الفهرس 
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Abstract
The objectives of this research were divided into two parts. The first aimed to investigate the pharmaceutical wet granulation process and subsequent manufacturing of tablets of high dose drug formulation in a new gentle-wing high shear granulator using design of experiment approach. Moreover, the relationship between the granulation parameters (i.e. process and formulation variables) and the resulting granules and tablets have been investigated. The second part of this study aimed to explore the influence of process and formulation variables on the homogeneity and content uniformity of low dose drug formulations using gentle-wing high shear mixer during dry mixing, granulation and compression steps. In part I of the current study, experimental designs like full factorial design and a face centered central composite design were applied to investigate the influence of process variables (e.g. water amount, impeller speed, wet massing time and water addition rate) and formulation variables (e.g. binder and disintegrant levels) on critical quality attributes of granules and corresponding tablets produced using a new gentle-wing high shear granulator. Acetaminophen as a high-dose drug was used as a model drug compound and povidone K30 was used as a binder and added to the formulation in a dry state. Granulation experiments were carried out using distilled water as the granulating liquid. The produced granules have been investigated for their size distribution, density and flowability. Moreover, the dried granules were then compressed into 10 mm flat tablets using instrumented rotary tablet press and analyzed for their, weight uniformity, breaking force/ crushing strength, friability and percent capping, disintegration time and in-vitro drug dissolution. Various regression models like linear, two factor interaction and quadratic models were applied to relate the measured responses of granules and corresponding tablets with both process and formulation variables. These models were then used to generate two-dimensional (contour plot) and three dimensional response surfaces (3D surface plot) to be used in the final analysis and predict the optimized granulation variables. Statistical analysis (ANOVA) showed that water amount, impeller speed and wet massing time as independent process variables have significant (p < 0.05) impact on granules and corresponding tablets characteristics. However, addition rate of granulating liquid was the least consequential variable and showed a minimal impact on the granules and tablet properties. With respect to formulation variables, the study also showed that binder and disintegrant concentration have significant (p < 0.05) effect on granules and tablets attributes. Furthermore, the correlations between granules and tablets properties were also demonstrated. Finally, this part of study demonstrates that the effectiveness of high shear wet granulation using gentle-wing granulator could be improved by choosing a proper combination of starting materials and process parameters. Furthermore, understanding the impact of granulation parameters (either process or formulation variables) on critical quality attributes of granules and tablets provides a basis for process optimization and scaling. In part II of the study a 22 full factorial design was carried out to investigate the influence of process variables (e.g. impeller speed, chopper speed, mixing time and sampling location) and formulation variables (e.g. percentage of drug loading) on the homogeneity and content uniformity of low dose drug formulation using a new gentle-wing high shear mixer. Albuterol Sulphate (salbutamol, a ß2 agonist) was used as a model drug in this part of the current work. The albuterol sulphate and other excipients were mixed in a high shear mixer at different impeller and chopper speeds from 0 to 30 mins according to the applied design. At each time point, triplicate samples were taken from 9 different locations in the mixer and the albuterol content was analyzed spectrophotometrically at λmax of 276 nm. The homogeneity of powder blends was verified by calculation of relative standard deviation (RSD) of the drug content at each mixing time. Statistical analysis (ANOVA) showed that impeller speeds and mixing times had a significant (p< 0.05) effect on the homogeneity and content uniformity of the powder blend. Thus, acceptable content uniformity of low dose drug formulation could be attained with the proper selection of impeller speed, chopper speed, and mixing time using gentle-wing high shear mixer. On the other hand, the percentage of drug amount (1% w/w and 5% w/w of microcrystalline cellulose based formulation) have significant (p< 0.05) effect on the content uniformity of powder blends during dry mixing step in gentle-wing high shear mixer as well as significant (p < 0.05) effect on the content uniformity of corresponding tablets during the compression cycle. Furthermore, for 1% w/w and 5% w/w formulations, wet incorporation of the drug in the granulation system provides tablets with an excellent content uniformity and very low RSD (~ 0.61%) during the whole tableting cycle compared to dry incorporation as well as direct compression method. Thus, for low dose soluble drugs like albuterol sulphate, acceptable and highly efficient content uniformity was achieved by dissolving the drug in the granulating liquid and spraying it onto the excipients. Finally, this part of study creates a platform to the formulator in choosing a suitable mixing condition to provide a proper content uniformity for low dose formulation using gentle-wing high shear mixer.