Influence of Plasdone™ S630 Ultra-an Improved Copovidone on the Processability and Oxidative Degradation of Quetiapine Fumarate Amorphous Solid Dispersions Prepared via Hot-Melt Extrusion Technique.

In a formulation, traces of peroxides in copovidone can impact the stability of drug substances that are prone to oxidation. The present study aimed to investigate the impact of peroxides in novel Plasdone™ S630 Ultra and compare it with regular Plasdone™ S630 on the oxidative degradation of quetiapine fumarate amorphous solid dispersions prepared via hot-melt extrusion technique. The miscibility of copovidones with drug was determined using the Hansen solubility parameter, and the results indicated a miscible drug-polymer system. Melt viscosity as a function of temperature was determined for the drug-polymer physical mixture to identify the suitable hot-melt extrusion processing temperature. The binary drug and polymer (30:70 weight ratio) amorphous solid dispersions were prepared at a processing temperature of 160°C. Differential scanning calorimetry and Fourier transform infrared spectroscopy studies of amorphous solid dispersions revealed the formation of a single-phase amorphous system with intermolecular hydrogen bonding between the drug and polymer. The milled extrudates were compressed into tablets by using extragranular components and evaluated for tabletability. Stability studies of the milled extrudates and tablet formulations were performed to monitor the oxidative degradation impurity (N-oxide). The N-oxide impurity levels in the quetiapine fumarate - Plasdone™ S630 Ultra milled extrudates and tablet formulations were reduced by 2- and 3-folds, respectively, compared to those in quetiapine fumarate - Plasdone™ S630. The reduced oxidative degradation and improved hot-melt extrusion processability of Plasdone™ S630 Ultra make it a better choice for oxidation-labile drugs over Plasdone™ S630 copovidone.

Oral administration of a synthetic vinyl-ether plasmalogen normalizes open field activity in a mouse model of rhizomelic chondrodysplasia punctata.

Rhizomelic chondrodysplasia punctata (RCDP) is a rare genetic disorder caused by mutations in peroxisomal genes essential for plasmalogen biosynthesis. Plasmalogens are a class of membrane glycerophospholipids containing a vinyl-ether-linked fatty alcohol at the sn-1 position that affect functions including vesicular transport, membrane protein function and free radical scavenging. A logical rationale for the treatment of RCDP is therefore the therapeutic augmentation of plasmalogens. The objective of this work was to provide a preliminary characterization of a novel vinyl-ether synthetic plasmalogen, PPI-1040, in support of its potential utility as an oral therapeutic option for RCDP. First, wild-type mice were treated with 13C6-labeled PPI-1040, which showed that the sn-1 vinyl-ether and the sn-3 phosphoethanolamine groups remained intact during digestion and absorption. Next, a 4-week treatment of adult plasmalogen-deficient Pex7hypo/null mice with PPI-1040 showed normalization of plasmalogen levels in plasma, and variable increases in plasmalogen levels in erythrocytes and peripheral tissues (liver, small intestine, skeletal muscle and heart). Augmentation was not observed in brain, lung and kidney. Functionally, PPI-1040 treatment normalized the hyperactive behavior observed in the Pex7hypo/null mice as determined by open field test, with a significant inverse correlation between activity and plasma plasmalogen levels. Parallel treatment with an equal amount of ether plasmalogen precursor, PPI-1011, did not effectively augment plasmalogen levels or reduce hyperactivity. Our findings show, for the first time, that a synthetic vinyl-ether plasmalogen is orally bioavailable and can improve plasmalogen levels in an RCDP mouse model. Further exploration of its clinical utility is warranted.This article has an associated First Person interview with the joint first authors of the paper.

Evaluation of [68Ga]DO3A-VS-Cys40-Exendin-4 as a PET Probe for Imaging Human Transplanted Islets in the Liver.

[68Ga]DO3A-VS-Cys40-Exendin-4, a glucagon-like peptide 1 receptor agonist, was evaluated as a potential PET tracer for the quantitation of human islets transplanted to the liver. The short-lived PET radionuclide 68Ga, available on a regular basis from a 68Ge/68Ga generator, is an attractive choice. Human C-peptide was measured to evaluate human islet function post-transplantation and prior to microPET imaging. [68Ga]DO3A-VS-Cys40-Exendin-4 was radiosynthesized and evaluated for PET imaging of transplanted human islets in the liver of healthy NOD/SCID mice. The biodistribution of the tracer was evaluated to determine the uptake into various organs, and qPCR of liver samples was conducted to confirm engrafted islet numbers after PET imaging. Measurement of human C-peptide indicated that higher engrafted islet mass resulted in higher human C-peptide levels in post-transplantation. The microPET imaging yielded high resolution images of liver-engrafted islets and also showed significant retention in mouse livers at 8 weeks post-transplantation. Biodistribution studies in mice revealed that liver uptake of [68Ga]DO3A-VS-Cys40-Exendin-4 was approximately 6-fold higher in mice that received 1000 islet equivalent (IEQ) than in non-transplanted mice. qPCR analysis of insulin expression suggested that islet engraftment numbers were close to 1000 IEQ transplanted. In conclusion, human islets transplanted into the livers of mice exhibited significant uptake of [68Ga]DO3A-VS-Cys40-Exendin-4 compared to the livers of untreated mice; and imaging of the mice using PET showed the human islets clearly with high contrast against liver tissue, enabling accurate quantitation of islet mass. Further validation of [68Ga]DO3A-VS-Cys40-Exendin-4 as an islet imaging probe for future clinical application is ongoing.

Synthesis, molecular properties prediction and biological evaluation of indole-vinyl sulfone derivatives as novel tubulin polymerization inhibitors targeting the colchicine binding site.

Twenty-two novel indole-vinyl sulfone derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors. The physicochemical and drug-likeness properties of all target compounds were predicted by Osiris calculations. All compounds were evaluated for their antiproliferative activities, among them, compound 7f exhibited the most potent activity against a panel of cancer cell lines, which was 2-7 folds more potent than our previously reported compound 4. Especially, 7f displayed about 8-fold improvement of selective index as compared with compound 4, indicating that 7f might have lower toxicity. Besides, 7f inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further investigations showed that compound 7f effectively disrupted microtubule network, caused cell cycle arrest at G2/M phase and induced cell apoptosis in K562 cells. Moreover, 7f reduced the cell migration and disrupted capillary-like tube formation in HUVEC cells. Importantly, the in vivo anti-tumor activity of 7f was validated in H22 liver cancer xenograft mouse model without apparent toxicity, suggesting that 7f is a promising anti-tubulin agent for cancer therapy.

Effect of plasticizers on manufacturing ritonavir/copovidone solid dispersions via hot-melt extrusion: Preformulation, physicochemical characterization, and pharmacokinetics in rats.

In this study, novel ritonavir solid dispersion (RTV SD) formulations were prepared with copovidone (PVPVA 64) and optimized plasticizers via hot-melt extrusion (HME) at different extrusion temperature to evaluate the effect of plasticizers on the process of HME. The optimized drug-loading content of RTV SD formulations was around 15% and RTV was converted to the amorphous state and integrated through physical interactions (possibly hydrogen bonding) with the polymeric carrier. Using Span 20 or HSPC as plasticizer, the HME extrusion temperature of RTV SD formulations suggested a decrease of 10 °C or 20 °C. Furthermore, the in vitro release and the in vivo pharmacokinetics analyses both showed that RTV SD formulations using Span 20 or HSPC as plasticizer possessed better release profiles and bioavailability over RTV bulk powder but showed equal physicochemical characteristics compared to RTV SD formulations without plasticizer. According to the increased drug solubility, enhanced dissolution profiles, superior bioavailability, but decreased extrusion temperature in HME process, the RTV SD formulation using HSPC as plasticizer could be potentially applied in the clinic as an efficient drug delivery system, and HSPC is recommended as an efficient plasticizer for manufacturing RTV SD formulations via HME.

Species differences in pancreatic binding of DO3A-VS-Cys40-Exendin4.

AIMS: Radiolabeled Exendin-4 has been proposed as suitable imaging marker for pancreatic beta cell mass quantification mediated by Glucagon-like peptide-1 receptor (GLP-1R). However, noticeable species variations in basal pancreatic uptake as well as uptake reduction degree due to selective beta cell ablation were observed. METHODS: In vitro and ex vivo autoradiography studies of pancreas were performed using [177Lu]Lu-DO3A-VS-Cys40-Exendin4, in order to investigate the mechanism of uptake as well as the islet uptake contrast in mouse, rat, pig, and non-human primate. The autoradiography results were compared to the in vivo pancreatic uptake as assessed by [68Ga]Ga-DO3A-VS-Cys40-Exendin4 Positron Emission Tomography (PET) in the same species. In vitro, ex vivo, and in vivo data formed the basis for calculating the theoretical in vivo contribution of each pancreatic compartment. RESULTS: [177Lu]Lu-DO3A-VS-Cys40-Exendin4 displayed the highest islet-to-exocrine pancreas ratio (IPR) in rat (IPR 45) followed by non-human primate and mouse at similar levels (IPR approximately 5) while pigs exhibited negligible IPR (1.1). In vivo pancreas uptake was mainly GLP-1R mediated in all species, but the magnitude of uptake under basal physiology varied significantly in decreasing order: non-human primate, mouse, pig, and rat. The theoretical calculation of islet contribution to the total pancreatic PET signal predicted the in vivo observation of differences in pancreatic uptake of [68Ga]Ga-DO3A-VS-Cys40-Exendin4. CONCLUSIONS: IPR as well as the exocrine GLP-1R density is the main determinants of the species variability in pancreatic uptake. Thus, the IPR in human is an important factor for assessing the potential of GLP-1R as an imaging biomarker for pancreatic beta cells.

Study of the Transformations of Micro/Nano-crystalline Acetaminophen Polymorphs in Drug-Polymer Binary Mixtures.

This study elucidates the physical properties of sono-crystallised micro/nano-sized acetaminophen/paracetamol (PMOL) and monitors its possible transformation from polymorphic form I (monoclinic) to form II (orthorhombic). Hydrophilic Plasdone® S630 copovidone (S630), N-vinyl-2-pyrrolidone and vinyl acetate copolymer, and methacrylate-based cationic copolymer, Eudragit® EPO (EPO), were used as polymeric carriers to prepare drug/polymer binary mixtures. Commercially available PMOL was crystallised under ultra sound sonication to produce micro/nano-sized (0.2-10 microns) crystals in monoclinic form. Homogeneous binary blends of drug-polymer mixtures at various drug concentrations were obtained via a thorough mixing. The analysis conducted via the single X-ray crystallography determined the detailed structure of the crystallised PMOL in its monoclinic form. The solid state and the morphology analyses of the PMOL in the binary blends evaluated via differential scanning calorimetry (DSC), modulated temperature DSC (MTDSC), scanning electron microscopy (SEM) and hot stage microscopy (HSM) revealed the crystalline existence of the drug within the amorphous polymeric matrices. The application of temperature controlled X-ray diffraction (VTXRPD) to study the polymorphism of PMOL showed that the most stable form I (monoclinic) was altered to its less stable form II (orthorhombic) at high temperature (>112°C) in the binary blends regardless of the drug amount. Thus, VTXRD was used as a useful tool to monitor polymorphic transformations of crystalline drug (e.g. PMOL) to assess their thermal stability in terms of pharmaceutical product development and research.

The study of the effect of thiazoline ammonium 4-chlorophenyl-2-hydroxy-4-oxo-2-butenoate on blood coagulation upon intragastric and subcutaneous administration.

We studied the effects of subcutaneous and intragastrical administration of synthesized compound thiazoline ammonium 4-chlorophenyl-2-hydroxy-4-oxo-2-butenoate (FS 169) on blood clotting in vitro and in vivo in rabbits. Compound FS 169 significantly prolongs clotting time in vitro; its activity is comparable with that of heparin. When administered subcutaneously, the substance is rapidly absorbed and significantly reduces blood clotting by 102.9% from the initial clotting time within 30 min. After intragastric administration of the substance, maximum activity (133.0% of the baseline clotting time) was observed in 30 min after administration. The drug effect upon subcutaneous and intragastrical administration lasted for 2 h.

The pharmacokinetics and pharmacodynamics of Kollidon VA64 dissociate its protective effects from membrane resealing after controlled cortical impact in mice.

Membrane-resealing agents such as poloxamer P188 improve the outcome in experimental brain injury paradigms; however, whether membrane resealing is a key mechanism for protection has not been shown in vivo. We previously reported that Kollidon VA64, a polymeric membrane-resealing agent, reduces cell membrane permeability and improves brain edema, brain tissue damage, and functional outcome after controlled cortical impact in mice, without rescuing resealed cells from death. To reconcile these disparate findings, we used a dual-pulse labeling protocol to determine membrane-resealing kinetics by VA64/P188 in vivo. Membrane resealing after controlled cortical impact in mice by intravenous or intracerebroventricular VA64 and poloxamer P188 was transient, with most cells becoming repermeabilized within 2 hours, even with multiple-dose paradigms that maintained high VA64 blood levels. Moreover, VA64 reduced cytotoxic brain edema in a water intoxication model devoid of plasmalemma permeability (P<0.05 versus P188, VA30, mannitol, and vehicle). We conclude that VA64 reduces cytotoxic and traumatic brain edema independent of membrane resealing. The results suggest that classic membrane-resealing agents such as poloxamer P188, and the newly discovered VA64, exert protective effects in central nervous system injury paradigms by mechanisms other than or in addition to maintaining permeable cell membranes sealed.

Facile Preparation of a Thiol-Reactive (18)F-Labeling Agent and Synthesis of (18)F-DEG-VS-NT for PET Imaging of a Neurotensin Receptor-Positive Tumor.

UNLABELLED: Accumulating evidence suggests that neurotensin receptors (NTRs) play key roles in cancer growth and survival. In this study, we developed a simple and efficient method to radiolabel neurotensin peptide with (18)F for NTR-targeted imaging. METHODS: The thiol-reactive reagent (18)F-(2-(2-(2-fluoroethoxy)ethoxy)ethylsulfonyl)ethane ((18)F-DEG-VS) was facilely prepared through 1-step radiofluorination. After high-pressure liquid chromatography purification, (18)F-DEG-VS was incubated with the c(RGDyC) and c(RGDyK) peptide mixture to evaluate its specificity toward the reactive thiol. Thiolated neurotensin peptide was then labeled with (18)F using this novel synthon, and the resulting imaging probe was subjected to receptor-binding assay and small-animal PET studies in a murine xenograft model. The imaging results and metabolic stability of (18)F-DEG-VS-NT were compared with the thiol-specific maleimide derivative N-[2-(4-(18)F-fluorobenzamido)ethyl]maleimide-neurotensin ((18)F-FBEM-NT). RESULTS: (18)F-DEG-VS was obtained in high labeling yield. The reaction of (19)F-DEG-VS was highly specific for thiols at neutral pH, whereas the lysine of c(RGDyK) reacted at a pH greater than 8.5. (18)F-DEG-VS-c(RGDyC) was the preferred product when both c(RGDyK) and c(RGDyC) were incubated together with (18)F-DEG-VS. Thiolated neurotensin peptide (Cys-NT) efficiently reacted with (18)F-DEG-VS, with a 95% labeling yield (decay-corrected). The radiochemical purity of the (18)F-DEG-VS-NT was greater than 98%, and the specific activity was about 19.2 ± 4.3 TBq/mmol. Noninvasive small-animal PET demonstrated that (18)F-DEG-VS-NT had an NTR-specific tumor uptake in subcutaneous HT-29 xenografts. The tumor-to-muscle, tumor-to-liver, and tumor-to-kidney ratios reached 30.65 ± 22.31, 11.86 ± 1.98, and 1.91 ± 0.43 at 2 h after injection, respectively, based on the biodistribution study. Receptor specificity was demonstrated by blocking experiment. Compared with (18)F-FBEM-NT, (18)F-DEG-VS-NT was synthesized with fewer steps and provided significantly improved imaging quality in vivo. CONCLUSION: We have established a facile (18)F-labeling method for site-specific labeling of the Cys-NT. Using this method, we synthesized an NTR-targeted PET agent, which demonstrated high tumor-to-background contrast.

Acid-labile mPEG-vinyl ether-1,2-dioleylglycerol lipids with tunable pH sensitivity: synthesis and structural effects on hydrolysis rates, DOPE liposome release performance, and pharmacokinetics.

A family of 3-methoxypoly(ethylene glycol)-vinyl ether-1,2-dioleylglycerol (mPEG-VE-DOG) lipopolymer conjugates, designed on the basis of DFT calculations to possess a wide range of proton affinities, was synthesized and tested for their hydrolysis kinetics in neutral and acidic buffers. Extruded ∼100 nm liposomes containing these constructs in ≥90 mol % 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) produced dispersions that retained their calcein cargo for more than 2 days at pH 7.5, but released the encapsulated contents over a wide range of time scales as a function of the electronic properties of the vinyl ether linkage, the solution pH, and the mPEG-VE-DOG composition in the membrane. The in vivo performance of two different 90:10 DOPE:mPEG-VE-DOG compositions was also evaluated for blood circulation time and biodistribution in mice, using (125)I-tyraminylinulin as a label. The pharmacokinetic profiles gave a t(1/2) of 7 and 3 h for 90:10 DOPE:ST302 and 90:10 DOPE:ST502, respectively, with the liposomes being cleared predominantly by liver and spleen uptake. The behavior of these DOPE:mPEG-VE-DOG formulations is consistent with their relative rates of vinyl ether hydrolysis, i.e., the more acid-sensitive mPEG-VE-DOG derivatives produced faster leakage rates from DOPE:mPEG-VE-DOG liposomes, but decreased the blood circulation times in mice. These findings suggest that the vinyl ether-based PEG-lipid derivatives are promising agents for stabilizing acid-sensitive DOPE liposomes to produce formulations with a priori control over their pH responsiveness in vitro. Our data also suggest, however, that the same factors that contribute to enhanced acid sensitivity of the DOPE:mPEG-VE-DOG dispersions are also likely responsible for their reduced pharmacokinetic profiles.

Alpha,beta-unsaturated N-acylpyrrole peptidyl derivatives: new proteasome inhibitors.

Because of the encouraging results obtained using vinyl ester derivatives, we synthesized and tested a novel series of peptide-based proteasome inhibitors bearing a new pharmacophore unit at the C-terminal. N-Acylpyrrole moiety is a potential substrate for Michael addition by catalytic threonine. Several analogues have demonstrated a selective inhibition of the multicatalytic complex beta1 subunits, the capacity to permeate cellular membrane, and good pharmacokinetics properties.

Fragrance material review on 2-(1-methylpropyl)-1-vinylcyclohexyl acetate.

A toxicologic and dermatologic review of 2-(1-methylpropyl)-1-vinylcyclohexyl acetate when used as a fragrance ingredient is presented.

Fragrance material review on 1-methyl-4-(1-methylvinyl)cyclohexyl acetate.

A toxicologic and dermatologic review of 1-Methyl-4-(1-methylvinyl)cyclohexyl acetate when used as a fragrance ingredient is presented.

Gold-labeled block copolymer micelles reveal gold aggregates at multiple subcellular sites.

There is increasing interest in the usefulness of block copolymer micelles as drug delivery vehicles. However, their subcellular distribution has not been explored extensively, mostly because of the lack of adequately labeled block copolymers. In a previous study, we showed that fluorescently labeled block copolymer micelles entered living cells and co-localized with cytoplasmic organelles selectively labeled with fluorescent dyes. The details of the observed co-localizations were, however, limited by the resolution of the fluorescence approach, which is ca. 500 nm. Using transmission electron microscopy (TEM), we established time- and concentration-dependent subcellular distributions of gold-labeled micelles within human embryonic kidney (HEK 293) cells and human lung carcinoma (A549) cells. Gold particles were incorporated into poly(4-vinylpyridine)-block-poly(ethylene oxide) (P4VP21-b-PEO45) micelles. Data from dynamic light scattering (DLS) and TEM analyses revealed that the sizes of the gold particles ranged from 4 to 8 nm. The cells survived up to 24 h in the presence of low gold-labeled micelle concentrations (0.73 microg/mL), but cell death occurred at higher concentrations (i.e., kidney cells are more susceptible than lung cells). Over 24 h periods of equivalent exposure, lung cells internalized significantly more gold-incorporated micelles than kidney cells. Although micelles were added to the cell culture media as dispersed colloidal particles, the presence of serum in these media caused aggregation. These aggregates occurred mainly close to the cell plasma membrane at early times (5-10 min); however, at later times (24 h) aggregated particles were seen inside endosomes and lysozomes. Thus, gold-incorporated (labeled) micelles can serve as a valuable extension of the fluorescence approach to visualizing the localization of micelles in subcellular compartments, improving the resolution by at least 20-fold.

Stability and release of antiviral drugs from ethylene vinyl acetate (EVA) copolymer.

The use of polymer based drug delivery systems in dentistry is a relatively new area of research with the exception of the inhibition of secondary caries by the release of fluoride ions from polyalkenoate cements and their predecessors silicate cements. The present study was to test on orally biocompatible material, ethylene vinyl acetate copolymer (EVA), for release of antiviral drugs at oral therapeutic levels over extended periods of time. We also determined their stability during film casting and release. Materials studied include gancyclovir (GCY), acyclovir (ACY), dichloromethane (DCM), and ethylene vinyl acetate (EVA). The square films (3 x 3 x 0.1 cm) were prepared from the dry sheet obtained by solvent evaporation of polymer casting solutions. These solutions were made of EVA and the drug (40:1) in 70 ml of dichloromethane at 38 degrees C. Then drug release characteristics from the drug loaded films were examined at 37 degrees C for a minimum of 14 days in 10 ml medium (ddwater) replaced daily. Kinetics of drug release were followed by spectral measurements using previously determined lambda(max) values (GCY = 250 nm; ACY = 253 nm). A minimum of three samples was tested and reproducible results were obtained. Drug stability (ACY) during film casting and its release was determined using 1H NMR spectrometer (Bruker DRX-500 and 400). Rate of drug release was determined from the part of the curve (rate vs. time) after the onset of the "burst." Although GCY has a larger molecular weight (255) than ACY (225), GCY exhibited about three times higher rate of release than ACY. This difference in rate values may be explained due to its relatively greater solubility in EVA, facilitating faster diffusion of the molecules through the channels present in EVA. This is consistent with the observation that the rate at which drug molecules diffuse through the channels of the polymer, can be increased by decreasing the molecular weight. In the case of ACY, the molecules may be undergoing molecular associations, perhaps dimerization or trimerization in addition to its lower solubility in EVA. The diffusion of ACY tends to be slower under these circumstances compared to GCY resulting in lower rate value than in the case of GCY. Biological studies revealed that ACY exhibited a remarkable decrease in a number of viral organisms present in virus infected cell culture system using real-time polymerase chain reaction (RT-PCR). NMR analysis indicates that the chemical structure of the drug remains stable during film casting process and release.

Synthesis and antibacterial activity of novel C12 vinyl ketolides.

A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae.

Controlled release of drug via methylcellulose-carboxyvinylpolymer interpolymer complex solid dispersion.

The purpose of this research was to examine the controlled release of phenacetin (PHE) from solid dispersion by the formation of an interpolymer complex between methylcellulose (MC) and carboxyvinylpolymer (CP). The PHE/polymer composition ratio was fixed at 20:80 (w/w) in the solid dispersion. The effect of the MC/CP ratio and molecular weight of MC on the PHE release was studied. The release of PHE from the solid-dispersion granules depended on the MC/CP ratio, with a ratio of 50:50 giving the lowest rate of release. In aqueous solution, this MC/CP ratio resulted in the lowest transmittance, suggesting a maximal extent of interpolymer complex formation between MC and CP. Furthermore, at a MC/CP ratio of 50:50, the release of PHE from the solid dispersion granules decreased as the molecular weight of the MC increased, reaching a plateau at molecular weights >or=180,000. The contributions of diffusion and polymer relaxation to PHE release increased as the molecular weight of the MC increased. This study shows that it is feasible to control the release of PHE from MC-CP solid dispersion granules by modulating complex formation between MC and CP, which can be accomplished by altering the MC/CP ratio and the molecular weight of MC.

Incorporation of low molecular weight biocides into polystyrene-divinyl benzene beads with controlled release characteristics.

Triclosan and phosphonium salt biocides have been separately incorporated into polystyrene-divinylbenzene (PS-DVB) beads by suspension polymerization. Ultraviolet (UV) absorption measurements have been used to monitor the release of these low molecular weight biocides out of the PS-DVB beads immersed in water-ethanol mixtures and in physiological saline. The release of the biocide agents is strongly dependent on either the DVB or/and the antimicrobial composition ratio in the beads. An increase of biocide incorporation in the PS/DVB beads was accompanied by a corresponding enhancement of its concentration in liquid mixtures. On the contrary, higher cross-linking densities hindered the biocide migration out of the beads by diminishing its release rate into either the aqueous ethanol solutions or the natural serum. Moreover, Fourier transform Raman (FT-Raman) spectra and Attenuated Total Reflectance Infrared (ATR-FTIR) measurements of the PS-DVB-Triclosan and PS-DVB-phosphonium salt beads, before and after their immersion in water-ethanol solutions, gave a similar qualitative evidence of the biocide release.