The hottest powder mixing from art to science

Powder mixing: from art to science

the mixing of dry powder may be the most common operation process in pharmaceutical production, but this process may also be the least understood. Since the composition of each drug is unique, no two mixing processes are exactly the same. The unpredictability of powder mixing makes engineers try to explain empirical phenomena quantitatively. The Rutgers University research team, led by engineering professors Benjamin Glasser and Troy shinbrot, is working towards this goal

at present, their research has achieved exciting results. First of all, they believe that the longer the mixing time is, the faster the mixing speed is, and it is not necessarily possible to get a more homogeneous mixture. Homogeneous mixtures may form turbulence, resulting in separate stratification of components

in an experiment, researchers found that glass balls of different sizes can form uniform mixing at a lower mixing rate, but when the mixing rate increases, they will be stratified to varying degrees. Researchers were able to identify granular structures that promote the formation of layered structures and affect uniform mixing. Similar phenomena can also be observed and predicted in pollution control and meteorology. But at this point, engineers did not fully understand the meaning of mixing powder or particles. Professor shinbrot explained, "for the properties of particles in the whole range from solid to liquid, we have no corresponding predictive formula for transport and mixing." For liquids, there is a similar formula, which can predict the enhancement of the ability of the transmission and mixing system to deal with trade protectionism. Engineers can also use the improved elastic model to predict similar solid systems and the improved viscous model to predict similar liquid systems

for powder mixing equipment, it needs creativity to establish a model, and at the same time, it also needs to abide by the corresponding rules and a large number of experiments. If the particle size changes slightly, the mixing mode must also be adjusted accordingly, including conventional laminar flow and disordered turbulence mode. "If we can predict the flow pattern in the mixing process, we can design equipment and control the mixing process with a higher degree of automation, and with environmental factors such as humidity, material properties such as particle size and viscosity." Shinbrot added. Almost any mixing mode, such as overturning, ribbon mixing or vibration mixing, can get mixed or separated products according to the changes of particle size, density and shape. In practice, this means that a mixing equipment can get powder aggregates with poor mixing effect or even very dry, but if only a very small amount of water vapor is added to the mixing process, it is possible to get products with good mixing effect

at this point, the only predictable thing in the powder mixing process is the unpredictability of the process, although research shows that this situation may change in the future. These changes can greatly improve production efficiency. Shinbrot also admitted that they do not have the ability to predict at present, so mixed analysis should include repeated experiments after statistical sampling, which is a very risky and inefficient method for concentration sensitive pharmaceutical processes

pat promotes the continuous mixing process

while researchers are committed to the development of prediction systems, suppliers are developing a mixing equipment that can operate continuously, has automatic weighing and feeding characteristics, and advanced analysis means. Compared with the previous process, continuous mixing has obvious advantages, such as less traces, lower cost, less labor required to produce the same product, and also saves processes such as suspension of production, resumption of production, cleaning and replacement. Because this equipment is a straight-line flow system, there are no parts with restrictive mixing equipment such as valves, so the continuous mixing equipment is easier to clean. Steve knauth, the domestic sales manager of Munson machinery company, said that the uncertainty under normal circumstances and the lack of analysis methods hindered the application of continuous mixing technology in the past. The feeding operation did not achieve enough accuracy to ensure that the mixed products were discharged from the terminal. He also mentioned that at present, any manufacturer in any industry can obtain measurable stability in every production and provide appropriate feeding methods as long as they have feeding equipment that can measure the weight

this is very helpful for improving control. After observing, Dr. Thomas chirkot, the laboratory manager of Patterson Kelley, pointed out that with the introduction of more new analytical equipment, it has become very easy to install feedback systems in the middle and end of a hybrid equipment. Users can think that process analysis technology (PAT) has promoted the development of continuous mixing technology. Only minor adjustments are needed to adapt the mixing equipment to the operation of continuous process. On the one hand, the mixing equipment in the past has stopped using, and the model of continuous operation requires upstream and downstream supporting parts and accurate packing equipment. In some cases, mixed products can also be removed by adding a suction system

size is another problem. Due to the low operable capacity and the high capacity required for a large amount of control, knauth said, "the smallest equipment we can produce at present is larger than the size necessary for the pharmaceutical process. The design of the mixing equipment is very critical. At the same time, stable and continuous product measurement during feeding is also very important." He added, "because no matter whether the feeding proportion is correct or not, the mixing equipment will faithfully mix all the raw materials delivered by the feeding system."

the feeding mechanism is gradually improving. K-Tron company achieves the balance of added components by applying load-bearing units and weight loss, providing support for the feeding mechanism for manufacturers of continuous mixing equipment. The lost weight is used to measure the weight loss of the accumulator and the accumulator after charging. When other disturbances occur, software is used to control the balance of other added components. K-Tron's feeding system uses an air vacuum generator to continuously feed the transport accumulator. The rest of the feedback is provided by the process analysis at the output terminal

although intermittent mixing will still dominate in the foreseeable future, pharmaceutical manufacturers have not given up their efforts to develop continuous mixing systems. Chirkot predicts that if the mixing of dry powder is easier to achieve continuous operation, many drug manufacturers will try this technological transformation. Some equipment vendors are preparing for this transformation. Patterson Kelley has been selling continuous mixing equipment for 35 years. The company launched a set of overturned mixing equipment that can adapt to continuous process on April's Interphex. The output of the equipment can reach 100kg/h. Munson machinery also plans to introduce continuous powder mixing equipment for pharmaceutical manufacturers

ultrasonic mixing vs shaking, shaking and rolling

at present, some new mixing processes have also been developed, such as ultrasonic mixing. Jim Cady, vice president of design integration technology (DIT), believes that this process is the first new mixing technology in many years. This technology was invented by macrosonix, a linear motor manufacturer in Richmond, Panama, under a very accidental circumstance. When the company carried out the test of motor design, its engineers noticed that ultrasound could fluidize, overturn and quickly mix solid powder. Since macrosonix has no business about mixing, it has made contact with DIT, which helps to develop and put ultrasonic mixing technology on the market. DIT's ultrasonic mixing equipment uses a multi reluctance linear motor to produce ultrasonic fluidization. Ultrasonic fluidization produces bubbles in the mixing area of powder and high density. The shape of the mixing space helps to concentrate the ultrasonic energy into the mixing area. Some people believe that ultrasonic mixing can quickly adapt to various types of mixing, and the effect is better than technology, including the mixing of particles of different sizes, shapes and special weights. At the same time, unlike mechanical mixing, ultrasonic mixing equipment is more efficient in dealing with powder with higher density than that with smaller density

but this technology also has its limitations. The biggest disadvantage is that the maximum amount of raw materials processed each time can only reach 200L. According to Ronald burr, a developer of macrosonix, the capacity can be increased by adding more linear motors, but the relevant development has not yet achieved results

ultrasonic mixing is not very effective for powder containing water, which may be due to the damage of ultrasonic by water. The current mixing equipment is only limited to intermittent operation applications, but DIT is testing the design of continuous mixing. "This is the future development direction of mixing equipment," Cady said

standard process analysis technology (PAT)

applying process analysis technology (PAT) to powder mixing equipment is one of the main goals of FDA process analysis technology (PAT). There are many clues in the mixing process, which can be decoded by the real-time diagnosis system and applied to the process control, without stopping production, sampling, detecting and restarting the equipment

several companies have conducted research in this field. Spectral dimensions recently launched a pat mixing analysis equipment - mixing monitor. The size of this equipment matches the production of pharmaceutical active ingredients

unlike traditional NIR powder analysis equipment, this hybrid monitor collects near-infrared images rather than point measurements. NIR measures the average mixing characteristics, and spectral dimensions' hyperspectral or chemical imaging can quickly identify and image the arrangement and size of mixed components, so as to obtain more complete information of mixing, and the collection of these information does not need to open the mixing equipment for sampling

hyperspectral imaging can perform three-dimensional imaging of materials. The first and second dimensions are plane coordinates, and the third dimension is NIR spectrum. Compared with single point acquisition, which can only see a little information, hyperspectral imaging can display spatial, chemical, structural and functional information at the same time. Stereoscopic images can be observed through wavelength analysis images, or each point on the image can be analyzed as part of the so-called spatial analysis spectrum

spectral dimensions has previously used this technology to analyze the final product in almost the same way. NIR chemical imaging can quickly determine the distribution of solid drug dosage components and the distribution of excipients and active drug components in capsules. Neil Lewis of spectral dimensions said, "a simple spectrum can only provide measurement information at every point of different wavelengths. On the other hand, chemical imaging can capture all images at many different wavelengths or in a selected series of wavelengths. This is conducive to quickly and effectively determining subtle differences in mixed substances, which are often likely to have a significant impact on the properties of the final product."

the core hardware of the product includes a high-quality near-infrared camera and a set of liquid crystal adjustable filtering equipment for wavelength identification. Strengthen the ability to deal with trade protectionism