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Hard capsules of traditional Chinese medicine(TCM) have different degrees of hygroscopicity, which affects the stability and efficacy of drugs. In this paper, 30 kinds of commercially available TCM capsules were used as the research object. The hygroscopicity curves of capsule contents, capsule shells, and capsules were tested respectively, and the first-order kinetic equation was used for fitting. The results show that during the 24 h hygroscopicity process, the capsule shell can reduce the weight gain caused by the hygroscopicity of the contents by 0.80%-53.0% and the hygroscopicity rate of the capsule contents by 1.74%-91.3%, indicating that the capsule shell has a strong delay effect on the hygroscopicity of the contents of the TCM capsules. Seven physical parameters of the contents of 30 kinds of TCM capsules were determined, and 14 prescription process-related parameters were sorted out. A partial least squares model for predicting the hygroscopicity rate of the contents of TCM capsules(with shell) for 24 h was established. It is found that the hygroscopicity rate of the capsule shell is positively correlated with the hygroscopicity of the contents of TCM capsules(with shell), suggesting that the capsule shell with a low hygroscopicity rate is helpful for moisture prevention. In addition, the pre-treatment process route of the preparation and the type of molding raw materials affect the hygroscopicity. A larger proportion of the extract in the capsule content and a smaller proportion of the fine powder of the decoction pieces indicate stronger hygroscopicity of the capsule content. The 24 h hygroscopicity rate of 15% was used as the classification node of hygroscopicity strength, and the hygroscopicity rate constant of 0.58 was used as the classification node of hygroscopicity speed. The classification system of hygroscopicity behaviors of TCM capsules was established: the varieties with strong and fast hygroscopicity accounted for about 6.67%, while those with strong and slow hygroscopicity accounted for about 33.3%; the varieties with weak and fast hygroscopicity accounted for about 26.7%, while those with weak and slow hygroscopicity accounted for about 33.3%. The classification system is helpful to quantify and compare the hygroscopicity behavior of different TCM capsules and provides a reference for the quality improvement, moisture prevention technologies, and material research of TCM capsules.
Subject(s)
Medicine, Chinese Traditional , Wettability , Capsules , Powders , Technology , Drugs, Chinese HerbalABSTRACT
Traditional Chinese medicine （TCM） effervescent tablets have the characteristics of rapid disintegration， good taste， and convenient taking， but there are some technical difficulties in the preparation and storage process， which are mainly reflected in the sticking， easy moisture absorption， poor compressibility， and poor stability. The basic physical properties of TCM powder （extract powder， raw powder） are the main cause of these technical problems， and also the key to control the quality of TCM effervescent tablets. Powder modification technology has shown good effects in solving the above problems. The author intended to review the research in the above aspects in recent years， and proposed the following strategies for applying powder modification technology to solve the problems in the production process of TCM effervescent tablets from the three aspects of raw materials， excipients and preparation intermediates：①The application of co-processing technology to the treatment of raw materials and auxiliary materials can solve the problems of sticking， poor compressibility， delayed disintegration， and poor stability. ②Using surface coating technology to treat raw materials and preparation intermediates can improve poor fluidity， poor compressibility and delayed disintegration. ③The hygroscopicity of the preparation can be reduced by using microencapsulation technology to treat the raw material. ④The inclusion technology can improve the clarity and stability of the preparation.
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This study aims to construct a dynamic two-dimensional characterization technique for the hygroscopicity of traditional Chinese medicine extracts and investigate the effect of material properties of powders on hygroscopicity. The dynamic hygroscopicity-time curves of the powders were measured at 25 ℃ and 75% humidity, and the semi-equilibrium hygroscopicity time (t1/2) and equilibrium hygroscopicity (F∞) were derived as two-dimensional evaluation indicators. Finally, the correlation between the material properties and the hygroscopic behavior was analyzed by principal component analysis (PCA) and partial least squares analysis (PLS). The results showed that the dynamic two-dimensional characterization system of hygroscopicity constructed with 1/t1/2 = 0.1 h-1 and F∞ = 15% as the center can classify the hygroscopic behavior of traditional Chinese medicine extracts into four categories: fast hygroscopicity with strong hygroscopicity, slow hygroscopicity with strong hygroscopicity, fast hygroscopicity with weak hygroscopicity and slow hygroscopicity with weak hygroscopicity. The moisture absorption was negatively correlated with D50, D90, ρb and ρt; the moisture absorption rate was negatively correlated with D10, D50, D90, ρb, ρt, and positively correlated with moisture content. The hygroscopicity dynamic two-dimensional characterization indicators of Chinese medicine extracts (CMEs) constructed in this study matched with the physical properties. The method of dynamic multi-dimensional characterization technology is feasible and scientific, and the idea has strong promotional value.
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This study was designed to investigate the correlations of the spatial structure properties of Chinese medicinal extracts with hygroscopicity and the anti-hygroscopic techniques. With Poria extract used as the model drug, pregelatinised starch and microcrystalline cellulose at different ratios were added into Poria fluid extract for preparing powder particles with diverse spatial structures using different drying processes. Then, their hygroscopic behaviours were characterized by equilibrium hygroscopicity(F~∞) and semi-hygroscopic time(t_(1/2)). The correlations of the hygroscopicity of each powder with the spatial structure properties such as particle size(D_(90)), porosity(ε), true density(ρ_t), and surface element distribution were analyzed using partial least-squares method. The F~∞ and t_(1/2) values of Poria extract prepared by three drying methods were sorted in a descending order as follows: F~∞(spray drying>drying at ordinary pressure>drying at reduced pressure); t_(1/2)(drying at reduced pressure>drying at ordinary pressure>spray drying). The powder obtained by spray drying showed a spherical structure with the smallest particle size and intra-particle ε but relatively stronger hygroscopicity. The large-scale surface element enrichment of the powders dried by reduced pressure effectively reduced their hygroscopicity. F~∞ and t_(1/2) were negatively correlated with ε but positively with D_(90), and the interactive influence of each spatial structural properties was not significant. There existed a correlation between the spatial structure of the powder particles of Chinese medicine extracts and their hygroscopicity, and the hygroscopicity could be improved by designing the spatial structure. This study has provided some practical basis for developing the moisture-proof technology of Chinese medicinal preparations.
Subject(s)
China , Particle Size , Plant Extracts , Powders , Technology , WettabilityABSTRACT
Sacubitril valsartan sodium (LCZ696) is an ionic cocrystal drug. The purpose of this study was to explore the cocrystal features of LC696 by establishing a variety of characterization methods, and thus provide basic research data for effective quality control. The cocrystal characteristics of LCZ696 and its tablets were identified by applying analytical means including powder X-ray diffraction (PXRD), fourier transform infrared spectroscopy (FTIR), Raman spectra (RM), differential scanning calorimetry (DSC) and solid-state nuclear magnetic resonance spectroscopy (ssNMR). The crystalline water and hygroscopicity of LCZ696 were analyzed by thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), hygroscopicity test and Karl Fischer reaction method. The results show that PXRD, FTIR, DSC and ssNMR can effectively distinguish the features of LCZ696 cocrystal, sacubitril monomer, valsartan monomer, and sacubitril-valsartan (1∶1) mixture. RM can be used as a supplementary approach. Combined with the analysis by TGA, DVS, hygroscopicity test and Karl Fischer reaction method results, LCZ696 contains 2.5 crystalline water molecules and is very hygroscopic; we recommend that LCZ696 be stored in an environment with a relative humidity below 60%. By characterizing the crystal features we can establish quality control measure and evaluate the stability of the drug tablets. This study provides data in support for the establishment of the LCZ696 quality standard.
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To control the risks of powder caking and capsule shell embrittlement of Guizhi Fuling Capsules, a predictive model for hygroscopicity of contents in Guizhi Fuling Capsules was built. A total of 90 batches of samples, including raw materials, intermediate powders and capsules, were collected during the manufacturing of Guizhi Fuling Capsules. According to the production sequence, 47 batches were used as the calibration set, and the properties of raw materials and the four intermediate powders were comprehensively characterized by the physical fingerprint. Then, the partial least squares(PLS) model was developed with the content hygroscopicity as the response variable. The variable importance in projection(VIP), variance inflation factor(VIF) and regression coefficients were used to screen out potential critical material attributes(pCMAs). As a result, five pCMAs from 54 physical parameters were screened out. Furthermore, different models were built by different combinations of pCMAs, and their predictive robustness of 43 batches was evaluated on the basis of the validation set. Finally, the tap density(D_c) of wet granules obtained from wet granulation and the angle of repose(α) of raw materials were identified as the critical material attributes(CMAs) affecting the hygroscopicity of the contents of Guizhi Fuling Capsules. The prediction model established with the two CMAs as independent variables had an average relative prediction error of 2.68% for samples in the validation set, indicating a good accuracy of prediction. This paper proved the feasibility of predictive modeling toward the control of critical quality attributes of Chinese medicine oral solid dosage(OSD). The combination of the continuous quality improvement, the industrial big data and the process modeling technique paved the way for the intelligent manufacturing of Chinese medicine oral solid preparations.
Subject(s)
Capsules , Drug Compounding , Drugs, Chinese Herbal/chemistry , Powders , WettabilityABSTRACT
Objective: Using ultrafine hydroxypropyl cellulose (HPC) powders as coating material to prepare moisture barrier coating film for Compound Danshen Tablets by an innovative electrostatic powder coating technology. The effects of coating prescription and process parameters on coating efficiency and coating film properties were investigated, so as to provide new ideas for moistureproof coating of moisture sensitive traditional Chinese medicine such as Compound Danshen Tablets. Methods: Free films were prepared by applying an electrostatic deposition process, and the effects of liquid plasticizer on the mechanical properties and the water vapor permeability were investigated. And the Compound Danshen Tablets were dry coated with ultrafine powders by the electrostatic coating technology. The effects of coating formulations and processing conditions on the moisture sorption behavior of the barrier film coated tablets were studied. Results: The coating efficiency could be manipulated by adjusting the charging voltage of the electrostatic spray gun and the amount of the liquid plasticizer. Compared with static curing process, dynamic curing process was capable to produce a satisfactory film with an enhanced moisture barrier function for the herbal medicines. The best coating process parameters were plasticizer spraying time 3 min and titanium dioxide addition ratio 1%. The minimum hygroscopicity was achieved when the coating level was increased to 6.7%. Conclusion: The moisture-protective effect by using a novel electrostatic coating technology with ultrafine powders was efficiently achieved, suggesting that it was a promising alternative for the protection for the moisture sensitive drugs.
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Objective: To investigate the application characteristics of excipient copovidone in co-grinding process and the feasibility of co-grinding products for improving the dissolution of curcumin, using curcumin as a model drug in vitro. Methods: The prepared products were obtained by curcumin and various proportions (0%, 1%, 3%) of copovidone in co-grinding process, which were characterized by laser particle size analyzer, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and X-ray powder diffraction (XRPD). The in vitro dissolution of milled products was evaluated in two media, and their accelerated stability was investigated. Results: In comparison with pure curcumin, the particle size of milled products decreased with the lower crystallinity by XRPD analysis, but the hygroscopicity and DSC thermograms showed no significant difference. Moreover, compared with pure curcumin, the products exhibited significant improvement of in vitro dissolution. Also, there was no significant difference in the dissolution behavior of products placed under the accelerated conditions (40 ℃, RH 75%) for three months, indicating their good stability. Conclusion: As a new excipient, copovidone could effectively enhance the dissolution of curcumin via co- grinding process. This study provided a feasible strategy for improving the solubility and even oral bioavailability of poorly soluble drugs.
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OBJECTIVE: To investigate the hygroscopicity of vitamin B12 and the related problems of its chemical reference substance (CRS) that should be paid attention to. METHODS: UV absorption coefficient was determined at 361 nm, using water as solvent. Dynamic vapor absorption analysis (DVS) was applied to evaluate the moisture sorption trend and capacities of vitamin B12 under different humilities. RESULTS: Owing to the strong hygroscopicity of vitamin B12, deviation in the process of weighing might result in smaller UV absorption coefficient compared with the actual value, especially for dried and low moisture content raw materials in high-humidity environment. CONCLUSION: In the study of drug quality control for vitamin B12, the strong hygroscopicity of the raw material should be paid attention to, particularly in the research and application of vitamin B12 CRS.
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Commonly used dosage forms of fermented Cordyceps powder products are capsules and tablets. The hygroscopicity of the powder,as one of the important parameters in the tableting process,has important effects on the tabletting process of the tablets. How to improve the hygroscopicity of powder is of great significance for the development of new composite particles. Therefore,particle design technology was used in this study to prepare composite particle powder,and its hygroscopicity was compared with fermented Cordyceps powder and physically mixed powder. By preparing three different types of powders,the equilibrium moisture absorption,particle size,scanning electron micrograph,angle of repose,contact angle and compression degree were compared to observe the effect of traditional Chinese medicine particle design technology on improving the hygroscopicity of the fermented Cordyceps powder. The results showed that the equilibrium moisture absorption was 21. 2%,19. 6%,14. 5% respectively for the fermented Cordyceps powder,physically mixed powder and composite particle powder; the median diameter was(49. 751± 0. 280),(59. 183± 0. 170),(12. 842±0. 080) μm,respectively; the mode diameter was(185. 479±1. 372),(173. 964± 1. 104),(61. 671± 0. 979) μm,respectively. In the scanning electron micrograph of the composite particle powder,it can be clearly seen that the fermented Cordyceps powder had hydrophobic gas phase nano-silica with a fixed shape and uniform size. The angle of repose was(50. 63 ± 0. 75) °,(49. 25 ± 0. 43) °,(48. 33±0. 84) ° respectively; the contact angle was(7. 4±0. 2) °,(8. 2±0. 3) °,(15. 0±2. 6) ° respectively; and the compression degree was(38. 2±1. 3) %,(35. 8±0. 2) %,(32. 5±2. 6) % respectively. This study showed that after treatment by the vibrating ultrafine pulverizer,the fermented Cordyceps powder particles had obvious and uniform small particle hydrophobic gas phase nano-silica adhered to form a partially wrapped coating structure,which reduced the contact surface of fermented Cordyceps powder with the outside world,thereby reducing the hygroscopicity of the composite particle powder. It further demonstrated that the hygroscopicity of fermented Cordyceps powder can be improved by particle design.
Subject(s)
Cordyceps , Fermentation , Medicine, Chinese Traditional , Particle Size , Powders , WettabilityABSTRACT
Objective To study the optimum molding process condition of dry granulating of Shenqi Fukang Granules (SFG). Methods Using primary formation rate and hygroscopicity rate as evaluation indicators; The optimal excipient ratio was optimized by L9(34) orthogonal test method. Results The ratio of dry extract-micro silica gel-soluble starch-maltodextrin 77.5:2.5:5:15 was the optimal ratio of excipients; Dry granulating conditions parameters: workshop temperature of 20 oC, relative humidity of 50%, extrusion pressure of 12 kg/cm3, side seal pressure of 14 kg/cm3, extrusion frequency of 22 Hz, granulation frequency of 52 Hz, and feeding frequency of 19 Hz. Conclusion The optimized SFG dry granulating molding process is stable and feasible. The finished product showed a fine liquidity, good dissolubility and little hygroscopicity, which provides a reliable experimental basis for large-scale production.
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Objective To investigate the effects of moisture-proof materials and contents on hygroscopicity of Yixinshu Capsules; To improve moisture-proof function of Yixinshu Capsules. Methods The hygroscopicity performance of Yixinshu Capsules was analyzed with the indexes of moisture absorption rate and critical relative humidity (CRH), and effects of soluble starch, maize starch, dextrin, lactose, mannitol, calcium hydrogen phosphate, ethylcellulose, microcrystalline cellulose, hypromellose and low-substituted hydroxypropyl cellulose on hygroscopicity of Yixinshu Capsules were compared. The effects of optimized excipients and capsule contents after granulation on hygroscopicity of Yixinshu Capsules were tested. Results Lactose, microcrystalline cellulose and mannitol were the most appropriate moisture-proof excipients for Yixinshu Capsules with balanced moisture absorption rate of 18.04%, for which the best proportion of Yixinshu Capsules to excipients was 1 to 0.1 (wt%). The balanced moisture absorption rate of the powders were 14.87%, 14.39%, and 15.38%, respectively, whereas the granules were 10.75%, 10.29%, and 11.13%, respectively. Conclusion The selected excipients can effectively reduce the hygroscopic rate of the Yixinshu Capsules, and its granules can promote the moisture resistance of Yixinshu Capsules.
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Objective To explore the moisture absorption and related components of aqueous extract of Salviae Miltiorrhizae Radix et Rhizoma. Methods The hygroscopicity of aqueous extract of Salviae Miltiorrhizae Radix et Rhizoma and its water and alcohol elution parts separated by macroporous resin was measured, and the contained low molecular sugars (monosaccharides, oligosaccharide), polysaccharide, protein, amino acid, tannins and salvianolic acid B, etc. were analyzed. Results D101 macroporous resin was used for separation and purification of aqueous extract of Salviae Miltiorrhizae Radix et Rhizoma. The hygroscopicity of water elution parts was enhanced;carbohydrate, protein and other hydrophilic substances content increased; the content of salvianolic acid B was reduced to 1.76 mg/g. While the hygroscopicity and hydrophilic substances of alcohol elution parts were greatly reduced; the content of salvianolic acid B increased to 146.57 mg/g. Conclusion The hygroscopicity of aqueous extract of Salviae Miltiorrhizae Radix et Rhizomais closely related to the contained strong hydrophilic components, such as low molecular sugars, etc. Using D101 macroporous resin to purify aqueous extract of Salviae Miltiorrhizae Radix et Rhizoma can not only effectively gather the contain phenolic acids active ingredients, but also sharply decrease the extract yield and extract moisture absorption.
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Based on different binders, the Leonurus Herba extract powders were fluidized and modified. The physical properties such as hygroscopicity, flowability, filling property and compression property were studied by various micromeritics methods before and after modification. The results showed that the physical properties of Leonurus Herba extract were close to those of microcrystalline cellulose, and its comprehensive flow index was between 61-75. Fluidization process can improve hygroscopicity, so the moisture absorption indexes of the samples were significantly lower than those of the original Leonurus Herba extract samples. With the plastic constant, compression ratio and yield stress, Heckel equation and Kawakita equation as the the investigation indicators, results showed that fluidization process based on binder water was superior to other methods in increasing the compressibility of the extracts. In low and medium pressure, the fluidized and modified extract can form the tablets with a certain strength. Fluidized transformation had a greater influence on the properties of original Leonurus Herba extracts, which was instructive to guide significance for the surface modification of pharmaceutical powders and provide the basis for the development of extract tablet.
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Objective:To confirm the relative humidity conditions of preparation of Hericium Erinaceus and Lumbricus ( HD) bio-transformation and the longest operation time under the conditions through the study on hygroscopicity of dry extract powder. Methods:The solution was prepared respectively in the environment with various humidity, and the moisture absorption rate and critical relative humidity ( CRH) of dry extract powder of HD biotransformation were measured, and then the mathematical model was built and the curves of moisture percentage vs relative humidity was drawn. The parameters of moisture absorption rate, and the relative humidity and operation time with the moisture percentage up to 5% were calculated. The analytic geometry and linear regression method were used to calculate CRH, so as to determine the air humidity control range and the conditions for the production and storage process. Results:The moisture absorption of HD dry extract powder could reach 5% when exposed to the air respectively with the relative humidity of 66. 0%, 80. 8%, 88. 2% and 99. 0% for 7. 088, 3. 953, 2. 892 and 0. 661 h. When the moisture percentage reached 5%, the rela-tive humidity and the shortest time was 50. 84% and 9. 937 h, respectively. The CRH of the dry extract powder of HD biotransforma-tion was 68. 12%. Conclusion:When the dry extract powder of HD biotransformation is under preparation, the relative humidity of en-vironment should be controlled below 50. 84% with the operation time shorter than 9. 937 h, or the relative humidity is controlled below 68. 12% with the operation time shorter than 6. 810 h. Under the above conditions, the moisture absorption rate of HD dry extract pow-der can be controlled below 5%, which does not affect the preparation.
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Objective:To improve the forming process of Jingning particle according to the influencing factors in its effectiveness, such as low yield, high moisture absorption and difficult dissolubility during oral administration. Methods:A new technology that im-mediate granulation after the extract was well mixed with lactose and dextrin and dried. The appearance, dissolubility, hygroscopicity and pellet formation rate ( granularity) were compared between the new technology and the old one, and the difference in critical rela-tive humidity was also studied. Results:The appearance, dissolubility and pellet formation rate of the new technology were all better than those of the old one, and the moisture absorption rate was reduced with the critical relative humidity up to 70%(25℃), which enhanced the granule stability. Conclusion:The pellet formation rate is improved by the new technology, which effectively solves the problems such as high moisture absorption and poor dissolubility, and the granule quality is improved.
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Optimal excipients were screened by studying the effect of different excipients on the hygroscopicity of the extract, testing polysaccharide in the preparation and blood glucose value. Single factor tests were performed with hygroscopicity, formability and fluidity as the indexes, and the moisture content, granule yield and angle of repose were combined with physical characters of the materials to screen the proportioning and dosage of excipients. Then the critical relative humidity of preferred Yinsang granules were measured. The optimum excipients for Yinsang hypoglycemic granules were mulberry leaf paste-microcrystalline cellulose-mactra veneriformis crude polysaccharides (10∶9∶1.67). The obtained granules had good formability and fluidity, which were not easy to absorb moisture for liquefaction, with a critical relative humidity of 73%. This formation process was reasonable and feasible, suitable for industrial production, which can significantly improve hygroscopicity and liquefaction properties of extracts, improve stability of Yinsang granules, and provide reference for screening of excipients for other preparations.
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OBJECTIVE: To analyze the relationship between hygroscopicity and water solubility of chemical drugs by using nonparametric test. METHODS: Dynamic vapor sorption (DVS) analysis was adopted to determine the hygroscopicity of 515 chemical drugs, and solubility test method was adopted to determine the water solubility of these drugs. All samples were divided into four levels according to their water solubility, and the relationship between hygroscopicity and water solubility was investigated by using Kruskal-Wallis&Wilcoxon rank sum test. RESULTS: There were significant differences in the hygroscopicity of drugs with different levels of water solubility, and the hygroscopicity of level 4 was significantly higher than that of level 1. Hygroscopicity was positively correlated with water solubility. CONCLUSION The hygroscopicity of chemical drugs is interpreted in terms of a physical property in this study, and the results provide an experimental foundation for further studies on the mechanism of hygroscopicity.
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To study the improvement of powder flowability and hygroscopicity of traditional Chinese medicine extract by surface coating modification technology. The 1% hydrophobic silica nanoparticles were used as surface modifier, and andrographis extract powder was taken as a model drug. Three different techniques were used for coating model drugs, with angle of repose, compressibility, flat angle and cohesion as the comprehensive evaluation indexes for the powder flowability. The powder particle size and the size distribution were measured by Mastersizer 2000. FEI scanning electron microscope was used to observe the surface morphology and structure of the powder. The percentage of Si element on the powder surface was measured by energy dispersive spectrometer. The hygroscopicity of powder was determined by Chinese pharmacopoeia method. All of the three techniques can improve the flowability of powder extract. In particular, hygroscopicity of extract powder can also be improved by dispersion and then high-speed mixing, which can produce a higher percentage of Si element on the powder surface. The improvement principle may be correlated with a modifier adhered to the powder surface.
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OBJECTIVE: To investigate the moisture sorption properties of chemical reference substances (CRSs) by using dynamic vapor sorption (DVS) analysis technology in order to establish the distribution conditions, packaging materials, and usages of national chemical reference substances. METHODS: DVS analysis was adopted to acquire the moisture sorption dynamic profiles of five chemical reference substances of different moisture sorption types to evaluate their moisture sorption trend and capacities under different humidities. RESULTS: According to moisture sorption dynamics, we can found the hygroscopicity of disodium etidronate, sodium aminosalicylate, valaciclovir hydrochloride, aspirin and bosentan, and we have given advices about how to use these CRSs and what kind of bottles they should be packed in. CONCLUSION: DVS analysis can be used to record moisture sorption data in real time and visually observe water-CRS interactions under different humidities, which is an important technology for guiding the establishment and distribution of CRSs.