Analysis of the amplification effect of non injection liquid and semi-solid preparation from the microscopic aspect

To enlarge (or reduce) the technological process, the final basis for the manufacturer to make a decision is the economics of the product process, that is, the price of raw materials, the cost of personnel, the cost of equipment related to production and the cost of equipment control If enlarging the production process can reduce the production cost of a single product, it is beneficial from the perspective of economics, which will bring additional economic benefits to manufacturers In this way, process amplification may prompt manufacturers to quickly promote products to the market, or improve the market distribution and response of products, so as to improve the market share of products In the pharmaceutical industry, because of the potential advantages of process amplification, you may think that most pharmaceutical companies will focus on ensuring the completion of process amplification However, the relative lack of published research reports and data related to amplification suggests that this is not the case Of course, on the other hand, we can also think that the lack of public research and data only reflects the need of manufacturers to maintain competitive advantage by means of confidentiality However, the lack of references can also be attributed to the complexity of unit operations in pharmaceutical processing If the pharmaceutical technicians think that amplification is only a proportion problem, that is: amplification ratio = large-scale production rate / small-scale production rate, then to solve the amplification problem can only be said to maintain the work of repeated tests and continuous debugging, rather than solve it through scientific methods In 1998, in a special paper on the amplification of decentralized system, block pointed out that: pharmaceutical process includes many types of unit operations (such as mixing, transfer, etc.), which causes the complexity of production process, and ultimately leads to the inability to calculate the level of production goods from the laboratory or commissioning stage according to simple extrapolation "The successful connection of one unit operation with another limits the functionality of the entire preparation process For each unit operation, it can be scaled up or down However, for the composite manufacturing process, it is not feasible because each unit operation has different effective scaling up Because of this, there are differences between the amplification of unit operation and that of composite operation, which may lead to unexpected problems in the amplification process What's more, some of the problems that don't matter in small-scale processes may be in commodities For example: only when we produce large m-products, we will encounter the problem of product storage and loading and unloading; moreover, heat will be generated during the mass production process, which may exceed the heat dissipation capacity of the system The above problems cannot be predicted through small-scale tests " (example of connection diagram of unit operation and unit operation) in addition, when the operation scale increases, unit operation may become a speed limit step In the mid-1980s, astaritae41 said that "there is no amplification algorithm, that is to say, we can't predict large-scale production process through small-scale results", which summarized the results of all amplification problems Compound unit operation is involved in the production of liquid and semi-solid preparations, which is the clue to solve the problem of enlargement of the two preparations Further investigation of core unit operation shows that the flow state and viscosity in the process can be changed by several orders of magnitude according to the different inspection scope, i.e the micro level (jim-cm) or the macro level (cm-m) To sum up, the key to effective amplification is to correctly evaluate and understand the macro and micro migration phenomena For example, grasp the diffusion and overall flow in the migration phenomenon Diffusion induced transport refers to the characteristic flow generated by micro movement of electrons, atoms and molecules, i.e mass, heat, power and electromagnetic energy flow from high concentration area to low concentration area However, whether advection or convection, the total flow includes the characteristic flow under macro conditions and the whole characteristic flow under artificial (mechanical agitation) or natural (density difference) conditions 1 In the past 40 years, some substantial efforts have benefited a lot from the study of migration phenomenon in liquid and semi-solid and the relationship between amplification and unit operation Specifically, the basic theoretical knowledge based on the computer simulation test and the theoretical model of migration phenomenon has replaced the theory obtained through experience These great achievements come from the first edition of classic monograph published by bird in 1960 In this monograph, the relationship among three main types of transfer (mass transfer, momentum transfer and power transfer) is studied Consistent with the general diffusion equation, all transfer phenomena follow the same model Flow (dimensionless) or the total migration rate per unit area in a certain direction The system characteristic of gradient multiplication can be used to express: in the formula, the concentration of Q (mass, thermal energy and electric energy, etc.) in γ - unit volume, that is, r = q / V; t - time; X - migration distance; accounting for a generalized diffusion coefficient; e - migration gradient or driving force The mass and heat transfer can be expressed by the ratio of each concentration Q to V, in which the concentration of mass m can be directly determined, and the heat concentration needs to be calculated by the following formula: in the formula, C is the specific heat capacity; t is the temperature Assuming that ρ C is constant, then ρ CT term can eliminate ρ C in the generalized diffusion equation, and then determine the heat concentration through temperature According to the analogy of the above method, the time partial derivative can be replaced by its own derivative, so the dynamic transmission can be expressed by the dynamic concentration μ: in the formula, V - Dynamic drillability Considering the effect of pressure and gravity, Navier Stokes relation can be used to control Newtonian fluid dynamics If the flow γ is calculated by three-dimensional space evaluation, it can be expressed by the following formula: Griskeycl points out that in the simplest case, the heat transfer and mass transfer characteristics can be expressed by Fick's diffusion law and Fourier's heat conduction law respectively As vectors, they all have certain strength in three-dimensional space X, y, z direction However, momentum or flow belongs to tensor, and its value needs to be determined by 9 variables, not 3 variables So it is similar to Newtonian fluid law, even in the simplest case of transmission, it also has more complex characteristics: in the formula, the shear stress in the direction of γ YX - X axis; (DVX / dy) - shear rate; η - Newtonian fluid viscosity coefficient That is to say, the solution of generalized diffusion equation is f (T, x, y, z) in the form of parabolic partial differential equation If the phenomenon is more complex (for example, local convection exists in the model), it is more difficult to analyze and solve the generalized diffusion equation However, when the differential equation is transformed into algebraic form, it is easier to get the numerical solution of the equation 2 Transfer phenomenon and its relationship with composite unit operation as mentioned above, all production processes of liquid and semi-solid preparation products include composite unit operation In fact, a large number of facts have proved that composite process is the main unit operation Even its indirect effects, such as heat transfer, may be the basis of the production process However, the mechanical study and quantitative description of the mixing process are still imperfect Nevertheless, reasonable prediction can be made based on sufficient basic principles and empirical data Dynamic mixing equipment presents diversity: mixing impeller is composed of dynamic or moving blades, mainly in the form of propelling scraper, turbine, paddle, spiral belt, vane and screw rod, etc In addition, the number of impeller, the number of blades of each impeller, the pitch of impeller blades and the position of impeller can be adjusted to make the performance of mixing equipment reach a satisfactory level Compared with the style of impeller, the shape of dispersion device or rotor / stator has a stronger effect on the mixing process Not only that, the clubbing operation can also be completed by jet mixer or static mixing equipment Today, the choice of mixing equipment is very confusing, which leads to the inability to achieve effective amplification Although there are more and more kinds of mixing equipment, we can find common problems to compare through the evaluation of mixing rate, degree and flow law In the low viscosity system, the mixing of the soluble liquid is realized through the transfer process, that is, the raw material is transferred to the mixing area (high shear stress or fully mixed area) through the flow (main flow or convection) In other words, the mass transfer of the mixing process depends on the laminar and turbulent flow (numerous whirlpools and gyrations of different sizes) along the known path Most of the high-intensity turbulent mixing occurs in the impeller area, and the flow of liquid drives the fresh liquid into the area To sum up: the characteristics of the mixing process are based on the flow law of the liquid in the mixing equipment Reynolds' classical study of liquid flow in pipes shows that once the critical value of dimensionless ratio variable is exceeded, the flow changes from layer to turbulence This ratio is called Reynolds number, and NRE can be expressed as follows: where, p-density; η - viscosity of Newtonian fluid; v = velocity; l-characteristic length The formula represents the Reynolds number of the impeller; D is the diameter of the impeller; n is the rotation speed of the impeller NRE is the ratio of inertial force to viscous force in the flow process When the flow of the fluid is dominant, the NRE value is higher, on the contrary, when the viscosity of the fluid is dominant, the NRE value is lower Therefore, the transition from laminar flow to turbulent flow is controlled by the density and viscosity of the fluid, the average velocity and the size of the flow area (the diameter of the pipe, the diameter of the settling particles) and other factors For straight cylindrical pipes, when nre4000, there is obvious turbulence When 21000.7), the mixing efficiency will be very low The main reason for the decrease is that the space between the impeller and the wall of the agitator is too small, which makes the path of liquid reflux blocked, and finally leads to the failure of strong axial flow However, in the above case, we can increase the speed of the impeller to enhance the mixing effect, but this process also needs to consider the thickness and angle of the impeller On the contrary, if the value of D / T is too small, the impeller can not produce a proper flow rate in the mixing tank If we consider the behavior of the system as a function of the Reynolds number NRE, we will benefit a lot from the hybrid operation Dimensionless parameters (dimensionless rate, V '= V / Nd; pump suction, NQ = q / Nd3; energy number, NP = (PGC / pn3d5); dimensionless mixing time, t = TMN) are used to represent the logarithmic function of NRE From the formula point of view, although density, viscosity, diameter of mixing vessel and rotating speed of mixing impeller are independent variables, there is an obvious internal relationship between the above variables after the introduction of Reynolds number Mixing time refers to the time required to achieve mixing for a predetermined quality, and mixing rate refers to the speed corresponding to the final state of mixing For a certain preparation equipment, the mixing time TM is determined by the nature of the raw material and the operating variables For the geometric similar system, if the geometric dimension of the system can be changed by a certain ratio, then the mixing time can be expressed by dimensionless number, that is, dimensionless θ m or TMN The Froude number is similar to the NRE number, indicating the ratio of the inertial force acting on the unit area of the liquid to the gravity Only when the density difference exists