Jon Hilden

R-curve behavior in alumina-zirconia composites with repeating graded layers

Abstract The single-edge-V-notched-beam testing geometry was used to measure the crack growth resistance (R-curve) behavior of multilayer graded alumina–zirconia composites for crack extensions parallel to the graded direction. Fracture mechanics weight function analysis was applied to explain the R-curve behavior of a compositional and grain-size graded microstructure. The results were then used to differentiate the influence of residual stress from other closure stresses, attributed to crack bridging, on the measured R-curve behavior.

In situ monitoring of wet granulation using online X-ray powder diffraction.

AbstractPurpose. Polymorphic transformations during the wet granulation of a metastable polymorph of flufenamic acid were monitored in situ using online X-ray powder diffraction. The resulting data were used in testing a proposed process induced transformation rate model, which allows the extent and occurrence of polymorphic transformations during wet granulation to be controlled by adjusting the granulation time. Methods. A small-scale, top mixing granulator was designed for compatibility with novel X-ray powder diffraction equipment (available from X-Ray Optical Systems of East Greenbush, NY). Results. The unique polycapillary optic and X-ray source allowed the transformation of the metastable to the stable polymorph to be followed during the granulation. Following a diffraction peak each for the metastable and stable forms demonstrated that polymorphic transformations during the wetting phase of granulation follow the trends predicted by the model. Conclusions. The advanced online monitoring may allow real-time control of the process by the adjustment of process parameters, such as granulation time, and clearly qualifies as a PAT (process analytical technology).

A First-Principles model for Prediction of Product dose Uniformity based on Drug Substance Particle Size Distribution

The unit dose uniformity (UDU) of low-dose drug products can be affected by active pharmaceutical ingredient (API) particle size. UDU relative standard deviation increases as the fraction of large API particles increases and/or as the unit dose decreases. Control of API particle size has traditionally been based on the empirical relationship of d(90) and/or d(50) statistics to drug product uniformity. Several articles have been written that have identified a theoretical relationship between these particle size statistics, dose, and the probability of meeting US Pharmacopeial UDU testing criteria (Huang CY, Ku S. 2010. Int J Pharm 383:70-80; Rohrs B, Amidon G, Meury R, Secreast P, King H, Skoug C. 2006. J Pharm Sci 95(5):1049-1059; Huang CY, Ku S. 2010. J Pharm Sci 99:4351-4362; Yalkowsky SH, Bolton S. 1990. Pharm Res 7(9):962-966). However, these theoretical relationships assume a fixed shape for the API particle size distribution (PSD, i.e., lognormal) and do not account for changes in the distribution shape. A more rigorous method for predicting the effect of a given PSD on UDU is to evaluate the contribution of individual particle size bins on UDU variability. The latter approach is taken in this work, and the derivation reveals that the individual contribution of particles size bins can be expressed completely in terms of a single-particle-size statistic, D[6,3]. D[6,3] is therefore a valid predictor of UDU, regardless of the shape of the PSD (e.g., multimodal) and can form the basis of a particle size control strategy for low-dose drug products.

Modeling the Formation of Debossed Features on a Pharmaceutical Tablet

PurposeThe objective of this work was to develop, validate, and implement a modeling methodology for predicting the shape and relative density fields in the vicinity of debossed features on a tablet surface. The resulting model was used to investigate the influence of debossed feature stroke angle and degree of pre-pick, which is expressed as a percentage of the stroke depth, as well as the influence of formulation lubricant on the aforementioned debossed feature parameters.MethodsAn experimental procedure for measuring formulation (modified) Drucker–Prager Cap parameters is described. These parameters are used in a finite element method simulation that models the formation of a debossed surface feature on a tablet. Techniques for validating the simulation and post-processing the results are also described.ResultsThe stroke angle and degree of pre-pick significantly influence the debossed feature dimensions, with larger degrees of pre-pick and stroke angles giving debossed features that more closely match the target (embossment) values. Lubrication plays a much weaker role, but did improve the fidelity of the debossed feature slightly. The differences between the debossed and target feature dimensions are due to elastic spring back of the material. The tablet relative density is smallest at the shoulders of the debossed feature and largest at the base of the valley. Although the relative density fields show no obvious trends with stroke angle, the fields are clearly more uniform as the degree of pre-pick increases. The addition of lubricant to the formulation also improves the relative density field uniformity for larger degrees of pre-pick.ConclusionsTo improve feature fidelity and decrease the likelihood of damage, larger pre-picks, larger stroke angles, and the addition of a formulation lubricant should be used.

Note on the Use of Diametrical Compression to Determine Tablet Tensile Strength

The diametrical compression (DC) test, as defined in United States Pharmacopeia <1217> and in American Society for Testing and Materials testing standard D 3967, has been used extensively to derive the tensile strength (TS) of pharmaceutical tablets from the measured breaking force. DC-derived TSs provide a good approach to measuring the consistency of tablet mechanical properties from one batch to the next. For these quality control type applications, method precision is required, but accuracy is not. In addition, DC has been used to calibrate parameters of the Druker Prager Cap model, a yield criterion expressing the failure of a powder compact under arbitrary 3D loading conditions. For this application, the DC method must not only provide suitable precision but also provide accuracy. In this work, we explore the accuracy of the DC method by comparing TS results to those of the 3-point bend test method (also defined in United States Pharmacopeia <1217>). We conclude that the true TS of a powder compact is approximately double the DC-derived value. Although historical literature assumes that tablets fracture under tension along the centerline of the tablet, analysis of the stress state suggests that tablets are likely to fracture under shear. The impact of this ∼50% error should be considered when accuracy of the TS result is required.

Tablet Compression Force as a Process Analytical Technology (PAT): 100% Inspection and Control of Tablet Weight Uniformity

The modern rotary pharmaceutical tablet press is capable of accepting or rejecting individual tablets based on the measured compression force of the tablet. Because during steady operation, each tablet is compressed to the same thickness, a larger compression force implies a heavier tablet. Tablets that are too heavy likely contain more than the desired content of drug substance. The measured compression force thus becomes an important input to the overall control strategy, and variability in the compression force from one tablet to the next corresponds directly with the uniformity of dosage units. This provides an extraordinary opportunity to use the instantaneous compression force signal as a process analytical technology to make product collection decisions on every individual tablet. Only 1 question requires investigation: how to set the main compression force limits to achieve the desired tablet weights? In this work, a small-scale characterization method and associated mathematical model are developed to answer this question.

Small-Scale Modeling of Pharmaceutical Powder Compression from Tap Density Testers, to Roller Compactors, and to the Tablet Press Using Big Data

IntroductionRoller compaction is commonly used in the pharmaceutical industry to improve powder flow and compositional uniformity. The process produces ribbons which are milled into granules. The ribbon solid fraction (SF) can affect both the granule size and the tensile strength of downstream tablets. Roll force, which is directly related to the applied stress on the powder in the nip region, is typically the most dominant process parameter controlling the ribbon solid fraction. This work is an extension of a previous study, leveraging mathematical modeling as part of a Quality by Design development strategy (Powder Technology, 2011, 213: 1–13).MethodsIn this paper, a semi-empirical unified powder compaction model is postulated describing powder solid fraction evolution as a function of applied stress in three geometries: the tapped cylinder (uniaxial strain—part of a standard tapped density measurement), the roller compaction geometry (plane strain deformation), and tablet compression (uniaxial strain). A historical database (CRAVE) containing data from many different formulations was leveraged to evaluate the model. The internally developed CRAVE database contains all aspects of drug product development batch records and was queried to retrieve tablet compression data along with corresponding roller compaction and tap density measurements for the same batch. Tablet compaction data and tap density data were used to calibrate a quadratic relationship between stress and the reciprocal of porosity. The quadratic relationship was used to predict the roll stress and corresponding roll force required to attain the reported ribbon SF.ResultsThe predicted roll force was found to be consistent with the actual roll force values recorded across 136 different formulations in 136 batch records. In addition, significant correlations were found between the first and the second order constants of the quadratic relationship, suggesting that a single formulation-dependent fitting parameter may be used to define the complete SF versus stress relationship. The fitting parameter could be established by compressing a single tablet and measuring the powder tapped density.ConclusionIt was concluded that characterization of this parameter at a small scale can help define the required process parameters for both roller compactors and tablet presses at a large scale.

Effects of Triple Line Tension on the Surface Topography of Polycrystals

A balance of surface energies exists where grain boundaries meet the surface of a flat solid specimen. The energy balance leads to grain boundary grooving on the surface, and the establishment of the equilibrium dihedral angle. Triple junctions are defined at the intersections of three grain boundaries. Surface grooves are typically observed to be the deepest at the triple junctions. In this work, a simple model is constructed of a polycrystalline thin film using Surface Evolver numerical software. The equilibrium sur face groove depths at triple junctions are investigated as a function of triple junction line tension. Results show that line tension can affect grain boundary groove depths for grain sizes less than ∼1 μ m.

Guidance on Drug Substance Particle Size Controls for Solid Oral Dose Forms

Drug substance particle size is a critical property affecting drug product performance. Smaller particles dissolve faster and may improve bioavailability of the drug as a result. Smaller particles are typically dispersed more uniformly, leading to lower inter-tablet potency variation. Unfortunately, smaller particles can also result in poor powder handling characteristics or other processing issues. For example, powders can fail to flow through hoppers or stick to tooling surfaces, leading to poor tablet weight uniformity or tablet appearance issues. During crystallization, smaller particles can also be difficult to filter from the crystallization media. This can lead to higher levels of residual solvents and other impurities. Particle design and size selection are therefore critical to achieving a balance between manufacturability, bioavailability, and content uniformity. In this chapter, the impact of particle size on bioavailability is introduced and the impact on content uniformity is considered in depth. Control of the variability of tablet potency is discussed in relation to the overall particle size distribution. The risk-based selection of a positive control such as a screen to limit the maximum allowable particle size is discussed in relation to the occurrence of rare, but highly super-potent tablets.

Assessment of Intragranular and Extragranular Fracture in the Development of Tablet Tensile Strength

When a tablet is compacted from deformable granules and then broken, the fracture plane may cleave granules in 2 (intragranular fracture) or separate neighboring granules (extragranular fracture). In this study, a novel method was developed to quantify the extent of intragranular versus extragranular fracture by compacting tablets from multicolored ideal granules and evaluating fracture surfaces. The proportions of intragranular and extragranular fracture were quantified and modeled in light of a new metric; the deformation potential, Δ, reflecting the solid fraction increase as an initial granule bed is compressed into a final tablet. Results show that a measurable tablet strength is achieved at Δ > 0.18, but intragranular fracture is not observed until Δ > 0.21. At very large Δ, tablets experience almost exclusively intragranular fracture, yet the tablet tensile strength is considerably lower than that of a tablet compacted from raw powders versus precompacted granules. Thus, secondary compaction of granules appears to weaken the granule matrix, leading to reduced tablet tensile strength even in the presence of strong extragranular bonding.