(694b) Formulating Amorphous Solid Dispersions into Oral Dosage Forms: A Fast to Market Integrated Approach

A large percentage of new drug candidates in the R&D pipeline exhibit low bioavailability due to limited dissolution in the gastrointestinal tract, which can be improved by formulating them as amorphous solid dispersions (ASD). In an ASD, the poorly water-soluble drug is dispersed within a polymeric matrix, stabilizing the drug molecules in an amorphous state, which is more soluble than the crystalline state. Therefore, the development of oral dosage forms using ASDs has drawn significant attention in the pharmaceutical industry due to its potential for improving solubility of poorly water-soluble drugs, leading to increased dissolution rates and ultimately higher bioavailability. This strategy ensures that patients receive the full therapeutic benefit of the medication

This abstract describes an integrated, lean and material sparing methodology for formulation development of ASD-based oral dosage forms, encompassing (i) selection of ASD formulation, (ii) bridging particle engineering with definition of tablet formulation, (iii) analytical characterization, and (iv) scale-up. A case study will be presented to depict this methodology.

Selection of ASD formulation

The selection of an appropriate stabilizing polymer and drug-to-polymer ratio is crucial to achieve the desired drug dissolution performance and physical stability. This optimization process is tailored to the specific characteristics of each drug aiming at maximizing performance, stability and patient compliance by minimizing table size / number of tablets per day. The physical stability of the ASD is assessed through in silico screening by estimating the drug-polymer miscibility using the Flory-Huggins and machine learning models, the likelihood of phase separation during droplet drying, and the glass transition temperature. Based on API relevant features, the most suitable processing technology, such as hot melt extrusion (HME), spray drying, or co-precipitation, is selected to manufacture the ASD prototypes as intermediate powders that are representative. Finally, the lead prototypes can be chosen based on biorelevant dissolution performance and solid-state characterization, already considering accelerated stability data, to ensure the quality and performance of the final product.

Bridging particle engineering with the definition of tablet formulation

A robust formulation database is essential for risk-based decision-making during the formulation development process. Leveraging prior knowledge on the processing of spray dried intermediates as tablets/capsules and a consolidated empirical database, suitable excipients and their respective concentration ranges can be identified.

For the final tablet formulation, experimental designs, such as factorial designs, are employed to systematically evaluate the impact of ASD attributes, namely particle size distribution and bulk density, on tablet formulation and process development. Typically, not more than four prototypes are necessary to facilitate comprehensive formulation evaluation with minimal material consumption. Moreover, by formulating with representative materials of larger scales, scale-up challenges may be anticipated and mitigated through particle engineering coupled with downstream process development, aiming at low-risk scalability of the developed formulations which is particularly relevant for First-in-Human supply where typically API availability is limited and cost-effective development is of utmost importance.

Analytical characterization

Throughout development, fit for purpose analytical characterization methods are employed to assess the physical and chemical properties of ASD-based oral dosage forms. Imaging methods, such as Raman imaging and micro-CT, offer insights into the distribution of excipients, solid-state characterization, and tablet surface characteristics. Physical attributes, including powder flow, rheology, and solid fraction measurements, provide valuable information for optimizing formulation performance and manufacturability. Furthermore, biorelevant dissolution studies aid in process and formulation optimization by simulating physiological conditions and predicting in vivo performance. This holistic approach to analytical characterization ensures the development of robust formulations with enhanced bioavailability towards consistent therapeutic efficacy.

Scale-up

Computational tools play a pivotal role in accelerating formulation development and optimization processes. Roller compaction modeling offers insights into the process parameters required for direct conversion from slugging to roller compaction, while also highlighting potential challenges such as the loss of compactability using unified compaction curves.

Additionally, compaction simulation studies allow to anticipate and address scale-up issues by simulating large-scale behavior using minimal material. By accurately predicting the behavior of formulations under industrial compaction conditions, potential challenges can be identified and addressed proactively, thereby streamlining the scale-up process.

This presentation intends to show the numerous benefits of an integrated methodology coupled with data-driven tools for pharmaceutical development. Reduction in material consumption and shortened development times are achieved through the optimization of formulation parameters and the utilization of predictive modeling techniques towards reducing the risk for clinical supply. Consequently, ASD-based oral dosage forms are enabled for commercial viability with minimal effort, thereby addressing critical challenges in drug development and enhancing patient access to efficacious therapies.