Pharmaceutical Technology - May 2018

Pharmaceutical Technology eBook - Biologics and Sterile Drug Manufacturing

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Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2018 35 endpoint is established when the sample reaches a constant weight. Points to consider for TGA. TGA measures mass changes as the sample is heated in a controlled en- vironment. Samples should be prepared in a low- humidity glove box. If the TGA is located outside of a low-humidity glove box, the sample should be protected to prevent moisture uptake from the at- mosphere during transfer to the TGA instrument by placing the sample pan in a small glass dish with desiccant and a lid. The common practice of targeting a sample size of 10 mg of lyophilized material in the sample pan can be difficult depending on the sample bulk density. Problems can arise when working with samples that are light and f luffy, or electrostatic. Any variation in the packing of the material and dispensing into the sample pan can have an inf lu- ence on the desorption rate, and therefore, weight loss results. Valuable data can be obtained from the TGA method; adsorbed water can be distinguished from absorbed water, which can be distinguished from the water of hydration or water due to degrada- tion (6). Because a small sample size is appropriate, this method is particularly useful with very small quantities of product. However, analyzing the thermograms can be more diff icult. With larger sample sizes, the weight-loss events on the resulting thermograms are of greater magnitude and more defined, mak- ing for easier detection and analysis. The transi- tions will still be there in a smaller sample size; however, they may lack definition and be more difficult to detect and analyze. Analyzing thermo- grams can be subjective due to challenges defining the start and end point of an event. Karl Fischer titration method. Karl Fischer titration is one of the most widely used analytical methods for residual moisture determination for lyophilized products (7,8). The method is suitable for a variety of dry products and, depending upon the amount of moisture to be measured, has multiple options for the best applicable method. Direct volumetric dispensing of the reagent is suitable for materials that have a relatively high level of residual moisture content in the range of 25–250 mg of water present in the sample. Lyophilized products typically have a low level of residual moisture content; a more sensitive method is warranted. Generating the reagent electrochemically, known as the coulometric method, is considered a micro- method and is best suited when the residual mois- ture content is in the range of 0.5–5 mg of water. The ability to generate the iodine electrochemi- cally allows the method to be better suited for the small quantities of water, such as the levels typi- cally found in lyophilized finished products. Direct Karl Fischer titration is the most commonly used method; however, it may not be the most appropri- ate method for all products. Both the volumetric and coulometric titration methods use the same principle with respect to the chemical reaction to determine the water content. The method is based on the Bunsen Reaction between iodine and water in the presence of excess sulfur dioxide. A detailed description and images of the process can be found online (4). Two main types of titration systems are used to perform Karl Fischer coulometric method: a fritted cell or fritless cell. In a fritted-cell system, the anode and cathode that form the electrolytic cell are separated by a semi-permeable membrane called a diaphragm or frit (Figure 4). The frit pre-

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