الفهرس 
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Abstract
The compounds analyzed throughout this work were commonly used in pharmaceutical preparations. These compounds included Vinpocetine, α-tocopheryl acetate, Fexofenadine hydrochloride, Ibuprofen, Methyl Paraben, Propyl Paraben, Hydrocortisone acetate, Pioglitazone Hydrochloride, Rosiglitazone, Glyburide, Glipizide, Gliclazide, Glimiperide, Gliquidone and Repaglinide.
This thesis consists of four chapters:
Chapter 1: was divided into two section:
o A: general introduction about the physicochemical properties as well as structures and pharmacological action of compounds investigated in this work.
o B: General introduction about the quality by design (QbD) concepts in pharmaceutical development and the application of these concepts to the analytical method development as well as the rule of experimental design and computer modeling in QbD frameworks.
Chapter 2:
In this chapter, three-dimensional desirability spaces were introduced as a graphical representation method of design space. This was illustrated in context of application of quality by design concepts on development of a stability indicating gradient RP-HPLC method for determination of vinpocetine and α-tocopheryl acetate in a capsule dosage form. A mechanistic retention model to optimize gradient time, initial organic solvent concentration and ternary solvent ratio was constructed for each compound from six experimental runs. Then desirability function
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of each optimized criteria and subsequently the global desirability function were calculated throughout the knowledge space. The three dimensional desirability spaces was plotted as zones exceeding a threshold value of desirability index in space defined by the three optimized method parameters. Probabilistic mapping of desirability index aided selection of design space within the potential desirability subspaces. Three dimensional desirability spaces offered better visualization and potential design spaces for method as a function of three method parameters with ability to assign priorities to these critical quality as compared with corresponding resolution spaces.
Chapter 3:
In this chapter, robustness was emphasized as an important validation element that may constitute a target for HPLC method development task. Therefore, an improved strategy for calculation of design spaces in RP-HPLC method development was proposed within a quality by design framework. The proposed strategy calculated design space by mapping of probability to pass a simulated robustness testing. In agreement with ICH Q2(R) definition of robustness, the robustness testing was simulated as deliberate shifts in each method parameter following a full factorial design. Additionally, peak location error was propagated to the calculations. The main objective for this strategy was ensuring validity of design space calculated domain regarding method robustness thus complying with quality by design concepts. A test mixture of six compounds differing in physicochemical properties was used. The separation of these compounds was optimized against three experimental parameters; gradient time, pH and ternary solvent ratio and two calculated parameters; initial organic solvent composition and instrument dwell volume. Probability to pass simulated robustness testing
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