Showing papers by "Changquan Calvin Sun published in 2019"
TL;DR: The first elastically bendable single-component pharmaceutical crystal, celecoxib, was reported in this paper, which exhibited both therapeutic effects and elastic mechanical behavior, and could be used to manufacture functional microdevices with novel medical applications.
Abstract: 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.
78 citations
TL;DR: The first pharmaceutical twistable hydrogen-bonded two-dimensional plastic hydrate crystal of a well-known psychoactive drug, caffeine (CAH) was reported in this paper.
Abstract: 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...
67 citations
TL;DR: This work systematically compared the predictive accuracy of the mechanical properties of α-oxalic acid anhydrous and dihydrate as a model system and found that crystal plasticity can be accurately predicted based on energy framework combined with topological analysis and DFT calculated elasticity tensor.
Abstract: Understanding of the structure–mechanical properties relationship in organic crystals can potentially facilitate the design of crystals with desired mechanical properties through crystal engineerin...
52 citations
TL;DR: 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 is discovered.
51 citations
TL;DR: The record high active pharmaceutical ingredient loading in this work illustrates the potential for spherical crystallization to enable high drug loading when developing a tablet product using the DC manufacturing process.
49 citations
TL;DR: It is shown that a nanocoating of chitosan (a pharmaceutically acceptable polymer) can be deposited on the surface of amorphous indomethacin by electrostatic deposition, leading to significant improvement of physical stability, wetting by aqueous media, dissolution rate, powder flow, and tabletability.
Abstract: As a result of its higher molecular mobility, the surface of an amorphous drug can grow crystals much more rapidly than the bulk, causing poor stability and slow dissolution of drug products. We show that a nanocoating of chitosan (a pharmaceutically acceptable polymer) can be deposited on the surface of amorphous indomethacin by electrostatic deposition, leading to significant improvement of physical stability, wetting by aqueous media, dissolution rate, powder flow, and tabletability. The coating condition was chosen so that the positively charged polymer deposits on the negatively charged drug. Chitosan coating is superior to gelatin coating with respect to stability against crystallization and agglomeration of coated particles.
35 citations
TL;DR: 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, including tabletability, compressibility, tablet brittleness, die-wall stress transmission, and strain rate sensitivity.
30 citations
TL;DR: In this paper, the crystal growth kinetics of amorphous celecoxib (CEL), an anti-inflammatory BCS class II drug, were investigated for developing effective stabilization strategies to enhance solubi.
Abstract: The crystal growth kinetics of amorphous celecoxib (CEL), an anti-inflammatory BCS class II drug, was systematically investigated for developing effective stabilization strategies to enhance solubi...
30 citations
TL;DR: A phase pure ITZ-SUB cocrystal, which could not be obtained by traditional cocrystallization methods, was successfully prepared by rotary evaporation and spray drying.
Abstract: Cocrystallization represents an emerging approach to tackle the issues associated with pharmaceutical product performance and processing, owing to its capability of modifying a variety of physicochemical properties. In this study, we sought to modify the crystal form of itraconazole (ITZ) with suberic acid (SUB) via rapid solvent removal methods, namely rotary evaporation and spray drying. A phase pure ITZ-SUB cocrystal, which could not be obtained by traditional cocrystallization methods, was successfully prepared by rotary evaporation. The new cocrystal was confirmed by powder X-ray diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. Spray drying was further employed for particle engineering of ITZ-SUB to achieve optimal pulmonary delivery. By manipulating the critical processing parameters, inhalable ITZ-SUB agglomerates with a mass median aerodynamic diameter of 2.56 ± 2.27 μm and fine particle fraction of 64.10% w/w were reproducibly prepared. The inhalable po...
26 citations
TL;DR: In this paper, the dissolution of ritonavir (RTV) tablets was found to deteriorate in an acidic environment when the concentration of SLS exceeded the critical micelle concentration.
25 citations
TL;DR: 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, and the specific rate must reach a threshold value to attain adequate tabletability.
TL;DR: Spherical cocrystallization (SCC) as discussed by the authors is an integrated crystal and particle engineering approach to generate spherical cocrystal agglomerates (SCA) between a poorly soluble drug.
Abstract: Spherical cocrystallization (SCC), an integrated crystal and particle engineering approach, was successfully applied to generate spherical cocrystal agglomerates (SCA) between a poorly soluble drug...
TL;DR: It is shown in this work that, at comparable particle sizes, the acesulfame potassium exhibited pronouncedly reduced propensity to punch sticking than aces sulfur, which could be clearly explained based on their different crystal mechanical properties and surface characteristics.
Abstract: 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.
TL;DR: The results suggested that chito-cubosomes could be a promising drug carrier for enhancing oral absorption with sustained release behavior.
Abstract: 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.
TL;DR: In this paper, the authors developed a method for reproducibly preparing phase pure cocrystal polymorph robustly by controlling the crystallization medium and determined their free energy diagram, by using intrinsic dissolution rates at 5 −37 °C and thermal data near melting temperature.
Abstract: 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.
TL;DR: To overcome the high melt viscosity of HPC, higher barrel temperatures and higher specific mechanical energy were required to attain suitable granules, and higher levels of gabapentin degradant were observed in HPC‐based formulations.
TL;DR: Reducing the dissolution rate is expected to improve bioavailability and therapeutic activity of sulfuramethizole and reduce the half-life of SMZ.
Abstract: Sulfamethizole (SMZ) is an antibiotic drug with good solubility but short in vivo half-life. Thus, reducing the dissolution rate is expected to improve bioavailability and therapeutic activity thro...
TL;DR: 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.
TL;DR: In this paper, the particulate properties of a material after primary manufacturing have a large impact on the secondary manufacturing processes and powder characteristics leading to poor flowability are discussed. But, the authors do not consider the effects of these properties on the performance of secondary manufacturing.
TL;DR: This article used spherical crystallization to improve the flowability and tabletability of a high-dose drug with a high drug loading, which makes formulating a highdrug loading tablet challenging.
Abstract: Griseofulvin (GSF) is a high dose drug exhibiting poor flowability and tabletability, which makes formulating a high drug loading tablet challenging. In using spherical crystallization to improve f...
TL;DR: 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.
Abstract: 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.
TL;DR: The aim of this work was to assess the influence of storage conditions on powder flowability, which is a crucial property in powder processing, and to detect the storage-related change in flowability induced by varying storage conditions.
TL;DR: It was found that BSA and lysozyme are highly hygroscopic, and their tablet manufacturability is sensitive to the humidity, and strategies to inhibit protein degradation should be explored before their tablet dosage form development.
Abstract: 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.
TL;DR: The critical water activity at a fixed temperature and transition temperature (Tt) in water between an anhydrate and its corresponding hydrate determine their physical stability as mentioned in this paper, and hence, the stability of anhydrates can be improved.
Abstract: The critical water activity (aw,c) at a fixed temperature and transition temperature (Tt) in water between an anhydrate and its corresponding hydrate determine their physical stability. Hence, thei...
TL;DR: In this article, the interfacial bonding strength of four different layer combinations between microcrystalline cellulose (MCC) and lactose (Lac) was assessed by measuring surface waviness and porosity.
TL;DR: The crystal structures of four INZ cocrystals with analogous crystal coformers were probed to understand the relationships among molecular packing, H-bonding dimensionality, single-crystal plastici... as mentioned in this paper.
Abstract: The crystal structures of four INZ cocrystals with analogous crystal coformers were probed to understand the relationships among molecular packing, H-bonding dimensionality, single-crystal plastici...
TL;DR: In this article, the effect of particle size on interfacial bonding strength of bilayer tablets was studied using microcrystalline cellulose (MCC) and lactose anhydrate.
TL;DR: In this article, a dual particle engineering approach is used to form a segregation-resistant drug-carrier composite to improve the content uniformity of low-dose direct compression (DC) tablets.
TL;DR: It has been shown that powder cohesion is proportional to fc, where the proportionality constant is a function of angle of linearized yield locus, (1-sinθ)/(2cosθ).
TL;DR: Important pharmaceutical properties, such as solubility, dissolution, and thermal stability, of the drug-surfactant salt [NORH+][LS-]·1.5 H2O have been characterized and understood based on crystallographic and energetic analyses of the crystal structure.
Abstract: 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...