A multivariate formulation and process development platform for direct compression.

The efficient development of robust tableting processes is challenging due to the lack of mechanistic understanding on the impact of raw material properties and process parameters on tablet quality. The experimental determination of the effect of process and formulation parameters on tablet properties and subsequent optimization is labor-intensive, expensive and time-consuming. The combined use of an extensive raw material property database, process simulation tools and multivariate modeling allows more efficient and more optimized development of the direct compression (DC) process. In this study, key material attributes and in-process mechanical properties with a potential effect on tablet processability and tablet properties were identified. In a first step, an extensive characterization of 55 raw materials (over 100 material descriptors) (Van Snick et al., 2018) and 26 formulation blends (31 material descriptors) (Dhondt et al., 2022) was performed. These blends were subsequently compacted on a compaction simulator under multiple process conditions through a design of experiments (DoE) approach. A T-shaped partial least squares (T-PLS) model was established which correlates tablet quality attributes with process settings, raw material properties and blend ratios. During future development of the DC formulation and process for a new active pharmaceutical ingredient (API), this model can then be used to provide a preliminary formulation and compaction process settings as starting point to be further optimized during development trials based on well-defined raw material characteristics and compaction tests. This study hence contributes to a better understanding on the impact of raw material properties and process settings on a DC process and final properties of the produced tablets; and provides a platform allowing a more efficient and more optimized development of a robust tableting process.

A multivariate methodology for material sparing characterization and blend design in drug product development.

This study developed a material and time saving method for powder characterization. Building on an earlier developed raw material property database for use towards development of pharmaceutical dry powder processes, blends were selected in an efficient way to include maximal variability of the underlying raw material dataset. For both raw materials and blends, powder characterization methods were kept to a minimum by selecting the testing methods that described the highest amount of variability in physical powder properties based on principal component analysis (PCA). This method selection was made by identifying the overarching properties described by the principal components of the PCA model. Ring shear testing, powder bed compressibility, bulk/tapped density, helium pycnometry, loss on drying and aeration were identified as the most discriminating characterization techniques from this dataset to detect differences in physical powder properties. This ensured a workload reduction while most of the powder variability that could be detected was still included. The methodology proposed in this paper could be used as a material-saving alternative to the current "Design of Experiment" approach, which will be investigated further for applicability to speed up the development of formulations and processes for new drug products and building an end-to-end predictive platform.

Prediction of tablet weight variability in continuous manufacturing.

This paper provides a method for prediction of weight variability of tablets made in rotary tablet presses as a function of material attributes and processing parameters. The goal was to be able to predict whether or not a formulation is suitable for direct compaction continuous manufacturing using the tablet weight variability as a criterion. The work focused on identifying the significant factors affecting the weight variability in tablets, within the design space studied. A wide range of blends with different powder properties were prepared. It was shown that among powder properties, cohesion, bulk density, and particle size were the most significant and sufficient material attributes to explain tablet weight variability. A response surface model was built and validated with three different blends. The model is not formulation dependent and can be expanded to include other blend properties or processing parameters effects.

A multivariate raw material property database to facilitate drug product development and enable in-silico design of pharmaceutical dry powder processes.

In current study a holistic material characterization approach was proposed and an extensive raw material property database was developed including a wide variety of APIs and excipients with different functionalities. In total 55 different materials were characterized and described by over 100 raw material descriptors related to particle size and shape distribution, specific surface area, bulk, tapped and true density, compressibility, electrostatic charge, moisture content, hygroscopicity, permeability, flowability and wall friction. Principal component analysis (PCA) was applied to reveal similarities and dissimilarities between materials and to identify overarching properties. The developed PCA model allows to rationalize the number of critical characterization techniques in routine characterization and to identify surrogates for use during early drug product development stages when limited amounts of active pharmaceutical ingredients are available. Additionally, the developed database will be the basis to build predictive models for in silico process and formulation development based on (a selection of) property descriptors.

Lubricant-Induced Crystallization of Itraconazole From Tablets Made of Electrospun Amorphous Solid Dispersion.

Investigation of downstream processing of nanofibrous amorphous solid dispersions to generate tablet formulation is in a quite early phase. Development of high speed electrospinning opened up the possibility to study tableting of electrospun solid dispersions (containing polyvinylpyrrolidone-vinyl acetate and itraconazole [ITR] in this case). This work was conducted to investigate the influence of excipients on dissolution properties and the feasibility of scaled-up rotary press tableting. The dissolution rates from tablets proved to be mainly composition dependent. Magnesium stearate acted as a nucleation promoting agent (providing an active hydrophobic environment for crystallization of ITR) hindering the total dissolution of ITR. This crystallization process proved to be temperature dependent as well. However, the extent of dissolution of more than 95% was realizable when a less hydrophobic lubricant, sodium stearyl fumarate (soluble in the medium), was applied. Magnesium stearate induced crystallization even if it was put in the dissolution medium next to proper tablets. After optimization of the composition, scaled-up tableting on a rotary press was carried out. Appropriate dissolution of ITR from tablets was maintained for 3 months at 25°C/60% relative humidity. HPLC measurements confirmed that ITR was chemically stable both in the course of downstream processing and storage.