Search

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.

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

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.

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.

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.

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.

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...

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.

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.

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.

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.

Tablet brittleness index (TBI) quantifies tablet fracture behavior, which strongly correlates with tablet porosity and tensile strength. The goal of this work was to quantify the influence of lubrication on tablet brittleness. Magnesium stearate was used as a lubricant. Several common tablet excipients, i.e., starch, lactose, microcrystalline cellulose (MCC), and dibasic calcium phosphate anhydrate (DCPA), and a binary mixture between lactose and MCC were studied. Tablet tensile strength (σ) and TBI at zero porosity (σ0 and TBI0) were obtained from nonlinear regression of data of all powders to evaluate the relationship between brittleness and bonding strength of pore-free tablets. The results show that lubrication by magnesium stearate led to decrease in σ0 and increase in TBI0. The effect was more profound for both a longer blending time and a higher amount of magnesium stearate. In addition, the TBI of the binary mixture was successfully predicted from the fitted parameters of lactose and MCC using the power mixing rule. Such effects of lubrication on tablet brittleness should be considered during formulation development to avoid unexpected quality issues.

Graphical Abstract Unlabelled image, 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.

Flashing at tablet edges, an inevitable phenomenon when tableting a plastically deforming material under a high pressure, can introduce significant errors to tablet density and porosity determinations due to overestimated tablet thickness when tablet were measured out-of-die. Errors in tablet density determination also lead to errors in true density obtained by the Sun method, which is suitable for water-containing solids. Errors in true density and tablet porosity propagate to fundamental parameters, derived from common equations, for quantifying mechanical properties of compacts. In this work, we have developed and validated a method to eliminate tablet flashing using sand paper. Using binary mixtures of water-containing plastic materials, we have further demonstrated the impressive improvement in powder deformability assessment by using accurate density of tablets free from flashing.

Multiple unit pellet system(s), MUPS, is one of the most commonly used means for achieving modified drug release through oral administration. MUPS is usually delivered as capsules that contain drug bearing beads coated with a release modulating functional layer. While the routine manufacture of tablets of MUPS by direct compression is highly desired, it is faced with the problem of poor tableting properties or altered drug release behavior due to the rupture of the functional coating layer. The use of a significant amount of cushion material alleviates these problems, but is also challenged with the problem of segregation and reduced drug loading. We hypothesize that top-coating the beads with a layer of highly bonding polymer can enable direct tableting of beads without compromising the functional coating layer and avoid segregation problem. Using functionally coated pyridoxine and caffeine beads, we confirmed that top coating with Polyvinylpyrrolidone sufficiently plasticized with water can enable the preparation of strong tablets at even low compaction pressures. Drug release profiles of tablets are comparable to those of uncompressed beads, indicating negligible amount of damage, if any, to the functional coating layer. In conclusion, it has been demonstrated that top polymer coating may provide a promising universally applicable strategy to realize the goal of delivering MUPS in the form of tablet.

A commonly used pharmaceutical surfactant, sodium lauryl sulfate (SLS), has been reported to reduce the dissolution rate of drugs due to the formation of a less soluble drug-lauryl sulfate salt. In this study, we provide direct crystallographic evidence of the formation of salt between SLS and norfloxacin (NOR), [NORH

Lubricants are important for both preserving the tooling of high-speed tablet presses and attaining quality tablets. Magnesium stearate (MgSt) is most commonly used due to its superior lubrication efficiency; however, it can lead to negative effects on tabletability and dissolution. In this study, we have systematically evaluated two poloxamers, P188 and P407, for their suitability as alternative tablet lubricants. For two excipients with different mechanical properties, i.e., microcrystalline cellulose and lactose, both poloxamers exhibit acceptable lubrication efficiency without negatively impacting tabletability. Compared to 1% MgSt, the performance of 2% of both poloxamers in an experimental tablet formulation of ritonavir led to better lubrication, higher tabletability, and enhanced in vitro drug release. Thus, the use of P188 and P407 as alternative tablet lubricants deserves further evaluations.

This study aimed at systematically investigating the role of distributive comb mixing element (GLC) and neutral dispersive mixing kneading block element (K90) on the structure and physical properties of granules containing high-dose of poorly water-soluble drug. Albendazole was used as the model drug at 50 wt% drug loading. Lactose monohydrate and microcrystalline cellulose were used as diluent, and 3 w/v% hydroxypropyl cellulose aqueous solution was used as binder liquid. It was found that the use of GLC element resulted in formation of granules with higher internal porosity, more homogeneous binder distribution, smaller particle size, superior compaction properties and tabletability while K90 kneading element produced relatively larger and denser granules with less homogeneous binder distribution where binder was mainly concentrated in larger granules. The use of downstream GLC element was shown to result in an approximately 8% and 57% reduction in the D50 for 0.2 and 0.3 liquid-to-solid ratios, demonstrating a significantly higher sensitivity of granule size to screw profile at higher liquid-to-solid ratios. The axial mixing efficiency was assessed by measuring the residence time distribution of the granulation process with screw profiles containing K90 and GLC elements. It was found that granules had longer mean residence time and broader residence time distribution within GLC element due to enhanced backmixing and axial dispersion processes. The continuous “fragmentation-reagglomeration” cycle was proposed to be the main advantage of distributive GLC element in granulation of hydrophobic powders.

Ligustrazine (or Tetramethylpyrazine, TMP) is an active pharmaceutical ingredient that faces the challenges of bitter taste and low oral bioavailability by the commercial phosphate salt (TMP-Pho). We tackled these challenges by forming salts with two sweeteners, acesulfame (Acs) and saccharine (Sac). Both salts effectively masked the bitter taste of TMP. Compared to TMP-Pho, TMP-Sac shows 43% lower solubility and 11% lower permeability while TMP-Acs shows higher (two-fold) solubility but 24% lower permeability. Both TMP-Acs and TMP-Sac exhibited approximately 40% higher bioavailability through reducing the rate of TMP absorption. Thus, salt formation with both sweeteners simultaneously addressed the challenges brought about by the bitter taste and lower bioavailability of TMP.

To identify the minimum interfacial bonding strength (IBS) required for bilayer tablets to sustain the stresses experienced during manufacturing, transportation, and handling. Bilayer tablets of a number of formulations with systematically varied IBS were prepared on a materials testing macine. Five bilayer tablets with the same IBS were repeatedly dropped at a fixed height in a friabilator and integrity of the interface was periodically examined. The number of tablets free from observable defects at the interface was plotted as a function of the number of drops. The IBS for all five tablets to remain intact after 1000 drops was taken as the minimum IBS for a given formulation. The minimum IBS depends on both layer composition and tablet size. For bilayer tablets made with more brittle materials or a larger size, a higher minimum IBS is required to pass the survival test. The incorporation of HPMC leads to a lower minimum IBS. An IBS of 0.26 MPa is sufficient for all bilayer tablet formulations and sizes to pass the survival test in this work. A minimum IBS of 0.26 MPa is recommended as a tentative criterion for bilayer tablets of most materials to avoid quality issues arising from inadequate IBS.

To take full advantage of the drug delivery benefits offered by bilayer tablets, the common issue of weak interfacial bonding strength (IBS) with manufacturing must be overcome. This work seeks to characterize the effects of composition in individual layers and compaction pressure on the IBS. Mixtures of MCC and lactose in different ratios with and without HPMC were used where the first layer was compacted with two different pressures (20 and 100 MPa) followed by a second layer compaction pressure of 200 MPa. After identifying the failure mode as either at the interface or within a layer, the complex trends of bilayer tablet IBS as a function of MCC content were explained by considering the interplay between particle bonding strength and bonding area at the interface.

To address the problem of precipitation of a poorly soluble drug during dissolution of highly soluble cocrystals by preparing granules intimately mixed with a water-soluble polymer. Effectiveness of polymers as precipitation inhibitors during the dissolution of carbamazepine–nicotinamide (CBZ-NCT) cocrystal was assessed based on induction time of crystallization from a supersaturated solution in presence of different polymers at two concentrations. Dissolution was evaluated by both intrinsic dissolution rate (IDR) and USP dissolution method. Powder manufacturability was assessed using a shear cell and compaction simulator to assess flowability and tabletability, respectively. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) was the most effective polymer against precipitation of CBZ and the IDR of a 1:1 (w/w) CBZ-NCT/HPMCAS mixture was the highest. The final formulation of 1:1 CBZ-NCT/HPMCAS granule exhibited excellent flowability, good tabletability, and significantly improved drug release rate than cocrystal formulations without HPMCAS or the CBZ formulation. The particle engineering strategy of modifying the diffusion layer on the surface of highly soluble cocrystal with a polymer is effective for inhibiting premature precipitation of CBZ. Assisted with predictive tools for characterizing powder flowability and tabletability, the design of high quality tablet product with improved drug release rate and manufacturability can be achieved in an efficient manner.

Mechanical properties of a material, such as hardness and elastic modulus, depend on porosity exponentially. Thus, an accurate characterization of material mechanical properties requires correct porosity, which depends on the accuracy of measured true density. Helium pycnometry is the most common technique for determining true density of a powder material but it is not suitable for materials containing volatile components. For unstable hydrates, dehydration during measurement releases water and invalidates the ideal gas law used for calculating sample volume. Consequently, measured true density is over-estimated, which causes gross errors in mechanical properties extrapolated to zero porosity. This work shows that physical stability and the dehydration kinetics, determined by both water-bonding structures and bonding energy, directly affect the magnitude of error in measured true density.

The storage of bulk powders in suboptimal conditions can affect their handling, processing, and performance. The aim of this work was to assess the influence of storage conditions on powder flowability, which is a crucial property in powder processing. The 7 model compounds were common tablet excipients with varying crystallinity ranging from amorphous to partially crystalline, and 2 crystalline materials. The water sorption-desorption isotherms of all the excipients were analyzed with dynamic vapor sorption, and the kinetics of the water sorption at 75% relative humidity were investigated using isothermal microcalorimetry. In addition, the powders were conditioned at 3 relative humidities 23%, 43%, and 75% at ambient temperature, and their flowability was measured using 3 different techniques: ring shear testing, basic flowability energy, and flow through an orifice. All 3 methods were able to detect the storage-related change in flowability induced by varying storage conditions. With increasing storage humidity, a trend toward a decrease in powder flowability could be detected with the chosen instruments. Furthermore, the same rank order of powder flowability could be observed using the flow through an orifice and ring shear testing method.

Celecoxib, an anti-inflammatory drug for pain and arthritis, is currently only available in capsule form. To reduce the onset time for a faster action and to lower the manufacturing cost, the tablet dosage form is more preferred. However, the commercial celecoxib (Form III) is not suitable for direct compression (DC) tablet manufacture due to poor flow, low bulk density, and tablet lamination. In this work, we overcome these challenges using a pharmaceutically acceptable dimethyl sulfoxide (DMSO) solvate of celecoxib. Aided with the DMSO solvate, an acceptable DC tablet formulation was successfully developed to manufacture tablets containing 200 mg celecoxib, with satisfactory manufacturability, disintegration, and in vitro dissolution performance.

peer-reviewed The mechanical properties of powders determine the ease of manufacture and ultimately the quality of the oral solid dosage forms. Although poor mechanical properties of an active pharmaceutical ingredient (API) can be mitigated by using suitable excipients in a formulation, the effectiveness of that approach is limited for high dose drugs or multidrug tablets. In this context, improving the mechanical properties of the APIs through solid form optimisation is a good strategy to address such a challenge. This work explores the powder and tableting properties of various lamotrigine (LAM) solid forms with the aim to facilitate direct compression by overcoming the poor tablet ability of LAM. The two drug-drug crystals of LAM with nicotinamide and valproic acid demonstrate superior flowability and tablet ability over LAM. The improved powder properties are rationalised by structure analysis using energy framework, scanning electron microscopy, and Heckel analysis.

Dry granulation using roller compaction is an important unit operation in the pharmaceutical industry. In contrast to many wet granulation techniques applied in pharmaceuticals, dry granulation is a continuous process and it is a suitable processing solution for moisture and heat-sensitive active compounds. During dry granulation, the powder is compacted between two rolls to form compacts (ribbons). These ribbons are subsequently milled into granules and finally, compressed into tablets. One of critical process parameters is the porosity of these ribbons critically influencing the granule properties and final product quality. In this work, model ribbons with varying porosity were prepared at different roll pressures and roll speeds. The ribbons were further milled to granules and these granules were compacted into tablets. Using near-infrared chemical imaging (NIR-CI) together with a chemometric data analysis as a surrogate method, we visualized the porosity distribution in the ribbons. It was also demonstrated that the particle size of milled granules could be estimated with a probe-based single-point NIR measurement. This information could be related to downstream processing, since ribbons with lower porosity resulted in granules with larger size and corresponding tablets from these larger granules had lower tensile strength. Our study confirms the potential of NIR-CI and NIR spectroscopy for process monitoring and control of continuously operating roller compaction line.

Highly soluble cocrystals can be used to improve bioavailability of a poorly soluble drug, through generating supersaturation, when absorption is limited by drug dissolution. Dihydromyricetin (DMY) is a biopharmaceutics classification system (BCS) IV drug, exhibiting dissolution limited absorption. Two novel soluble cocrystals of (±)DMY with caffeine and urea were prepared, and their physicochemical properties were evaluated for suitability in formulation development. Although having a much higher solubility than (±)DMY, both cocrystals undergo rapid precipitation during dissolution and form the poorly soluble (±)DMY dihydrate in aqueous media. This negates the potential advantage offered by the high solubility of the two cocrystals in enhancing the dissolution rate and in vivo bioavailability. To solve this problem, we have systematically evaluated suitable crystallization inhibitors to maintain the supersaturation generated by cocrystal dissolution over a prolonged period of time. At 37 °C, an approxima...

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.

To summarize the microstructure – property relationship of pharmaceutical tablets and approaches to improve tablet properties through tablet microstructure engineering. The main topics reviewed here include: 1) influence of material properties and manufacturing process parameters on the evolution of tablet microstructure; 2) impact of tablet structure on tablet properties; 3) assessment of tablet microstructure; 4) development and engineering of tablet microstructure. Microstructure plays a decisive role on important pharmaceutical properties of a tablet, such as disintegration, drug release, and mechanical strength. Useful information on mechanical properties of a powder can be obtained from analyzing tablet porosity—pressure data. When helium pycnometry fails to accurately measure true density of a water-containing powder, non-linear regression of tablet density—pressure data is a useful alternative method. A component that is more uniformly distributed in a tablet generally exerts more influence on the overall tablet properties. During formulation development, it is highly recommended to examine the relationship between any property of interest and tablet porosity when possible. Tablet microstructure can be engineered by judicious selection of formulation composition, including the use of the optimum solid form of the drug and appropriate type and amount of excipients, and controlling manufacturing process.