Identifying Critical Binder Attributes to Facilitate Binder Selection for Efficient Formulation Development in a Continuous Twin Screw Wet Granulation Process

Concise overview of the critical binder attributes influencing the binder effectiveness for a poorly and highly soluble formulation

The suitability of pharmaceutical binders for continuous twin-screw wet granulation was investigated as the pharmaceutical industry is undergoing a switch from batch to continuous manufacturing. Binder selection for twin-screw wet granulation should rely on a scientific approach to enable efficient formulation development. Therefore, the current study identified binder attributes affecting the binder effectiveness in a wet granulation process of a highly soluble model excipient (mannitol). For this formulation, higher binder effectiveness was linked to fast activation of the binder properties (i.e., fast binder dissolution kinetics combined with low viscosity attributes and good wetting properties by the binder). As the impact of binder attributes on the granulation process of a poorly soluble formulation (dicalcium phosphate) was previously investigated, this enabled a comprehensive comparison between both formulations in current research focusing on binder selection. This comparison revealed that binder attributes that are important to guide binder selection differ in function of the solubility of the formulation. The identification of critical binder attributes in the current study enables rational and efficient binder selection for twin-screw granulation of well soluble and poorly soluble formulations. Binder addition proved especially valuable for a poorly soluble formulation.

Download the full publication here: Identifying Critical Binder Attributes to Facilitate Binder Selection for Efficient Formulation Development in a Continuous Twin ScrewWet Granulation Process

or continue reading here: Vandevivere, L.; Vangampelaere, M.; Portier, C.; de Backere, C.; Häusler, O.; De Beer, T.; Vervaet, C.; Vanhoorne, V. Identifying Critical Binder Attributes to Facilitate Binder Selection for Efficient Formulation Development in a Continuous Twin Screw Wet Granulation Process. Pharmaceutics 2021, 13, 210. https://doi.org/10.3390/pharmaceutics13020210

Materials

Mannitol 50 C (Pearlitol^® 50 C, Roquette Frères, Lestrem, France) was used as a highly soluble model excipient. Hydroxypropyl (HP) pea starch (Lycoat^® RS 720, Roquette Frères, Lestrem, France), HPMC E5 and E15 (Methocel^®E5 and E15, Dow Chemical Company, Rheinmünster, Germany), maltodextrin with a DE of 12, obtained from maize starch (Lycatab^® DSH, Roquette Frères, Lestrem, France), maltodextrin with a dextrose equivalent (DE) of 2 and 6, obtained from waxy maize starch (Glucidex^® 2 and 6, Roquette Frères, Lestrem, France), polyvinyl alcohol (PVA) 4-88 (Parteck^® MXP, Merck Darmstadt, Germany), PVP K12, K30 and K90 (Kollidon^® K12, K30 and K90, BASF, Ludwigshafen, Germany), and sodium octenyl succinate starch (SOS) CO 01 (Cleargum^® CO 01, Roquette Frères, Lestrem, France) were used as pharmaceutical binders. Magnesium stearate (MgSt VEG E 470b, WIGA Pharma, Hamburg, Germany) was used as a lubricant during tableting.

Conclusions

A thorough study on binder selection for continuous twin-screw granulation was performed. First, binder effectiveness was investigated for a highly soluble formulation (mannitol). Binders with different attributes were selected and were added to the granulation process via the dry addition method. As binders were extensively characterized, their attributes could be linked to binder effectiveness via PCA. Clustered binders on the PCA score scatter plot showing the same binder effectiveness. It was therefore concluded that the behavior of binders during processing depended on their intrinsic physical properties. Additionally, good tablet quality was obtained with all binders, except for HPMC yielding tablets with low tensile strength and high friability.

The second part of the current study showed that binder effectiveness depended on the solubility of the formulation caused by different requirements in terms of processability (L/S-ratio). Binder addition proved especially valuable for a poorly soluble formulation, as bond-forming solely relies on the binder. Moreover, a suitable binder needs to be selected, as the intrinsic binder effect was more pronounced for the DCP formulation. When a highly soluble excipient was used, binder addition was only required to achieve the lowest possible granule friability, as low granule friability was already obtained using the pure excipient (i.e., without binder).

Critical binder attributes influencing the binder effectiveness were identified for a poorly and highly soluble formulation: fast activation of binder properties was of key importance for a highly soluble formulation achieved by fast dissolution kinetics, low viscosity and good wetting properties of the binder. When the binder was activated, good wetting of mannitol by the binder positively affected the binder’s effectiveness. Low surface tension was demonstrated to be important to achieve the lowest granule friability. For a poorly soluble formulation, a low surface tension and a proper binder wetting combined with good wetting properties of dispersive surfaces resulted in high binder effectiveness. In addition, high viscosity attributes and slow dissolution kinetics positively affected the binder effectiveness. It is important to notice that the effectiveness of binders cannot be attributed to only one single binder characteristic but to an interplay of different properties.

The effect of the binder types with the use of a more realistic drug formulation (e.g., containing a high dosage level of paracetamol or ibuprofen) on downstream processing needs further investigation, as binder attributes impact the properties of the final dosage form. Furthermore, drug release profiles should be taken into account. This will guide a scientific-based binder selection when a formulation for processing via TSG is composed.

excipients formulation