International Journal of Pharmaceutics (v.442, #1-2)

Editorial by Çetin Çetinkaya; Bruno C. Hancock; Geoff G.Z. Zhang (1-2).

The degree of compression of spherical granular solids controls the evolution of microstructure and bond probability during compaction by Josefina Nordström; Ann-Sofie Persson; Lucia Lazorova; Göran Frenning; Göran Alderborn (3-12).
The effect of degree of compression on the evolution of tablet microstructure and bond probability during compression of granular solids has been studied. Microcrystalline cellulose pellets of low (about 11%) and of high (about 32%) porosity were used. Tablets were compacted at 50, 100 and 150 MPa applied pressures and the degree of compression and the tensile strength of the tablets determined. The tablets were subjected to mercury intrusion measurements and from the pore size distributions, a void diameter and the porosities of the voids and the intra-granular pores were calculated.The pore size distributions of the tablets had peaks associated with the voids and the intra-granular pores. The void and intra-granular porosities of the tablets were dependent on the original pellet porosity while the total tablet porosity was independent. The separation distance between pellets was generally lower for tablets formed from high porosity pellets and the void size related linearly to the degree of compression. Tensile strength of tablets was higher for tablets of high porosity pellets and a scaled tablet tensile strength related linearly to the degree of compression above a percolation threshold. In conclusion, the degree of compression controlled the separation distance and the probability of forming bonds between pellets in the tablet.
Keywords: Tablets; Pore structure; Microstructure; Degree of compression; Tensile strength; Percolation theory;

Understanding how a material's response to stress changes as the stress is applied at different rates is important in predicting performance of pharmaceutical powders during tablet compression. Widely used methods for determining strain rate sensitivity (SRS) are empirically based and can often provide inconsistent or misleading results. Indentation creep data, collected during hardness tests on compacts formed from several common tableting excipients, were used to predict each material's relative sensitivity to changes in strain rate. Linear relationships between Ln(indentation hardness) and Ln(strain rate) were observed for all materials tested. The slope values taken from these relationships were compared to traditional strain rate sensitivity estimates based on in-die Heckel analysis. Overall, the results from the two methods were quite similar, but several advantages were evident in the creep data. The most notable advantage was the ability to characterize strain rate sensitivity derived from plastic behavior with little influence of elastic deformation. For example, two grades of corn starch had very similar creep behavior, but their yield pressures were affected very differently when the compaction rate was increased. This inconsistency was related to the difference in the viscoelastic recovery exhibited by these two materials. This new method promises to allow a better understanding of strain rate effects observed during tablet manufacturing.
Keywords: Strain rate sensitivity; Heckel analysis; Powder compaction; Plastic deformation; Indentation hardness; Indentation creep; Tableting;

Ultrasonic real-time in-die monitoring of the tablet compaction process—A proof of concept study by James D. Stephens; Brian R. Kowalczyk; Bruno C. Hancock; Goldi Kaul; Cetin Cetinkaya (20-26).
The mechanical properties of a drug tablet can affect its performance (e.g., dissolution profile and its physical robustness. An ultrasonic system for real-time in-die tablet mechanical property monitoring during compaction has been demonstrated. The reported set-up is a proof of concept compaction monitoring system which includes an ultrasonic transducer mounted inside the upper punch of the compaction apparatus. This upper punch is utilized to acquire ultrasonic pressure wave phase velocity waveforms and extract the time-of-flight of pressure waves travelling within the compact at a number of compaction force levels during compaction. The reflection coefficients for the waves reflecting from punch tip–powder bed interface are extracted from the acquired waveforms. The reflection coefficient decreases with an increase in compaction force, indicating solidification. The data acquisition methods give an average apparent Young's moduli in the range of 8–20 GPa extracted during the compaction and release/decompression phases in real-time. A monitoring system employing such methods is capable of determining material properties and the integrity of the tablet during compaction. As compared to the millisecond time-scale dwell time of a typical commercial compaction press, the micro-second pulse duration and ToF of an acoustic pulse are sufficiently fast for real-time monitoring.
Keywords: Real-time quality monitoring; In-die testing; Compaction monitoring; Ultrasonic characterization; Process Analytic Technology (PAT);

Real-time tablet formation monitoring with ultrasound measurements in eccentric single station tablet press by Jari T.T. Leskinen; Simo-Pekka Simonaho; Mikko Hakulinen; Jarkko Ketolainen (27-34).
A real-time ultrasound measurement system for tablet compression monitoring is introduced. The measurement system was tested in actual manufacturing environment and found to be capable of measuring the ultrasound response of the tabletting process from bulk to tablet. The tablet sets were compressed and the ultrasound measurements were conducted as implemented in eccentric single station tabletting apparatus in through transmission geometry. The speed of sound and ultrasound spectrum was measured during dynamic compression for microcrystalline cellulose/paracetamol tablets. The ultrasound system introduced in this study was found to be suitable for tabletting process monitoring as the mechanical properties of compressed tablets can be estimated during compression using the ultrasound system. In addition, it was found that the ultrasound was sensitive to the mixing time of magnesium stearate and the concentration of paracetamol. Thus, ultrasound measurements made during the compression can be used to monitor the tablet formation process.
Keywords: Tablet; Tabletting; Compression; Ultrasound; Speed of sound; Mechanical properties; Tensile strength;

Wireless transmission of ultrasonic waveforms for monitoring drug tablet properties and defects by J.D. Stephens; M.V. Lakshmaiah; B.R. Kowalczyk; B.C. Hancock; C. Cetinkaya (35-41).
The geometric and mechanical properties of pharmaceutical materials are crucial to their structural, functional and therapeutic effectiveness. The implementation of automated and convenient quality monitoring procedures is an attempt to balance control of quality against the level of testing; within acceptable levels of probability and costs. The capability of rapid/extensive inspections with minimal time and manufacturing interruption make non-contact quality monitoring systems a desirable approach to optimize this balance. In the current study, a wireless transceiver proof of concept system developed for the real-time quality monitoring of tablets during compaction is presented and demonstrated. The effectiveness of ultrasonic wave transmission through the punch–tablet interface is the boundary condition that dictates the viability of the acoustic in-die compaction monitoring approach. These measurements in the current experimental set-up can be used in determining various mechanical and geometric properties of a compact, such as the tablet thickness, mass density, elasticity and/or integrity of the tablet core, and bonding quality between layers depending on the given parameters, as it is compacted. In the current study, it is demonstrated that the reflection of an ultrasonic pulse generated by a transducer embedded in an upper punch from the lower punch–tablet interface can be acquired by the same transducer in the upper punch and the analog waveform can be transmitted to a computer by means of wireless communications for further signal processing and property extraction. The evolution of apparent Young's moduli of a powder bed during a full-compaction cycle is derived from the ultrasonic time of flight of an acoustic waveform acquired during compaction in-die.
Keywords: Wireless transmitter; Drug tablets; Real-time quality monitoring systems; In-die online monitoring; Process analytical technology (PAT);

During pharmaceutical compaction, the interaction between the punch and the powder determines the formation and the aspect of the surface of the compact. In industry, the properties of the punch surface, which play a key role in this interaction, are sometimes changed by fixing an intermediate layer onto the punch to prevent sticking problems. In this article, the case of a polymer insert layer was studied.Firstly, sugar spheres were compacted with and without the polymer insert fixed onto the punches. After compaction with uncovered punches, the surface particles, which had been subjected to high deformation, were flattened on one side. However, it was observed, using confocal X-ray microfluorescence, that this kind of deformation was limited to the surface and that the bulk particles, which underwent a more isotropic deformation, still exhibited an approximately round shape.Secondly, the influence of the surface structure on the mechanical properties of the compacts was studied. The indentation hardness and the tensile strength of compacts of microcrystalline cellulose (MCC) and anhydrous calcium phosphate (aCP) were studied. No differences were found for the compacts of MCC produced with the two kinds of punches, but the compacts of aCP obtained with uncovered punches presented a higher hardness and a higher tensile strength than those obtained with covered punches.
Keywords: Pharmaceutical compaction; Mechanical properties; Surface; Sticking; Polymer insert;

Powder flow of mixtures is complex and not properly understood. The selection of drug–excipient blends with inadequate powder flow can lead to quality issues of the final dosage form. Therefore, this work aims at a better understanding of how changes in powder flow of binary blends can lead to weight variability in pharmaceutical capsule filling. We used image-analysis-based powder avalanching and shear cell testing to study blends of paracetamol and microcrystalline cellulose. A pilot-scale machine with dosator principle was employed for encapsulation. As a result, the powder flow properties improved generally with rising amounts of microcrystalline cellulose. However, a negative correlation was observed between avalanche angle and angle of internal friction. Results were discussed and percolation theory was considered to explain abrupt changes in the observed flow properties. This was particularly helpful for analysis of the capsule-filling data, since capsule weight variability displayed a threshold behavior as a function of the mixture fraction. The capsule weight variability correlated with the angle of internal friction as well as with the angle and the energy of avalanches. Based on the results we proposed a strategy of how to design minimal weight variability into powder-filled capsules.
Keywords: Binary mixtures; Critical behavior; Percolation theory; Quality by Design; Capsule filling; Mass uniformity;

The break force of flat faced tablets subject to diametrical compression (often referred to as “hardness”) can be related to the tensile strength of the material using the Hertz contact theory. For curved tablets analytical solutions do not exist and an empirical equation developed by Pitt and Newton (1988) is usually used. In this paper we measure the break force of curved faced tablets having a range of curvatures pressed at various compaction forces. An empirical equation is proposed to relate the break force of curved faced tablets to the material tensile strength. The proposed equation is simplified and reduced to a form that is consistent with developed by Hertz theory for flat faced tablets.
Keywords: Pharmaceutical tablet; Break force; Curved tablet; Tensile strength;

The aim of this study was to develop a responsive disintegration test apparatus that is particularly suitable for rapidly disintegrating tablets (RDTs). The designed RDT disintegration apparatus consisted of disintegration compartment, stereomicroscope and high speed video camera. Computational fluid dynamics (CFD) was used to simulate 3 different designs of the compartment and to predict velocity and pressure patterns inside the compartment. The CFD preprocessor established the compartment models and the CFD solver determined the numerical solutions of the governing equations that described disintegration medium flow. Simulation was validated by good agreement between CFD and experimental results. Based on the results, the most suitable disintegration compartment was selected. Six types of commercial RDTs were used and disintegration times of these tablets were determined using the designed RDT disintegration apparatus and the USP disintegration apparatus. The results obtained using the designed apparatus correlated well to those obtained by the USP apparatus. Thus, the applied CFD approach had the potential to predict the fluid hydrodynamics for the design of optimal disintegration apparatus. The designed visiometric liquid jet-mediated disintegration apparatus for RDT provided efficient and precise determination of very short disintegration times of rapidly disintegrating dosage forms.
Keywords: Rapidly disintegrating tablets; Computational fluid dynamics; Visiometric liquid jet-mediated; Disintegration apparatus; Visualization; Fluid hydrodynamics; Disintegration time;

Motivated by our recent study showing improved flow and dissolution rate of the active pharmaceutical ingredient (API) powders (20 μm) produced via simultaneous micronization and surface modification through continuous fluid energy milling (FEM) process, the performance of blends and direct compacted tablets with high drug loading is examined. Performance of 50 μm API powders dry coated without micronization is also considered for comparison. Blends of micronized, non-micronized, dry coated or uncoated API powders at 30, 60 and 70% drug loading, are examined. The results show that the blends containing dry coated API powders, even micronized ones, have excellent flowability and high bulk density compared to the blends containing uncoated API, which are required for direct compaction. As the drug loading increases, the difference between dry coated and uncoated blends is more pronounced, as seen in the proposed bulk density-FFC phase map. Dry coating led to improved tablet compactibility profiles, corresponding with the improvements in blend compressibility. The most significant advantage is in tablet dissolution where for all drug loadings, the t 80 for the tablets with dry coated APIs was well under 5 min, indicating that this approach can produce nearly instant release direct compacted tablets at high drug loadings.
Keywords: Ibuprofen; Fine API powders; API blends; Dry coating; Micronization; Flowability; Direct compaction; Dissolution;