(T1030-09-60) Key Materials Attributes, Process Challenges and Fast-Track Stability Evaluation in Designing the Immediate-Release Formulation for Alzheimer’s and Parkinson’s Disease

Purpose: The purpose of this research was to develop a powder blend for encapsulation using a poor-flowing drug substance indicated for Alzheimer’s disease. The data exhibited herein highlights the foremost challenges in identifying suitable excipients, their interactions, and optimizing the formulation to achieve product characteristics suitable for early clinical trial development.

Methods: Subphases of the prototype development focused on excipient compatibility, blend creation and encapsulation, and product performance, including dissolution and related substances.A compatibility study between the drug substance and nine candidate excipients was conducted under accelerated stress conditions of 60°C/75% RH for 3, 5, and 10 days. Excipients were selected based on physicochemical properties, including particle size, density, and flowability, to ensure optimal in-process performance and blend behavior. Compatibility was assessed to predict potential interactions that could impact the stability and uniformity of the final drug product. Following the excipient selection, three drug product batches were manufactured using a direct blending process in an 8 Quart PK blender and 0.5 cu. ft blender set at 25 rpm followed by manual encapsulation in HPMC Size #1 capsules. The formulations were evaluated for physical appearance and qualitative flowability, blend uniformity, and content uniformity after encapsulation. Material attributes, such as particle size and density of both drug substance and excipients, were correlated with manufacturing performance and product quality outcomes. Finally, in vitro dissolution studies and related substance analyses were conducted to characterize the performance and stability of the final product. Dissolution was performed using a USP Type II apparatus in 900 mL of 0.1 N HCl, stirred at 50 rpm for 45 minutes, with standard immediate release acceptance criteria of NLT 85% in 15 minutes.

Results: Drug substance incompatibility with certain excipients was evident via appearance, where the direct blends adopted a dark red color during incubation, which was later attributed to the presence of metal in the excipients, particularly in lubricants resulting from the chelation between the drug substance and excipients. This color development was most prominent with sodium stearyl fumarate (Figure 1). The excipients with the most favorable compatibility in lubricants were stearic acid, NF and glyceryl di-behenate. Direct blend, encapsulation, and dissolution studies with the compatible excipients, and various ratios thereof, further defined the optimal compositions. Specifically, three batches were created with the following compositions, producing different blend- and content-uniformity values (Table 1). Only the third and final configuration achieved blend- and content-uniformity values with an RSD below 3% and AV of below 10%. Lastly, while dissolution performance of the three batches was recorded at 45 minutes (91, 94, and 102%, respectively), Batch #3 was more prominent and met the immediate release acceptance criteria of NLT 85% at 15 minutes (Figure 2). Based on these results, Batch #3 was selected as the final formulation for confirmation and scaleup studies to support clinical development.

Conclusion: A direct blend formulation containing a poorly flowing drug substance was created with properties and performance suitable for encapsulation. Not only did the final formulation exhibit desired product characteristics and met all acceptance criteria for blend uniformity, content uniformity, and dissolution performance, the excipients selected were shown to be compatible with the drug substance under accelerated stress conditions.

API Excipients compatibility

Formulation composition and BU, CU data

Dissolution data