Tu Lee

Initial Salt Screening Procedures for Manufacturing Ibuprofen

The aim of this paper is to design initial salt screening procedures for manufacturing ibuprofen. Salt forms of a pharmaceutical acid racemic (R,S)-(±)-ibuprofen and their “developable” synthetic routes were ferreted out simultaneously through the screening of seven bases of sodium hydroxide, potassium hydroxide, l-arginine, l-histidine, l-lysine, diethanolamine, and tris(hydroxymethyl)aminomethane (THAM), and the match with the use of nine organic solvents of methanol, dimethyl sulfoxide, ethanol, N, N-dimethylformamide, acetonitrile, isopropyl alcohol, 1,4-dioxane, acetone, and tetrahydrofuran mainly in the presence of water in 20 mL scintillation vials. Racemic (R,S)-(±)-sodium ibuprofen dihydrate, a well-known ibuprofen salt and the newly discovered racemic (R,S)-(±)-THAM ibuprofen, appeared as white-squared powders with a molecular weight of 327.42 g/mol, a melting point of 160.17°C, and the apparent solubility product, K′sp, of 6.0 × 10−4 M2 at 25°C were successfully synthesized by the initial salt screening methods. The new amine salt of ibuprofen was monoclinic and had a space group of P21/c and lattice parameters of a = 17.578(8)°, b = 10.428(4)°, c = 9.991(4) Å, α = 90.00°, β = 97.17(1)°, γ = 90.00°, and V = 1,817.05(244) Å3. The aspect ratio of the amine salt crystals of ibuprofen of ≈ 1.0 implied that the crystals had a better flowability than the sodium salt counterparts. This amine salt of ibuprofen was more stable in moist or dried atmospheres and was more hydrophobic than the sodium salt of ibuprofen. Moreover, the slow dissolution of this amine salt of ibuprofen might have made it less bitter and more suitable as a sustained release drug than the sodium salt of ibuprofen. The future work is to search for the different polymorphs of this amine salt of ibuprofen and to extend the initial salt screening working logics to the formation of co-crystals.

A Cross-Performance Relationship Between Carr's Index and Dissolution Rate Constant : The Study of Acetaminophen Batches

The aim of this paper is to promote a simple and scalable approach to accelerate the formulation development of wet granules using acetaminophen batches as a model system. Only two thorough experiments with five processing steps of: crystallization → dry blending → wet granulation → drying → dissolution, were required to establish a specific linear relationship between the overall effect of the particle size distribution and the dissolution performance for a given formulation of any batch of acetaminophen. With this specific linear relationship at hand, dissolution rates of the granules prepared from batches of acetaminophen with various particle size distribution could be predicted without the need of doing any wet granulation, drying and dissolution for the same formulation. It was found that the Carrs Index, C, an overall manifestation of particle size distribution, of only a few grams of the dry blended acetaminophen was good enough to be linearly related to the dissolution rate constant, k, of the formulated granules by ln k = α ln C + ln A (or exponentially by a power law of k = ACα) where A was the exponential factor and α was the power index. A and α were dependent on the mass transfer of acetaminophen powders and the rheological properties of the formulated dry blended powders, respectively. The three linear relationships for 75, 62, and 30 wt % formulations were ln k = 2.9 ln C –12.3, ln k = 2.8 ln C –12.5, and ln k = 4.2 ln C –18.0, respectively. The power laws for 75, 62, and 30 wt % formulations were k = 4.7 × 10−6 C2.9, k = 3.9 × 10−6 C2.8, and k = 1.5 × 10−8 C4.2, respectively. The formulation used in our study contained acetaminophen, microcrystalline cellulose, and polyvinylpyrrolidone. The validation of the linearity between k and C was verified (1) by acetaminophen batches from different processes and sources, (2) by the various formulation compositions of acetaminophen of 75, 62, and 30 wt%, and (3) by the growth mechanisms of wet granulation and the resultant granular structures determined by dry sieve analysis, optical microscopy (OM), mercury intrusion porosimetry (MIP), the Brunauer-Emmett-Teller (BET) method, scanning electron microscopy (SEM), and Fourier transformed infrared (FT-IR) microscopic mapping. In general, granules grown from the small-size ranged acetaminophen powders of a given formulation had a higher C. Since the growth mechanism was dominated by agglomeration, the granules were more porous, higher in surface area, more homogenous, and higher in dissolution rate constant, k, as opposed to granules grown from the large-size ranged acetaminophen powders of a given formulation having a lower, C, whose growth was dominated via consolidation and layer-by-layer mechanism and resulted in a lower dissolution rate constant, k.

Crystallization process development of metal–organic frameworks by linking secondary building units, lattice nucleation and luminescence: insight into reproducibility

The interdependence of crystallinity, secondary building unit (SBU) formation, linker vacancy, crystal habit, photoluminescence, and surface area for UiO-66 and In-MIL-68, respectively, produced by different processing modes has been fully investigated and linked together to comprehend the relationships among SBU synthesis pathways, structures, and functional properties. The solid-state properties of UiO-66 were found to be process-sensitive, but those of In-MIL-68 except for crystal habits were mode independent, most likely due to the versatile Zr6(μ3-O)4(μ3-OH)4(CO2)12 SBU formation steps with more competing events for UiO-66 and the relatively straightforward {In(μ-O2CR)2(μ-OH)}∞ chain SBU formation steps for In-MIL-68. The reproducibility of the desired properties of metal–organic frameworks (MOFs) relies on the crystallization process designed for specific SBU formation and nucleation trajectory.

Uniform SiGe/Si quantum well nanorod and nanodot arrays fabricated using nanosphere lithography

This study fabricates the optically active uniform SiGe/Si multiple quantum well (MQW) nanorod and nanodot arrays from the Si0.4Ge0.6/Si MQWs using nanosphere lithography (NSL) combined with the reactive ion etching (RIE) process. Compared to the as-grown sample, we observe an obvious blueshift in photoluminescence (PL) spectra for the SiGe/Si MQW nanorod and nanodot arrays, which can be attributed to the transition of PL emission from the upper multiple quantum dot-like SiGe layers to the lower MQWs. A possible mechanism associated with carrier localization is also proposed for the PL enhancement. In addition, the SiGe/Si MQW nanorod arrays are shown to exhibit excellent antireflective characteristics over a wide wavelength range. These results indicate that SiGe/Si MQW nanorod arrays fabricated using NSL combined with RIE would be potentially useful as an optoelectronic material operating in the telecommunication range.

Propagation of Biochirality: Crossovers and Nonclassical Crystallization Kinetics of Aspartic Acid in Water

All experimental procedures discussed could be treated as a screening tool for probing the existence of molecular association among the chiral molecules and the solvent system. The molecular association phases of a racemic conglomerate solution (CS) and a racemic compound solution (RCS), and the templating effect of aspartic acid solid surface were observed to minimize the chance of redissolving racemic conglomerate and racemic compound aspartic acid in water and reforming an RCS in crossovers experiments. Only 1 %wt% of l-aspartic acid was adequate enough to induce a transformation from a racemic compound aspartic acid to a racemic conglomerate aspartic acid. This would make the propagation of biochirality more feasible and sound. However, tetrapeptide, (l-aspartic acid)4 , failed to induce enantioseparation as templates purely by crystallization. Nonclassical crystallization theory was needed to take into account the existence of a CS. Fundamental parameters of the crystallization kinetics such as the induction time, interfacial energy, Gibbs energetic barrier, nucleation rate, and critical size of stable nuclei of: (i) racemic compound aspartic acid, (ii) racemic compound aspartic acid seeded with 1 %wt% l-aspartic acid, (iii) racemic conglomerate aspartic acid, and (iv) l-aspartic acid were evaluated and compared with different initial supersaturation ratios. Morphological studies of crystals grown from the crystallization kinetics were also carried out.

Biomimetic Taste Receptors with Chiral Recognition by Photoluminescent Metal-Organic Frameworks Chelated with Polyaniline Helices

The adsorption of phenylaniline (Phe) enantiomers on (+)-polyaniline (PAN)-chelated [In(OH)(bdc)]n microcrystals was carefully designed and studied by using the Job titration, circular dichroism, X-ray photoelectron spectroscopy, and photoluminescence to mimic heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors in selective, but not specific, ligand binding with chiral recognition and signal transduction. Six essential working principles across different length scales are unraveled: 1) a chiral (+)-PAN (host), 2) specific sites for Phe-(+)/PAN (guest-host) binding, 3) a conformational change of (+)-PAN after binding with Phe enantiomers, 4) different degrees of packing for (+)-PAN, 5) interactions between (+)-PAN and the underlying signal-generating framework (i.e., [In(OH)(bdc)]n microcrystals), and 6) a systematic photoluminescent signal combination by using principal-component analysis from the other three polymer-chelated metal-organic frameworkds (MOFs), such as poly(acrylic acid) (PAA), sodium alginate (SA), and polyvinylpyrrolidone (PVP) to enhance the selectivity and discrimination capabilities.

The Prediction of the Dissolution Rate Constant by Mixing Rules: The Study of Acetaminophen Batches

The purpose of this article is to promote two simple and scalable methods to accelerate the formulation development of formulated granules using acetaminophen as a model system. In method I, formulated granules made from the batch of small particle–sized acetaminophen (1) by ball milling the batch of large particle–sized acetaminophen (2), and the mixture of the two batches at equal weights (mix) gave the dissolution rate constants (k) of k1 = 0.43 ± 0.15 minutes−1, k2 = 0.18 ± 0.01 minutes−1, and kmix = 0.30 ± 0.03 minutes−1 for 75 wt percent formulation; k1 = 0.75 ± 0.01 minutes−1, k2 = 0.18 ± 0.01 minutes−1, and kmix = 0.34 ± 0.03 minutes−1 for 62 wt percent formulation; and k1 = 0.28 ± 0.01 minutes−1, k2 = 0.16 ± 0.01 minutes−1, and kmix = 0.22 ± 0.02 minutes−1 for 30 wt percent formulation. In method II, the mixture of the formulated granules produced by mixing the formulated granules from the two batches at equal weights gave dissolution rate constants of kmix = 0.30 ± 0.03 minutes−1, 0.30 ± 0.02 minutes−1, and 0.22 ± 0.01 minutes−1 for 75 wt percent, 62 wt percent, and 30 wt percent formulations, respectively. After fitting the three data points of k1, k2, and kmix to the 10 mixing rules in materials science—series mixing rule, Hashin and Shtrikman upper bound, logarithmic mixing, Looyenga mixing rule, effective media approximation (EMA), three-point lower bound, Torquato approximation, three-point upper bound, Maxwell mixing rule, and parallel mixing rule—we found that the selection of the best suited mixing rules based on k1, k2, and kmix was solely dependent on the formulations under a given operating condition and regardless of whether the system was a powder mixture or a granular mixture. The values of k1, k2, and kmix in both the 75 wt percent and 30 wt percent formulations were enveloped by the parallel mixing rule and Maxwell mixing rule, whereas the values of k1, k2, and kmix for the 62 wt percent formulation were encompassed by the logarithmic mixing rule, Hashin and Shtrikman upper bound, and the series mixing rule. Apparently, the best suited mixing rules could be used to predict the right proportions of either the powder mixture (Method I) or the granular mixture (Method II) for obtaining any other desired dissolution rate constant, kmix, whose value fell in between the values of k1 and k2.

BIOMIMETIC FABRICATION OF MATERIALS-THE MINIMALIST APPROACH

The interfacial chemistry between inorganic ceramics and defined organic surfaces is the focus of intense investigation. Partially compressed Langmuir-Blodgett monolayers of anionic porphyrins have been used as modified nucleation sites for calcium carbonate. The porphyrin monolayer has an ordered array of carboxylates, and hence the system serves as a minimalist template for the modeling of complex biogenic acidic glycoproteins for biomineralization. The initial results suggest the formation of calcite with morphologically distinct calcitic rhombs with truncated, 3-edged corners and intricately articulated facial cavities. Stearic acid monolayers yield distinctly different calcite crystals, indicative that the geometrically defined carboxylate array is probably important. Phosphatidylcholine vesicles have been used as a tool for the formation of membrane encapsulated iron-oxides. Gramicindin A ion channels have been embedded in vesicles to kinetically alter the formation and growth of iron oxides, starting with intravesicular ferrous chloride. The results indicate that the presence of ion channels lead to the formation of magnetite vis-a-vis maghemite formation in vesicles lacking the ion channels. The use of ion channels has important implications in probable signal transduction processes during biomineralization pathways.

A Taste and Odor Sensing by Photoluminescence Responses of Luminescent Metal Organic Frameworks

The sensors of taste and odor play important roles of recognition as well as reception. In our research, the taste and odor sensing capabilities were based on the photoluminescence (PL) responses of luminescent metal-organic frameworks (MOFs). For the sensing of taste, [In(OH)(bdc)]n (bdc = 1,4-benzenedicarboxylate) and [Tb(btc)] (MOF-76, btc = benzene-1,3,5-tricarboxylate), were tested on aqueous solutions of five basic tastants such as sucrose (sweet), caffeine (bitter), citric acid (sour), sodium chloride (salty) and monosodium glutamate (umami). The photoluminescence (PL) responses of polyacrylic acid-chelated [In(OH)bdc]n and lanthanide Tb(btc) were used to demonstrate the applicability of MOF-based biomimetic tongue through: (1) identification of five tastes: sweet, bitter, sour, salty and umami, by 3-D PCA (principle component analysis) to distinguish the corresponding tastants, (2) quantification of the strength of five tastes determined by the relationships between the PL intensity and the τ scale of taste. For the sensing of odor, [In(OH)(bdc)]n and [Zn4O(bdc)3] (MOF-5) were exposed to the odorants such as cumin, cinnamon, vanillin, p-xylene, m-xylene, o-xylene, water, and ethanol. Similarly, the MOF-based biomimetic nose could distinguish the odors of the analytes based on a pattern recognition method (i.e., principal component analysis) constructed by the 2-D map of PL emission responses.