Simulation of roller compaction by combination of a compaction simulator and oscillating mill - A material sparing approach.

This study investigates the feasibility of a compaction simulator and oscillating mill to mimic a roller compactor as a material sparing approach for process development. Microcrystalline cellulose and dicalcium phosphate dihydrate were selected to represent soft and hard materials, respectively. The relative density of ribbons and riblets was determined using a pycnometer and granules size distribution was determined by laser diffraction. Tablet tensile strength and relative density were determined using a hardness tester and pycnometer, respectively. This study showed that the relative density of riblets and ribbons were similar between 1 and 12 kN/cm, which indicates that the compaction simulator adequately mimics the compaction of the roller compactor using a Kp of 1. The size distribution of granules produced by the oscillating mill and roller compactor were similar, which indicates that the oscillating mill adequately mimics the roller compactor when using a similar gap and sieve design. Finally, the tablet tensile strength and relative density were similar independent of the applied granulation method and deformation behaviour of the material. In conclusion, the use of a compaction simulator and an oscillating mill in combination adequality mimics the roller compactor, which ultimately can save large amounts of material and time during process development.

Bench to batch: Linking pharmaceutical powder flow characterisation, intermediate bulk container discharge and video observations.

Five well known excipients and a model drug substance with varied particle properties and bulk behaviour were chosen for the study. Based on the results APAP, NaCMC-XL, mannitol and DCPA were selected for a design to understand the impact of different blends. Two pilot scale unvented IBCs were used in the study. The IBC discharge rates were measured using a catch balance and the mode of flow and powder behaviour inside the IBC was recorded using a camera. The videos inside the IBC showed that regardless of flow mode, for powder to flow from the IBC an air burst was necessary. This was similar to observations when emptying water from a bottle. The extent of the air flow inside the IBC was strong and could possibly result in fluidisation segregation. The discharge curves of 15° and 30° hopper half angles were very similar, which was explained by the vertical air movement in the steeper hopper, which reduces the particle acceleration. Several good indicators of flow/no flow in the IBCs were found. However, for predicting the discharge rate there was a linear correlation between flow through an orifice and IBC discharge rate.

Enhancing tabletability of high-dose tablets by tailoring properties of spray-dried insulin particles.

The oral delivery of proteins and peptides provides an attractive dosing option due to its high patient compliance. However, as oral formulations of such macromolecules require the addition of typically poorly compactable permeation enhancers, the compression behaviour in tableting processes can become challenging. In this study, we show that poor compression behaviour can be overcome by tailoring the properties of peptide or protein particles, especially in high-dose tablet formulations. Spray-dried particles with varying particle size and morphology were produced and characterized. The particles were then evaluated for tabletability in well- and poorly tabletable formulations. Tabletability was found to be enhanced most with small and non-hollow spray-dried insulin particles in both formulations. The enhancement was more pronounced in the poorly tabletable formulation than in the well-tabletable one. Thus, the API particle properties play a key role, when evaluating manufacturability of poorly tabletable formulations.

Faster to First-time-in-Human: Prediction of the liquid solid ratio for continuous wet granulation.

In early development, when active pharmaceutical ingredient (API) is in short supply, it would be beneficial to reduce the number of experiments by predicting a suitable L/S ratio before starting the product development. The aim of the study was to decrease development time and the amount of API needed for the process development of high drug load formulations for continuous twin-screw wet granulation (TSWG). Mixer torque rheometry was used as a pre-formulation tool to predict the suitable L/S ratios for granulation experiments. Three different values that were based on the MTR curves, were determined and assessed for their ability to predict the suitable L/S ratio for TSWG. Three APIs (allopurinol, paracetamol and metformin HCl) were used as model substances in high drug load formulations containing 60% drug substance. The MCC-mannitol ratio was varied to assess the optimal composition for the high-dose formulations. The API solubility affected the mixer torque rheometer (MTR) curves and the optimum L/S ratio for TSWG. The highly soluble metformin needed a much lower L/S ratio compared with allopurinol and paracetamol. A design space was determined for each API based on granule flowability and tablet tensile strength. The flowability of the granules and tensile strength of the tablets improved with an increasing L/S ratio. The MCC-mannitol filler ratio had a significant effect on tabletability for paracetamol and metformin, and these APIs having poor compaction properties needed higher MCC ratios to achieve the 2 MPa limit. The MCC-mannitol ratio had no effect on the granule flow properties. Instead, API properties had the largest influence on both granule flow properties and tensile strength. Based on this study, both the L/S ratio and MCC-mannitol ratio are crucial in controlling the critical quality attributes in high drug load formulations processed by TSWG. The optimum flow and tablet mechanical properties were achieved when using 75:25 MCC-mannitol ratio. Both start of the slope and 2/3 of the L/S ratio at the maximum torque in MTR provided a solid guideline to aim for in a TSWG experiment.

Twin-screw granulation and high-shear granulation: The influence of mannitol grade on granule and tablet properties.

Granule structure has a key influence on tablet critical quality attributes. The ability to control this structure through excipient choice is an important part of formulation development. Mannitol is a popular diluent and the choice of input grade has been shown to impact granule properties. Allopurinol formulations containing two grades of mannitol (Pearlitol 160C and 200SD) were prepared by wet-granulation (twin-screw and high-shear) at different liquid/solid ratios (0.3 and 0.6 g/g). The particle and bulk properties were characterised by a range of techniques and linked to flow performance and tablet tensile strength during compression on a rotary tablet press. During granulation, 200SD underwent a polymorphic transition from a mixture of α and ß to predominantly ß. This transition was accompanied by a morphology change. Mannitol needles were formed, giving more porous granules with a higher specific surface area, which led to poorer flow properties but higher tablet tensile strength. This study concludes that understanding the effect of mannitol grade is a crucial part of formulation selection.

A big data approach to pharmaceutical flow properties.

Flowability is a key consideration during the formulation and process development of oral solid dosage forms as it can have a critical impact on product quality. With a limited number of examples available in the literature, there is a need to better understand and share the typical flow properties of pharmaceutical materials. Here, historical data (3909 experiments) from a shear cell apparatus were extracted and analysed. These data were composed of different material types, including APIs, excipients, blends and granules from nearly a decade of development projects. APIs were found to have poor flow properties (ffc <2), while other materials (excipients, blends and granules) generally had good flow properties. This analysis provided an enhanced understanding of the typical flow properties of pharmaceutical materials. By combining these data with information on the process and achieved drug load, it was possible to characterise our current operating space as a process flow map which could be used to focus future development.

Sucrose/Glucose molecular alloys by cryomilling.

We report here for the first time a series of amorphous sucrose/glucose molecular alloys prepared by cryomilling. Differential scanning calorimetry, X-ray powder diffraction and solution proton nuclear magnetic resonance showed that cryomilling drives a direct transformation from a two-phase mixture of crystalline sucrose and glucose, to a single-phase amorphous sucrose/glucose molecular alloy. The molecular alloys displayed a single Tg which varied linearly with composition. The effect of atmospheric moisture and the possibility of localised melting of the material because of milling-related friction were also discussed.