Use of a Platform Formulation Technology to De-Risk Solid-State Variation in Drug Development

Active pharmaceutical ingredients (APIs) can exist in multiple crystal forms, known as polymorphs, that are chemically identical. Polymorphs of an API can appear over the course of development and lead to deviations across batches affecting stability, tableting properties, flowability, solubility, and release kinetics, and may ultimately result in a change in processability and drug (product) performance. These changes must be identified and addressed and as such, can have a significant impact on the success of the program, project timelines, and the investment of resources. While crystal structure prediction techniques can be used to identify possible polymorphs, their stability and morphological differences, especially the presence of unstable polymorphs, must be addressed to ensure product efficacy and safety.

A study by Cordeiro, et al., determined whether different formulation strategies could be used to stabilize molecules such as menthol which have a high polymorphism risk and a high risk of recrystallizing from the amorphous form.1 Results of the study demonstrated a robust stabilization of menthol molecules by absorption onto the surface of a mesoporous silica carrier.

This white paper describes use of mesoporous silica as a porous carrier formulation technology to stabilize unstable polymorphs and to optimize solid state properties. The strategy can be used across a broad range of APIs and can thus serve as a platform technology for consistent particle properties leading to more efficient formulation development processes.

Mesoporous Silica as a Carrier for Unstable Polymorphs

Parteck® SLC excipient is a mesoporous silica that can serve as a porous solid carrier for formulations of APIs in which unstable polymorphs may be present. The excipient is based on silicon dioxide and is generally regarded as safe (GRAS) by regulatory authorities. The silica particles have a D50 of 17–25 µm with a bulk density of 0.32 g/mL, which can be increased when loading an API within the pore structure. Parteck® SLC excipient by Merck offers a very large surface area of 500 m2/g which is essential for performance as a carrier and has a very small average size of approximately 6 nm disordered pores which are essential for sterically stabilizing the amorphous form of APIs (Table 1).

Table 1.
Properties of Parteck® SLC mesoporous silica.
Chemical formula: SiO2
Pharmacopoeial monograph: Silicon Dioxide (USP) and Silica,
colloidal hydrated (Ph. Eur.)
Regulatory status: Generally Regarded As Safe (GRAS)*

* By the U.S. Food and Drug Administration
** Parteck® SLC loaded with 30% ibuprofen.
Density is increased upon loading with API.

Stabilization Mechanism

The API is stabilized in the amorphous form due to its interaction with the carrier via the large surface area (Figure 1). The risk of detecting another polymorph during the development phase is reduced because the amorphous stabilization prevents crystallization.

To demonstrate the stabilization mechanism of mesoporous silica, fenofibrate, a poorly soluble molecule, was loaded onto Parteck® SLC excipient using the impregnation method; fenofibrate was dissolved in acetone. The differential scanning calorimetry (DSC) graph in Figure 2 shows that the fenofibrate was present in its amorphous state when loaded on the Parteck® SLC excipient at 30%.  As a reference, the crystalline API was included in the analysis. If the API is present in its crystalline solid-state, a melting endotherm occurs, as indicated by a downwards spike; if the API is within its

 amorphous form, this spike does not occur.

A range of APIs with different chemistries, hydrophobicities, and molecular weights have been stabilized in the amorphous form by loading onto the Parteck® SLC excipient (Table 2). Parteck® SLC excipient is also a best-in-class technology for stabilizing amorphous forms of molecules which tend to recrystallize (poor glass former; GFA-I molecules such as carbamazepine) and are particularly difficult to formulate.2

Improving Galenical and Particle Properties

As shown in Table 2, APIs with different chemistries
and physiochemical properties can be stabilized in
their amorphous state using Parteck® SLC excipient.
The following studies investigated the effect of
loading various APIs onto Parteck® SLC excipient on
critical properties of the solid formulation process
such as particle size, flowability, and compression.
Results demonstrated that the technology can be
used across different APIs to improve solid state
performance. Consistent particle properties opens

up the opportunity to use Parteck® SLC excipient as
a platform technology in formulation development to
improve process performance, formulation process
efficiency, and drug performance.
A series of different APIs were loaded onto Parteck®
SLC excipient and the resulting particle size determined
to evaluate whether the excipient can be used
successfully independent of the API and in the same
formulation composition. The results showed that a
similar medium particle size was achieved, regardless
of the API, which is a prerequisite for use of the
technology as general formulation approach (Figure 3).