In this webinar, the importance of an integrated development of both the spray dried intermediate (SDI) and the formulation, is highlighted. By bridging particle engineering of the drug product intermediate and the final dosage formulation, one is able to perform a concurrent optimization of drug performance and process performance, with respect to yield, throughput and process robustness throughout the process train. This is achieved by using QbD tools, such as Design of Experiments and mechanistic modelling, to integrate all the competing factors in formulation development, and establish the optimal processing conditions and material attributes.
Up to 90% of the drugs in the pharmaceutical pipeline are classified as poorly soluble according to the Biopharmaceutical Classification System. Different enabling platforms are available to address low solubility of drugs, including lipid formulations, size reduction, complexation with cyclodextrins and amorphous solid dispersions (ASDs). Among these, amorphous solid dispersions have emerged as one of the preferred methods to increase the aqueous solubility of drugs. Amorphous solid dispersions can be obtained by combining an API with a stabilizing polymer using hot melt extrusion, spray drying or co-precipitation, among others. This webinar will focus on ASDs obtained by spray drying, which is one of the most versatile processes to obtain ASDs since it is a continuous, scalable and commercially demonstrated process that can also be used for particle engineering. ASDs are typically formulated as tablets for oral delivery. Formulation of an ASD presents a different set of challenges from the ones encountered when formulating crystalline APIs. This is both due to the presence of the stabilizing polymer and the need to provide a complete release of the API without inducing recrystallization. The purpose of the polymer in the dispersion is to stabilize the amorphous state of the API and inhibit recrystallization during dissolution, and the polymer is often present in larger quantities than the API. Commonly used polymers include HPMCAS, PVPVA and HPMC. The large ASD load added to the vastly different material properties of ASD formulations also limits the feasibility of platform approaches to tablet formulation development, often employed for low drug loading tablets. ASDs are typically hygroscopic and moisture sensitive which reduces the feasibility of using wet granulation processes to improve the mechanical properties, commonly used for crystalline formulations.
When considering the downstream process, both direct compression and dry granulation can be used for ASDs. Direct compression is preferred due to the simplified process stream, but for the formulation of high ASD load tablets, this option poses additional challenges. The low density of hollow particles obtained by spray drying exhibit poor flow which results in variable die filling performance and tablet weight. In order to obtain an adequate direct compression performance with an ASD formulation, optimizing the spray dried particles is critical. As an alternative, dry granulation can be used for densification and granule size increase. The use of a granulation technique that compacts the SDI into a ribbon, which is later milled, for obtaining granules mitigates the adverse impact of the SDI attributes on the downstream process. In this case, the spray dryer development can be focused on improving throughput and yield, while the optimization of the tableting operation is achieved through the fine tuning of the roller compaction parameters. A disadvantage of roller compaction is the loss in compactability resulting from work hardening. Again, a compromise must be met where the densification level is adequate for achieving tablet weight uniformity without compromising compactability.
Concerning drug exposure, for traditional immediate release dosage forms based on crystalline drugs, maximizing the dissolution performance focuses on ensuring complete dissolution of the drug within a defined time period. In the case of an ASD-laden tablet, one must also take into account that the amorphous solubility is metastable and the drug will eventually recrystallize, which ultimately limits bioavailability. Furthermore, drug release performance of an ASD can be impacted by both the SDI formulation and particle engineering as well as the tablet formulation and downstream processing. The case-studies illustrated in this webinar demonstrate how particle engineering can influence the performance and downstream process of an ASD and the importance of integrating spray drying with downstream process development for maximizing the potential of this solubilization platform. The use of QbD tools such as Design of Experiments and mechanistic modelling can be used to integrate all the competing factors and bridge particle engineering and the final dosage formulation to establish the optimal processing conditions and material attributes.
Key Learning Objectives:
- Specific aspects of formulating amorphous solid dispersions into oral dosage forms
- Impact of spray dried dispersions properties in downstream processing
- Optimization strategies for downstream processing of amorphous solid dispersions
Keywords: Amorphous Solid Dispersions, Spray Dried Intermediate