Solution and Scale-up Issues

2 Concepts and Phenomenon Involved in a Co-crystallization Process in Solution 

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If the desired yield target cannot be achieved then an antisolvent system can be selected using the same techniques. The antisolvent should be fully miscible with the primary solvent and have a low solubility for the solute. It should be noted that the addition of an antisolvent to reduce solubility and generate supersaturation may introduce scale up issues, caused by the differences in micro-mixing performance between the laboratory and manufacturing plant. 

To summarize, the significant aspects of pharmaceutical scale-up are presented in this book in order to illustrate potential concerns, theoretical considerations, and practical solutions based on the experience of the contributing authors. In no way do we claim a comprehensive treatment of the subject. A prudent reader may use this handbook as a reference and an initial resource for further study of the scale-up issues. 

Currently, after each step in the synthesis process, a sample is analyzed to approve or reject the operation. Not only is this inefficient for the industry in general, this is also a stumbling block for a rapid scale-up. Controls and measurements of the process need to be accomplished in situ, which is again an issue that requires the chemists and chemical engineers to work together toward a solution. It may, in fact, involve lab-on-a-chip technologies and microreactors that were presented by other speakers in this workshop. 

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. 

In the plant used for academic purposes [4], both the solvent and exhausted CO2 are wasted. In an industrial plant both streams should be recycled after purification, for obvious economic reasons. The precipitator size and plant-flow-rates are obtained by increasing 80-fold the relative quantities used in the pilot plant [4]. This scale factor was suggested by the company that supplied the drug. Two vessels, P, in parallel are needed while the former is running, the latter can be cleaned and the solid product can be recovered. Cleaning and product-recovery expenses are not directly evaluated in this example. In the pilot plant, the flow of THF-polymer-drug solution was 0.072 kg/h, and the CO2 flowed in the quantity of 1.08 kg/h (the ratio CO2 to solution equals 15). The precipitator was a 0.4-liter vessel. The actual precipitator scale-up is not considered here. The main factor to consider in scaling-up the precipitator is the nozzle scale-up. The nozzle-size, nozzle-shape, and number of nozzles per reactor volume, determine the precipitate size in a complex and still incompletely understood way [5-8], It is assumed that issues related to the injectors are already solved. 

Absorption of olefin from olefin/paraffin mixtures has been scaled up to the pilot plant scale, and a number of successful trials were performed in the early 1990s. Separation factors of 200 or more were obtained, producing 99.7 % pure ethylene. However, slow degradation of the silver nitrate solution is a problem, and a portion of the recirculating degraded silver nitrate solution must be bled off and replaced with fresh solution continuously. Boundary layer problems on the liquid side of the membrane are also a serious issue in these devices [21]. 

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