Optimizing drug delivery systems using systematic "design of experiments." Part I: fundamental aspects.

Design of an impeccable drug delivery product normally encompasses multiple objectives. For decades, this task has been attempted through trial and error, supplemented with the previous experience, knowledge, and wisdom of the formulator. Optimization of a pharmaceutical formulation or process using this traditional approach involves changing one variable at a time. Using this methodology, the solution of a specific problematic formulation characteristic can certainly be achieved, but attainment of the true optimal composition is never guaranteed. And for improvement in one characteristic, one has to trade off for degeneration in another. This customary approach of developing a drug product or process has been proved to be not only uneconomical in terms of time, money, and effort, but also unfavorable to fix errors, unpredictable, and at times even unsuccessful. On the other hand, the modern formulation optimization approaches, employing systematic Design of Experiments (DoE), are extensively practiced in the development of diverse kinds of drug delivery devices to improve such irregularities. Such systematic approaches are far more advantageous, because they require fewer experiments to achieve an optimum formulation, make problem tracing and rectification quite easier, reveal drug/polymer interactions, simulate the product performance, and comprehend the process to assist in better formulation development and subsequent scale-up. Optimization techniques using DoE represent effective and cost-effective analytical tools to yield the "best solution" to a particular "problem." Through quantification of drug delivery systems, these approaches provide a depth of understanding as well as an ability to explore and defend ranges for formulation factors, where experimentation is completed before optimization is attempted. The key elements of a DoE optimization methodology encompass planning the study objectives, screening of influential variables, experimental designs, postulation of mathematical models for various chosen response characteristics, fitting experimental data into these model(s), mapping and generating graphic outcomes, and design validation using model-based response surface methodology. The broad topic of DoE optimization methodology is covered in two parts. Part I of the review attempts to provide thought-through and thorough information on diverse DoE aspects organized in a seven-step sequence. Besides dealing with basic DoE terminology for the novice, the article covers the niceties of several important experimental designs, mathematical models, and optimum search techniques using numeric and graphical methods, with special emphasis on computer-based approaches, artificial neural networks, and judicious selection of designs and models.