The impact of stress history of deformable dry granules on the mechanical properties of tablets

A mechanistic understanding of the relationship among the granule composition, individual granule property, downstream robust processing, and the final tablet attributes is critical for rational development of a quality tablet. However, in the dry granulation literature, milled granules that are polydisperse in solid fraction, size, and shape are extensively used for compaction studies. Thus, the effect of an individual granule property or an individual component on the compaction properties of dry granules was not adequately separated. To advance the mechanistic understanding of the effect of dry granulation on tensile strength of tablets, individual granule properties such as size, solid fraction, and granule composition need to be decoupled, precisely controlled, and independently varied. To accomplish this, in this thesis, small cylindrical biconvex compacts of powder were used as model dry granules for compaction studies, which have the advantage of being monodisperse in both size and solid fraction. In addition, size and solid fraction of monodisperse granules and their composition were independently varied and precisely controlled. The novel use of monodisperse granules brings a new perspective on understanding the compaction properties of deformable dry granules. The effect of granule size and solid fraction on tensile strength of tablets was deconvoluted using monodisperse granules as well as milled granules of microcrystalline cellulose (MCC). A strong linear relationship (with negative slope) exists between the tablet tensile strength and granule solid fraction. In contrary to popular perception, granule size has no statistical impact on the tablet tensile strength. A smooth or rough fracture surface of tablets prepared from low or high solid fraction granules, respectively indicates differences in fracture of the tablets. ^ Subsequently, a novel method was developed to map the fracture surfaces of tablets. The proportion of intra-granular versus extra-granular fracture of tablets was quantified by image analysis. Low solid fraction granules deform extensively, neighboring granule surfaces intermingle closely, and produce homogeneous tablet matrices. At a high deformation potential (defined as, tablet solid fraction - initial solid fraction of the packed granule bed), tablets fracture indiscriminately both intra-granularly (fracture of individual granules) and extra-granularly (separation of neighboring granules). In contrast, at a low deformation potential, tablets preferentially fracture extra-granularly. The proportion of intra-granular fracture is a function of the deformation potential only. Tensile strength of tablets increase nearly linearly with the deformation potential and the slope of the linear relationship is larger for higher tablet solid fraction. At or below the critical deformation potential the tablet structure is not coherent and it does not fracture intragranularly. ^ Calibration of the Drucker Prager Cap (DPC) model parameters provides a means for a deeper understanding of the impact of dry granulation, granule SF, and granule composition (MCC/mannitol ratio) on the compaction properties of granules. MCC of any granulation status requires the same in-die compaction stress state for densification to a given tablet solid fraction. Only cohesion of materials and tensile strength of tablets are a strong linear function of MCC granule solid fraction. However, properties such as cohesion and diametrical tensile strength go through a maximum as the mannitol level increases in the binary granules, and clearly do not follow the linear mixing rule. Other properties either approximately follow the linear mixing rule (e.g., hydrostatic yield strength, young\u27s modulus and Poisson’s ratio) where some interactions between the constituents are present, or not sensitive to the composition (e.g., internal angle of friction). In general, the properties of a multicomponent system may not be precisely estimated from the properties of individual components, simply by using the linear mixing rule

Effects of the granule composition on the compaction behavior of deformable dry granules

Calibration of the Drucker Prager Cap (DPC) model parameters provides a means for a deeper understanding of the impact of granule composition on the compaction properties of dry granules independent of their solid fraction (SF). In this study, monodisperse granules of mixtures of microcrystalline cellulose and mannitol (0%, 25%, 50%, 75% and 100% mannitol) prepared as small cylindrical compacts with well-defined size, shape and SF (0.58) were used as model dry granules. DPC parameters--namely, cohesion, internal friction angle, cap eccentricity, and hydrostatic yield strength of materials--were determined from the diametrical and uniaxial compression, and in-die compaction tests. Elastic properties such as Young’s modulus and Poisson’s ratios were also determined from the in-die compaction test. Higher level of MNT in granules required a lower compression pressure to obtain a low SF tablet but higher compression pressure to obtain a high SF tablets. Properties such as cohesion and diametrical tensile strength go through a maximum as the mannitol level increases in the binary granules, and clearly do not follow the linear mixing rule. At an industrially-relevant tablet solid fraction of 0.88, granules with 75% mannitol exhibited the highest cohesion, and produced the strongest tablet. Other properties either approximately follow the linear mixing rule (e.g., hydrostatic yield strength, young's modulus and Poisson’s ratio) where some interactions between the constituents are present, or not sensitive to the composition (e.g., internal angle of friction). In general, the compaction behavior of granules of a multicomponent system may not be precisely estimated from the properties of individual components, simply by using the linear mixing rule

Compaction mechanics of plastically deformable dry granules

To improve the understanding of how dry granulation and in particular, granule solid fraction (SF) impact the compaction behavior of plastically deformable microcrystalline cellulose (MCC), in this study, the Drucker Prager Cap (DPC) model parameters were calibrated using monodisperse MCC dry granules as model granules. Dry granules were produced as directly compressed small cylindrical compacts of MCC with SF in the range of 0.40 to 0.70 which were monodisperse in both size and SF. Virgin MCC powder and granules were compressed into tablets with SF in the range of 0.70 to 0.90. The DPC parameters (cohesion, internal friction angle, cap eccentricity, and hydrostatic yield stress), Young's modulus and Poisson's ratio were experimentally determined from diametrical and uniaxial compression, and in-die compaction tests. Results showed that calibration of the shear failure surface only may be adequate for MCC granules when the DPC model is completely calibrated for virgin MCC. Increasing granule SF significantly decreased the cohesion only. All other parameters were impacted by the tablet SF only. In the 2D yield surface, only the shear failure surface expanded as the granule SF increased. MCC of any granulation status requires the same in-die compaction stress state for densification to a given tablet solid fraction

The Lepton Flavour Violating Higgs Decays at the HL-LHC and the ILC

Run-I results from the CMS collaboration show an excess of events in the decay h → μτe with a local significances of 2.4σ. This could be the first hint of flavour violation in the Higgs sector. We summarise the bounds on the flavour violating Yukawa couplings from direct searches, low energy measurements and projected future experiments. We discuss the sensitivity of upcoming HL-LHC runs and future lepton colliders in measuring lepton-flavour violating couplings using an effective field theory framework. For the HL-LHC we find limits on BR(h → μτ ) and BR(h → eτ ) ≲ O(0.5)%O(0.5)% and on BR(h → eμ) ≲ O(0.02)%O(0.02)% . For an ILC with center-of-mass energy of 1 TeV we expect BR(h → eτ) and BR(h → μτ ) to be measurable down to O(0.2)%O(0.2)%

Dextrose monohydrate as a non-animal sourced alternative diluent in high shear wet granulation tablet formulations

<p>The feasibility of dextrose monohydrate as a non-animal sourced diluent in high shear wet granulation (HSWG) tablet formulations was determined. Impacts of granulation solution amount and addition time, wet massing time, impeller speed, powder and solution binder, and dry milling speed and screen opening size on granule size, friability and density, and tablet solid fraction (SF) and tensile strength (TS) were evaluated. The stability of theophylline tablets TS, disintegration time (DT) and <i>in vitro</i> dissolution were also studied. Following post-granulation drying at 60 °C, dextrose monohydrate lost 9% water and converted into the anhydrate form. Higher granulation solution amounts and faster addition, faster impeller speeds, and solution binder produced larger, denser and stronger (less friable) granules. All granules were compressed into tablets with acceptable TS. Contrary to what is normally observed, denser and larger granules (at ≥21% water level) produced tablets with a higher TS. The TS of the weakest tablets increased the most after storage at both 25 °C/60% RH and 40 °C/75% RH. Tablet DT was higher for stronger granules and after storage. Tablet dissolution profiles for 21% or less water were comparable and did not change on stability. However, the dissolution profile for tablets prepared with 24% water was slower initially and continued to decrease on stability. The results indicate a granulation water amount of not more than 21% is required to achieve acceptable tablet properties. This study clearly demonstrated the utility of dextrose monohydrate as a non-animal sourced diluent in a HSWG tablet formulation.</p