Continuous Synthesis of Cinnarizine Salt with Malic Acid by Applying Green Chemistry Using Water-Assisted Twin Screw Extrusion.

Organic solvent-free process or green chemistry is needed for manufacturing pharmaceutical salts to avoid various environmental, safety, and manufacturing cost issues involved. In this study, a cinnarizine (CNZ) salt with malic acid at a 1:1 molar ratio was successfully prepared by twin screw extrusion (TSE) with water assistance. The feasibility of salt formation was first evaluated by screening several carboxylic acids by neat grinding (NG) and liquid-assisted grinding (LAG) using a mortar and pestle, which indicated that malic acid and succinic acid could form salts with CNZ. Further studies on salt formation were conducted using malic acid. The examination by hot-stage microscopy revealed that the addition of water could facilitate the formation and crystallization of CNZ-malic acid salt even though CNZ is poorly water-soluble. The feasibility of salt formation was confirmed by determining the pH-solubility relationship between CNZ and malic acid, where a pHmax of 2.7 and a salt solubility of 2.47 mg/mL were observed. Authentic salt crystals were prepared by solution crystallization from organic solvents for examining crystal properties and structure by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR) spectroscopy, solid-state 13C and 15N nuclear magnetic resonance (NMR), and single-crystal X-ray diffraction (SXD). These techniques also established that a salt, and not a cocrystal, was indeed formed. The CNZ salt crystals were then prepared by TSE of a 1:1 CNZ-malic acid mixture, where the addition of small amounts of water resulted in a complete conversion of the mixture into the salt form. The salts prepared by solvent crystallization and water-assisted TSE had identical properties, and their moisture sorption profiles were also similar, indicating that TSE is a viable method for salt preparation by green chemistry. Since TSE can be conducted in a continuous manner, the results of the present investigation, if combined with other continuous processes, suggest the possibility of continuous manufacturing of drug products from the synthesis of active pharmaceutical ingredients (APIs) to the production of final dosage forms.

New Lidocaine-Based Pharmaceutical Cocrystals: Preparation, Characterization, and Influence of the Racemic vs. Enantiopure Coformer on the Physico-Chemical Properties.

This study describes the preparation, characterization, and influence of the enantiopure vs. racemic coformer on the physico-chemical properties of a pharmaceutical cocrystal. For that purpose, two new 1:1 cocrystals, namely lidocaine:dl-menthol and lidocaine:d-menthol, were prepared. The menthol racemate-based cocrystal was evaluated by means of X-ray diffraction, infrared spectroscopy, Raman, thermal analysis, and solubility experiments. The results were exhaustively compared with the first menthol-based pharmaceutical cocrystal, i.e., lidocaine:l-menthol, discovered in our group 12 years ago. Furthermore, the stable lidocaine/dl-menthol phase diagram has been screened, thoroughly evaluated, and compared to the enantiopure phase diagram. Thus, it has been proven that the racemic vs. enantiopure coformer leads to increased solubility and improved dissolution of lidocaine due to the low stable form induced by menthol molecular disorder in the lidocaine:dl-menthol cocrystal. To date, the 1:1 lidocaine:dl-menthol cocrystal is the third menthol-based pharmaceutical cocrystal, after the 1:1 lidocaine:l-menthol and the 1:2 lopinavir:l-menthol cocrystals reported in 2010 and 2022, respectively. Overall, this study shows promising potential for designing new materials with both improved characteristics and functional properties in the fields of pharmaceutical sciences and crystal engineering.

Crystallization of Form II Paracetamol with the Assistance of Carboxylic Acids toward Batch and Continuous Processes.

Form II paracetamol has captured the interest of researchers due to its improved compressibility. However, its low stability has made it difficult to be produced on a large scale with good reproducibility. In the present study, the selective polymorphic formation of paracetamol was carried out by cooling crystallization with four types of additives: adipic acid, fumaric acid, oxalic acid, and succinic acid. It was found that: (1) the more additives that were added, the higher the probability of forming Form II paracetamol; (2) Form II paracetamol could be induced by seeding the paracetamol aqueous solution with Form II paracetamol and fumaric acid crystals, and not the other three carboxylic acids; (3) a new solution complex of paracetamol-oxalic acid, evidenced by the solubility diagram, was responsible for the selective nucleation of Form II paracetamol in the oxalic acid aqueous solution; and (4) the range of the degree of supersaturation for nucleating Form II paracetamol was extended with the assistance of oxalic acid or fumaric acid. In large-scale crystallization, Form II paracetamol was produced by the continuous crystallization of 44 mg of paracetamol/mL in 50 wt% of fumaric acid aqueous solution with a flow rate of 150 mL/min.

A Novel Hydrate Form of Sodium Dodecyl Sulfate and Its Crystallization Process.

A novel hydrate form of sodium dodecyl sulfate (SDS) was firstly discovered through a hydrate screening with the use of organic solvents, while SDS is generally prepared solely in aqueous media. Surprisingly, a novel SDS hydrate form with needle-shaped crystals produced by adding acetonitrile to a 20 wt % SDS aqueous solution at a ratio of 3:1 (v/v) and further cooling to around 5 °C could be found with a trace amount in one of the two purchased SDS products that we examined. After comprehensive solid-state characterizations by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), Fourier transform infrared (FTIR), Raman spectroscopy, dynamic vapor sorption (DVS), and elemental analysis (EA), it is also successfully made directly from the synthesis of SDS through esterification and saponification. Four times the equal proportion of acetone was added into the reaction solution at an interval of 5 min to separate the side product, sodium sulfate, from the mother liquor. The desired novel hydrate form of SDS was then obtained by cooling the filtered mother liquor to 5 °C and aged for 8 h for a preferential growth.

Recovery of Active Pharmaceutical Ingredients from Unused Solid Dosage-Form Drugs.

The concept of drug recycle by recovering active pharmaceutical ingredients (APIs) from unused tablets and capsules was demonstrated using acetaminophen, tetracycline HCl, and (R,S)-(±)-ibuprofen as case examples. The recovery process comprised three core unit operations: solid-liquid extraction, filtration, and crystallization. Recovery yields of 58.7 wt %, 73.1 wt %, and 67.6 wt % for acetaminophen, tetracycline HCl, and (R,S)-(±)-ibuprofen were achieved, respectively. More importantly, all of the APIs were of high purity based on high-performance liquid chromatography assay. The crystal forms of the recovered APIs were in conformity with the standards.

Reproducible Crystallization of Sodium Dodecyl Sulfate·1/8 Hydrate by Evaporation, Antisolvent Addition, and Cooling.

Sodium dodecyl sulfate (SDS)·1/8 hydrate (NaC12H25SO4·1/8H2O) crystals were successfully produced by evaporation, antisolvent addition, cooling crystallization, and isothermal aging in a common stirred tank. A clear 33.3 wt % SDS aqueous solution was concentrated by evaporation to a 60 wt % coagel consisting of numerous SDS hydrates and water. The coagel was transformed to a clear solution when two times the volume of acetone relative to the water remaining were added. By this fluid property, a controlled crystallization was made possible in a homogeneous solution. Moreover, acetone with a water-to-acetone volume ratio of 1:15 was then added as an antisolvent to induce crystallization of SDS·1/8 hydrate by cubic addition. Finally, cooling crystallization and isothermal aging were carried out to further increase the yields and gave monodispersed particle size. The stability test showed that the produced SDS·1/8 hydrate could be stored at various relative humidity environments for at least 5 days.

Continuous Preparation of 1:1 Haloperidol-Maleic Acid Salt by a Novel Solvent-Free Method Using a Twin Screw Melt Extruder.

Salts are generally prepared by acid-base reaction in relatively large volumes of organic solvents, followed by crystallization. In this study, the potential for preparing a pharmaceutical salt between haloperidol and maleic acid by a novel solvent-free method using a twin-screw melt extruder was investigated. The pH-solubility relationship between haloperidol and maleic acid in aqueous medium was first determined, which demonstrated that 1:1 salt formation between them was feasible (pHmax 4.8; salt solubility 4.7 mg/mL). Extrusion of a 1:1 mixture of haloperidol and maleic acid at the extruder barrel temperature of 60 °C resulted in the formation of a highly crystalline salt. The effects of operating temperature and screw configuration on salt formation were also investigated, and those two were identified as key processing parameters. Salts were also prepared by solution crystallization from ethyl acetate, liquid-assisted grinding, and heat-assisted grinding and compared with those obtained by melt extrusion by using DSC, PXRD, TGA, and optical microscopy. While similar salts were obtained by all methods, both melt extrusion and solution crystallization yielded highly crystalline materials with identical enthalpies of melting. During the pH-solubility study, a salt hydrate form was also identified, which, upon heating, converted to anhydrate similar to that obtained by other methods. There were previous reports of the formation of cocrystals, but not salts, by melt extrusion. 1H NMR and single-crystal X-ray diffraction confirmed that a salt was indeed formed in the present study. The haloperidol-maleic acid salt obtained was nonhygroscopic in the moisture sorption study and converted to the hydrate form only upon mixing with water. Thus, we are reporting for the first time a relatively simple and solvent-free twin-screw melt extrusion method for the preparation of a pharmaceutical salt that provides material comparable to that obtained by solution crystallization and is amenable to continuous manufacturing and easy scale up.

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.

Effects of baffle configuration and tank size on spherical agglomerates of dimethyl fumarate in a common stirred tank.

To pave the way for technology transfer and scale up of the spherical agglomeration (SA) process for dimethyl fumarate, effects of the US, European and Kawashima type baffles and 0.5, 2.0 and 10 L-sized common stirred tank were studied. It was found that the particle size distribution varied significantly. However, the size-related properties such as dissolution profile and flowability of agglomerates from the same size cut after sieving could remain unchanged. The interior structure-related properties such as particle density and mechanical property of agglomerates upon baffle change and scale up from the same size cut were decayed and the agglomerates could become denser and stronger by prolonged maturation time. To maintain the same size distribution, agglomerates from any batch could have been separated and classified by sieving and then blended back together artificially by the desired weight% of each cut.

Identification of traditional medicinal plant extracts with novel anti-influenza activity.

The emergence of drug resistant variants of the influenza virus has led to a need to identify novel and effective antiviral agents. As an alternative to synthetic drugs, the consolidation of empirical knowledge with ethnopharmacological evidence of medicinal plants offers a novel platform for the development of antiviral drugs. The aim of this study was to identify plant extracts with proven activity against the influenza virus. Extracts of fifty medicinal plants, originating from the tropical rainforests of Borneo used as herbal medicines by traditional healers to treat flu-like symptoms, were tested against the H1N1 and H3N1 subtypes of the virus. In the initial phase, in vitro micro-inhibition assays along with cytotoxicity screening were performed on MDCK cells. Most plant extracts were found to be minimally cytotoxic, indicating that the compounds linked to an ethnomedical framework were relatively innocuous, and eleven crude extracts exhibited viral inhibition against both the strains. All extracts inhibited the enzymatic activity of viral neuraminidase and four extracts were also shown to act through the hemagglutination inhibition (HI) pathway. Moreover, the samples that acted through both HI and neuraminidase inhibition (NI) evidenced more than 90% reduction in virus adsorption and penetration, thereby indicating potent action in the early stages of viral replication. Concurrent studies involving Receptor Destroying Enzyme treatments of HI extracts indicated the presence of sialic acid-like component(s) that could be responsible for hemagglutination inhibition. The manifestation of both modes of viral inhibition in a single extract suggests that there may be a synergistic effect implicating more than one active component. Overall, our results provide substantive support for the use of Borneo traditional plants as promising sources of novel anti-influenza drug candidates. Furthermore, the pathways involving inhibition of hemagglutination could be a solution to the global occurrence of viral strains resistant to neuraminidase drugs.

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.

A biomimetic tongue by photoluminescent metal-organic frameworks.

The taste sensing capabilities of a "biomimetic tongue" based on the photoluminescence (PL) responses of metal-organic frameworks (MOFs), [In(OH)(bdc)]n (bdc=1,4-benzenedicarboxylate), [Tb(btc)]n (MOF-76, btc=benzene-1,3,5-tricarboxylate), and [Ca3(btc)2(DMF)2(H2O)2]·3H2O are proven on aqueous solutions of five basic tastants: sucrose (sweet), caffeine (bitter), citric acid (sour), sodium chloride (salty) and monosodium glutamate (umami). For [In(OH)(bdc)]n, the tastant interacts stereochemically with poly(acrylic acid) (PAA) and alters its conformations. The frequency and magnitude of chelation between COO(-) pendant groups of PAA and In(3+) nodes of [In(OH)(bdc)]n framework influence the corresponding PL reponses. For MOF-76, the tastant interacts with incorporated water in MOF-76 through hydrogen bonding. The limitation of O-H bond stretching of water results in the enhancement of the PL intensity. For [Ca3(BTC)2(DMF)2(H2O)2]·3H2O, it is added as a third MOF component to increase the precision on taste discrimination. The significance of MOF-based "biomimetic tongue" includes: (1) PAA on [In(OH)(bdc)]n mimics the taste receptor cells (TRCs) for their structural flexibility, (2) the Weber-Fechner law of human sensing that sensation is proportional to the logarithm of the stimulus intensity is observed between the PL emission response of MOF-76 and the concentration of tastant, (3) the strength of taste is quantified by the τ scale and the PL emission intensity of MOF-76, which are dependent on the logarithmic tastant concentration, (4) the tastant is identified by the shape of the 3D principal component analysis contour map (i.e., pattern recognition method), and (5) the fabrication of [In(OH)(bdc)]n/PAA film by brushing is illustrated.

Peptidoglycan enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, focal adhesion kinase, Akt, and AP-1- dependent pathway.

Peptidoglycan (PGN), the major component of the cell wall of Gram-positive bacteria, activates the innate immune system of the host and induces the release of cytokines and chemokines. We investigated the signaling pathway involved in IL-6 production stimulated by PGN in rheumatoid arthritis synovial fibroblasts. PGN caused concentration- and time-dependent increases in IL-6 production. PGN-mediated IL-6 production was attenuated by TLR2 small interfering RNA and nucleotide-binding oligomerization domain 2 small interfering RNA. Pretreatment with PI3K inhibitor (Ly294002 and wortmannin), Akt inhibitor, and AP-1 inhibitor (tanshinone IIA) also inhibited the potentiating action of PGN. PGN increased the focal adhesion kinase (FAK), PI3K, and Akt phosphorylation. Stimulation of rheumatoid arthritis synovial fibroblast cells with PGN increased the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to the AP-1 element on the IL-6 promoter. PGN mediated an increase in the accumulation of phosphorylated c-Jun in the nucleus, AP-1-luciferase activity, and c-Jun binding to AP-1 element was inhibited by Ly294002, Akt inhibitor, and FAK mutant. Our results suggest that PGN increased IL-6 production in human synovial fibroblasts via the TLR2 receptor/FAK/PI3K/Akt and AP-1 signaling pathway.

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 degrees C, and the apparent solubility product, K'(sp), of 6.0 x 10(-4) M(2) at 25 degrees C were successfully synthesized by the initial salt screening methods. The new amine salt of ibuprofen was monoclinic and had a space group of P2(1)/c and lattice parameters of a = 17.578(8) degrees, b = 10.428(4) degrees, c = 9.991(4) A, alpha = 90.00 degrees , beta = 97.17(1) degrees, gamma = 90.00 degrees, and V = 1,817.05(244) A(3). The aspect ratio of the amine salt crystals of ibuprofen of approximately 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.

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 k(1) = 0.43 +/- 0.15 minutes(-1), k(2) = 0.18 +/- 0.01 minutes(-1), and k(mix) = 0.30 +/- 0.03 minutes(-1) for 75 wt percent formulation; k(1) = 0.75 +/- 0.01 minutes(-1), k(2) = 0.18 +/- 0.01 minutes(-1), and k(mix) = 0.34 +/- 0.03 minutes(-1) for 62 wt percent formulation; and k(1) = 0.28 +/- 0.01 minutes(-1), k(2) = 0.16 +/- 0.01 minutes(-1), and k(mix) = 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 k(mix) = 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 k(1), k(2), and k(mix) 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 k(1), k(2), and k(mix) 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 k(1), k(2), and k(mix) 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 k(1), k(2), and k(mix) 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, k(mix), whose value fell in between the values of k(1) and k(2).

Dissolution enhancement by bio-inspired mesocrystals: the study of racemic (R,S)-(+/-)-sodium ibuprofen dihydrate.

PURPOSE: The aim of this paper is to enhance the dissolution rate of racemic (R,S)-(+/-)-sodium ibuprofen dihydrate via a bio-inspired method of growing mesocrystals. MATERIALS AND METHODS: Mesocrystals of racemic (R,S)-(+/-)-sodium ibuprofen dihydrate were successfully prepared from a supersaturated aqueous solution of racemic (R,S)-(+/-)-sodium ibuprofen dihydrate having the initial degree of supersaturation, S ( 0 ), of 1.326 and the initial saturated concentration, C*, of 0.986 mol/l at 25 degrees C with sodium dodecyl sulfate (SDS) at a concentration of 0.10 g/l. Dynamic light scattering, scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, and optical microscopy with cross polarizers were employed to understand the formation mechanism and to characterize the superstructures of the SDS generated mesocrystals. RESULTS: The SDS generated mesocrystals were the assembly of the oriented attachment of racemic (R,S)-(+/-)-sodium ibuprofen dihydrate nano-sized platelets under the mediation of the side-to-side interaction between SDS and racemic (R,S)-(+/-)-sodium ibuprofen dihydrate. The SDS generated mesocrystals contained a mixture of the racemic compounds in alpha- and beta-forms and the resolved racemic conglomerate in gamma-form with no detectable amount of SDS. The dissolution rate of the SDS generated mesocrystals was more rapid than the one of its counterpart made by conventional crystallization pathway. CONCLUSIONS: The crystallization of racemic (R,S)-(+/-)-sodium ibuprofen dihydrate in the presence of SDS yielded well-faceted, well-separated, but almost perfectly three-dimensionally aligned nano-sized platelets. This kind of bio-inspired mesocrystal superstructure has definitely opened a new doorway for crystal engineering and pre-formulation design in pharmaceutical industry. The future work is to study the mesocrystal formation of some other active pharmaceutical ingredients in organic solvent systems and to develop an efficient method for screening the additives.

Thrombin-induced IL-6 production in human synovial fibroblasts is mediated by PAR1, phospholipase C, protein kinase C alpha, c-Src, NF-kappa B and p300 pathway.

Thrombin is a key factor in the stimulation of fibrin deposition, angiogenesis and proinflammatory processes. Abnormalities in these processes are primary features of rheumatoid arthritis (RA) in synovial tissues. We investigated the signaling pathway involved in IL-6 production caused by thrombin in synovial fibroblasts. Thrombin caused concentration- and time-dependent increases in IL-6 production. By using pharmacological inhibitors or activators or genetic inhibition by the protease activated receptor (PAR), siRNA revealed that the PAR1 receptor but not other PAR receptors is involved in thrombin-mediated up-regulation of IL-6. Thrombin-mediated IL-6 production was attenuated by thrombin inhibitor (PPACK), phospholipase C inhibitor (U73122), protein kinase C alpha inhibitor (Ro320432), Src inhibitor (PP2), NF-kappaB inhibitor (PDTC), I kappa B protease inhibitor (TPCK), or NF-kappaB inhibitor peptide. Stimulation of synovial fibroblasts with thrombin activated I kappa B kinase alpha/beta (IKK alpha/beta), I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation at Ser(276), p65 and p50 translocation from the cytosol to the nucleus, and kappaB-luciferase activity. Thrombin-mediated an increase of IKK alpha/beta activity, kappaB-luciferase activity and p65 and p50 binding to the NF-kappaB element was inhibited by PPACK, U73122, Ro320432 and PP2. The binding of p65 and p50 to the NF-kappaB elements, as well as the recruitment of p300 and the enhancement of p50 acetylation on the IL-6 promoter was enhanced by thrombin. Our results suggest that thrombin increased IL-6 production in synovial fibroblasts via the PAR1 receptor/PI-PLC/PKC alpha/c-Src/NF-kappaB and p300 signaling pathway.

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 Carr's 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 = alpha ln C + ln A (or exponentially by a power law of k = AC(alpha)) where A was the exponential factor and alpha was the power index. A and alpha 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 x 10(-6) C(2.9), k = 3.9 x 10(-6) C(2.8), and k = 1.5 x 10(-8) C(4.2), 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.