2021-09-15

UV Online Automatic Detection Dissolution System

RT600-UV UV Online Automatic Detection Dissolution System is the latest product launched by Raytor Instruments based on the third generation dissolution operating system. RT600-UV dissolution system includes dissolution apparatus, automatic sampling workstation and UV-Vis spectrophotometer. RT600-UV supports automatic dissolution sampling and automatic UV online detection, which is more convenient for drug research and development and routine detection, and greatly improves work efficiency. (1) Each dissolution vessel has an independent sample colorimetric flow cell and pipe to effectively avoid cross contamination between samples of different dissolution vessels. (2) The dissolution operating system controls the automatic dissolution apparatus, automatic sampling workstation and UV-Vis spectrophotometer, and supports the preset and call of the dissolution UV online automatic detection method. The dissolution system will automatically complete the automatic dissolution sampling and automatic online UV detection according to the preset method. The test results will be fed back to the interface of the dissolution operating system in real time and automatically monitored Automatically generate protected electronic data d0cuments in real time. (3)Raytor's advanced dissolution operating system can ensure full compliance with data integrity requirements, audit tracking requirements, account management requirements and other regulatory requirements. Raytor UV online automatic detection dissolution system has excellent accuracy and stability, and can ensure the accuracy and stability of test results even in the face of harsh test conditions. Accuracy Thanks to the advanced automatic sampling technology of Raytors Instruments, the accuracy of RT600-UV dissolution system can reach a high level. Excellent accuracy can ensure that the UV online test can truly reflect the real-time dissolution of samples, and the test results are more real and reliable. Test Case: Performed manual sampling test and UV online test respectively, and the continuous detected the salicylic acid solution with the concentration of 6, 9, 12,18, 24,36 μg / ml. Taking salicylic acid concentration as X axis and sample absorbance (Abs) as Y axis, established a linear regression curve, and calculated the R square value of each curve was. The results of UV online test showed excellent linear correlation, and the R square value was 0.9995, which had no significant difference from the manual sampling control group (0.9999). Established a linear regression curve using the absorbance (Abs) of the manual sampling control group as the X-axis, and the absorbance (Abs) of the UV online test group is the Y-axis. Its R square value is 0.9996. The results show that Raytor online UV automatic detection dissolution system has excellent accuracy. Repeatability The test results need not only accuracy, but also repeatability. Raytor UV  online automatic detection dissolution system has excellent repeatability to ensure that the UV online test results of continuous automatic sampling are stable and reliable. Test Case: Use RT600-UV dissolution system to continuously perform on-line sampling for 10 times for the sample solution of the same concentration (each sampling interval is 5 minutes). For example, in the sample test group with lower concentration, the relative standard deviation (RSD) of 10 test results is 1.2%, and the difference between the average absorbance of UV online test (0.2916) and that of manual sampling test (0.2904) is 0.4%. The test results fully show that Raytor UV online automatic detection dissolution system has excellent accuracy and stability at the same time. Multichannel UV Online Detection Raytor UV online automatic detection dissolution system can connect 8-channel UV online detection pipe at the same time. Among them, 6 channel pipes are used for online detection of sample dissolution rate, 1 channel pipe is used for blank calibration, and 1 channel pipe is reserved for reference test. Through the operating system, the automatic dissolution test procedure of "drug dosing → test running → sampling →  UV detection" can be simply realized, and the experimental efficiency can be greatly improved. Test Case: Perform dissolution test by using the RT600-UV dissolution system with dissolution parameters as : Basket method; Speed: 100RPM; Dissolution medium: 900ml pure water; Temperature: 37.0 ℃; UV detection wavelength: 257nm. After the automatic synchronous dosing of the sample, the system will automatically sample every 5 minutes and perform UV online detection. The concentration of the sample solution is converted through the absorbance results, and the dissolution rate is further obtained. The test results of sample dissolution rate are as follows: The UV online detection results of different channels are in good agreement, and the sample dissolution can be presented accurately and in real time. Raytor UV online automatic detection dissolution system makes the drug dissolution test more accurate, convenient and efficient.

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2021-09-15

Development and Application of Flow-Through Cell Method in Early Formulation Development

This paper mainly refers to the research papers of Jiang B. Fang et al: Development and Application of a Biorelevant Dissolution Method Using USP Apparatus 4 in Early Phase Formulation Development, summarizes the suggestions on the optimization of the flow cell method and the research cases of the flow cell method in the early formulation development. 1. Introduction to Flow-Through Cell Method In the 1950s, the flow-through cell method was applied to the drug dissolution test of oral preparations. In the 1990s, the flow-through cell method was officially incorporated into the United States Pharmacopoeia and became USP Apparatus 4Compared with the traditional QC dissolution method (basket method / paddle method), the flow-through cell  method has the following advantages:(1) During the whole dissolution experiment of insoluble drugs, good sink conditions can be maintained. (2) It can easily change the dissolution medium and change the flow rate to simulate the conditions in vivo. (3) It can more effectively simulate the hydrodynamics in the gastrointestinal tract. (4) It is suitable for in vitro release test of different formulation, including tablets, capsules, suppositories, powders, etc. (5) The in vivo and in vitro correlation of dissolution test results is better. Many literatures point out that the application of traditional QC dissolution method has certain limitations in guiding the development of early drug formulation. The dissolution test by flow-through cell method is carried out in an environment closely similar to the physiological conditions in vivo, including pH environment, hydrodynamics and duration. Therefore, the test results of flow-through cell method have potential ability to predict the bioavailability of drugs in vivo. 2. Optimization of  Flow-Through Cell Method (1)Flow RateThe flow rate of dissolution medium is generally recommended to be in the range of 4 ~ 16ml / min, although higher flow rate can and has been adopted. In this study, the flow rate is 8ml / min (22.6mm diameter cell), and its average flow velocity is about 0.00033m/s, which is considered to be close to the flow velocity of fluid in the body (for example, the velocity of intestinal fluid is generally 0.0002 ~ 0.0008 m/s). In addition, the research literature does not recommend the use of lower flow rate. When the flow rate is lower than 6 ml/min, the dissolution curve becomes more unstable. A similar phenomenon was observed when a small flow-through cell with a diameter of 12 mm was used. This may be due to the decrease of hydrodynamic flow uniformity due to low flow rate. (2)Dissolution MediumFour standard biologically relevant dissolution media were used: SGF, SIF, FeSSIF and FaSSIF, which represent similar pH and components under gastric, intestinal, fasting or eating conditions, respectively. Generally, SGF is used first, and then SIF is switched. FeSSIF and FaSSIF are used instead of SIF when food impact assessment is required. (3)Other Method ParametersThe bottom of the flow-through cell is filled with glass beads with a diameter of 1mm; A 0.7 µm filter is installed on the top of the flow-through cell; Use glass wool when necessary to reduce back pressure, etc. 3. Research Cases The research literature lists four research cases using flow-through cell: Research Case 1: Batch to batch variability The API a of research case 1 is BCS Class II compound, weakly basic, and the pKa value is 1.5. It was prepared into 10mg immediate release (IR) tablets for early clinical research. The dissolution results of the original clinical supply batch (Lot 1) tested by theflow-through cell method are very similar to the in vivo plasma concentration curve of the clinical study of this batch. However, when the QC dissolution method (paddle method, 900 ml, 0.1 N HCl, 50 rpm) was used, it was found that the in vitro dissolution rate of remanufactured product Lot  2 of the same formula was slightly slower than that of original Lot 1. Since the quantitative standard of in vitro release has not been established in the early stage of clinical development, it is difficult to determine whether Lot 2 is suitable to continue as a clinical supply batch. The results of flow-through cell method showed that the in vitro release of Lot 2 was significantly different from that of Lot 1. Compared with the original batch (Lot 1), the cumulative dissolution rate of compound A was only 60%. The preclinical crossover study of these two batches was conducted with beagle dogs. The results showed that the C max of Lot 2 decreased by about 70% and the AUG decreased by about 65%, which further confirmed the test results of the flow-through cell method. Research Case 2: Effect of pH Regulator The main drug component B of research case 2 is BCS Class II compound, methanesulfonate, with a pKa value of 5.1. Both formulations (Lot 2 and Lot 3) used fumaric acid as pH regulator, in which Lot 2 contained 15% fumaric acid (intragranular) and Lot 3 contained 20% fumaric acid (intragranular 15% and extragranular 5%). Two other formulations without pH regulators were used as the control group (Lot 1 and Lot 4). When SGF was used first and then the dissolution medium was changed to SIF, the dissolution results of flow-through cell method showed that all four formulations had similar concentration and time distribution curves and similar cumulative dissolution rates. Several pharmacokinetic studies (male beagle dogs) also showed that there was no significant difference in AUC of all tested formulas, which was in good agreement with the in vitro data. However, when SIF is used as dissolution medium alone, there is a significant difference in the dissolution results of flow-through cell method between the formulations with and without pH regulator, and Lot 2 and Lot 3 are significantly higher. The results show that if the drug will disintegrate and release in the environment with low pH (strong acidity), such as in the stomach, the weak acid may not play the expected role of improving drug bioavailability as a pH regulator. If the drug is released at a higher pH (neutral or alkaline), the use of weak acids as pH regulators can play the expected role. Research Case 3: Influence of Formulation Design and Excipients The main drug component C of research case 3 is BCS Class II compound, weak acid, with pKa values of 4.0 and 7.9. The excipients of the two formulations are similar but slightly different: Lot 1 formulation uses microcrystalline cellulose (pH 101), lactose monohydrate (impalpable 313) and HPMC; Lot 2 formulation used microcrystalline cellulose (pH 102), lactose monohydrate (fastflo 316), and no HPMC. The results of the two formulations using the traditional QC dissolution method are very similar. However, the test results of flow-through cell method show that the in vitro dissolution result of Lot 1 is much better than that of Lot 2, so it is predicted that the in vivo performance of Lot 1 will be better than that of Lot 2. This in vitro prediction result was later confirmed by non clinical in vivo pharmacokinetic data: Although the T max values of Lot 1 and lot 2 are similar, Lot 1 has about 3 times larger C max value and about 4 times larger Aug value than Lot 2. Research Case 4: Assessment and Prediction of Food Impact The effect of food on the absorption and bioavailability of small molecule drugs is one of the key factors to be considered in the process of drug development. In the early stages of development, it is necessary to understand and predict the impact of food to maximize drug bioavailability and help design the most effective animal and human clinical studies. By comparing the test results of FeSSIF and FaSSIF as dissolution medium, the flow-through cell method can be used to eva1uate the effect of food in vitro. The research literature shows the results of in vitro food impact assessment of lansoprazole rapid disintegration tablets and danazol capsules. Lansoprazole has better bioavailability in fasting state, which is consistent with the test results of flow-through cell method. At the same time, it can be found that the in vitro dissolution curve of flow-through cell method under fasting state is very similar to the in vivo blood drug concentration curve (as shown in the figure below). For danazol, it is reported that its bioavailability after eating is at least three times higher than that during fasting. The in vitro dissolution test results of flow-through cell method (as shown in the figure below) are consistent with this conclusion. Summary The authors use the in vivo bioavailability results of commercially available drugs to guide the development of flow-through cell dissolution method, so as to ensure that the selected method parameters, such as flow rate, are optimized in hydrodynamics. This method is a biologically related in vitro dissolution method with standard parameters and has high universality. Since there is no need for a large number of product specific development, this not only saves the development time of the method, but also directly tests the powder or particles without using the dosage form in the early stage of compound development. The flow-through cell method can effectively study the drug release in vitro in biological related environment, and predict the in vivo performance of different types of drug compounds and solid oral dosage forms.

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