Document Type
Dissertation
Date of Award
5-31-2019
Degree Name
Doctor of Philosophy in Chemical Engineering - (Ph.D.)
Department
Chemical and Materials Engineering
First Advisor
Rajesh N. Dave
Second Advisor
Ecevit Atalay Bilgili
Third Advisor
Lisa Axe
Fourth Advisor
Xiaoyang Xu
Fifth Advisor
Yeli Zhang
Abstract
Excipients with good flowability, bulk density as well as compaction properties are desired for use in tableting since they play important roles in formulation development and processing, including, handling, mixing, feeding and compaction. However, it is often difficult to manufacture excipients that simultaneously possess all three desirable properties, particularly if their size is fine. In addition, it is desirable that the excipients promote direct compression of poorly compactable fine cohesive drug powders at sufficiently high drug loading, and not just achieve the desired high functional properties in placebo formulations. This dissertation aims to developed engineered excipients towards this unmet industry need through achieving three major objectives: (1) Applying dry particle coating to develop fine grade of high functional excipients that have these desired properties. (2) Employing commercially feasible dry coating methods for preparing high functional excipients and demonstrating their applicability to developing formulations with fine cohesive and poorly compactable active pharmaceutical ingredients (APIs). (3) Developing a mathematical model to quantify the tablet tensile strength based on materials properties.
To achieve the first objective a material sparing method was used. As-received grades of MCC were dry coated with 1 wt% silica R972P and Aerosil 200, along with selected cases using M-5P. The results indicated that as expected, the bulk density and flowability of dry coated MCCs were significantly improved, while there was an appreciable loss of compaction. To minimize the loss of compaction, attributed to decreased surface energy after coating, while maintaining improved bulk density and flowability, the effect of the type of silica was examined. Remarkably, use of Aerosil 200 led to significant improvements in bulk density and flowability with minimal reduction in compaction. The properties of the surface-engineered excipients were compared with as received and selected commercially available specialized pharmaceutical excipients. It was found that surface engineered excipients have a potential to achieve as good overall performance as any other materials in the market. Further, Avicel PH-102 was used as a model starting material and was milled and coated with two grades of silicas (R972 and A200) using a fluid energy mill (FEM) as a scaling up process to achieve the second objective. More specifically, a new group of high functional excipients with fine particle size were developed by simultaneous micronization and coating with 1 wt% R972 or 1 wt% A200 using FEM as a continuous process technique. It was shown that by carefully controlling the operation parameters of fluid energy mill, the new grades excipients which have improved bulk density, flowability as well as compactibility could be achieved. The results presented in this study have shown that simultaneous micronization and dry coating, which is a solventless, environmentally friendly technique, and continuous process makes it possible for an exemplary fine excipient having a high surface area to achieve good flowability, high bulk density as well as good compaction properties. In addition, the developed high functional excipients were studied for direct compression of binary blends containing fine cohesive poorly-compactable APIs. Avicel PH-105 (20.1 gm) dry coated with 1 wt% hydrophilic silica A200 as an engineered excipient was blended with fine (11.3μm) or semi-fine (30.2μm) Acetaminophen, or Ibuprofen 50 (55.4μm) in binary blends at low, medium and high drug loadings (10%, 30%, 60%). The blend uniformity, bulk density, flowability, as well as tablet properties such as friability, weight variation and strength demonstrate overall better performance compared to blends with Avicel PH-105, Prosolv 50 or Prosolv 90 as the excipient. These results along with processability maps of bulk density vs. FFC and tablet tensile strength vs. FFC indicate dry coated Avicel PH-105 could enable direct compaction for IBU50 and cAPAP at all drug loadings, and up to 30% drug loading for mAPAP. In contrast, Prosolv 90 failed for IBU50 at 60% drug loading, and for mAPAP at all drug loadings. Prosolv 50 could only enable direct compaction for IBU50 at all drug loadings. These unexpected outcomes suggest that for direct compaction of very fine, cohesive APIs at higher drug loadings, surface modified fine excipients perform better. A surprising outcome is the improvement in tablet strength for blends with dry coated Avicel PH-105 compared to uncoated Avicel PH-105 at higher drug loading, especially considering previous works showed that silica dry coating decreases the placebo tablet tensile strength. Lastly, a mathematical model was proposed to quantify the tablet tensile strength based on material properties. The proposed model not only can be used to qualitatively describe the tensile strength of the tablets, but also can be used to predict the tensile strength quantitatively. Limited experiments have been used to validate the proposed model. The results showed a good correlation between the proposed model and experimental results. In conclusion, fine grades of high functional excipients intended for direct compaction, especially at higher loading of fine cohesive and poorly compactable APIs, were successfully developed, accompanied by a mathematical model to quantify the tablet tensile strength based on materials properties.
Recommended Citation
Chen, Liang, "Engineered excipients via dry particle coating" (2019). Dissertations. 1825.
https://digitalcommons.njit.edu/dissertations/1825
