This article discusses the process used to formulate and prepare Taohong Siwu, a traditional Chinese medicine, as a dispersible tablet. We performed single-factor and orthogonal experiments to screen the prescription excipients, optimize the formulation process, and produce dispersible Taohong Siwu tablets.
Here, we optimize the process used to formulate and prepare dispersible Taohong Siwu tablets and provide a foundation for expanding their clinical application. Taking dispersion uniformity and disintegration time as the indices for investigation, we used a single-factor test to match and filter the excipient categories for Taohong Siwu tablets. The formulation was optimized by an orthogonal test design. The content and dissolution rates of the effective substances in dispersible Taohong Siwu tablets when prepared with optimized prescriptions were determined by ultra-high performance liquid chromatography (UPLC), and the optimal preparation process was determined.
The optimal composition for dispersible Taohong Siwu tablets was 17% Taohong Siwu extract powder, 1% magnesium stearate, 49% microcrystalline cellulose, 20% cross-linked polyvinylpyrrolidone, and 13% sodium carboxymethyl starch. When dispersible Taohong Siwu tablets were prepared by direct compression and the optimized prescription powder was uniformly dispersed within 3 min, the dissolution rate reached more than 90% within 50 min.When prepared according to the optimized methods,dispersible Taohong Siwu tablets disintegrate rapidly in water with good dispersion uniformity and controllable quality.
Taohong Siwu decoction is a prescription composed of peach kernel, safflower, angelica, white peony, ligusticum chuanxiong, and rehmannia1,2 that can be used to promote blood flow and reduce detumescence and pain3,4. Previous research has found that Taohong Siwu Tang is difficult to preserve and easily affected by mildew and other factors. Furthermore, the commonly used clinical decoction is inconvenient to transport, while the decoction procedure is laborious and subject to variations in quality. Therefore, there is an urgent need to develop a new formulation for Taohong Siwu tablets.
Dispersible tablets are those that can be rapidly disintegrated in water and distributed in uniform suspensions5. In traditional Chinese medicine (TCM), the main drug in dispersible tablets is normally prepared from the raw materials of the TCM powder, extracts, and other appropriate excipients6. Compared with conventional liquid preparations and ordinary tablets, dispersible tablets, as a new dosage form, are more rapidly absorbed in the human body, exhibit better stability, are easy to take and transport, and exhibit a series of beneficial characteristics, such as rapid disintegration, high bioavailability, and good dispersion uniformity7,8.
The orthogonal test design method utilizes an orthogonal table to scientifically select the test conditions, arrange a reasonable test plan, and then use the mathematical concepts of range and variance to analyze the test results and generate an optimal plan9,10. In this study, we are particularly interested in certain key characteristics: the uniformity of dispersion, neatness, and comparability. Orthogonal experimental designs can also be adapted to incorporate a fractional and factorial design. In the present study, we use an orthogonal experimental design to screen and optimize the excipient types, excipient ratios, and drug loading data for dispersible Taohong Siwu tablets. Compared with traditional decoctions of Chinese medicine, the dispersible Taohong Siwu tablets prepared by the methodology described herein are easy to take, easy to preserve, and highly resistant to mildew.
1. Preparation of the Taohong extract
2. Screening of the fillers
3. Disintegrant selection
4. Optimization of the filler and disintegrant dosage
5. Screening of the drug loading
NOTE: Following the filler and disintegrant tests, the optimal contents of microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, and magnesium stearate were determined to be 4.4 g, 1.8 g, 1.2 g, and 0.1 g, respectively.
6. Quality evaluation of the Taohong Siwu dispersible tablets
7. Characterization
In this study, we used a traditional method to prepare liquid extracts of Taohong Siwu decoction and prepared an herbal powder by concentration and drying. By keeping the herbal powder, disintegrant, and lubricant unchanged, we screened r-lactose, pregelatinized starch, and microcrystalline cellulose as fillers to determine the disintegration time. Although the disintegration time with lactose as the disintegrant was better than that with pregelatinized starch and microcrystalline cellulose, the hardness and surface finish did not meet the required standards; thus, microcrystalline cellulose was selected as the filler.
To select an appropriate disintegrant, we established three prescriptions with the same herbal powder, filler, and lubricant: prescription 1 (cross-linked polyvinylpyrrolidone and low-substituted hydroxypropyl cellulose), prescription 2 (low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch), and prescription 3 (crosslinked polyvinylpyrrolidone and sodium carboxymethyl starch); the ratio was 1:1 in each case. Taking appearance, disintegration time, and dispersion uniformity as the inspection indicators, we found the combined disintegration time and dispersion uniformity of crosslinked polyvinylpyrrolidone and sodium was optimal. Next, we performed orthogonal testing to identify the optimal filler and disintegrant content. The best results were obtained with 4.4 g of microcrystalline cellulose (MCC, Factor A), 1.8 g of crosslinked polyvinylpyrrolidone (PVPP, Factor B), and 1.2 g of sodium carboxymethyl starch (CMS-Na, Factor C). Once we had identified the optimal dosage and proportions of filler and disintegrant, we next identified the optimal amount of herbal powder by investigating the disintegration time, dispersion uniformity, and hardness of different proportions. Figure 3 shows that the four prescriptions passed the dispersion uniformity assessment. However, with a larger drug load, we observed a longer disintegration time and a reduction in harness. The final prescription was identified as 1.5 g of medicinal powder, 4.4 g of microcrystalline cellulose, 1.8 g of cross-linked polyvinylpyrrolidone, 1.2 g of sodium carboxymethyl starch, and 0.1 g of magnesium stearate. The final specification was 0.30 g per tablet and four tablets per administration (three times per day); this was equivalent to 1.068 g of the crude drug.
Content determination and dissolution testing showed that the content of amygdalin in each dispersible tablet was 0.257 mg. In the dissolution test, the dissolution rates of the six batches of dispersible tablets at 50 min were 98%, 99%, 96%, 97%, 97%, and 98%, respectively, thus indicating that the dissolution rate of dispersible Taohong Siwu tablets was good.
Figure 1: The mean trend for the test indices. The average trend chart for the test indicators. Factor A in the figure is the content of Taohong Siwu medicine powder, factor B is the content of PVPP, factor C is the content of CMS-Na, and factor D is the blank error group. The numbers in each factor represent different contents (see Table 3 for details). The value on the y-axis represents the K value, and lower K values indicate better results. Please click here to view a larger version of this figure.
Figure 2: Laetrile standard curve. The standard curve of amygdalin, with the x-axis representing the injection volume, and the y-axis representing the peak area. Please click here to view a larger version of this figure.
Figure 3: Drug load screening results. This figure shows the drug load results; the left y-axis is the time, the right y-axis is the hardness, and the four prescriptions on the x-axis represent different drug load volumes. Please click here to view a larger version of this figure.
serial number | medicinal powder (g) | PVPP (g) | MCC (g) | pregelatinized starch (g) | lactose (g) | Disintegration time limit (s) | Exterior |
1 | 0.5 | 1 | 3.4 | 26 | clean | ||
2 | 0.5 | 1 | 3.4 | 54 | clean | ||
3 | 0.5 | 1 | 3.4 | 16 | common |
Table 1: Filler selection results. The main drug content and PVPP dosage in the three prescriptions remained unchanged; prescription 1 used MCC as the filler, prescription 2 used pregelatinized starch as the filler, and prescription 3 used lactose as the filler. From these, lactose as the filler had the shortest disintegration time, but the gloss was not up to standard.
Disintegrant prescription | Exterior | Disintegration time limit (s) | Dispersion uniformity (s) |
PVPP+L-HPC | clean | 39 | 39 |
L-HPC+CMS-Na | clean | 40 | 52 |
PVPP+CMS-Na | clean | 42 | 40 |
Table 2: Disintegrant combination screening. Under conditions with the main drug and filler remaining unchanged, different disintegrant combinations were tested in terms of their disintegration time limit and dispersion uniformity. Prescription 1 was PVPP + L-HPC, prescription 2 was L-HPC + CMS-Na, and prescription 3 was PVPP + CMS-Na, among which the combination of PVPP + CMS-Na had the shortest disintegration time limit.
Level | A (g) | B (g) | C (g) | D (g) |
1 | 3.4 | 0.6 | 0.4 | blank |
2 | 4.4 | 1.2 | 0.8 | blank |
3 | 5.4 | 1.8 | 1.2 | blank |
Table 3: Factor levels for orthogonal designs. The dosage of the main drug of each prescription remained unchanged. Factor A is the dosage of filler MCC, factor B is the dosage of PVPP, factor C is the dosage of CMS-Na, and factor D is the blank error.
Numbering | A (g) | B (g) | C (g) | D (blank) | Disintegration time limit (s) |
1 | 1 | 1 | 1 | 1 | 69 |
2 | 1 | 2 | 2 | 2 | 123 |
3 | 1 | 3 | 3 | 3 | 40 |
4 | 2 | 1 | 2 | 3 | 43 |
5 | 2 | 2 | 3 | 1 | 31 |
6 | 2 | 3 | 1 | 2 | 39 |
7 | 3 | 1 | 3 | 2 | 78 |
8 | 3 | 2 | 1 | 3 | 59 |
9 | 3 | 3 | 2 | 1 | 34 |
K1 | 232 | 190 | 167 | 134 | |
K2 | 113 | 213 | 200 | 240 | |
K3 | 171 | 113 | 149 | 142 | |
K1 | 77.333 | 66.333 | 55.667 | 44.667 | |
K2 | 37.667 | 71 | 66.667 | 80 | |
K3 | 57 | 37.667 | 49.667 | 47.333 | |
R | 39.667 | 33.333 | 17 | 35.333 | |
primary and secondary | RA>RD>RB>RC |
Table 4: Orthogonal experimental arrangement and experimental results.
source of variance | sum of squared deviations | degrees of freedom | mean square | F value | salience |
A | 236.667 | 2 | 1180.333 | 1.016 | >0.05 |
B | 1828.667 | 2 | 914.333 | 0.787 | >0.05 |
C | 446 | 2 | 223 | 0.192 | >0.05 |
D (error) | 2322.667 | 2 | 1161.333 |
Table 5: Variance analysis results.
Prescription | Medicinal powder (g) | MCC (g) | PVPP (g) | CMS-Na (g) | Magnesium stearate (g) |
1 | 1 | 4.4 | 1.8 | 1.2 | 0.1 |
2 | 1.5 | 4.4 | 1.8 | 1.2 | 0.1 |
3 | 2 | 4.4 | 1.8 | 1.2 | 0.1 |
4 | 2.5 | 4.4 | 1.8 | 1.2 | 0.1 |
Table 6: Drug load formulations. The dosage of MCC, PVPP, and CMS-Na for each prescription remained unchanged. The dosage of the main drug in prescription 1 was 1 g, in prescription 2 was 1.5 g, in prescription 3 was 2 g, and in prescription 4 was 2.5 g.
Batch number | Exterior | Average sheet weight (g) | Weight difference (g) | Average hardness (N) | Disintegration time limit (s) | Dispersion uniformity (s) |
20220710 | clean | 0.1978 | qualified | 22 | 39 | 43 |
20220711 | clean | 0.186 | qualified | 21 | 35 | 41 |
20220712 | clean | 0.1948 | qualified | 18 | 29 | 32 |
Table 7: Quality evaluation for the dispersible Taohong Siwu tablets. An appearance analysis, average weight analysis, weight difference check, hardness check, disintegration time limit check, and dispersion uniformity check were performed for the three batches of samples.
In this study, we tested the effect of filler, disintegrant, and medicinal powder dosage on the disintegration time and dispersion uniformity of dispersible tablets using an orthogonal design. We found that the preferred formulation disintegrated rapidly. When selecting the most appropriate filler, we found that although lactose exhibited the shortest disintegration time, the hardness of these tablets was not sufficient. Furthermore, the surface of the tablets was not smooth enough, and there was evidence of powder loss and loose tablets. As such, lactose did not meet the requirements of an appropriate filler; therefore, we selected microcrystalline cellulose as the optimal filler. Microcrystalline cellulose is a polymer in the form of powder or short rods with strong fluidity and without a fibrous structure13. Moreover, microcrystalline cellulose is odorless, non-toxic, easy to disintegrate, and non-reactive with drugs. This polymer is an important excipient in the pharmaceutical industry and can efficiently bond drug components to promote drug molding14. Furthermore, this polymer can facilitate the decomposition of drug components while enhancing drug strength and is used mainly as an excipient, filler, or drug release modifier for the preparation of drug tablets, drug granules, and drug capsules15,16.
Disintegrants have good water absorption and swelling properties and can promote the uniform dispersion of dispersible tablets in water. At present, the most commonly used disintegrants in dispersible tablets are L-HPC, cross-linked PVPP, and CMS-Na17. In this experiment, the combination of cross-linked PVPP and CMS-Na exhibited the shortest disintegration time. Most dispersible tablets use two or more disintegrants. Combinations of disintegrants can improve the disintegration effect and reduce costs18. When screening drug loading, we found that as the drug load increased, the hardness of the tablets decreased; this effect may be related to the nature of the medicinal material powder19. Finally, the process used to prepare the dispersible tablets (containing four ingredients) was optimized by formulation. This was followed by the indexing of the disintegration time and dispersion uniformity. The final ingredients were medicinal powder (17%), microcrystalline cellulose (49%), cross-linked polyvinylpyrrolidone (20%), sodium carboxymethyl starch (13%), and magnesium stearate accounting (1%).
Compared with traditional Chinese medicine decoctions, dispersible tablets can exert good therapeutic effects with high bioavailability, good stability, and easy portability, especially for patients who find it difficult to take decoctions and experience difficulties with swallowing20,21. In traditional Chinese medicine, the main drug in dispersible tablets is not usually a single compound; rather, the drug is composed of a complex mixture of ingredients. Furthermore, such powders have a relatively high viscosity and are usually able to absorb moisture. Ordinary tablets containing Chinese herbal medicine powder as the main drug are associated with a wide variety of problems, including a long disintegration time and poor dispersion uniformity, which influence the curative effect. Therefore, in the present research, we designed a new formulation, dispersible tablets, for the Taohong Siwu decoction to solve the problems associated with traditional decoctions, thus expanding the range of applications and promoting absorption in the body22. In this research, we extracted a dry powder from medicinal materials by applying the water extraction method. Traditional decoction methods involve complex ingredients that can be extracted according to the effective components and the characteristics of the active ingredients. Furthermore, the content of the active ingredients can be increased in dispersible tablets. The separation of impurities in medicinal materials and the preservation of their active ingredients is a problem that should be considered carefully during preparation. It is also important to provide favorable conditions for the preparation of subsequent dispersible tablets. Traditional decoctions such as the Taohong Siwu decoction generally have a high sugar content. Herbal powders can be readily prepared so that they absorb moisture. Therefore, it is important to take precautions when drying during the preparation. Furthermore, the finished tablets should be resistant to moisture.
It should be noted that this study only investigated one index component in the content determination experiments; this represents a notable limitation to this study, although our work provides a key foundation for subsequent in-depth research. Transforming a decoction of Taohong Siwuinto a dispersible tablet that is convenient for patients, more practical, and more feasible is also in line with the developing trends in traditional Chinese medicine preparations.
The authors have nothing to disclose.
This research was supported by the National Natural Science Foundation of China (Grant No. 82074059), the Open Fund for Key Laboratory of Xin'an Medical Ministry of Education, Anhui University of Traditional Chinese Medicine (No.2022XAYX07), the Anhui Provincial Key Laboratory of Traditional Chinese Medicine Compound Open Fund funded project (No.2019AKLCMF03), the Anhui Province Academic Leader Reserve Candidate Funding Project (No. 2022H287), and the Anhui Provincial Health Research Key Project (AHWJ2022a013)
Acetonitrile | OCEANPAK | A22T0218 | |
Carboxymethyl starch sodium | Maclean | C12976293 | |
Crosslinked Polyvinylpyrrolidone | Maclean | C12976293 | |
Disintegration time limit tester | Tianjin Guoming Pharmaceutical Equipment Co., Ltd. | BJ-2 | |
Electric heating constant temperature drying oven | Shanghai Sanfa Scientific Instrument Co., Ltd. | DHG-9202·2 | |
Electric thermostatic water bath | Shanghai Sanfa Scientific Instrument Co., Ltd. | DK-S24 | |
Electronic Balance | Sartorius Scientific Instruments (Beijing) Co., Ltd. | SQP | |
Intelligent Dissolution Tester | Tianda Tianfa Technology Co., Ltd. | ZRS-8L | |
Lactose | Maclean | C12942141 | |
Low-Substituted Hydroxypropyl Cellulose | Anhui Shanhe Pharmaceutical Excipients Co., Ltd. | 190219 | |
Magnesium stearate | Maclean | C12894996 | |
Methyl Alcohol | TEDIA High Purity Solvents | 22075365 | |
Microcrystalline cellulose | Maclean | 13028716 | |
Single punch tablet machine | Nantong Shengkaia Machinery Co., Ltd. | TDP-2A | |
Tablet hardness tester | Shanghai Huanghai Drug Testing Instrument Co., Ltd. | YPJ-200B | |
Taohong Siwu Soup Extract | self made | ||
Taoren, Honghua, etc. traditional Chinese medicine | The First Affiliated Hospital of Anhui University of Chinese Medicine | ||
Waters Acquity H-Class Ultra High Liquid Chromatography |