Category: Manufacturing and Bioprocessing
Purpose: The growth regime map considers the granule liquid saturation, Smax, and the Stokes deformation number, Stdef, as the two variables that determine the growth regime. While some experimental data have been reported, validation of the regime map boundaries remains elusive. The current study presents a methodological approach for quantifying the boundary between the "nucleation" and "induction" growth regimes.
Methods: A model formulation was employed for the granulation process characterization studies comprising 37.8% cellulose derivatives, 6.4% pregelatinized starch, 1.9% extragranular magnesium stearate, 0.5% sodium lauryl sulfate, and 53.4% model drug substance. The model drug substance has a solubility >9mg/mL across the physiological pH range, and an X90 particle size of approximately 10-15µm.
Granulating liquid properties (aqueous sodium lauryl sulfate) were characterized for surface tension (K100, Krüss GmbH, Hamburg, Germany), viscosity (Discovery HR-2, TA Instruments, New Castle, DE, USA), density (Kimble pyncometer) and contact angle between the binder liquid and powder formulation (Kruss GmbH, Hamburg, Germany).
Wet granulation experiments were performed at 10L and 600L scales. Small scale batches were granulated (10L Glatt Powrex), dried (GEA MP1), milled (Quadro Comil U10) and blended (Creative Design and Machine 3L tumble bin). Full scale batches were granulated (600L T.K. Fielder), dried (Glatt WST-200), milled (Quadro Comil 196S) and blended (Tote Systems 16ft3 tumble bin). Granules were compressed into flat faced round tablets for tensile strength and solid fraction determination (FlexiTab single station press), and also into oval convex tablets (Korsch XL100 or Fette 2090 press). Data were compared across scales using scale-independent terms for binder liquid quantity using liquid to solid ratio (L/S) and impeller speed using Froude number (NFr). Experiments were performed with L/S of 0.45-0.85, NFr of 0.027-0.602
Samples were taken at 0, 25, 50, 75 and 100% of the theoretical liquid addition, and at 1 min increments during wet massing. Samples were characterized for properties including porosity (GeoPyc® 1360, Micromeritics, Norcross, Georgia, USA) and particle size (laser light diffraction).
Results: Smax increased as L/S increased. At 0.55 L/S minimal increase in Smax occurred during wet massing indicating that the granules undergo minimal densification. This is an indication of a slowly deforming system with a long induction period. Increases in L/S to 0.70 and 0.85 result in rank order increases in Smax during wet massing. Minimal growth is observed at 0.55 L/S, with a subsequent rank order of increased particle size with increased L/S and Smax, indicating that at 0.55 L/S the system is predominantly in the nucleation regime, but at L/S >0.70 has transitioned to induction growth. The extent of granule porosity reduction during the wet massing time increased with increasing Smax (Figure-1).
A clear rank order exists with tensile strength reducing greatly with increasing Smax, related to the reduction in granule porosity as a result of induction growth. Granules at 0.55 L/S had tensile strength >3MPa at 0.85SF indicating granules in the nucleation regime, which have a greater percent of fine particles and therefore surface area for bonding, are highly compactible. As the L/S increases and the process moves into the induction growth regime, the tablet tensile strength is greatly reduced with tablets at 0.70 and 0.85 L/S having tensile strength of ~1.8MPa and ~0.35MPa at 0.85SF respectively.
The negative effects of the low compactibility are evident (Figure-2), with the tablets at 0.55 L/S having clear debossing and smooth surface. Tablets at 0.70 L/S showed minor pitting in the surface with the outline of individual granules becoming apparent. At 0.85 L/S individual granules are clearly evident in the surface, consistent with poorly compactible low porosity granules which do not deform sufficiently under compaction.
As Smax increases, or Stdef decreases, the granule porosity decreases. The corresponding tablet tensile strength also decreases. Figure-3 enables visualization of the nucleation to induction regime boundary in its most likely form; as a gradual transition in granule consolidation where the porosity of the granules decreases as additional binder liquid is added to the system, or excess impact energy is imparted onto the granules, leading to consolidation and movement of binder liquid to the granule surfaces.
Conclusion: A novel approach to understanding and defining the boundary between nucleation and induction growth of wet granules has been reported. In particular manipulating the L/S ratio, and monitoring the reduction in granule porosity as a function of wet massing time provides an effective approach to quantitating the boundary. Further analysis of Smax and compactibility data allows a critical granule porosity to be established as a basis for developing a control strategy. The attention to granule porosity allows a mechanistic interpretation of the growth behavior, rather than simply relying upon size measurements. The approach was successfully superimposed onto the existing growth regime map framework, and established that the boundary between regimes is seen as a gradual transition rather than abrupt binary state.