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The objective of this work was to investigate the molecular origin of the differences in the thermal expansivity of four ROY polymorphs (Y, R, OP, and ON) using variable temperature single crystal X-ray diffractometry (VT-SCXRD). Thermal expansivity was found to be directly influenced by the crystal packing and the number and type of directional interactions, such as hydrogen bonds, involved in packing. Polymorphs with layered molecular packing, i.e., ON, OP, and R, show higher volume expansivity, where the axial component of the expansion is the largest in the directions perpendicular to the hydrogen-bonded layers and the smallest along the layers. Polymorph Y shows the least volume expansivity, which corresponds to the presence of a denser hydrogen-bonded network structure in the crystal, and absence of apparent molecular layers. The largest overall expansivity is observed for polymorph ON that lacks intermolecular hydrogen bonds and exhibits a layered packing pattern along two axes. The differences in the thermal expansivity of the ROY polymorphs lead to violations of the density rule in polymorph stability prediction due to crossover in crystal density with change in temperature, which means the rank order of crystal density of polymorphs is temperature-dependent. Thus, at absolute zero, the most thermodynamically stable polymorph Y is predicted to not have the highest density, which violates the density rule. Likewise, for all enantiotropic polymorphs undergoing the density crossover phenomenon, the density rule is valid only within the temperature range bracketed by the temperatures of density crossover (Td) and thermodynamic transition (Tt). For all monotropic polymorphs, the density rule is valid only above Td.

Despite the ability to characterize the plasticity of powders in a material-sparing and expedited manner, the in-die Heckel analysis has been widely criticized for its sensitivity to several factors, such as particle elastic deformation, tooling size, lubrication, and speed. Using materials exhibiting a wide range of mechanical properties, we show that the in-die Py correlates strongly with three established plasticity parameters obtained from the out-of-die Heckel analysis, Kuentz-Leuenberger analysis, and macroindentation. Thus, the in-die Py is a reliable parameter for quantifying powder plasticity in a material-sparing and expedited manner.

Micronized particles are commonly used to improve the content uniformity (CU), dissolution performance, and bioavailability of active pharmaceutical ingredients (API). Different particle engineering routes have been developed to prepare micron-sized API in a specific size range to deliver desirable biopharmaceutical performance. However, such API particles still risk varying bulk powder properties critical to successful manufacturing of quality drug products due to different particle shapes, size distribution, and surface energetics, arising from the anisotropy of API crystals. In this work, we systematically investigated key bulk properties of 10 different batches of Odanacatib prepared through either jet milling or fast precipitation, all of which meet the particle size specification established to ensure equivalent biopharmaceutical performance. However, they exhibited significantly different powder properties, solid-state properties, dissolution, and tablet CU. Among the 10 batches, a directly precipitated sample exhibited overall best performance, considering tabletability, dissolution, and CU. This work highlights the measurable impact of processing route on API properties and the importance of selecting a suitable processing route for preparing fine particles with optimal properties and performance.

Dry powder inhalers are often formulated by attaching micronized drug particles onto carrier particles, which are generally lactose. In this study, commercially available lactose was air jet milled to produce unique slab-like coarse carrier particles, which have larger and rougher surfaces compared to other commercially available lactose. Two key processing factors, i.e., classifier speed and jet milling pressure, were systematically investigated. The largest fraction of slab-like particles in the resulting powder was obtained at a classifier speed of 3000 rpm. The slab-like coarse carrier particles are expected to exhibit superior performance than commercial lactose due to their unique surface properties.

From an analysis of the geometry of the yield locus and the Mohr's circle for determining unconfined yield strength (fc) in shear cell testing, it has been shown that powder cohesion is proportional to fc, where the proportionality constant is a function of angle of linearized yield locus, (1-sinθ)/(2cosθ). While both parameters are routinely included in shear cell data, only one parameter is needed to characterize flow properties of a new powder.

Metronidazole (MTZ) is an antibacterial drug widely used for the treatment of protozoan and anaerobic infections in humans and animals. However, its low bioavailability necessitates the frequent administration of a high dose to attain an effective plasma concentration profile for therapy. To reduce the dose of MTZ, we have prepared a new cocrystal between MTZ and ethyl gallate (EG). The solid-state properties of MTZ-EG were characterized using complimentary techniques, including thermal, spectroscopic, microscopic, and X-ray crystallographic methods. The MTZ-EG cocrystal exhibits a higher solubility and faster dissolution than MTZ. The bioavailability of MTZ in rats was increased by 36% when MTZ-EG was used.

The ability to predict tableting properties of a powder mixture from individual components is of both fundamental and practical importance to the efficient formulation development of tablet products. A common tableting classification system (TCS) of binary powder mixtures facilitates the systematic development of new knowledge in this direction. Based on the dependence of tablet tensile strength on weight fraction in a binary mixture, three main types of tableting behavior are identified. Each type is further divided to arrive at a total of 15 sub-classes. The proposed classification system lays a framework for a better understanding of powder interactions during compaction. Potential applications and limitations of this classification system are discussed.

Loratadine (Lor) is an antihistamine drug commonly used to relieve the symptoms of allergy. It has high permeability but low solubility under physiological conditions. To overcome the problem of low solubility, we synthesized and characterized two Loratadine multi-component crystalline phases with oxalic acid (Oxa), i.e., a 1:1 Lor-Oxa conjugate acid-base (CAB) cocrystal (Lor-Oxa CAB) and a 2:1 Lor-Oxa cocrystal monohydrate (Lor-Oxa hydrate). Both cocrystals exhibited an enhanced solubility and intrinsic dissolution rate (IDR) compared to Lor and adequate physical stability. The intrinsic dissolution rate of Lor-Oxa CAB is 95 times that of Lor, which makes it a promising candidate for tablet formulation development.

The relationship between crystal structure and mechanical properties is commonly studied by identifying slip planes through inspecting crystal structures visually, with a focus on the hydrogen bonding interactions. While useful, the visualization method lacks quantitative insight, and the identification of slip planes is subjective. Sometimes, crystal plasticity predicted from structure visualization does not match experimental crystal plasticity and powder tabletability as observed in three polymorphic systems, 6-chloro-2,4-dinitroaniline, indomethacin, and febuxostat. Here, we explored the feasibility of more reliably identifying slip planes by the energy framework approach, combined with analysis of potential slip layer topology. In all three cases, this new approach identified slip planes that are consistent with the observed mechanical plasticity and compaction behavior. Thus, it is superior to the visualization method for crystal structure analysis aimed at identifying active slip planes in organic crystals. [ABSTRACT FROM AUTHOR]

Some active pharmaceutical ingredients possess poor mechanical properties and are not suitable for tableting. Using fine sand (silicon dioxide), we show that a core/shell structure, where a core particle (sand) is coated with a thin layer of polyvinylpyrrolidone (PVP), can profoundly improve powder compaction properties. Sand coated with 5% PVP could be compressed into intact tablets. Under a given compaction pressure, tablet tensile strength increases dramatically with the amount of coating. This is in sharp contrast to poor compaction properties of physical mixtures, where intact tablets cannot be made when PVP content is 20% or less. The profoundly improved tabletability of core/shell particles is attributed to the formation of a continuous three-dimensional bonding network in the tablet. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4458-4462, 2010 [ABSTRACT FROM AUTHOR]

Theophylline and methyl gallate can form a 1 : 1 co-crystal. Their tableting performance follows the order of theophylline > co-crystal methyl gallate. While co-crystallization profoundly improves the tabletability of methyl gallate, it significantly deteriorates that of theophylline. This difference in bulk compaction behaviour originates from the dissimilar crystal plasticity and elasticity, which results from unique molecular packing features in the respective crystal lattices. The presence of a three-dimensional hydrogen bonded network gives rise to very low plasticity in the methyl gallate crystal, which leads to its poor tabletability. In contrast, the layers of two-dimensional rigid, hydrogen bonded molecules in the co-crystal improve the crystal plasticity, by facilitating slip with shear that, in turn, enhances tabletability. However, theophylline undergoes plastic deformation more readily when compared to the co-crystal, because the slip layers in theophylline are composed of hydrogen bonded columns, which provide additional flexibility for slip. As a consequence, theophylline crystals have significantly enhanced tabletability. [ABSTRACT FROM AUTHOR]

The concept of materials science tetrahedron (MST) concisely depicts the inter-dependent relationship among the structure, properties, performance, and processing of a drug. Similar to its role in traditional materials science, MST encompasses the development in the emerging field of pharmaceutical materials science and forms a scientific foundation to the design and development of new drug products. Examples are given to demonstrate the applicability of MST to both pharmaceutical research and product development. It is proposed that a systematic implementation of MST can expedite the transformation of pharmaceutical product development from an art to a science. By following the principle of MST, integration of research among different laboratories can be attained. The pharmaceutical science community as a whole can conduct more efficient, collaborative, and coherent research. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1671–1687, 2009 [ABSTRACT FROM AUTHOR]

A batch of poorly flowing citric acid anhydrate was exposed to 69.9% relative humidity to prepare pure monohydrate with nearly identical particle size and morphology but different surface properties. Flow properties of the powders were tested using a ring shear cell. Results show the hydration can significantly improve flow properties of anhydrous citric acid. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:1744–1749, 2009 [ABSTRACT FROM AUTHOR]

By the formation of a 1:1 cocrystal of caffeine and methyl gallate, we demonstrated that powder compaction properties could be profoundly improved. The selection criterion for cocrystal exhibiting superior compaction properties was the presence of slip planes in crystal structure. Bulk cocrystal was prepared by suspending powders of the two pure compounds in ethanol. Fine powders of similar particle size distribution were compressed. Within the whole range of compaction pressure, the tablet tensile strength of methyl gallate was very poor (<0.5 MPa) and severe lamination and sticking occurred in almost all tablets. Tabletability of caffeine was acceptable at <150 MPa. However, at >180 MPa, severe lamination of caffeine tablets suddenly occurred. Tablet tensile strength dropped sharply at >240 MPa. In contrast, the tabletability of the cocrystal was excellent over the entire pressure range. Tablet tensile strength of the cocrystal was ∼2 times that of caffeine at <200 MPa, and the ratio gradually increased with increasing pressure, e.g., ∼8 fold at 350 MPa. Poor tablet tensile strength was always associated with high elastic recovery and low plasticity. The good plasticity and tabletability of the cocrystal validated the selection criterion, i.e., the presence of slip planes in crystal structure. [ABSTRACT FROM AUTHOR]

A mechanistic understanding of the over-granulation problem during high shear wet granulation (HSWG) process can guide efficient development of robust formulation and manufacturing process. Using microcrystalline cellulose (MCC) as a model compound, we demonstrate that size enlargement is an important mechanism for over-granulation in HSWG. A higher granulation water level results in larger granules and lower tabletability. With increasing water, granules enlarge sharply when water level is higher than 65%. Granule tabletability deteriorates with increasing granule size and becomes over-granulated when more than 70% water is used. For a batch of over-granulated granule that is ground and sieved, tabletability of the sieved fractions decreases with increasing granule size. The tabletability of the finest fraction (45–90 µm) is nearly four times that of the largest fraction (300–425 µm). These results show that size reduction can be an effective strategy to address the problem of over-granulation. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3322–3325, 2010 [ABSTRACT FROM AUTHOR]