Switch of tablet manufacturing from high shear granulation to twin-screw granulation using quality by design approach.

This study aimed to transfer a high shear granulation (HSG) process to a twin-screw granulation (TSG) process while maintaining equivalent dissolution profiles. Ibuprofen (IBP) was used as poorly soluble model drug. Granules were obtained by HSG or TSG according to a full factorial design. The liquid-to-solid ratio and wet massing time (HSG) or powder throughput (TSG) were selected as factors. The granules were compressed to tablets with immediate release and a drug load of 50% (w/w). Quality attributes (QAs) of the granules, especially the granule strength (GS), and the resulting tablets were evaluated. The effect of process parameters on the QAs was statistically analyzed. The comparison of HSG tablets with TSG tablets revealed that TSG tablets showed higher tensile strength and lower ejection force than HSG tablets. The dissolution profiles of the tablets in different pH media were also evaluated. Equivalent dissolution profiles in all four media (e.g., f2 values ≥ 54 in pH5.5) were obtained by adjusting process parameters. It was concluded that the GS was the most important QA for dissolution.

Towards better understanding of the influence of process parameters in roll compaction/dry granulation on throughput, ribbon microhardness and granule failure load.

A key quality attribute for solid oral dosage forms is their hardness and ability to withstand breaking or grinding. If the product is to be manufactured continuously, it can be of interest to monitor the hardness of the material at different stages of manufacturing. Using the controlled process parameters of roll compaction/dry granulation specific compaction force, roll speed and gap width, hardness of the resulting ribbons and granules can be predicted. For the first time, in this study two yield variables (corrected torque of the granulation unit and throughput of material) are used to predict the granules failure load. The increase in granule hardness was monitored in-line when the specific compaction force was increased during the compaction process. This opens the way for in-line control of material hardness, and its use for feedback and feedforward control loops for future continuous manufacturing processes.

Exploratory studies in heat-assisted continuous twin-screw dry granulation: A novel alternative technique to conventional dry granulation.

Dry granulation is the preferred technique for solvent-sensitive products, especially drugs with stability problems such as hydrolysis. Twin-screw granulation is a continuous granulation technique, offering a potential alternative to conventional dry granulation techniques such as roller compaction. The major advantage of twin-screw granulation is the ability to adjust process parameters of dry granulation without compromising the compression properties. This study was aimed to perform exploratory studies of heat-assisted continuous twin-screw dry granulation process to formulate sustained release tablets for APIs with different melting points: theophylline, acetaminophen and lidocaine hydrochloride hydrate. Granulation feasibility was studied with different binders (e.g. Klucel™ EF, Kollidon® VA64), sustained release agents (e.g. Klucel™ MF, Eudragit® RSPO) and diluents at various drug loads. The processing conditions were below the melting point or glass transition temperature of the formulation ingredients. After successful granulation, DSC and XRD studies revealed the crystalline nature of the granules and FTIR studies showed no interaction of the API with the excipients. The granules were compressed into sustained release tablets without any compressibility issues. The tablets were stable after testing for 6 months at 25 °C/60% RH. This novel continuous dry granulation technique may offer an excellent alternative to conventional dry granulation techniques.

Impact of Different Dry and Wet Granulation Techniques on Granule and Tablet Properties: A Comparative Study.

Four granulation techniques were compared evaluating their impact on granule properties and the tablet tensile strength. A common formulation was chosen to be processed with both wet and dry granulation techniques: roll compaction/dry granulation, high-shear granulation, twin-screw granulation, and fluidized-bed granulation. The produced granules were characterized in terms of granule size distribution, X-ray powder diffraction, scanning electron microscopy, porosity, and strength. Granules were tableted, and the tablets were evaluated in terms of tensile strength and mass variation. A particular focus was given to granule strength measurements. Granule strength showed to be strongly affected by the used granulation technique. Moreover, a nonlinear inverse correlation was identified between granule strength and tablet tensile strength. High-shear granulation produced the densest and strongest granules, which presented the lowest tablet tensile strength. Granules manufactured by roll compaction/dry granulation showed no loss in tabletability with the used formulation even for the more compacted and strong granules. Tablets produced by the fluidized-bed granulation showed the best properties in terms of tensile strength and mass variation. However, twin-screw granulation presented comparable results for the specific formulation evaluated in the study, thus revealing a great potential of this technique.

The evolution of granule fracture strength as a function of impeller tip speed and granule size for a novel reverse-phase wet granulation process.

The feasibility of a novel reverse-phase wet granulation process has been established previously and several potential advantages over the conventional process have been highlighted (Wade et al., 2014a,b,b). Due to fundamental differences in the growth mechanism and granule consolidation behaviour between the two processes the reverse-phase approach generally formed granules with a greater mass mean diameter and a lower intragranular porosity than those formed by the conventional granulation process under the same liquid saturation and impeller tip speed conditions. The lower intragranular porosity was hypothesised to result in an increase in the granule strength and subsequent decrease in tablet tensile strength. Consequently, the aim of this study was to compare the effect of impeller tip speed and granule size on the strength and compaction properties of granules prepared using both the reverse-phase and conventional granulation processes. For the conventional granulation process an increase in the impeller tip speed from 1.57 to 4.71 ms(-1) (200-600 RPM) resulted in an increase in the mean granule strength (p<0.05) for all granule size fractions and as the granule size fraction increased from 425-600 to 2000-3350 µm the mean fracture strength decreased (p<0.05). For the reverse-phase process an increase in impeller tip speed had no effect (p>0.05) on mean granule strength whereas, like the conventional process, an increase in granule size fraction from 425-600 to 2000-3350 µm resulted in a decrease (p<0.05) in the mean fracture strength. No correlation was found between mean granule fracture strength and the tablet tensile strength (p>0.05) for either granulation approach. These data support the rejection of the original hypothesis which stated that an increase in granule strength may result in a decrease in the tablet tensile strength. The similar tablet tensile strength observed between the conventional and reverse-phase granulation processes indicated that while mechanistic differences exist in the formation of the granules, which resulted in significant granule-scale fracture strength differences, the granule compaction properties at pharmaceutically relevant tableting pressures were unaffected.