofChinesePharmacopoeia(General Rule 0104), 10 g of the granules was weighed, added with 200 mL of hot water and stirred for 5 min. The material was added into a centrifuge tube and centrifuged at 8 000 r/min for 4 min. The supernatant was discarded, and the residue was dried at 65 ℃ to constant weight, and accurately weighed. The solubility was calculated.

Calculation formula: Solubility (%)=(Weight of solubilized part-Total weight of granule)×100%

3.4.2Determination of moisture absorption rate. First, the prepared granules was weighed, 3 g each, a total of 12 parts. The weighed granules were spread in a weighing bottle that had been dried to a constant weight. The weighing bottle was then put in a desiccator with a relative humidity of 75% after opening the cap, and taken out after 72-96 h until the moisture absorption of the granules reached equilibrium and weighed. The moisture absorption rate was calculated[9].

Calculation formula: Moisture absorption rate (%)=[(Sample weight after moisture absorption-Initial sample weight)/Initial sample weight]×100%

3.4.3Measurement of angle of repose. The funnel fixing method was adopted, and three funnels were connected in series. The height of the funnel mouth from a horizontally placed graph paper was (H). The granules were poured from the top of the funnel along the funnel wall until the cone point formed on the graph paper touched the mouth of the funnel. The diameter of the cone formed by the granules on the graph paper was 2R, and the angle of repose α (tgα=H/R)[10]was calculated. The average value of each type of granules was obtained from three repetitions.

It can be seen from Table 3 that under the same relative density of thick paste and the addition of the same proportion of excipients, the granulation effects of dextrin and starch were better. Dextrin was selected as the final granulating excipient after comprehensive inspection.

3.5 Forming process verificationAn appropriate amount of the thick paste was taken, 3 parts in total, each of which was added with 2 times the amount of dextrin, followed by mixing well and making into a soft material. Each obtained soft material was granulated with a 14-mesh granulating screen, and the obtained granules were put into an oven at 65 °C for drying, and then taken out and shaped. The three groups of granules were measured according to the measurement methods under "Measurement of forming rate", "Determination of solubility", "Determination of moisture absorption rate" and "Measurement of angle of repose". The results are shown in Table 4.

Table 4 Verification results of forming process of Yi medicine Tongfeng Granules

It can be seen from Table 4 that the forming process of Yi medicine Tongfeng Granules was easy in granulation, and the obtained granules had a high forming rate, good fluidity, and met the requirements of the pharmacopoeia, indicating that the forming process is reasonable and feasible.

3.6 Investigation of critical relative humidity (CRH)Different saturated salt solutions were prepared according to Table 5 and placed in desiccators at a constant room temperature (25 ℃) to equilibrate for 24 h, so that the humidity inside the desiccators reached equilibrium. Then, 2 g of granules was weighed accurately, added in a weighing bottle that had been dried to a constant weight, spread evenly. Each bottle was uncovered and put in a desiccator filled with saturated salt solution, which was then sealed. After equilibrating at a constant room temperature (25 ℃) for 72 h, the bottles were taken out and weighed, and the moisture absorption rate was calculated[11]. A graph was drawn with the relative humidity as the abscissa and the moisture absorption rate as the ordinate. A tangent line was drawn at the moisture absorption inflection point, and the corresponding point on the abscissa of the intersection point of two tangent lines was the critical relative humidity. The results are shown in Fig.1.

Calculation formula: Moisture absorption rate (%)=[(Weight after moisture absorption-Initial weight)/Initial weight]×100%

It can be seen from Fig.1 that 72% was the critical relative humidity. In order to ensure stable storage of the granules, Yi medicine Tongfeng Granules should be stored in an environment with a relative humidity below 72%.

Table 5 Moisture absorption of granules under different humidity conditions

Fig.1 Critical relative humidity curve of Yi medicine Tongfeng Granules

4 Discussion

Yi doctors attribute gout to the category of "Sise". Yi people are a high-risk group of gout due to the influences of geographical environment, dietary structure, and living habits. Yi doctors clinically apply compatible medicinal materials capable of eliminating dampness and heat to treat the symptoms of gout. The medicinal materials they use can reconcile the pancreas, stomach and spleen and regulate and clear qi to cure the root cause, achieving definite clinical effect[12-14]. The medicine is taken as a decoction, while it is inconvenience to carry and difficult to store and to use[15]. Therefore, its dosage form is changed, so that it can relieve the suffering of more gout patients. Compared with other dosage forms, granules have the dosage and preparation method closer to that of traditional decoctions[16], can retain effective ingredients and effects of each medicine in the prescription to the greatest extent, and are convenient to carry, easy to store, clean and hygienic, so it is known and accepted by the general public[17]. Sugar-containing granules are not suitable for people who suffer from gout and diabetes, obesity, hypertension and other diseases at the same time, so sugar-free granules are selected.

In experiments, extracts are obtained by decocting natural medicinal materials, contain a certain amount of water, and have strong viscosity. During the preparation of granules, the selected excipients should be those with good water absorption and low moisture absorption. Long-term storage of granules in the natural environment is prone to mildew and other phenomena, and it is necessary to determine the best storage conditions for granules by measuring the CRH value.