Study On PreParation Process And Quality Standard Of Xiao’er Ganmaoning Granules

Xiao’er Ganmaoning Granules is a new form of Xiao’er Ganmaoning Syrup in the market. According to "Methods of Medicine Registration and Management", this product belongs to classification No.8of registration. Xiao’er Ganmaoning Granules is a non-prescribed medicine for cold, and the formula comprises15Chinese medicine materials including Mentha haplocalycis Herba, Schizonepetae Spica, Armeniacae Semen Amarum, Arctii Fructus, Scutellariae Radix, Platycodonis Radix, Peucedani Radix, Angelicae dahuricae Radix, Gardeniae Fructus Tostum, Crataegi Fructus Praeparatus, Massa Medicata Ferment at a Praeparatus, Hordei Fructus Germinatus Praeparatus, Phragmitis Rhizoma, Lonicerae japonica Flos and Forsythiae Fructus. The product has the effects of heat clearing and stopping coughing, and it is used for pediatric wind hot cold such as fever, sweat, sneezes, running noses, sore throats and cough.Since Xiao’er Ganmaoning Syrup was an old product in the market, the weak research basis and lower level process brought some problems. The syrup was easily contaminated by microbes during production and storage, which could cause rancidity, odor, gas and other deterioration. Moreover, sediments as sugar crystals were produced during storage and might affect the product quality. Therefore, preservatives were added into the syrup and that was not good for children’s health. In the other hand, Xiao’er Ganmaoning Syrup was multiple-dose contained as120ml or100ml each bottle, while the dosage was5to20ml each time, these could provide an inaccurate dosage for children. And once it’s been opened, the syrup might be contaminated which causing difficulties in storage and a waste of product.To solve the problems of Xiao’er Ganmaoning Syrup, this project changed the syrup form into granules. The extraction process of the two produces was the same, while the formation techniques had some differences.This project focused on the optimization of extraction and purification process, the formation techniques, the quality standards and stability studies for Xiao’er Ganmaoning Granules.1Study on extraction process for the total volatile oil of Mentha haplocalycis Herba and Schizonepetae Spica.The extraction conditions for the total volatile oil of Mentha haplocalycis Herba and Schizonepetae Spica were examined by the evolution index of extracted volatile oil amount. And the determined extraction process was, add10times water to Mentha haplocalycis Herba and Schizonepetae Spica without soaking, then extract the volatile oil by steam distillation for4hour.2Study on the process of volatile oil inclusionUsing the inclusion yield and inclusion rate as evolution index, the influence of feed proportion, inclusion temperature and agitation time on the inclusion effect had been examined by L9(34) orthogonal design. As the result, the inclusion conditions were determined as, feed proportion was1:8, inclusion temperature was45℃, and stirring for1hour.3Study on extraction process of12Chinese medicine materialsThe extraction conditions were established by the preparation of Xiao’er Ganmaoning Syrup, that was, extracted12Chinese medicine materials including Arctii Fructus, two times (2hour for the first time and1hour for the second time), yet the amount of water was not required. In this project, using extraction rate of arctiin as evolution index, we examined soaking time and water amount, and finally validated the condition as adding10times water to extract without soaking.4Study on technology of preparation and formationUsing one-step pelletization techniques to prepare the granules, to optimize the amount of sugar, molding rate, moisture, dissolubility, bulk density and critical relative humidity were studied as reference indicators. And we used single factor experiment to determine the relative density, feed rate, air inlet temperature and material temperature during liquid extract spraying.It has established the technological parameters for one-step pelletization techniques, that is, the volatile oil, β-cyclodextrin and sugar of the prescription amount is taken and homogeneous mixed in one-step granulator, the relative density of the liquid extract is1.20～1.25(60℃), then add the aqua armeniaca, mix, spray, and proceed one-step pelletization with air inlet temperature80～100℃, feed rate30～50g/min and material temperature50～70℃.5Study on quality standardThe quality standard for Xiao’er Ganmaoning syrup is too simple to control the product quality, that there are only TLC identifications for menthol and nepeta oil and no assay test is required. According to the formula, preparation and major functions, the study of quality standard for Xiao’er Ganmaoning has been carried on. Therefore, Armeniacae Semen Amarum is tested by chemical differentiation, and Mentha haplocalycis Herba, Schizonepetae Spica, Arctii Fructus, Gardeniae Fructus Tostum, Scutellariae Radix, Lonicerae japonica Flos and Forsythiae Fructus are identified by TLC. We also studied the TLC identification methods for Platycodonis Radix, Peucedani Radix, Crataegi Fructus Praeparatus, Phragmitis Rhizoma, whereas for the problem of specificity, the methods will not list into the standard at this stage. Since Lonicerae japonica Flos and Forsythiae Fructus are the main medicine in the formula, according to the China Pharmacopeia2010, the content of chlorogenic acid may not be less than1.5%, and the content of glucoside mignonette may not be less than0.050%in dry Lonicerae japonica Flos. In addition, the content of forsythin in dry Forsythiae Fructus may not be less than0.15%. By this measure, the contents of these two components are not enough for easily detecting after the granule preparation. However, the main function of Arctii Fructus includes evacuating wind hot, moistening the lung and relieving sore-throat, and it is used as an adjuvant drug for wind hot cold, coughing much sputum and sore throat. And the China Pharmacopeia2010requires the content of arctiin in Arctii Fructus may not be less than5.0%. Hence, the assay method is established to test the content of arctiin.6Stability StudyThe stability study was proceeded on three batches of the product with batch number091026,091028and091030. The results showed that in the accelerated test (temperature40℃±2℃, relative humidity75%±5%), the traits, grain size, dissolubility, TLC identification, content and microbial limit all fit the specified requirements in6month. And in the long-term test (room temperature), all the indexes fit the requirements in24month. The results indicate that this medicine is effective within24months, and it needs to seal during storage.Through L9(34) orthogonal experiments, this project studied3main factors influencing the inclusion of Mentha and SpicaSchizonepetae volatile oil, and the3factors were feed proportion, inclusion temperature and agitation time. The sum of squares of deviations, variance and the value F of these3factors were calculated, and then the variance analysis method was used to compare the effect to inclusion of the3 factors. However, due to the small sample size of orthogonal design, there was no significant difference between the results of3factors. Therefore, we finally decided the optimum inclusion parameters by using object analysis method.To sum up, Xiao’er Ganmaoning Granules contain less than0.7g sugar in each gram, and the single dose of the sugar is about1.75g in2.5g granules, which is much less than that in the syrup. Also, the granules has single-dose package, leads to accurate taken dosage. With small size and light weight, the granules are convenient in transporting, storing, carrying and using. As the granules are solid, the quality can maintain stable without preservatives. To ensure the curative effect, the stability of the volatile oil is improved by the process of inclusion with (3-cyclodextrin. Ultimately, one-step pelletization techniques were used to product the granules, and the process of mix, granulation and drying was completed in one step. This technique provides even granules with color consistency, good fluidity, high production efficiency and automatic controlled process. In the meantime, as the granulation process is accomplished in the sealed granulator, the productive process will not be contaminated and the quality of the product will be proved.