Scale-of-agitation methods

The basic principles employed in the preparation of parenteral products do not vary from those widely used in other sterile and non-sterile liquid preparations. However, it is imperative that all calculations are made in an accurate and most precise manner. Therefore, an issue of a parenteral solution scale-up essentially becomes a liquid scale-up task, which requires a high degree of accuracy. A practical yet scientifically sound means of performing this scale-up analysis of liquid parenteral systems is presented below. The approach is based on the scale of agitation method. For singlephase liquid systems, the primary scale-up criterion is equal liquid motion when comparing pilot-size batches to a larger production-size batches. 

The basis of the scale-of-agitation approach is a geometric scale-up with the power law exponent, = 1 (Table 1). This provides for equal fluid velocities in both large- and small-scale equipment. Furthermore, several dimensionless groups are used to relate the fluid properties to the physical properties of the equipment being considered. In particular, bulk-fluid velocity comparisons are made around the largest blade in the system. This method is best suited for turbulent flow agitation in which tanks are assumed to be vertical cylinders. 

To illustrate the actual application of the scale-of-agitation approach to scale-up, the above method was applied to the scale-up of typical injectables solution from 378-L pilot batch to a 3780-L production-size batch. The example product is a Newtonian fluid with density of 1.018 g/cm and a viscosity of 0.0588 g/cm/sec (5.88 cps). The tank used in the manufacturing of the pilot batch had the following parameters ... 

This method can be easily used to show the logic behind the scale-up from original R D batches to production-scale batches. Although scale-of agitation analysis has its limitations, especially in mixing of suspension, non-Newtonian fluids, and gas dispersions, similar analysis could be applied to these systems, provided that pertinent system variables were used. These variables may include superficial gas velocity, dimensionless aeration numbers for gas systems, and terminal settling velocity for suspensions. 

Methods. Initially a range of different nonlonlc surfactant-oil mixtures containing 30 w/w surfactant were screened for their ability to self-emulsify in water at 25 and 37°C. Gentle agitation was provided by a glass stirrer as described by Pouton (liL). The efficiency of self-emulslflcatlon was assessed subjectively on a scale of 1 to 5 (bad to excellent) by visual observation. 

In large-scale industrial applications, emulsion polymerization is carried out in kettles that have adequate means of agitation and are equipped with reflux condensers. If one of the monomers is a gas or a low-boiling liquid, the polymerization is performed in a closed system capable of sustaining the pressure developed as a consequence of the increased temperature. An interesting method to control the temperature is to start with only a part of the batch in the kettle after the reaction has started and the liberated heat of the reaction has caused an increase of the temperature of the kettle content, additional cold monomer emulsion or water is gradually added to keep the temperature at the desired level. 

Nucleation can often be induced by agitation, mechanical shock, friction and extreme pressures within solutions and melts, as shown by the early experiments of Young (1911) and Berkeley (1912). The erratic effects of external influences such as electric and magnetic fields, spark discharges, ultra-violet light. X-rays, 7-rays, sonic and ultrasonic irradiation have also been studied over many years (Khamskii, 1969) but so far none of these methods has found any significant application in large-scale crystallization practice. 

The stirred bed reactor is one method which has been employed on a fairly large scale for agitating a solid reacting with a gas. At the same time it allows the solid to flow from one end of the reactor to the other, and a counter-current system can be used if required. 

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