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This special edition of the Journal of Pharmaceutical Sciences is dedicated to Professor Raj Suryanarayanan (Professor and WilliamMildred Peters Endowed Chair, University of Minnesota, School of Pharmacy) and honors his extensive and distinguished career as a scientist, educator and mentor. The goal of this commentary is to provide an overview of Professor Suryanarayanan's noteworthy career path and summarize his key research contributions. The commentary concludes with the personal summaries by guest editors.

Molecular crystals have shown remarkable adaptability in response to a range of external stimuli. Here, we survey this emerging field and provide a critical overview of the experimental, computational and instrumental tools being used to design and apply such materials.

Assessing in vivo performance to inform formulation selection and development decisions is an important aspect of drug development. Biopredictive dissolution methodologies for oral dosage forms have been developed to understand in vivo performance, assist in formulation development/optimization, and forecast the outcome of bioequivalence studies by combining them with simulation tools to predict plasma profiles in humans. However, unlike compendial dissolution methodologies, the various biopredictive methodologies have not yet been harmonized or standardized. This manuscript presents the initial phases of an effort to develop best practices and move toward standardization of the biopredictive methodologies through the Product Quality Research Institute (PQRI, https://pqri.org) entitled “The standardization of in vitro predictive dissolution methodologies and in silico bioequivalence study Working Group.” This Working Group (WG) is comprised of participants from 10 pharmaceutical companies and academic institutes. The project will be accomplished in a total of five phases including assessing the performance of dissolution protocols designed by the individual WG members, and then building “best practice” protocols based on the initial dissolution profiles. After refining the “best practice” protocols to produce equivalent dissolution profiles, those will be combined with physiologically based biopharmaceutics models (PBBM) to predict plasma profiles. In this manuscript, the first two of the five phases are reported, namely generating biopredictive dissolution profiles for ibuprofen and dipyridamole and using those dissolution profiles with PBBM to match the clinical plasma profiles. Key experimental parameters are identified, and this knowledge will be applied to build the “best practice” protocol in the next phase. Graphical Abstract

Cocrystallization with saccharine (SAC) significantly improved photostability of dimetronidazole (DMZ), an veterinary antibiotic.

Flowability parameters of powders measured by a shear cell is expected to depend on shear cell size, but details of that effect are lacking. In this work, we have systematically evaluated this using a number of powders under three preshear normal stresses using a ring shear tester. The flowability index (ffc) of a limestone powder (BCR 116) exhibited relatively small differences when measured on three shear cells of different sizes, S (~9.5 cm3) 22 μm was more than 15% higher using S than M. Large differences between data from M and L were found for powders with a median particle size >125 μm. Therefore, one must exercise caution when comparing flow properties of powders characterized using different shear cells.

Indentation hardness, H, is an important mechanical property that quantifies the resistance to deformation by a material. For pharmaceutical powders, H can be determined using a macroindentation method, provided they can form intact tablets suitable for testing. This work demonstrates a method for determining the hardness of problematic materials that cannot form suitable tablets for macroindentation. The method entails predicting the hardness of a given powder at zero porosity (H

Using an artificial stomach and duodenum (ASD), we investigated the pH-dependent precipitation of erlotinib (ERL) during dissolution in the gastrointestinal (GI) tract by varying the rate of gastric fluid secretion (RGFS). Results show that decreasing RGFS from 2.5 to 0.5 mL/min leads to an increased degree of supersaturation in the duodenum fluid due to elevated pH, resulting in precipitation of ERL and a reduced area under the curve (AUC) of the concentration - time profiles from 14,000 to 3,000 (μg‧min)/mL. Such a change in AUC is expected to lower the bioavailability of ERL, a BCS II drug, in patients with a low RGFS. This example demonstrates the potential use of ASD as an effective tool for guiding the efficient development of robust tablet formulations by better understanding the impact of GI tract pH on the fate of drugs in the duodenal fluid.

Scanning electron microscopy-based energy dispersive X-ray spectroscopy (SEM-EDS) is proposed as a versatile tool for quantifying surface area coverage (SAC) by magnesium stearate (MgSt) on pharmaceutical tablets and particles. Our approach involved fast elemental mapping and subsequent SAC quantitation by image analysis. The study was conducted using a multi-component system, but the particle-level mapping was limited to active pharmaceutical ingredient (API) crystals. For both tablets and API particles, the calculated SAC against MgSt loading afforded a positive linear correlation over the range of MgSt levels examined in this work. On the tablet surface, MgSt was found to be preferentially concentrated at or in the close vicinity of grain boundaries, supporting the idea of compression-driven migration and relocation of MgSt within the tablet. On the particle surface, only discrete aggregates of MgSt were observed, as opposed to the widely accepted phenomenon of the formation of a thin lubricant film around host particles. The selection of proper SEM-EDS operating conditions and the challenges confronted in particle surface mapping are discussed in detail.

A novel 1:1 cocrystal between two cardiovascular drugs, aspirin (ASA) and ligustrazine (tetramethylpyrazine, TMP) has been synthesized and characterized. The structure of this drug-drug cocrystal, ASA-TMP, was determined using single crystal X-ray crystallography. The ASA-TMP cocrystal exhibits a significantly reduced sublimation tendency than TMP. Importantly, cocrystallization simultaneously improves bioavailability of both parent drugs. This suggests the possibility of developing a more effective antithrombosis drug therapy given the synergistic pharmacological effects of the two parent drugs.

Water of crystallization has been observed to increase plasticity, decrease crystal hardness, and improve powder compressibility and tabletability of organic crystals. This work is aimed at gaining a molecular level insight into this observation.We systematically analyzed crystal structures of five stoichiometric hydrate systems, using several complementary techniques of analysis, including energy framework, water environment, overall packing change, hydrate stability, and slip plane identification.The plasticizing effect by lattice water is always accompanied by an introduction of more facile slip planes, lower packing efficiency, and lower density in all hydrate systems examined in this work. Three distinct mechanisms include 1) changing the distribution of intermolecular interactions without significantly changing the packing of molecules to introduce more facile slip planes; 2) changing packing feature into a flat layered structure so that more facile slip planes are introduced; 3) reducing the interlayer interaction energies and increasing the anisotropy.Although the specific mechanisms for these five systems differ, all five hydrates are featured with more facile slip planes, lower packing efficiency, and lower density.

The three point bending method is commonly used for determining Young's modulus, E. However, the literature E values of some common pharmaceutical excipients, determined by three point bending, exhibit orders of magnitude variability that cannot be fully explained by normal variations in material properties. To understand the root cause for the large variations, we assessed several potential experimental factors, including instrument stiffness, data analysis method, test speed, alignment between loading beam and specimen surface, and ratio of sample thickness to distance between two supports. Our results show that E value is sensitive to 1) deformation of instrument under force, 2) force-displacement data analysis method, 3) misalignment between loading beam and specimen surface, 4) flashing at the edge of a specimen, 5) accuracy of the true density. Finally, strategies to improve the accuracy of E determination by the three point bending method were recommended.

Roller compaction (RC) is a common granulation process for manufacturing solid dosage forms. However, its applicability to the growing number of powders with very low bulk densities and high cohesiveness can be limited due to poor powder feeding. Although deaeration with a vacuum in the feeding line is an effective approach to enhance the powder feeding performance, a systematic assessment of its effects on RC process is lacking. In this work, we have examined the effect of vacuum on the processability of RC using an extremely poorly flowing powder, colloidal silica, and two grades of microcrystalline cellulose (MCC). A processable range is defined by roll speed and screw speed that attain stable feeding under the roller-gap controlled mode. A 0.35 barg vacuum level was sufficient to make the colloidal silica processable and a higher vacuum level solved the subfeeding issue and significantly expanded the RC operation range. In contrast, deaeration slightly narrowed the processable range for MCC PH105 and PH101, while only minimally affects the relationship between roll speed and screw speed. The effects of vacuum on the processability of these materials qualitatively correlated with the sensitivity of their bulk densities to pressure. A better understood effects of material properties (bulk density), process parameters (roller gap), and deaeration (vacuum level) on RC processability of powders help to determine an appropriate use of a vacuum line to improve the RC process.

Two novel salt cocrystals of berberine chloride (BCl) with 4-aminobenzoic acid (BCl-4ABA) and 4-hydroxybenzoic acid (BCl-4HBA) and one new berberine salt with 2,6-dihydroxybenzoic acid (B)

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., Graphical abstract Unlabelled Image