Dr. Sandeep Kumar, Formulation Development manager, Colorcon, sheds light on how selecting an excipient in early formulation development is critical to developing a robust scalable SOD formulation and can help the transition from capsule to tablet formulations.
Solid oral dosage forms still represent 50% of all new drug applications over the last three-year period, with 49% of applications submitted in a tablet format, of which 84% were coated, and 24% as capsules. While new dosage form technologies are coming to the market, such as 3D printing or “gummies”, the majority of most drug product manufacturers and patients consider tablets to be the preferred dosage format. However, for early safety and dose ranging studies, dose flexibility in the formulation is key and therefore capsule drug product formulations are considered the most convenient.
In order to reformulate from a capsule to a tablet dosage form, the formulator would need to re-assess the capsule powder blend for flow and tabletability. Sometimes this requires both qualitative and quantitative changes to the excipients used, to enable a robust scalable tablet dosage form. Colorcon propose a pragmatic approach to early formulation development, where multifunctional excipients like Starch 1500, StarCap and StarTab can be incorporated into formulated excipient blends that help to speed up formulation development; and not only provide excellent encapsulation performance, but also enable essentially the same qualitative composition to be utilised for both encapsulation and tablet manufacture.
Developing a scalable tablet formulation requires the same attributes as a capsule dosage form. You need to ensure the drug substance properties such as flow and compressibility are robust and do not change over the drug development cycle. However, drug substance manufacturers often make changes to optimise the manufacturing process, which can lead to changes in the drug substance physical attributes and ultimately result in drug product manufacturing challenges.
Design-space for tablet to capsule development
One of the strategies to help de-risk drug product development and the subsequent transition from capsule to tablet formulations, is to ensure reliable, established suppliers are used that provide high-quality, consistent excipients. Excipients with multiple functionalities, for example Starch 1500 are preferred, which can act as a diluent, binder and disintegrant with moisture scavenging functionality.
At Colorcon we are exploring the concept of using excipient blends with multifunctional ingredients to help customers with early formulation screening and to develop individualised drug products with flexible and scalable manufacturing capability built in.
Typically, starting excipients are selected based on physical attributes for the concept design, and often include 3 parts:
a. Plastically deforming multifunctional material - StarTab (disintegrant/filler/flow aid/binder)
b. Plastically deforming compression enhancer - Microcrystalline Cellulose (filler/dry binder)
c. Brittle deforming material - mannitol (soluble filler).
A matrix of starting compositions with these model excipients has been explored in an experimental design with range 10 to 80% w/w. The inclusion of StarTab in these concepts provides disintegration, flow aid and optional binder functionality, while microcrystalline supports additional tablet tensile strength and mannitol helps mitigate tablet delamination and strain rate sensitivities sometimes associated with plastically deforming materials at high compression speeds.
Figure 1. shows the tabletability profiles of three excipient blends from the experimental design, with StarTab, microcrystalline cellulose and mannitol in various combination. StarTab when mixed with these excipients produces tablets of tensile strength >1.8 MPa and ≤25% strain rate sensitivity (SRS); indicating robust tablets that would be suitable for scale-up manufacture. The strain rate sensitivity (SRS) of these formulations for compression was determined at low speed (2 mm/sec) and high speed (300 mm/sec) and the composition, SRS values and disintegration times are given in Table 1.
Figure 1. Tabletability profile of various blend ratio of StarTab with MCC and mannitol.
Table 1. Compositions of the formulation blends
Figure 2. shows the compressibility profiles (compaction pressure vs solid fraction) of three excipient blends of StarTab with microcrystalline cellulose and mannitol. The data demonstrates that all these combinations have solid fraction of ≤0.9, at nominal compression pressure of 200 MPa, indicating negligible risk of over compression.
Figure 2. Compressibility profile of various blend ratio of StarTab with MCC and mannitol.
Figure 3. shows the compactability profiles (solid fraction vs tensile strength) of three excipient blends of StarTab with microcrystalline cellulose and mannitol. The data demonstrates that for formulation A and B, the tensile strength is higher than formulation C at same solid fraction levels, this is likely due to higher levels of mannitol in the formulation C leading to reduced tensile strength.
Figure 3. Compactability profile of various blend ratio of StarTab with MCC and mannitol.
Overall we see from this work that a balanced formula with a 2:1:1 ratio of MCC : StarTab : mannitol provides a good combination of high tablet strength at low compaction pressures, low strain rate sensitivity and rapid tablet disintegration time.
A tool for rapid drug formulation screening
Excipient choice for early formulation development is critical to develop a robust scalable SOD formulation and formulators often assess a combination of excipients to achieve the desired quality target product profile. This is often a trial-and-error process involving iterative testing. It is also not uncommon in drug development to need to reduce or increase the dose following clinical study outcomes, and this sometimes requires changes to the manufacturing process. Using excipient blends with multifunctional excipients like StarTab could offer several advantages to the formulator, as a qualitatively equivalent formula could be used in both wet or dry processes without concern about drug substance compatibility, thus offering added benefits for manufacturing flexibility.