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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...

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.

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 1:1 caffeine (CAF) and 3-nitrobenzoic acid (NBA) cocrystal (CAF:NBA) displays polymorphism. Each polymorph shares the same docking synthon that connects individual CAF and NBA molecules within the asymmetric unit; however, the extended intermolecular interactions are significantly different between the two polymorphic modifications. These alternative interaction topologies translate to distinct structural motifs, mechanical properties, and compaction performance. To assist our molecular interpretation of the structure-mechanics-performance relationships for these cocrystal polymorphs, we combine powder Brillouin light scattering (p-BLS) to determine the mechanical properties with energy frameworks calculations to identify potentially available slip systems that may facilitate plastic deformation. The previously reported Form 1 for CAF:NBA adopts a 2D-layered crystal structure with a conventional 3.4 Å layer-to-layer separation distance. For Form 2, a columnar structure of 1D-tapes is displayed with CAF:NBA dimers running parallel to the (110) crystallographic direction. Consistent with the layered crystal structure, the shear modulus for Form 1 is significantly reduced relative to Form 2, and moreover, our p-BLS spectra for Form 1 clearly display the presence of low-velocity shear modes, which support the expectation of a low-energy slip system available for facile plastic deformation. Our energy frameworks calculations confirm that Form 1 displays a favorable slip system for plastic deformation. Combining our experimental and computational data indicates that the structural organization in Form 1 of CAF:NBA improves the compressibility and plasticity of the material, and from our tabletability studies, each of these contributions confers superior tableting performance to that of Form 1. Overall, mechanical and energy framework data permit a clear interpretation of the functional performance of polymorphic solids. This could serve as a robust screening approach for early pharmaceutical solid form selection and development.

The effect of particle size on interfacial bonding strength (IBS) of bilayer tablets was studied using microcrystalline cellulose (MCC) and lactose anhydrate. When MCC is in the first layer, IBS is generally lower and more sensitive to particle size and mechanical properties of the second layer material. In contrast, when lactose is in the first layer, the IBS is higher and less influenced by either of these factors. On the other hand, the use of MCC in the second layer leads to higher IBS than lactose. The dependence of IBS on material and particle size can be explained by bonding area (BA) - bonding strength (BS) interplay. IBS generally increases with increasing BA, which is favored by larger particles in the second layer. However, variations in particle size of the first layer powder did not significantly affect IBS.

The interfacial bonding strength (IBS) of four different layer combinations between microcrystalline cellulose (MCC) and lactose (Lac), i.e., MCC/MCC, Lac/Lac, MCC/Lac and Lac/MCC (1st/2nd) was assessed. In these studies, various first layer (P1) and second layer compaction pressures (P2) were used to test the hypothesis that IBS is controlled by bonding area (BA) and bonding strength (BS) interplay at the interface. The BA was evaluated by measurement of the surface waviness and porosity, while BS was assessed by the tablet strength at zero porosity. Lower P1 leads to higher porosity of the first layer, and higher P2 generally leads to greater surface waviness at the interface, both favor a larger BA and thereby higher IBS. However, higher P2 causes a larger difference in radial expansion when the two layers differ, which weakens IBS. The materials in the two layers determine BS, which follows the descending order of MCC/MCC > MCC/Lac (Lac/MCC) > Lac/Lac. The trends in the effects of these factors on IBS support the hypothesis.

Mannitol and lactose are commonly used fillers in pharmaceutical tablets, available in several commercial grades that are produced using different manufacturing processes. These grades significantly differ in particulate and powder properties that impact tablet manufacturability. Choice of sub-optimum type or grade of excipient in tablet formulation can lead to manufacturing problems and difficulties, which are magnified during a continuous manufacturing process. Previous characterization of tableting performance of these materials was limited in scope and under conditions not always realistic to the commercial production of tablets. This work seeks to comprehensively characterize the compaction properties of 11 mannitol and 5 lactose grades using a compaction simulator at both slow and fast tableting speeds. These include tabletability, compressibility, tablet brittleness, die-wall stress transmission, and strain rate sensitivity. A chemometrical analysis of data, using the partial least square technique, was performed to construct a model to provide accurate prediction of tablet tensile strength for mannitol grades. Such knowledge facilitates the selection of suitable tablet filler to attain high quality tablet products.

We report here the first pharmaceutical twistable hydrogen-bonded two-dimensional plastic hydrate crystal of a well-known psychoactive drug, caffeine (CAH). The availability of two pairs of plastic...

Powder adhesion or sticking onto punches is one of the outstanding issues in pharmaceutical tablet manufacturing. We show in this work that, at comparable particle sizes, the acesulfame potassium exhibited pronouncedly reduced propensity to punch sticking than acesulfame. Detailed analyses revealed strong correlation between sticking propensity and crystal mechanical properties and surface chemistry. The free acid was highly plastic with high cohesive strength, while the salt form was brittle. During compaction, surfaces of acesulfame in contact with the punch face are abundant in electronegative functional groups, while those of the salt consist of mainly hydrophobic groups. Thus, acesulfame underwent stronger interactions with the electron-deficient punch. Consequently, the strikingly different onset and severity of sticking propensity between the two solid forms of acesulfame could be clearly explained based on their different crystal mechanical properties and surface characteristics. By providing molecular insight into the outstanding problem of punch sticking in tablet manufacturing, this work expands the list of pharmaceutical applications of crystal engineering.

Twin-screw melt granulation (TSMG) was applied to process a powder blend consisting of 80% gabapentin (GABA) and 20% hydroxypropyl cellulose. The effect of screw profile and processing conditions on the process-induced transformation and chemical degradation of gabapentin was studied. When a neutral kneading block was used, gabapentin underwent polymorphic transformation. A forward kneading block in combination with processing under torque conditions was required to minimize chemical degradation and to inhibit polymorphic transformation of gabapentin. Both the size of the extruded granules and gabapentin degradant level correlated positively with the specific rate, the ratio between feed rate and screw speed. At higher specific rate, the barrel was filled to a greater extent. The material packing and compressive forces were enhanced, as proven by the increased rupturing of CAMES® sensor beads and GABA crystal size reduction. This resulted in more interaction between the powder particles and facilitated granule growth. Simultaneously, this also resulted in higher degradant level. To attain adequate tabletability, the specific rate must reach a threshold value. The development of an optimum TSMG process requires balancing processing parameters based on the physical and chemical stability of GABA as well as its tabletability.

Understanding of the structure-mechanical properties relationship in organic crystals can potentially facilitate the design of crystals with desired mechanical properties through crystal engineering. To understand and predict crystal mechanical properties, including tableting behavior, a number of computational methods have been developed to analyze crystal structure. These include visualization, attachment energy calculation, topological analysis, energy framework, and elasticity tensor calculation. However, different methods often lead to conflicting predictions. There is a need for a computational tool kit for predicting crystal mechanical properties from crystal structures. Using α-oxalic acid anhydrous (OAA) and dihydrate (OAD) as a model system, we have systematically compared their predictive accuracy of the mechanical properties, experimentally determined using powder compaction and nanoindentation. We have found that crystal plasticity can be accurately predicted based on energy framework combined with topological analysis and DFT calculated elasticity tensor. Although very useful in characterizing crystal packing features, structure visualization, topology analysis, and attachment energy calculations alone are insufficient for accurately identifying the slip planes and predicting mechanical properties and tableting behavior of organic crystals.

The effect of thermal binders on the physicochemical properties of gabapentin, a thermally labile drug, in granules prepared using twin-screw melt granulation was investigated in this study. Hydroxypropyl cellulose (HPC), a thermoplastic high molecular-weight binder, was compared against conventional low molecular-weight semi-crystalline thermal binders PEG 8000 and Compritol. Both the chemical degradation and polymorph form change of gabapentin were analyzed. The effects of particle size and molecular weight of HPC on the properties of granules were also studied. To overcome the high melt viscosity of HPC, higher barrel temperatures and higher specific mechanical energy were required to attain suitable granules. As a result, higher levels of gabapentin degradant were observed in HPC-based formulations. However, gabapentin form change was not observed in all formulations. Smaller particle size and lower molecular weight of HPC led to faster granule growth. The tabletability of granules was insensitive to the variations in particle size and molecular weight of HPC. Gabapentin crystal size reduction, HPC size reduction, and HPC enrichment on granule surface were observed for HPC-based granules.

We report here the first elastically bendable single-component pharmaceutical crystal, celecoxib. Interlocked molecular packing without the slip plane and the presence of an isotropic hydrogen bond network are major structural features responsible for both the exceptional elastic flexibility and high stiffness of the celecoxib crystal as revealed by bending and nanomechanical studies. The molecular model of the exceptional elasticity is rationalized by the inhomogeneous spatial separations of molecules in the bent crystal, which is further confirmed by micro-Raman spectroscopy. The celecoxib crystal, exhibiting both therapeutic effects and elastic mechanical behavior, could be used to manufacture functional microdevices with novel medical applications.

Oral administration is advantageous compared to the commonly used parenteral administration for local therapeutic uses of biologics or mucosal vaccines, since it can specifically target the gastrointestinal (GI) tract. It offers better patient compliance, even though the general use of such a delivery route is often limited by potential drug degradation in the GI tract and poor absorption. Using bovine serum albumin (BSA) and lysozyme as two model proteins, we studied their solid-state properties, mechanical properties, and tabletability as well as effects of compaction pressure, particle size, and humidity on protein degradation. It was found that BSA and lysozyme are highly hygroscopic, and their tablet manufacturability (powder caking, punch sticking, and tablet lamination) is sensitive to the humidity. BSA and lysozyme exhibited high plasticity and excellent tabletability and remained amorphous at high pressure and humidity. As for protein stability, lysozyme was resistant to high pressure (up to 300 MPa) and high humidity (up to 93%). In contrast, BSA underwent aggregation upon compression, an effect that was more pronounced for smaller BSA particles. High humidity accelerated the aggregation of BSA during incubation, but it did not further synergize with mechanical stress to induce protein degradation. Thus, compression can potentially induce protein aggregation, but this effect is protein-dependent. Therefore, strategies (e.g., the use of excipients, optimized manufacturing processes) to inhibit protein degradation should be explored before their tablet dosage form development.

Berberine chloride (BCl) can exist as an anhydrate, monohydrate, dihydrate, and tetrahydrate. Therefore, it faces the problem of humidity dependent solid phase change when environmental humidity varies during manufacturing and storage of berberine tablets. We have discovered a new 1:1 cocrystal formed between berberine chloride and citric acid (BCl-CA) that exhibits better stability against variations in humidity while maintaining similar thermal stability, solubility, dissolution rate, and tabletability. Thus, BCl-CA is a good alternative crystal form for use in formulation to manufacture berberine tablets.

Content uniformity (CU) is a well-recognized challenge for low-dose direct compression (DC) tablet formulations. Using a dual particle engineering approach that involves a) forming a segregation-resistant drug-carrier composite to improve CU and b) nanocoating HPMC to enhance flowability, we have developed a platform DC formulation for preparing low-dose drug sustained-release (SR) tablets with excellent CU. In addition to demonstrated robustness in manufacturability, this platform formulation has the flexibility for modifying drug release rate. Thus, it is useful for expedited and material-sparing development of low dose SR tablets using the economical DC process.

The present study aims to develop cubosomes with surface cross-linked chitosan for sustained drug delivery and enhanced oral bioavailability of vinpocetine (VPT). GMO based liquid cubosomes with VPT loading were prepared by the high pressure homogenization method. In order to enhance the anti-digestion effect, chitosan was cross-linked on cubosomes by the Schiff reaction, followed by solidification via spray drying. The obtained spray-dried cubosomes (chito-cubosomes) are spherical microspheres with nano-sized holes on the surface. After reconstitution, the particle size and zeta potential of chito-cubosomes were determined to be ∼250 nm and +35.9 mV, respectively. In comparison to unmodified liquid cubosomes, chito-cubosomes exhibited a significant anti-digestion effect with a typical sustained release profile. In comparison to a VPT suspension, liquid cubosomes showed a 2.5-fold higher Cmax and 3.0-fold higher AUC0–∞, while chito-cubosomes further enhanced bioavailability (5.0-fold) with prolonged MRT (2.2-fold) and delayed Tmax (2.8-fold). The results suggested that chito-cubosomes could be a promising drug carrier for enhancing oral absorption with sustained release behavior.

The complex between sulfamethazine and saccharine (SMT–SAC) can exist in two polymorphs, one is a cocrystal and the other is a salt. It is important to fully characterize the two polymorphs for a better understanding of the rare polymorphism between a salt and a cocrystal. However, this effort was hindered by the difficulty in reproducibly preparing a large quantity of phase pure cocrystal polymorph (form II). Here, we developed a method for preparing phase pure cocrystal polymorph robustly by controlling the crystallization medium. Using bulk powders, we determined their free energy diagram, by using intrinsic dissolution rates at 5–37 °C and thermal data near melting temperature. We have shown that the two forms are monotropically related, with the cocrystal form II being more thermodynamically stable up to the melting temperature. We further probed their ionization states based on analyses of the position of protons, bond length, and molecular vibrational motions of pertinent functional groups. Finally, the cocrystal form II exhibited notable differences in moisture sorption and compaction properties, which may influence the choice of solid forms for further development of tablet products.

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.

Magnesium stearate (MgSt) is a widely used pharmaceutical lubricant in tablet manufacturing. However, batch-to-batch variability in hydrate form and surface area can lead to inconsistency in tablet performance. In this work, several unique MgSt samples were studied: traditional monohydrate samples with high surface area, dihydrate forms with high and low surface area, and disordered forms with low and medium water content. The effects of solid-state form and particle properties on lubrication efficiency, tabletability and dissolution were studied for tablets in a model direct compression formulation. It was found that the monohydrate and dihydrate forms had good lubrication efficiency compared to the disordered form, while the disordered form had the best tabletability. The dissolution rate correlated with surface area, where slower dissolution rates corresponded with higher MgSt surface areas. The dihydrate sample with lower surface area had the best performance for this model formulation, in terms of lubrication efficiency, tabletability and dissolution. Overall, it is concluded that the choice of the most appropriate grade of MgSt for a particular formulation depends on a comprehensive evaluation of the impact of MgSt properties on lubrication efficiency, tabletability and dissolution.

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.

We examined the potential of the spherical cocrystallization (SCC) technology in simultaneously enhancing tablet manufacturability and dissolution of poorly soluble drugs by developing a mini-tablet formulation of piroxicam. The manufacturing of mini-tablets using a direct compression (DC) process is more challenging than conventional tablets because of the much stricter requirement on the micromeritic properties of formulated powders. The SCC process in this work involved two steps: 1) preparing a new piroxicam-ferulic acid (PRX-FA) cocrystal, and 2) forming spherical agglomerates with the aid of a suitable bridging liquid. The PRX-FA cocrystal exhibited enhanced solubility as well as improved plasticity. The bridging liquid, a mixture of chloroform and ethyl acetate (EA) (1: 2, v/v), was chosen based on the high computed adsorption energy of chloroform and EA on morphologically dominating crystal faces of PRX-FA. The improved flowability, tabletability, and dissolution rate of spherical PRX-FA enabled the successful development of a DC mini-tablet formulation with a high PRX loading (41 wt%). This example shows that SCC is a powerful enabling technology for DC tablet formulation development of challenging drugs.

The purpose of this work is to develop an orally disintegrating tablet (ODT) of sildenafil (SIL) using a materials sparing and expedited development approach, enabled by the materials science tetrahedron principle and predictive technologies. To overcome the problem of bitter taste of SIL, an artificial sweetener, acesulfame (Acs), was used to form a sweet SIL salt (SIL-Acs) using an effective reaction crystallization process to prepare phase pure bulk SIL-Acs with a high yield. The SIL-Acs salt shows excellent thermal stability (Tm = 200.2 °C), low hygroscopicity, and acceptable dissolution rate. Formulation and process parameters were optimized based on powder flowability, tabletability, tablet disintegration time, and expedited friability. A particle engineering approach, i.e., nanocoating, was employed to attain adequate flowability of the SIL-Acs ODT formulation required for the direct compression process. The wide range of compression forces for making tablets exhibiting both fast disintegration time (≤30 s) and low friability (≤0.8%) suggested excellent flexibility in manufacturing SIL-Acs ODT. The development of a sildenafil ODT formulation, including solid form selection and characterization, crystallization method development, formulation development, and DC process optimization, only required 5 g of SIL citrate and 2 weeks of time.

To explain the different tabletability of two structurally similar H1-receptor antihistamine drugs, loratadine (LOR) and desloratadine (DES), based on the molecular basis of bonding area and bonding strength. LOR and DES were characterized by powder X-ray diffractometry, thermal analysis, and dynamic water sorption. The compressibility, tabletability, compactibility, and Heckel analysis of their bulk powders and formulations were evaluated. A combined energy framework and topological analysis was used to characterize the crystal structure – mechanical property relationship. Surface energy of bulk powder was assessed by contact angle measurement using the Owens/Wendt theory. Both LOR and DES bulk powders are phase pure and stable under compaction. The superior tabletability of LOR is attributed to both larger bonding area (BA) and higher interparticle bonding strength (BS). The larger BA of LOR results from its experimentally established higher plasticity, which is explained by the presence of more densely packed molecular layers with smooth surface topology. The higher BS of LOR corresponded to its significantly higher dispersive component of the surface energy. This work provides new insights into the molecular origins of BA and BS, which can be applied to improve mechanical properties and tableting performance of drugs through appropriate crystal engineering.

Magnesium stearate (MgSt) is a common lubricant used in tablet formulations to facilitate tablet manufacturing by reducing ejection force. The use of MgSt in tablet formulation is known to potentially deteriorate tabletability of plastic powders and slow down drug dissolution. Here, we report surprisingly profound deterioration in tabletability of microcrystalline cellulose by hand-mixing. We also show that the hand mixing process is highly variable. To ensure the reproducibility of tabletability assessment of powders, hand-mixing should be used with caution. For research that employs hand mixing, mixing procedure should be carefully controlled and reported.

Macrophages are sentinels of the immune system, which are often hijacked by tumor cells to assist tumor growth and metastasis. Herein our results showed that low dose salinomycin (SAL) in the range of 10-50 nM could efficiently induce M1 macrophage polarization in a dose- and time- dependent manner in vitro, with 30 nM SAL being optimal to generate M1-type macrophages from RAW246.7 cells. In animal study, intratumorally injected SAL (50 µg/kg) increased proportion of CD86 cells (by 28.9%), and decreased CD206 cells (by 14.2%) in transplant 4T1 tumors, in comparison with PBS group. Thus it resulted in significant regression in tumor growth (20% tumor inhibition) and pulmonary metastasis (reduced the number of metastatic nodes by 58%) in SAL group, whereas lipopolysaccharide (LPS) and paclitaxel (PTX) groups showed comparable number of metastatic lesions and volume of tumor. LPS treatment could as well lead to inflammatory reactions in tumor with SAL group, but resulted in systemic inflammation (elevated levels of IL-1α, IL-1β and TNF-α in serum), and PTX (10 μg/kg) treatment increased both types of macrophages. For the first time, we employed salinomycin below the dose of direct antitumor activity could effectively prime M1 type macrophage stimulation and regress tumor growth and metastasis.

Predicting tableting performance of mixtures from that of individual components is of practical importance for achieving efficient and robust tablet design. It has been commonly assumed that a solid form exhibiting better tabletability will result in better tabletability when formulated. However, we show that the rank order of tabletability between two powders can flip when mixed with another powder, a phenomenon termed tabletability flip. Using three examples, we show that the tabletability flip upon mixing with microcrystalline cellulose is activated by the switch of the dominating factor in the bonding area (BA) and bonding strength (BS) interplay that determines tablet tensile strength. A mechanistic understanding of this phenomenon can significantly improve the accuracy of predicted tableting performance of mixtures from that of individual powders.

This study investigated the effect of binder level on the physicochemical changes and tabletability of acetaminophen (APAP)-hydroxypropyl cellulose (HPC) granulated using twin-screw melt granulation. Even at 5% HPC level, the tablet tensile strength achieved up to 3.5 MPa. A minimum of 10% HPC was required for the process robustness. However, 20% HPC led to tabletability loss, attributable to the high mechanical strength of APAP granules. The over-granulated APAP granules had thick connected HPC scaffold and low porosity. Consequently, these granules were so strong that they underwent a lower degree of fracture under compression and higher elastic recovery during decompression. HPC was enriched on the surface of APAP extrudates at all HPC levels. Amorphous APAP was also observed on the extrudate surface at 20% HPC level, and it recrystallized within 24 h storage. To achieve a robust process and optimal improvement in APAP tabletability, the preferred HPC level was 10 to 15%.

To efficiently develop a tablet formulation of carbamazepine using a soluble cocrystal with excess coformer to maintain phase stability during dissolution. The carbamazepine – glutaric acid cocrystal (CBZ-GLA, 1:1) and excess glutaric acid (GLA) were mixed with suitable tablet excipients, which were selected to address powder flowability and tabletability deficiencies specifically. Tablet friability and dissolution profiles were evaluated to guide formulation optimization. Dry granules were prepared by milling simulated ribbons. A binary blend of CBZ-GLA and GLA had poor flowability and marginal tabletability. Therefore, silica coated Avicel PH-102 (sMCC) was applied as a binder to improve the flow property and tabletability. A formulation consisting of sMCC, CBZ-GLA, and GLA exhibited good manufacturability but did not show improved dissolution because of rapid precipitation of CBZ dihydrate when CBZ-GLA came in contact with water. Dry granulation of CBZ-GLA and GLA dramatically improved dissolution profile due to the intimate contact between CBZ-GLA and GLA. Such cocrystal - coformer granules also led to much improved tablet manufacturability and dissolution. The successful tablet development of CBZ-GLA, using < 3 g of the cocrystal in

The uniformity of active pharmaceutical ingredient (API) is a main challenge associated with manufacturing low dose tablets. Here, we present a binder enhanced API-microcrystalline cellulose (BEAM) approach to address this challenge. In the BEAM approach a powder is prepared by spraying a PVP hydro-alcoholic solution, which contains API at an appropriate concentration, onto a powder bed of microcrystalline cellulose (MCC) under high shear. BEAM powders of 5 model APIs, with solubility spanning a range of 5 orders of magnitude, all exhibited excellent flowability, tabletability, and low ejection force. Therefore, all BEAM powders could be directly compressed into tablets with excellent API uniformity and fast disintegration without using any other excipients. Compared to traditional ways to address content uniformity problems, this formulation strategy is much more robust and simpler, making it a potential platform technology for manufacturing tablets of potent APIs.

Punch sticking during tablet manufacturing is a common problem facing the pharmaceutical industry. Using several model compounds, effects of crystal size and shape of active pharmaceutical ingredients (API) on punch sticking propensity were systematically investigated in this work to provide molecular insights into the punch-sticking phenomenon. In contrast to the common belief that smaller API particles aggravate punch sticking, results show that particle size reduction can either reduce or enhance API punch sticking, depending on the complex interplay among the particle surface area, plasticity, cohesive strength, and specific surface functional groups. Therefore, other factors, such as crystal mechanical properties, surface chemistry of crystal facets exposed to the punch face, and choice of excipients in a formulation, should be considered for a more reliable prediction of the initiation and progression of punch sticking. The exposure of strong electronegative groups to the punch face facilitates the onset of sticking, while higher plasticity and cohesive strength aggravate sticking.

Appropriate lubrication is important in tablet manufacturing as it lowers punch sticking propensity and protects tooling by reducing friction between die wall and tablet during tablet manufacturing. Most commercial lubricants negatively impact tabletability and dissolution. A delicate balance is usually attained by trial and error to identify the optimal level of lubricant in a tablet formulation. In this work, we have evaluated the effectiveness of sodium lauryl sulfate (SLS), a surfactant, as a tableting lubricant. If adequate lubrication efficiency is achieved, the use of SLS may be suitable to mitigate problems associated with hydrophobic lubricants. Results show that SLS, when applied in the proper amount to typical pharmaceutical powder mixtures, achieved lubrication efficiency comparable to a grade of magnesium stearate (MgSt) without deteriorating tabletability. Moreover, SLS-containing tablets of celecoxib also exhibited improved in vitro dissolution compared to MgSt-containing tablets. The enhancement in dissolution properties was attributed to the improved wetting by the dissolution medium due to the presence of SLS.

A challenge in the dry granulation (DG) process is the generation of an excessive amount of fines during milling, which can cause problems in die filling due to poor flowability and content uniformity of tablets. Using a design of experiments (DOE) approach, we show that the amount of fines generated during milling decreases with either increasing ribbon density or screen size, while impeller speed has negligible effect. Moreover, under identical milling conditions, the percent fines can be accurately predicted from ribbon density. Thus, controlling ribbon density and screen size is important for optimizing the amount of fines produced during DG process. Because density has a central role in the outcome, it is a critical ribbon property that needs to be controlled to improve robustness of the DG process.

Recent advances in crystal engineering by cocrystallization have offered a promising approach for tackling undesirable physicochemical properties of drug substances. In this study, various structur...

Diphenhydramine (DPH) has been used with ibuprofen (IBU) or naproxen (NAP) in combined therapies to provide better clinical efficacy as an analgesic and sleep aid. We discovered that DPH can form protic ionic liquids (PILs) with IBU and NAP, which opens the opportunity for a new delivery mode of these combination drugs. [DPH][IBU] and [DPH][NAP] PILs exhibit low ionicity, as confirmed by Fourier transform infrared and 1H NMR spectroscopy, and accompanied by low diffusivity, high viscosity, and poor ionic conductivity. Evaluation of pharmaceutical properties of the two PILs showed that these PILs, despite high solubility and good wettability, exhibited low dissolution rates, owing to the poor dispersion of the PIL drops and the resultant small surface area during dissolution. However, when loaded into a mesoporous carrier, the PIL-carrier composites exhibited improved dissolution rates along with excellent flow properties and easy handling. Oral capsules of both PILs were developed using such composites. S...

Improving taste and tuning physicochemical properties of active pharmaceutical ingredients (API) by forming new salts or cocrystals with an artificial sweetener, such as saccharine (Sac) and acesulfame (Acs), is an effective crystal engineering strategy for facilitating successful delivery of bitter drugs. However, the number of reported solid forms of Acs is curiously lower (29) than that of Sac (275). An analysis of the literature revealed that the preparation of salts or cocrystals of Acs was hindered by the difficulty and cost in preparing Acs free acid from commercially available potassium salt (Acs-K). Here, we evaluated the broad applicability of an anion exchange reaction for preparing Acs solid forms using nine model compounds. In all cases, we successfully prepared Acs crystals, based on single crystal structure determination, simply from ion exchange between Acs-K and corresponding salts. The proton transfer propensity, hydrogen-bonding pattern, and amide group keto–enol tautomerism in the Acs ...

As an essential formulation component for large-scale tablet manufacturing, the lubricant preserves tooling by reducing die-wall friction. Unfortunately, lubrication also often results in adverse effects on tablet characteristics, such as prolonged disintegration, slowed dissolution, and reduced mechanical strength. Therefore, the choice of lubricant and its optimal concentration in a tablet formulation is a critical decision in tablet formulation development to attain low die-wall friction while minimizing negative impact on other tablet properties. Three commercially available tablet lubricants, i.e., magnesium stearate, sodium stearyl fumerate, and stearic acid, were systematically investigated in both plastic and brittle matrices to elucidate their effects on reducing die-wall friction, tablet strength, tablet hardness, tablet friability, and tablet disintegration kinetics. Clear understanding of the lubrication efficiency of commonly used lubricants as well as their impact on tablet characteristics would help future tablet formulation efforts.

Mechanical properties of pharmaceutical materials, e.g., Young's modulus (E), indentation hardness (H), and tensile strength (σt), play an important role in powder compaction process. However, few studies investigated the relationship among these parameters and consequence for tablet compression. Using microcrystalline cellulose, a plastic material, and dibasic calcium phosphate anhydrate, a brittle material, as well as their binary mixtures, we systematically examined the relationship among the three properties. It was found that Young's modulus was proportional to indentation hardness (H/E ≈ 0.036) regardless of the composition and compaction pressure. For a given material, tensile strength was also proportional to E and H but the relationship varied with materials. Higher E and H were required to attain the same σt for a more brittle material.

Continuous manufacturing of tablets has many advantages, including batch size flexibility, demand-adaptive scale up or scale down, consistent product quality, small operational foot print, and increased manufacturing efficiency. Simplicity makes direct compression the most suitable process for continuous tablet manufacturing. However, deficiencies in powder flow and compression of active pharmaceutical ingredients (APIs) limit the range of drug loading that can routinely be considered for direct compression. For the widespread adoption of continuous direct compression, effective API engineering strategies to address power flow and compression problems are needed. Appropriate implementation of these strategies would facilitate the design of high-quality robust drug products, as stipulated by the Quality-by-Design framework. Here, several crystal and particle engineering strategies for improving powder flow and compression properties are summarized. The focus is on the underlying materials science, which is the foundation for effective API engineering to enable successful continuous manufacturing by the direct compression process.

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 ...

Commercial baicalein (α form) exhibits deficient tabletability. Cocrystals of baicalein with nicotinamide, caffeine, and isoniazid were all shown to display excellent tabletability, despite the three coformers having high, medium, and poor tabletability, respectively. A crystal structure analysis using the energy framework approach revealed that the superior tabletability of these cocrystals always correlated with structural features rendering high plasticity irrespective of the coformer involved.

The crystallization of supercooled amorphous materials limits their successful applications. The spatial origin of crystallization, nucleation, is one of the most debated topics. We show that homogeneous crystallization may be initiated from tens of micrometers beneath the surface of a supercooled acetaminophen liquid.

Biological products, such as therapeutic proteins, vaccines and cell - based therapeutics have a rapidly growing global market. Monoclonal antibody represents a major portion of the biologics market. For biologics that target gastrointestinal tract, the oral delivery route offers many advantages, such as better patient compliance, easy administration and increased stability, over the parental route of administration. To lay the ground work for the oral delivery of biologics, we studied the solid state properties and effects of compaction pressure, particle size, and storage relative humidity on the stability of immunoglobulin G (IVIG). We employed complementary analytical and biophysical techniques, such as size exclusion chromatography and Dynamic light scattering to characterize the aggregates, circular dichroism and solid state Fourier-transform infrared spectroscopy to evaluate protein secondary structure and nano-DSC to probe thermal stability of protein conformations. Our results showed storage relative humidity could induce conformational changes and aggregation of IVIG. However, the IVIG binding activity did not significantly change with relative humidity. The commonly used compaction pressures did not promote protein aggregation, but noticeably reduced binding activity.

Clear understanding of the relationships among crystal structure, mechanical properties, and tableting performance is of enormous importance for successful development of tablet products. This study was aimed at systematically examining such relationships using four salts of diphenhydramine (DPH), a first-generation H-receptor antagonist, i.e., hydrochloride (DPH-HCl), citrate (DPH-Cit), saccharinate (DPH-Sac), and acesulfamate (DPH-Acs). The conformation and intermolecular interactions of DPH as well as crystal packing in the four salts were considerably different. Both the energy framework and visualization of the crystal structure revealed the greatest plasticity of DPH-Acs, which was characterized by drastically different intermolecular interactions in orthogonal directions. This was consistent with its facile bending behavior and the lowest hardness. The most plastic DPH-Acs also exhibited the best tabletability, which was accompanied by greater compressibility and compactibility as well as smaller e...

The tablet of multi-unit pellet system (TMUPS), using coated pellets, for controlled release of drugs is an effective therapeutic alternative to conventional immediate-release dosage forms. The main advantages of TMUPS include a) ease of swallowing and b) divisible without compromising the drug release characteristics of the individual units. TMUPS can be prepared more economically than pellet-filled capsules because of the much higher production rate of tableting process. In spite of the superiorities of TMUPS, its adoption has been challenged by manufacturing problems, such as compromised integrity of coated pellets and poor content uniformity. Herein, we provide an updated review on research, from both scientific literatures and patents, related to the compaction of TMUPS. Factors important for the successful production of TMUPS are summarized, including model drug property, potential cushioning agents, and novel techniques to protect pellets from damage. This review is intended to facilitate the future development of manufacturable TMUPS with drug release behavior similar to that of the original coated pellets.

Dapagliflozin (DAP) is a potent and selective sodium-glucose contransporter-2 inhibitor, for treating type 2 diabetes. DAP propanediol monohydrate (DAP-PDO-H2O, 1:1:1) is the solid form used in the current tablet product to address the severe hygroscopicity problem of DAP free form. DAP-PDO-H2O, however, suffers the problem of instability when exposed to high temperature, which renders it amorphous. In this work, we report on the preparation and evaluation of a new 1:1 cocrystal between DAP and citric acid (DAP-CA). The DAP-CA cocrystal exhibits superior stability against high temperature and high relative humidity without compromising dissolution and tableting performance. Thus, DAP-CA is a promising solid form for developing the next generation DAP tablet products with improved performance.

Both shear and tensile measurement methods have been used to quantify interfacial bonding strength of bilayer tablets. The shear method is more convenient to perform, but reproducible strength data requires careful control of the placement of tablet and contact point for shear force application. Moreover, data obtained from the shear method depend on the orientation of the bilayer tablet. Although more time-consuming to perform, the tensile method yields data that are straightforward to interpret. Thus, the tensile method is preferred in fundamental bilayer tableting research to minimize ambiguity in data interpretation. Using both shear and tensile methods, we measured the mechanical strength of bilayer tablets made of several different layer combinations of lactose and microcrystalline cellulose. We observed a good correlation between strength obtained by the tensile method and carefully conducted shear method. This suggests that the shear method may be used for routine quality test of bilayer tablets during manufacturing because of its speed and convenience, provided a protocol for careful control of the placement of the tablet interface, tablet orientation, and blade is implemented.