Up to 90% of the drugs in the pharmaceutical pipeline are classified as poorly soluble according to the Biopharmaceutical Classification System.1,2 Different enabling platforms are available to address low solubility of drugs, among which, amorphous solid dispersions (ASD) have emerged as one of the preferred methods to increase 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 paper will focus on ASD’s obtained by spray drying and the subsequent downstream processing. The link between the spray drying step and the additional operations required to obtain a tablet are often overlooked and opportunities for optimizing the downstream process and drug performance may be lost.
Here, we aim to clarify the interconnection of variables that contribute to the performance of an amorphous solid dispersion in the particle engineering step of spray dryer and the downstream tableting operation. The importance of an integrated development of both the spray dried intermediate (SDI) and the formulation is highlighted.
Formulation of ASD’s
ASD’s 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 in the solid form and inhibit recrystallization during dissolution. Commonly used polymers include HPMCAS, PVPVA and HPMC. Examples of marketed drugs using this platform are listed in Table 1.
Table 1. Commercial amorphous solid dispersions with respective daily dosage and tablet burden.
The data in Table 1 also illustrates the therapeutic doses of commercial ASD’s. The large API loads, combined with the presence of the stabilizing polymer result in a large proportion of the ASD in the final tablet. As a rule of thumb, it can be assumed that the properties of a formulation with less than 30% of ASD will be mostly excipient driven, but this is the exception rather the rule for the majority of ASD tablets. Consequently, often there is a significant contribution of the SDI material attributes on the downstream process and consequently on the final tablet properties. Figure 1 illustrates the excipient ratio as a function of tablet mass for different API ratios in the ASD for a 100 mg tablet. Favorable excipient ratios can only be achieved when the API/polymer proportion in the ASD is large and/or by increasing tablet mass significantly. In many cases, particle engineering of the SDI is required in order to achieve the desired tablet characteristics.
Figure 1. Excipients load in a 100 mg dosage ASD tablet as a function of tablet size.ASD are also typically hygroscopic and moisture sensitive which reduces the feasibility of using wet granulation processes to improve the mechanical properties, commonly used for crystalline formulations. A summary of the main differences between the formulation of crystalline and amorphous API is given in Figure 2.
Figure 2. Main differences for the formulation of crystalline APIs and ASD’s.When considering all aspects of formulating ASD’s, especially given the impact of the ASD properties in the downstream process and bioavailability, integrating process development of the drug product intermediate with the downstream process and formulation becomes critical for maximizing the performance of a drug. The use of Quality by Design (QbD) tools can reduce development time and effort while maximizing information on the interaction of all variables. A diagram illustrating the formulation challenge discussed here is show in Figure 3.
Figure 3. Interacting factors considered for formulation of ASD’s.Optimizing Downstream Performance
When considering the downstream process to formulate ASD’s, both direct compression and dry granulation can be used. Direct compression is preferred due to the sim-plified process stream, but for processing of high dose tablets, this option poses additional challenges. The low density, hollow particles, obtained by spray drying typically exhibit poor flowability 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 material attributes is critical. As an alternative, dry granulation can also be used for densification and granule size increase. A diagram of the processing options is discussed in the following sections and summarized in Figure 4.
Figure 4. Downstream processing options for ASD tablets production.Direct Compression
Particle engineering plays a critical role when direct compression is considered. In spray drying, this can be achieved by two main routes: i) manipulation of droplet size and ii) modifying drying rates. Imposing a fast drying by using high temperatures and low relative saturations lead to spherical particles that exhibit low density, whereas low drying rates result in denser and shriveled particles (Figure 5).
Figure 5. Impact of drying rate in particle morphology.Obtaining large and dense particles would seem the optimal strategy to generate non-cohesive material for a direct compression, however, a compromise must be made in relation to both the limitations of the spray drying equipment and the compactability of the blend. Large droplets exposed to low drying rates can lead to spray lengths of several meters. Large-scale pharmaceutical spray drying units are typically limited to 6 meters height. This poses a physical limitation to the spray length that can be processed. Working at low temperatures may also compromise yield due to accumulation of material with a higher residual solvent content.
Additionally, the larger and denser particles with optimized flowability also exhibit decreased compactability which can compromise physical integrity of the tablets in subsequent processing steps. A compromise between flowability and compactability must be met where the batch uniformity is guaranteed and tablets with appropriate mechanical properties are produced. This is illustrated in Figure 6, where the results of the downstream processing of a set of DoE spray drying trials is shown in terms of tableting performance and spray drying yield. Here, target tablet performance requirements were set as tablet weight variability less than 2.5% and tablet hardness at 20 kN greater than 180N, whereas the target spray drying yield was set to at least 90%.
Figure 6. Probability of matching the (left) target tableting performance and (right) target spray drying yield as function of particle density and size, which can be manipulated via the spray drying process parameters.As can be seen in Figure 6, the target SDI properties for optimal direct compression performance can be obtained by adjusting process parameters. However, this leads to a compromise in the yield of the spray drying process. In turn, maximizing yield requires operating at higher drying temperatures which generate poorly flowing material.
Dry Granulation
The second strategy for the downstream processing of an ASD into a tablet is introducing a dry granulation step. 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 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. A typical design space for the dry granulation is shown in Figure 7.
Figure 7. Probability of matching the target tableting performance in terms of weight uniformity (RSD<1.5%) and tablet hardness at 20 kN compression force (>200N) as a function or roller compaction parameters.The design space illustrates the design goal in roller compaction, which is to maximize granule flow within an acceptable loss in compactability. The optimal processing region is found where the extent of densification of the granules improves weight uniformity with compromising compactability.
Maximizing 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 could result in lower bioavailability. Furthermore, drug release performance of an ASD may be impacted by both the SDI formulation and particle engineering as well as the tablet formulation and downstream processing.
In terms of SDI attributes, dissolution may be impacted by both the particle size, bulk density and morphology of the SDI. Figure 8 illustrates the dissolution behavior dependence on particle size for an HPMCAS based solid dispersion at a loading of 40%. In this example, a change of particle size from 90 μm to 30 μm results in a two-fold increase of the Area Under the Curve using in-vitro biorelevant dissolution (AUCd), which is a significant improvement by particle engineering alone. The AUCd, obtained by integrating the dissolution profiles can be used as a surrogate of drug performance.
Figure 8. Drug exposure (in vitro) dependence on SDI particle size; biorelevant dissolution method in FaSSIF.Another example of the impact of particle engineering is shown in Figure 9. Contrary to the first example, the larger particles tend to yield higher AUCd values. This can be attributed to the dominant effect of the powder density in AUCd observed for this formulation. Larger densities lead to a three-fold decrease in the AUCd, for the range of material properties generated in this example.
Figure 9. Drug exposure (in vitro) dependence on (left) SDI particle size and (right) bulk density for a 50% API in PVPVA ASD.Conclusion
The case studies illustrated in this paper 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 in formulation development and establish the optimal processing conditions and material attributes.
References
- R. Lipp, “The Innovator Pipeline: Bioavailability Challenges and Advanced Oral Drug Delivery Opportunities,” American Pharmaceutical Review, 2013.
- FDA, “The Biopharmaceutics Classification System (BCS) Guidance,” FDA, 2009. [Online]. [Accessed November 2016].