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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.

Nanoindentation provides a convenient and high-throughput means for mapping mechanical properties and for measuring the strain rate sensitivity of a material. Here, nanoindentation was applied to the study of microcrystalline cellulose. Constant strain rate nanoindentation revealed a depth dependence of nanohardness and modulus, mostly attributed to material densification. Nanomechanical maps of storage modulus and hardness resolved the shape and size of voids present in larger particles. In smaller, denser particles, however, where storage modulus varied little spatially, there was still some spatial dependence of hardness, which can be explained by cellulose’s structural anisotropy. Additionally, hardness changed with the indentation strain rate in strain rate jump tests. The resulting strain rate sensitivity values were found to be in agreement with those obtained by other techniques in the literature.

In this study, various structurally similar aliphatic dicarboxylic acids, namely, succinic acid, glutaric acid, adipic acid, and pimelic acid, were employed as coformers to obtain phase pure cocrystals with berberine chloride (BCl) by a slow solvent evaporation method. The structures of the four novel salt-cocrystals of BCl were determined by single crystal X-ray diffraction analysis and their solid-state properties were characterized. Compared with BCl·2H2O, all the cocrystals showed a higher melting point, improved powder dissolution and intrinsic dissolution rate (IDR), and lower hygroscopicity. It is noteworthy that the melting points and IDRs of these cocrystals exhibit an odd-even alternation with the carbon chain length of the acids.

Understanding the structural origins of diverse mechanical behaviors of organic crystals is critical for designing functional materials for a number of technological applications. To facilitate thi...

Sulfamethazine (SMT) is a sulfonamide antibacterial drug used to treat or prevent infections in both humans and animals. However, SMT exhibits unfavorable taste and poor compaction behavior. To ove...

Reversible single-crystal-to-single-crystal phase transformation between two enantiotropic polymorphs of a pharmaceutical salt, diphenhydramine citrate, in both directions is accompanied by a transient expansion in the unit cell, allowing rotation of phenyl rings. Twinning of the lower symmetry polymorph facilitates the exceptional reproducibility and the lack of observable hysteresis in the phase change.

Cocrystals are an emerging class of crystalline materials composed of two or more different molecules in the same crystal lattice that are physically connected by non-ionic and non-covalent bonds. Formulating problematic drugs into cocrystals is a pragmatic strategy to manipulate solid state properties for new drug development and product reformulation. While research on cocrystals has been undergoing rapid growth over the past two decades, successful clinical translation of cocrystals is still limited. As the pharmaceutical properties of a cocrystal are decidedly dictated by the selection of cocrystal formers and resulting crystal structure, the present review begins with an overview of the current strategies in cocrystal design and preparation, followed by the potential applications of cocrystals in medicines. The major hurdles and missing knowledge gaps hindering the translation of pharmaceutical cocrystals into commercial reality are also mentioned. Finally, perspectives of cocrystals in alternative dosage forms other than for oral use, as well as latest topics of cocrystal research are highlighted. We believe that cocrystals play an important role in future drug discovery and development, offering a new direction for optimal drug delivery, combination therapy and personalized medicines.

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

In an effort to develop a tablet product of celecoxib by overcoming its poor physicochemical properties using a pharmaceutically acceptable solvate, we isolated two stoichiometric N-Methyl-2-Pyrrol...

Successful development of tablet formulations of many active pharmaceutical ingredients (APIs) is challenged by their poor manufacturability (e.g., flowability, tabletability) and dissolution chara...

An l-proline cocrystal of celecoxib was identified based on a computational approach for predicting crystal mechanical properties in order to significantly reduce the punch sticking propensity of c...

Six isostructural crystalline solvates of cele­coxib are reported and the inter­molecular inter­actions involving the solvent mol­ecules are described., Six isostructural crystalline solvates of the active pharmaceutical ingredient cele­coxib {4-[5-(4-methyl­phen­yl)-3-(tri­fluoro­meth­yl)pyrazol-1-yl]benzene­sul­fon­amide; C17H14F3N3O2S} are described, containing di­methyl­formamide (DMF, C3H7NO, 1), di­methyl­acetamide (DMA, C4H9NO, 2), N-methylpyrrolidin-2-one (NMP, C5H9NO, 3), tetra­methyl­urea (TMU, C5H12N2O, 4), 1,3-dimethyl-3,4,5,6-tetra­hydro­pyrimidin-2(1H)-one (DMPU, C6H12N2O, 5) or dimethyl sulfoxide (DMSO, C2H6OS, 6). The host cele­coxib structure contains one-dimensional channel voids accommodating the solvent mol­ecules, which accept hydrogen bonds from the NH2 groups of two cele­coxib mol­ecules. The solvent binding sites have local twofold rotation symmetry, which is consistent with the point symmetry of the solvent mol­ecule in 4 and 5, but introduces orientational disorder for the solvent mol­ecules in 1, 2, 3 and 6. Despite the isostructurality of 1–6, the unit-cell volume and solvent-accessible void space show significant variation. In particular, 4 and 5 show an enlarged and skewed unit cell, which can be attributed to a specific inter­action between an N—CH3 group in the solvent mol­ecule and the toluene group of cele­coxib. Inter­molecular inter­action energies calculated using the PIXEL method show that the total inter­action energy between the cele­coxib and solvent mol­ecules is broadly correlated with the mol­ecular volume of the solvent, except in 6, where the increased polarity of the S=O bond leads to greater overall stabilization com­pared to the similarly-sized DMF mol­ecule in 1. In the structures showing disorder, the most stable orientations of the solvent mol­ecules make C—H⋯O contacts to the S=O groups of cele­coxib.

Two conformational polymorphs of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) exhibited similar morphology but strikingly different mechanical flexibility, where the yellow needl...

Optimized physical properties (e.g., bulk, surface/interfacial, and mechanical properties) of active pharmaceutical ingredients (APIs) are key to the successful integration of drug substance and drug product manufacturing, robust drug product manufacturing operations, and ultimately to attaining consistent drug product critical quality attributes. However, an appreciable number of APIs have physical properties that cannot be managed via routes such as form selection, adjustments to the crystallization process parameters, or milling. Approaches to control physical properties in innovative ways offer the possibility of providing additional and unique opportunities to control API physical properties for both batch and continuous drug product manufacturing, ultimately resulting in simplified and more robust pharmaceutical manufacturing processes. Specifically, diverse opportunities to significantly enhance API physical properties are created if allowances are made for generating co-processed APIs by introducing nonactive components (e.g., excipients, additives, carriers) during drug substance manufacturing. The addition of a nonactive coformer during drug substance manufacturing is currently an accepted approach for cocrystals, and it would be beneficial if a similar allowance could be made for other nonactive components with the ability to modify the physical properties of the API. In many cases, co-processed APIs could enable continuous direct compression for small molecules, and longer term, this approach could be leveraged to simplify continuous end-to-end drug substance to drug product manufacturing processes for both small and large molecules. As with any novel technology, the regulatory expectations for co-processed APIs are not yet clearly defined, and this creates challenges for commercial implementation of these technologies by the pharmaceutical industry. The intent of this paper is to highlight the opportunities and growing interest in realizing the benefits of co-processed APIs, exemplified by a body of academic research and industrial examples. This work will highlight reasons why co-processed APIs would best be considered as drug substances from a regulatory perspective and emphasize the areas where regulatory strategies need to be established to allow for commercialization of innovative approaches in this area.

Punch-sticking during tablet compression is a common problem for many active pharmaceutical ingredients (APIs), which renders tablet formulation development challenging. Herein, we demonstrate that the punch-sticking propensity of a highly sticky API, celecoxib (CEL), can be effectively reduced by spherical crystallization enabled by a polymer assisted quasi-emulsion solvent diffusion (QESD) process. Among three commonly used pharmaceutical polymers, poly(vinylpyrrolidone) (PVP), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC), HPMC was the most effective in stabilizing the transient emulsion during QESD and retarding the coalescence of emulsion droplets and the initiation of CEL crystallization. These observations may arise from stronger intermolecular interactions between HPMC and CEL, consistent with solution

Density is an important material property for evaluating, or developing a tablet formulation. In-die compressibility data can be obtained using a small amount of powder with the help of a compaction simulator. However, compacts undergo volume expansion upon ejection from die. Therefore, accurate out-of-die compressibility profiles cannot be directly obtained from the in-die data. By splitting the tablet elastic recovery into three components (in-die axial, out-of-die axial, radial), we have shown that the in-die elastic recovery is linearly dependent on the compaction pressure within the range investigated, and the out-of-die elastic recovery is a material constant. Hence, we have developed a two-step data treatment (the Hirschberg-Sun approach) for deriving an accurate out-of-die compressibility profile from in-die and out-of-die data of two tablets compressed at a low and a high compaction pressure. The broad applicability of the approach was verified with a larger number of diverse materials.

The aim of this study was to design and evaluate a cocrystal capable of releasing a highly water soluble drug, isoniazid (INH), over a period of longer than several hours by forming a cocrystal wit...

Two new salts of ligustrazine (tetramethylpyrazine, TMP) with the sweeteners, saccharine (SAC) and acesulfame (ACS), have been synthesized through the anion exchange reaction. Single crystals of the new forms were prepared, and their structures were determined. The stability of the new salts against heat and humidity was tested and compared to the commercial hydrochloride and phosphate salts. The sublimation kinetics at various temperatures was analyzed using the Arrhenius equation. The results indicated that TMP-ACS exhibits significantly reduced sublimation tendency and hygroscopicity, which make it a more suitable salt for developing a tablet with acceptable shelf stability than the salts currently used in commercial products.

An analysis of compiled literature nanoindentation hardness (Hc) and elastic modulus (E) values of molecular crystals revealed a wide range of mechanical properties (0.001–1.80 GPa for Hc and 0.27–46.8 GPa for E). A global approximately linear relationship between E and Hc is observed and possible reasons for deviation from the line are discussed. A classification scheme for molecular crystals based on E and Hc is proposed. In addition, results suggest that the effectiveness of crystal engineering strategies in modifying both E and Hc follows the order cocrystallization/salt formation > polymorph formation > anisotropy. A clear understanding of the E and Hc landscape lays a foundation for effective optimization of the mechanical properties of molecular crystals through crystal engineering.

Powder caking can dramatically affect powder handling and downstream production processes. Understanding the key factors that contribute to bulk powder caking is crucial. This article introduces the Hirschberg caking device (HCD), which is a 3D-printed device allowing for parallel testing of powder caking in a cylindrical geometry. In the HCD setup, the powder sample is stored in controlled conditions in the sample holder. On removal of the sample holder, the caked powder will remain in the shape determined by the sample geometry while the remaining powder will fall down. Caking indices can be calculated based on image analysis and weight measurement. The results obtained for the caking of lactose monohydrate with the HCD were in good agreement with the results obtained by a ring shear tester. In addition, a strain tester was used to measure the strength of the formed cakes. Using this approach, critical storage conditions and the required concentration of a given anticaking agent (talc) for lactose monohydrate could be identified. This work demonstrates the potential of rapid prototyping in powder characterization by introducing a fast and affordable approach for exploring and trouble-shooting powder caking.

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.

The use of the surfactant, sodium lauryl sulfate (SLS), instead of enhancing drug dissolution, deteriorates the dissolution of some alkaline drugs through forming poorly soluble lauryl sulfate salts. The thermodynamic driving force for precipitation of such salts is the ratio of ion product in solution (Q) to the solubility product of the salt (Ksp). In this work, we have examined two formulation strategies for mitigating the negative effect of SLS on the dissolution of p-aminobenzoic acid (PABA) by reducing the Q value of its LS salt in the diffusion layer: 1) introducing alkalizing excipient, Na3PO4, to reduce the concentration of PABAH+ by elevating the microenvironment pH, and 2) introducing NaCl to reduce the LS- monomer concentration by depressing the critical micelle concentration (CMC) of SLS.

An amorphous solid dispersion (ASD) of sorafenib (SOR) in hydroxypropyl methylcellulose acetate succinate (HPMC-AS), prepared by coprecipitation, was used to develop an immediate release tablet with improved oral bioavailability. An ASD of 40% drug loading with HPMC-AS (M grade), which exhibited superior physical stability and enhanced dissolution, was selected for tablet development. Systematic characterization of powder properties of the ASD led to the choice of the dry granulation process to overcome poor flowability of the ASD. The designed tablet formulation was evaluated using a material-sparing and expedited approach to optimize compaction conditions for manufacturing ASD tablets with low friability and rapid disintegration. The resulting SOR ASD tablets exhibited approximately 50% higher relative bioavailability in dogs than the marketed SOR tablet product, Nexavar®.

Structure-property correlations in a wide variety of elastic molecular crystals indicate that (a) corrugated structures that can interlock readily (prevent plastic deformation either through geometrical or energetic considerations) and (b) a multitude of weak and dispersive intermolecular interactions that would act as structural buffers through easy rupture and reformation during deformation, are structural features that impart a crystal the ability to accommodate large elastic strains.1-4 Based on their studies on copper(II)acetylacetonate crystals (1, hereafter), Worthy et al. claimed that these criteria are “incorrect”.5 In order to examine their claim critically, we conducted detailed experiments on crystals of 1. Our flexure experiments show that they indeed readily undergo plastic deformation when bent on the (101) face, which contradicts Worthy et al.‘s assertion that the (101) face is highly elastic. Therefore, the crystal 1 is not an ideal model system for rejecting the prevailing and widely accepted-molecular mechanisms for exceptional elastic flexibility of organic crystals.