Showing papers in "Aaps Pharmscitech in 2002"
TL;DR: The results showed that the tested oils possess interesting larvicidal effects that make them suitable for application in integrated control strategies, and seem to be able to protect the core material against environmental agents and could be considered for use in controlled drug release systems.
Abstract: This study investigated the effects of some essential oils onLimantria dispar (Lepidoptera: Lymantridae, gypsy moth) larvae, one of the most serious pests of cork oak forests. The essential oils were first formulated as oil in water (o/w) emulsions and used in laboratory bioassays to assess their lethal concentration (LC50). Microcapsules containing the most promising, oils (Rosmarinus officinalis andThymus herba-barona) were then prepared by a phase separation process, followed by freeze-drying. The formulations thus obtained, characterized in terms of essential oil content and composition, morphology, storage stability, and release profile, were tested on gypsy moth larvae. The results showed that the tested oils possess interesting larvicidal effects that make them suitable for application in integrated control strategies. The microencapsulation process gave high encapsulation yields (over 98%) with both essential oils, which have different chemical compositions. The microcapsules had toxic effects at a concentration similar to that usually employed for localized treatments with microgranular synthetic pesticides. Toxicity appeared to be maximized when the microparticles adhered to the typical hair structures of several defoliator families. These formulations seem to be able to protect the core material against environmental agents and could be considered for use in controlled drug release systems. The natural active principles they contain could provide an alternative system in insect pest control.
182 citations
TL;DR: In this article, a system based on array detector technology was used to rapidly collect high-contrast NIR images of furosemide tablets, and five grades of experimental tablets were produced, ranging from well blended to unblended, and a quantitative measure of blending was determined by calculating the standard deviation of the distribution of pixel intensities in the PLS score images.
Abstract: The objective of this study was to evaluate near-infrared (NIR) spectroscopic imaging as a tool to assess a pharmaceutical quality assurance problem—blend uniformity in the final dosage product. A system based on array detector technology was used to rapidly collect high-contrast NIR images of furosemide tablets. By varying the mixing, 5 grades of experimental tablets containing the same amount of furosemide and microcrystalline cellulose were produced, ranging from well blended to unblended. For comparison, these tablets were also analyzed by traditional NIR spectroscopy, and both approaches were used to evaluate drug product homogeneity. NIR spectral imaging was capable of clearly differentiating between each grade of blending, both qualitatively and quantitatively. The spatial distribution of the components was based on the variation or contrast in pixel intensity, which is due to the NIR spectral contribution to each pixel. The chemical nature of each pixel could be identified by the localized spectrum associated with each pixel. Both univariate and partial least squares (PLS) images were evaluated. In the suboptimal blends, the regions of heterogeneity were obvious by visual inspection of the images. A quantitative measure of blending was determined by calculating the standard deviation of the distribution of pixel intensities in the PLS score images. The percent standard deviation increased progressively from 11% to 240% from well blended to unblended tablets. The NIR spectral imaging system provides a rapid approach for acquiring spatial and spectral information on pharmaceuticals. The technique has potential for a variety of applications in product quality assurance and could affect the control of manufacturing processes.
172 citations
TL;DR: Results from the intercalation process show that hydrotalcite is able to intercalate diclofenac with a simple procedure and with a good drug loading, and that it may be used to prepare modified release formulations.
Abstract: The purpose of this study was to investigate whether hydrotalcite is able to intercalate diclofenac, a nonsteroidal anti-inflammatory drug, and release it in a controlled manner. Layered Mg−Al hydrotalcite in the chloride form was used as a host, and the intercalation compound was prepared by Cl−/diclofenac anionic exchange. Drug release from the intercalation compound was performed in vitro in simulated intestinal fluid at pH 7.5 according to USP 24 and in a pH 7.0 solution designed to mimic the ionic conditions of the small intestine. Results from the intercalation process show that hydrotalcite is able to intercalate diclofenac with a simple procedure and with a good drug loading (55% wt/wt). The in vitro drug release was remarkably lower than that from the corresponding physical mixture at both pH 7.5 and pH 7.0. In the latter case, the release was not complete at 24 hours. The kinetic analysis shows the importance of the diffusion through the particle in controlling the drug release rate. The obtained results show that hydrotalcite may be used to prepare modified release formulations.
127 citations
TL;DR: The rheological behavior and the apparent viscosity values for different gel bases were measured before and after storage under freezing conditions at −4 °C and taken as measures for stability of network structure and the antifungal activity of fluconazole showed the widest zone of inhibition with gel microemulsion.
Abstract: The influence of the vehicle on the release and permeation of fluconazole, a topical antifungal drug dissolved in Jojoba oil was evaluated. Series of Cutina lipogels (Cutina CPA [cetyl palmitate], CBS [mixture of glyceryl stearate, cetearyl alcohol, cetyl palmitate, and cocoglycerides], MD [glyceryl stearate], and GMS [glyceryl monostearate]) in different concentrations as well as gel microemulsion were prepared. In-vitro drug release in Sorensens citrate buffer (pH 5.5) and permeation through the excised skin of hairless mice, using a modified Franz diffusion cell, were performed. The rheological behavior and the apparent viscosity values for different gel bases were measured before and after storage under freezing conditions at −4 °C and were taken as measures for stability of network structure.Candida albicans was used as a model fungus to evaluate the antifungal activity of the best formula achieved. The results of in vitro drug release and its percutaneous absorption showed that the highest values from gel microemulsion were assured. The rheological behavior of the prepared systems showed pseudoplastic (shear-thinning) flow indicating structural breakdown of the existing intermolecular interactions between polymeric chains. Moreover, the stability study revealed no significant difference between viscosity before and after storage for different formulae except for CPA Cutina lipogel (using analysis of variance [ANOVA] test at level of significance .05). The antifungal activity of fluconazole showed the widest zone of inhibition with gel microemulsion. The gel microemulsion is an excellent vehicle for fluconazole topical drug delivery.
123 citations
TL;DR: A description of different types and origins of impurities in relation to ICH guidelines and, degradation routes, including specific examples, are presented.
Abstract: The control of pharmaceutical impurities is currently a critical issue to the pharmaceutical industry. The International Conference on Harmonization (ICH) has formulated a workable guideline regarding the control of impurities. In this review, a description of different types and origins of impurities in relation to ICH guidelines and, degradation routes, including specific examples, are presented. The article further discusses measures regarding the control of impurities in pharmaceuticals
116 citations
TL;DR: It was found thatprotein concentration and atomizing nitrogen pressure had the greatest effects on the particle size of the protein powder, and results showed that protein concentration was the critical variable for determining product yield.
Abstract: The objective of this study was to examine the effects of formulation and process variables on particle size and other characteristics of a spray-dried model protein, bovine serum albumin (BSA), using a partial factorial design for experiments. Formulation variables tested include concentration and zinc:protein complexation ratio. Process variables explored were inlet temperature, liquid feed rate, drying air flow rate, and atomizing nitrogen pressure on a lab-scale spray dryer. Statistical data analysis was used to determine F ratios for each of the inputs, which provided a means of ranking the importance of variables relative to one another for each powder characteristic of interest. It was found that protein concentration and atomizing nitrogen pressure had the greatest effects on the particle size of the protein powder. For determining product yield, results showed that protein concentration was the critical variable. Finally, the outlet temperature was mostly influenced by inlet temperature and liquid feed rate. Mathematical models based on these input-output relationships were constructed; these models provide insight into some of the controllable variables of the spray-drying process.
94 citations
TL;DR: The observed responses were in close agreement with the predicted values of the optimized formulation, demonstrating the reliability of the optimization procedure in predicting the dissolution behavior of a self-emulsified drug delivery system.
Abstract: The aim of the present study was to prepare and evaluate an optimized, self-nanoemulsified drug delivery system of ubiquinone. A 3-factor, 3-level Box-Behnken design was used for the optimization procedure with the amounts of Polyoxyl 35 castor oil (X1), medium-chain mono- and diglyceride (X2), and lemon oil (X3) as the independent variables. The response variable was the cumulative percentage of ubiquinone emulsified in 10 minutes. Different ubiquinone release rates were obtained. The amount released ranged from 11% to 102.3%. Turbidity profile revealed 3 regions that were used to describe the progress of emulsion formation: lag phase, pseudolinear phase, and plateau turbidity. An increase in the amount of surfactant decreased turbidity values and caused a delay in lag time. Addition of cosurfactant enhanced the release rates. Increasing the amount of the eutectic agent was necessary to overcome drug precipitation especially at higher loading of surfactants and cosurfactants. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equation generated for the cumulative percentage emulsified in 10 minutes was Y1=90.9–22.1X1+5.03X2+13.95X3+12.13X1X2+15.13X1X3-14.40X12-6.25X32. The optimization model predicted a 93.4% release with X1, X2, and X3 levels of 35, 35, and 30 respectively.
91 citations
TL;DR: It was found that viscoelastic data, especially the strain sweep profiles of products containing Avicel CL-611 1% and 2%, correlated with the commercial formulation.
Abstract: The purpose of this study was to examine the viscoelastic properties of topical creams containing various concentrations of microcrystalline cellulose and sodium carboxymethyl cellulose (Avicel® CL-611) as a stabilizer. Avicel CL-611 was used at 4 different levels (1%, 2%, 4%, and 6% dispersion) to prepare topical creams, and hydrocortisone acetate was used as a model drug. The viscoelastic properties such as loss modulus (G), storage modulus (G), and loss tangent (tan δ) of these creams were measured using a TA Instruments AR 1000 Rheometer and compared to a commercially available formulation. Continuous flow test to determine the yield stress and thixotropic behavior, and dynamic mechanical tests for determining the linear viscosity time sweep data, were performed. Drug release from the various formulations was studied using an Enhancer TM Cell assembly. Formulations containing 1% and 2% Avicel CL-611 had relative viscosity, yield stress, and thixotropic values that were similar to those of the commercial formulation. The elastic modulus (G) of the 1% and 2% formulation was relatively high and did not cross the loss modulus (G), indicating that the gels were strong. In the commercial formulation,G increased after preshearing and broke down after 600 seconds. The strain sweep tests showed that for all formulations containing Avicel CL-611, theG was aboveG with a good distance between them. The gel strength and the predominance ofG can be ranked 6%>4%>2%. The strain profiles for the 1% and 2% formulations were similar to those of the commercial formulation. The δ values for the 1% and 2% formulations were similar, and the formulations containing 4% Avicel CL-611 had lower δ values, indicating greater elasticity. Drug release from the commercial preparation was fastest compared to the formulations prepared using Avicel CL-611, a correlation with the viscoelastic properties. It was found that viscoelastic data, especially the strain sweep profiles of products containing Avicel CL-611 1% and 2%, correlated with the commercial formulation. Rheological tests that measure the viscosity, yield stress, thixotropic behavior, other oscillatory parameters such asG andG are necessary tools in predicting performance of semisolids.
89 citations
TL;DR: This work studied the mechanisms of interaction between Eudragit RS100 and RL100 (RL) polymers with 3 nonsteroidal anti-inflammatory drugs: diflunisal (DIF), flurbiprofen (FLU), and piroxicam (PIR).
Abstract: This work studied the mechanisms of interaction between Eudragit RS100 (RS) and RL100 (RL) polymers with 3 nonsteroidal anti-inflammatory drugs: diflunisal (DIF), flurbiprofen (FLU), and piroxicam (PIR). Solid dispersions of polymers and drugs at different weight ratios were prepared by coevaporation of their ethanol solutions. The resulting coevaporates were characterized in the solid state (Fourier-transformed infrared spectroscopy (FT-IR) IR, differential scanning calorimetry, powder-x-ray diffractometry) as well as by studying the in vitro drug release in a gastroenteric environment. Absorption tests from drug solutions to the solid polymers were also performed to better explain the mechanism of interactions between them. The preparative conditions did not induce changes in the crystalline state of the drugs (amorphization or polymorphic change). Drugs strongly interacted with the ammonium groups present in polymers, giving an electrostatic interaction that reinforced the mere physical dispersion of drug molecules within polymer networks. Such interactions are related to the chemical structure of the drugs and to their dissociated or undissociated state. The dispersion of drugs in the polymer matrices strongly influenced their dissolution rate, which appeared slower and more gradual than those of the pure drugs, when polymer ratios were increased. RL coevaporates usually displayed higher dissolution rates. The kinetic evaluation of the dissolution profile, however, suggested that both the drug solubility in the external medium and its diffusion capacity within the polymer network are involved. In the sorption experiments, RL showed a greater adsorptive capacity than RS, in relation to the greater number of quaternary ammonium functions, which behave as activity sites for the electrostatic interactions. In the presence of Tris-HCl buffer (pH 7.4), drug adsorption was reduced, as a consequence of the competition of the chloride ions with drug anions for the polymer binding sites. In general, DIF and FLU displayed a similar interaction with RS and RL active sites; PIR's was different. The different molecular structures of these agents can justify such findings. The presence of a carboxyl group (instead of another dissociable acidic moiety, like the hydroxy-enolic one in the PIR molecule) could help explain the strong interaction with RS and RL polymers' quaternary ammonium centers. Preliminary studies like ours are important in helping develop better forecasting and increasing the understanding of the incorporation/release behavior of drugs from particulate delivery systems that can be made from these polymers.
89 citations
TL;DR: The main focus was to study the effect of cosolvent selection on the shape, size, formation efficiency, degree of crystallinity, x-ray diffraction (XRD) reflection pattern, and zeta potential value of the particles in a modified nanoprecipitation method.
Abstract: The aim of this study was to formulate nanoparticles from poly(I)lactide by a modified nanoprecipitation method. The main focus was to study the effect of cosolvent selection on the shape, size, formation efficiency, degree of crystallinity, x-ray diffraction (XRD) reflection pattern, and zeta potential value of the particles. Low-molecular-weight (2000 g/mol) poly(I)lactide was used as a polymer, and sodium cromoglycate was used as a drug. Acetone, ethanol, and methanol were selected as cosolvents. Optimal nanoparticles were achieved with ethanol as a cosolvent, and the formation efficiency of the particles was also higher with ethanol as compared with acetone or methanol. The particles formulated by ethanol and acetone appeared round and smooth, while with methanol they were slightly angular. When the volume of the inner phase was decreased during the nanoprecipitation process, the mean particle size was also decreased with all the solvents, but the particles were more prone to aggregate. The XRD reflection pattern and the degree of crystallinity were more dependent were more prone to aggregate. The XRD reflection pattern and the degree of crystallinity were more dependent on the amount of the solvents in the inner phase than on the properties of the individual cosolvents. The zeta potential values of all the particle batches were slightly negative, which partially explains the increased tendency toward particle aggregation.
89 citations
TL;DR: The mucoadhesive tablet formulated in this work releases nystatin quickly from the lactose layer and then in a sustained way, during approximately 6 hours, from the polymeric layer.
Abstract: The objective of this work was to design a mucoadhesive tablet with a potential use in the treatment of oral candidosis. A 2-layered tablet containing nystain was formulated. Lactose CD (direct compression), carbomer (CB), and hydroxypropylmethylcellulose (HPMC) were used as excipients. Tablets were obtained through direct compression. Properties such as in vitro mucoadhesion, water uptake, front movements, and drug release were evaluated. The immediate release layer was made of lactose CD (100 mg) and nystatin (30 mg). The CB:HPMC 9∶1 mixture showed the best mucoadhesion properties and was selected as excipient for the mucoadhesive polymeric layer (200 mg). The incorporation of nystatin (33.3 mg) in this layer affected the water uptake, which, in turn, modified the erosion front behavior. Nystatin showed a first-order release. The polymeric layer presented an anomalous kinetic (n=0.82) when this layer layer was individually evaluated. The mucoadhesive tablet formulated in this work releases nystatin quickly from the lactose layer and then in a sustained way, during approximately 6 hours. from the polymeric layer. The mixture CB:HPMC 9∶1 showed good in vitro mucoadhesion. A swelling-diffusion process modulates the release of nystatin from this layer. A non-Fickian (anomalous) kinetic was observed.
TL;DR: Kollicoat SR 30D has been demonstrated to effectively retard drug release from nonpareilbased systems, however, selected plasticizer type and subsequent curing condition play important roles in controlling drugRelease from such a system.
Abstract: A newly available polyvinylacetate aqueous dispersion, Kollicoat SR 30D, was evaluated with respect to its ability to modulate the in vitro release of a highly water-soluble model compound (diphenhydramine hydrochloride) from nonpareil-based systems. Kollicoat SR 30D premixed with a selected plasticizer (10% wt/wt propylene glycol, 2.5% triethyl citrate, or 2.5% dibutyl sebacute), talc, and red #30 lake dye was coated onto the drug beads in an Aeromatic Strea I fluid-bed drier with a Wurster insert using bottom spray. With propylene glycol as the plasticizer, increases in polymer coating level retarded drug release from beads in a stepwise fashion along with apparent permeability, indicating a consistent release mechanisms. Stability studies at 40°C/75% RH revealed gradual decreases in dissolution rate, and additional curing studies further confirmed the dependence of release kinetics on curing condition. Furthermore, the type of plasticizer was found to play a key role. Unplasticized formulations exhibited the fastest dissolution, followed by formulations plasticized with triethyl citrate, propylene glycol, and dibutyl sebacate. All 4 formulations (unplasticized and plasticized), nevertheless, revealed a marked difference between uncured and cured dissolution profiles. Kollicoat SR 30D has, thereby, been demonstrated to effectively retard drug release from nonpareilbased systems. However, selected plasticizer type and subsequent curing condition play important roles in controlling drug release from such a system.
TL;DR: The DP showed a remarkable influence on the physicochemical properties of the cellulose materials and, consequently, on the behavior of these materials during compression.
Abstract: This study investigated the influence of the degree of polymerization (DP) of cellulose materials (microcrystalline cellulose [MCC]) on some powder properties and the compression behavior of these materials. The DP was determined by measurements of viscosity (H). The weight average of molecular weight and the weight average of the different DPs were investigated after MCC was modified to cellulose tricarbanilate by light scattering measurements. The DP showed a remarkable influence on the physicochemical properties of the cellulose materials and, consequently, on the behavior of these materials during compression. MCC types with a high DP value showed greater water absorption than the types with a low DP value. No relevant relationship between the crystallinity index and the DP could be observed. DP 190 showed lower compactibility and compressibility parameters than DP 244 and 299. No significant differences could be observed between DP 244 and 299 when the same particle size fraction was compressed. Furthermore, the compressibility was increased by increasing the DP.
TL;DR: Delivery of dry powder formulations can be achieved by characterizing particle surfaces and predicting impact on dispersion through knowledge of particle surface properties, and an expression is proposed as a predictor of drug dispersion from carrier particles.
Abstract: The purpose of this study was to determine if aerosol delivery of drug loaded microparticles to lungs infected withMycobacterium tuberculosis may be achieved by predicting dispersion of dry powders through knowledge of particle surface properties. Particle sizes of rifampicin-loaded poly(lactide-co-glycolide) microparticles (R-PLGA), rifampicin alone, and lactose and maltodextrin carrier particles (bulk and 75-125-μm sieved fractions) were determined by electron microscopy for the projected area diameter (Dp) and laser diffraction for the volume diameter (Dv). Surface energies (Y) of R-PLGA, rifampicin alone, lactose, and maltodextrin were obtained by inverse phase gas chromatography, surface areas (Sa) by N2 adsorption, and cohesive energy densities by calculation. Particle dispersion was evaluated (Andersen nonviable impactor) for 10% blends of R-PLGA and rifampicin alone with bulk and sieved fractions of the carriers. Dp for R-PLGA and rifampicin alone was 3.02 and 2.83 μm, respectively. Dv was 13±1 and 2±1 μm for R-PLGA and rifampicin alone, respectively, indicating that R-PLGA was more aggregated. This was evident in Y of 35±1 and 19±6 mJ/m2 for R-PLGA and rifampicin alone. Dp for lactose and maltodextrin (sieved and bulk) was approximately 40 mm. Bulk maltodextrin (Dv=119±6 mm) was more aggregated than bulk lactose (Dv=54±2 mm). This was a result of the higher Sa for maltodextrin (0.54 m2/g) than for lactose (0.21 m2/g). The Y of bulk lactose and maltodextrin was 40±4 and 60±6 mJ/m2 and of sieved lactose and maltodextrin was 39±1 and 50±1 mJ/m2. Impaction studies yielded higher fine particle fractions of R-PLGA from sieved lactose, 13%±3%, than from sieved maltodextrin, 7%±1%, at 90 L/min. An expression, based on these data, is proposed as a predictor of drug dispersion from carrier particles.
TL;DR: This method provides a unique way of producing various shapes and drug loads of HAP microspheres that can be easily manufactured on a commercial scale.
Abstract: This investigation synthesized and characterized hydroxyapatite (HAP) microspheres, agglomerated microspheres, and implants containing ciprofloxacin. This delivery system is to be used as an implantable drug delivery system for the treatment of bone infections. The HAP microspheres were made by chemical precipitation followed by a spray-drying technique. Agglomerated microspheres were prepared by a wet granulation process using a granulator. Implants were prepared by direct compression of the granules on a Carver press. Ciprofloxacin was analyzed by high-performance liquid chromatography. Characterization of the HAP microspheres include particle size, size distribution, physical state of the drug in the microsphere, and microstructure of the drug delivery system before and after in vitro release. The particle size, porosity, and morphology of the microspheres were dependent on viscosity and concentration of the slurry as well as the atomization pressure used during spray drying. Even at the highest drug load (2% wt/wt), the drug was present in a noncrystalline state. The drug release from the agglomerated microspheres was quick and almost complete within 1 hour. However, compressing the same amount of agglomerated microspheres into an implant greatly reduced the rate of ciprofloxacin release. Only 12% (wt/wt) of the drug was released from the implant within 1 hour. The in vitro release of ciprofloxacin from these implants follows a diffusion-controlled mechanism. This method provides a unique way of producing various shapes and drug loads of HAP microspheres that can be easily manufactured on a commercial scale.
TL;DR: Preliminary data indicate that this formulation, containing microspheres with drug to polymer weight ratios of 1∶1 and Carbopol 974, can be proposed as a mucoadhesive vaginal delivery system for the controlled release of acriflavine.
Abstract: The aim of the study was the development of mucoadhesive vaginal tablets designed for the local controlled release of acriflavine, an antimicrobial drug used as a model. The tablets were prepared using drug-loaded chitosan microspheres and additional excipients (methylcellulose, sodium alginate, sodium carboxymethylcellulose, or. Carbopol 974). The microspheres were prepared by a spray-drying method, using the drug to polymer weight ratios 1∶1 and 1∶2 and were characterized in terms of morphology, encapsulation efficiency, and in vitro release behavior, as MIC (Minimum Inhibitory Concentration), MBC (Minimum Bacterial Concentration), and killing time (KT). The tablets were prepared by direct compression, characterized by in vitro drug release and in vitro mucoadhesive tests. The microparticles have sizes of 4 to 12 μm; the mean encapsulation yields are about 90%. Acriflavine, encapsulated into the polymer, maintains its antibacterial activity; killing time of the encapsulated drug is similar to that of the free drug. In vitro release profiles of tablets show differences depending on the excipient used. In particular Carbopol 974, which is highly cross-linked, is able to determine a drug-controlled release from the matrix tablets for more than 8 hours. The in vitro adhesion tests, carried out on the same formulation, show a good adhesive behavior. The formulation containing microspheres with drug to polymer weight ratios of 1∶1 and Carbopol 974 is characterized by the best release behavior and shows good mucoadhesive properties. These preliminary data indicate that this formulation can be proposed as a mucoadhesive vaginal delivery system for the controlled release of acriflavine.
TL;DR: In vitro drug release studies at 37°C indicated 50% budesonide release from the budesonid-PLA microparticles at the end of 28 days, indicating that the PCA process was successful in producing budesonite and budesonides-PLAmicroparticles.
Abstract: The objective of this study was to prepare and characterize microparticles of budesonide alone and budesonide and polylactic acid (PLA) using supercritical fluid (SCF) technology A precipitation with a compressed antisolvent (PCA) technique employing supercritical CO2 and a nozzle with 100-μm internal diameter was used to prepare microparticles of budesonide and budesonide-PLA The effect of various operating variables (temperature and pressure of CO2 and flow rates of drug-polymer solution and/or CO2) and formulation variables (025%, 05%, and 1% budesonide in methylene chloride) on the morphology and size distribution of the microparticles was determined using scanning electron microscopy In addition, budesonide-PLA particles were characterized for their surface charge and drug-polymer interactions using a zeta meter and differential scanning calorimetry (DSC), respectively Furthermore, in vitro budesonide release from budesonide-PLA microparticles was determined at 37°C Using the PCA process, budesonide and budesonide-PLA microparticles with mean diameters of 1 to 2 μm were prepared An increase in budesonide concentration (025%–1% wt/vol) resulted in budesonide microparticles that were fairly spherical and less aggiomerated In addition, the size of the microparticles increased with an increase in the drug-polymer solution flow rate (14–47 mL/min) or with a decrease in the CO2 flow rate (50–10 mL/min) Budesonide-PLA microparticles had a drug loading of 794%, equivalent to ∼80% encapsulation efficiency Budesonide-PLA microparticles had a zeta potential of— 37±4 mV, and DSC studies indicated that SCF processing of budesonide-PLA microparticles resulted in the loss of budesonide crystallinity Finally, in vitro drug release studies at 37°C indicated 50% budesonide release from the budesonide-PLA microparticles at the end of 28 days Thus, the PCA process was successful in producing budesonide and budesonide-PLA microparticles In addition, budesonide-PLA microparticles sustained budesonide release for 4 weeks
TL;DR: The aim of this work was to study the effect of the type of substituent of the cellulose ethers and the molecular mass on the state and dynamics of water in the respective hydrogels to specify the quantity of adsorbed water on the polymers or to calculate the average number of water molecules bound to a polymer repeating unit (PRU).
Abstract: The aim of this work was to study the effect of the type of substituent of the cellulose ethers and the molecular mass on the state and dynamics of water in the respective hydrogels to specify the quantity of adsorbed water on the polymers or, more explicitly, to calculate the average number of water molecules bound to a polymer repeating unit (PRU).1H NMR relaxation experiments were performed on equilibrated systems of cellulose ether polymers (HEC, HPC, HPMC K4M, and HPMC K100M) with water. In particular, the water proton spinlattice (T1) and spin-spin (T2) relaxation times were measured in these systems at room temperature. The observed proton NMRT1 andT2 of water in hydrogels at different cellulose ether concentrations at room temperature were shown to decrease with increasing polymer concentration. The relaxation rate 1/T1 is sensitive to the type of polymer substituent but insensitive to the polymer molecular mass. The rate 1/T2 appears much less influenced by the polymer substitution. The procedure developed for calculating the amount of water bound per PRU, based on the analysis of theT1 andT2 data, shows that this amount is the largest for HPC followed by HEC, HP MC K4M, and HPMC K100M. The results correlate well with the degree of hydrophilic substitution of the polymer chains. This NMR analysis deals with a single molecular layer of adsorbed water for the investigated cellulose ether polymers at all concentrations, while the rest of the water in the hydrogel is bulk-like. Therefore, the mesh size of polymer network in the view of a single molecular layer is not effectively changed.
TL;DR: It was determined that water-soluble prodrugs of 17β-estradiol can be administered nasally and are capable of producing high levels of estradiol in the CSF and as a result may have a significant value in the treatment of Alzheimer's disease.
Abstract: The utility of the nasal route for the systemic delivery of 17β-estradiol was studied using watersoluble prodrugs of 17β-estradiol. This delivery method was examined to determine if it will result in preferential delivery to the brain. Several alkyl prodrugs of 17β-estradiol were prepared and their physicochemical properties were determined. In vitro hydrolysis rate constants in buffer, rat plasma, and rat brain homogenate were determined by high-performance liquid chromatography. In vivo nasal experiments were carried out on rats. Levels of 17β-estradiol in plasma and cerebral spinal fluid (CSF) were determined with radioimunoassay using a gamma counter. The study revealed that the aqueous solubilities of the prodrugs were several orders of magnitude greater than 17β-estradiol with relatively fast in vitro conversion in rat plasma. Absorption was fast following nasal delivery of the prodrugs with high bioavailability. CSF 17β-estradiol concentration was higher following nasal delivery of the prodrugs compared to an equivalent intravenous dose. It was determined that water-soluble prodrugs of 17β-estradiol can be administered nasally. These prodrugs are capable of producing high levels of estradiol in the CSF and as a result may have a significant value in the treatment of Alzheimer's disease.
TL;DR: In this paper, a water-in-oil (W/O) emulsion with a narrow size distribution containing gelatin in the aqueous phase was created, and the average particle diameter was calculated to be 31.6 μm and the relative standard deviation, 7.3%.
Abstract: The purpose of this study was to prepare monodisperse gelatin microcapsules containing an active agent using microchannel (MC) emulsification, a novel technique for preparing water-in-oil (W/O) and oil-in-water (O/W) emulsions. As the first step in applying MC emulsification to the preparation of monodisperse gelatin microcapsules, simple gelatin microbeads were prepared using this technique. A W/O emulsion with a narrow size distribution containing gelatin in the aqueous phase was created as follows. First, the aqueous disperse phase was fed into the continuous phase through the MCs at 40°C (operating pressure: 3.9 kPa). The emulsion droplets had an average particle diameter of 40.7 μm and a relative standard deviation of 5.1%. The temperature of the collected emulsion was reduced and maintained at 25°C overnight. The gelatin microbeads had a smooth surface after overnight gelation; the average particle diameter was calculated to be 31.6 μm, and the relative standard deviation, 7.3%. The temperature was then lowered to 5°C by rapid air cooling and finally dried. The gelatin beads were dried and could be resuspended well in iso-octane. The had an average particle diameter of 15.6 μm, and a relative standard deviation of 5.9%. Using MC emulsification, we were able to prepare gelatin microbeads with a narrow size distribution. Since this emulsification technique requires only a low-energy input, it may create desirable experimental conditions for microencapsulation of unstable substances such as peptides and proteins. This method is promising for making monodisperse microbeads.
TL;DR: In this paper, the authors investigated particle and powder properties of various starch acetate powders, to study the effect of these properties on direct compression characteristics, and to evaluate the modification opportunity of physical properties for starch acetates by using various drying methods.
Abstract: The aim of the study was to investigate particle and powder properties of various starch acetate powders, to study the effect of these properties on direct compression characteristics, and to evaluate the modification opportunity of physical properties for starch acetate powders by using various drying methods. At the end of the production phase of starch acetate, the slurry of starch acetate was dried using various techniques. Particle, powder, and tableting properties of end products were investigated. Particle size, circularity, surface texture, water content and specific surface area varied according to the particular drying method of choice. However, all powders were freely flowing. Bulk and tapped densities of powders varied in the range of 0.29 to 0.44 g/cm3 and 0.39 to 0.56 g/cm3, respectively. Compaction characteristics revealed that all powders were easily deformed under compression, having yield pressure values of less than 66 MPa according to Heckel analysis. All powders possessed a significant interparticulate bond-forming capacity during compaction. The tensile strength values of tablets varied between 10 and 18 MPa. In conclusion, physical properties of starch acetate could be affected by various drying techniques. A large specific surface area and water content above 4% were favorable properties by direct compression, especially for small, irregular, and rough particles.
TL;DR: In providing the ability to control both the particle and crystal morphologies of active pharmaceutical ingredients, RESS proved potentially advantageous to crystal engineering and rapid crystallization kinetics were found vital in making RESS-based doping superior to conventional solvent-based cocrystallizations.
Abstract: The purpose of this study was to test the utility of rapid expansion of supercritical solution (RESS) based cocrystallizations in inducing polymorph conversion and crystal disruption of chlorpropamide (CPD). CPD crystals were recrystallized by the RESS process utilizing supercritical carbon dioxide as the solvent. The supercritical region investigated for solute extraction ranged from 45 to 100°C and 2000 to 8000 psi. While pure solute recrystallization formed stage I of these studies, stage II involved recrystallization of CPD in the presence of urea (model impurity). The composition, morphology, and crystallinity of the particles thus produced were characterized utilizing techniques such as microscopy, thermal analysis, x-ray powder diffractometry, and high-performance liquid chromatography. Also, comparative evaluation between RESS and evaporative crystallization from liquid solvents was performed. RESS recrystallizations of commercially available CPD (form A) resulted in polymorph conversion to metastable forms C and V, depending on the temperature and pressure of the recrystallizing solvent. Cocrystallization studies revealed the formation of eutectic mixtures and solid solutions of CPD+urea. Formation of the solid solutions resulted in the crystal disruption of CPD and subsequent amorphous conversion at urea levels higher than 40% wt/wt. Consistent with these results were the reductions in melting point (up to 9°C) and in the ΔHfvalues of CPD (up to 50%). Scanning electron microscopy revealed a particle size reduction of up to an order of magnitude upon RESS processing. Unlike RESS, recrystallizations from liquid organic solvents lacked the ability to affect polymorphic conversions. Also, the incorporation of urea into the lattice of CPD was found to be inadequate. In providing the ability to control both the particle and crystal morphologies of active pharmaceutical ingredients, RESS proved potentially advantageous to crystal engineering. Rapid crystallization kinetics were found vital in making RESS-based doping superior to conventional solvent-based cocrystallizations.
TL;DR: Apparatus III was demonstrated to be more convenient and efficient than apparatus II by providing various programmable options in sampling times, agitation rates, and medium changes, which suggested that the apparatus II approach has better potential for in vitro evaluation of colon-specific drug delivery systems.
Abstract: United States Pharmacopeia dissolution apparatus II (paddle) and III (reciprocating cylinder) coupled with automatic sampling devices and software were used to develop a testing procedure for acquiring release profiles of colon-specific drug delivery system (CODES™) drug formulations in multi-pH media using acetaminophen (APAP) as a model drug. System suitability was examined. Several important instrument parameters and formulation variables were evaluated. Release profiles in artificial gastric fluid (pH 1.2), intestinal fluid (pH 6.8), and pH 5.0 buffer were determined. As expected, the percent release of APAP from coated core tablets was highly pH dependent. A release profile exhibiting a negligible release in pH 1.2 and 6.8 buffers followed by a rapid release in pH 5.0 buffer was established. The drug release in pH 5.0 buffer increased significantly with the increase in the dip or paddle speed but was inversely related to the screen mesh observed at lower dip speeds. It was interesting to note that there was a close similarity (f2=80.6) between the release profiles at dip speed 5 dpm and paddle speed 100 rpm. In addition, the release rate was reduced significantly with the increase in acid-soluble Eudragit E coating levels, but lactulose loading showed only a negligible effect. In conclusion, the established reciprocating cylinder method at lower agitation rates can give release profiles equivalent to those for the paddle procedure for CODES™ drug pH-gradient release testing. Apparatus III was demonstrated to be more convenient and efficient than apparatus II by providing various programmable options in sampling times, agitation rates, and medium changes, which suggested that the apparatus II approach has better potential for in vitro evaluation of colon-specific drug delivery systems.
TL;DR: The impact of feed temperature variation and the conditions used to induce crystallization have been investigated, with respect to the physical form that is produced.
Abstract: Lactose solutions (20 g/100 mL) in distilled water were prepared and equilibrated at 25, 30, 40, and 50°C, then spray-dried using a Buchi 190 spray drier. The spraydrying variables were kept constant and were as described by Chidavaenzi et al, except for the feed rate, which was varied for each feed temperature to minimize fluctuations in the outlet temperature. The materials were collected and immediately desiccated over silica gel. Spray-drying is known to produce predominantly amorphous material because of rapid solidification. The detection and control of the amorphous portion of powdered material is of utmost importance, as different physical forms of materials have different physicochemical properties that give rise to significant differences in functionality when used in dosage forms. The influence of spray-drier feed concentration on the degree of crystallinity and the crystal form of lactose (β-lactose, anhydrous α-lactose, α-lactose monohydrate) has been described previously. It is known that the spray-drying process can be made to produce completely amorphous lactose particles. Furthermore, it is clear that the amorphous form is unstable and that it will revert to the crystalline form. In this work, the impact of feed temperature variation and the conditions used to induce crystallization have been investigated, with respect to the physical form that is produced. Crystallization of amorphous samples
TL;DR: In this article, a near infrared spectroscopic method was developed to determine drug content in a 20% (wt/wt) ibuprofen and spray-dried hydous lactose blend.
Abstract: A near infrared spectroscopic method was developed to determine drug content in a 20% (wt/wt) ibuprofen and spray-dried hydous lactose blend. A blending profile was obtained after blending for 0.5, 1, 3, 5, 10, and 20 minutes. Stream sampling was used to collect about 20 blend samples at each of the blending times from a laboratory scale V-blender. The samples collected were used to develop a near infrared calibration model. The calibration model was then used to determine the drug content of unknown samples from 2 validation blends. The validation blends were not included in the calibration model; they were used to evaluate the effectiveness of the calibration model. A total of 45 samples from the 2 validation blends were predicted by the near infrared calibration model and then analyzed by a validated UV spectrophotometric method. The root mean square error of prediction for the first validation blend was 5.69 mg/g and 3.30 mg/g for the samples from the second blend. A paired t test at the 95% confidence level did not indicate any differences between the drug content predicted by the near infrared spectroscopy (NIRS) method and the validated UV method for the 2 blends. The results show that the NIRS method could be developed while the blending profile is generated and used to thoroughly characterize a new formulation during development by analyzing a large number of samples. The new formulation could be transferred to a manufacturing plant with an NIRS method to facilitate blend uniformity analysis.
TL;DR: The results indicate that the combination of size exclusion fractionation with subsequent photon correlation spectroscopic particle size analysis and enzymatic PC assay can give both more detailed and more reliable insight into the particle size distribution of small liposomes than PCS alone.
Abstract: In this study, small liposomes obtained by high-pressure homogenization were fractionated according to their particle sizes by size exclusion chromatography (SEC). The subfractions were analyzed by photon correlation spectroscopy (PCS) as well as enzymatic phosphatidylcholine (PC) assay for their particle sizes and lipid contents, respectively. For small egg PC-liposomes, a size range of 15 nm to 60 nm was found, with 80% of the vesicles being smaller than 30 nm in size. This is in contradiction to a mean size of 85±32 nm as indicated by PCS without fractionation. The PCS technique appears to underestimate very small particles below 30 nm if (few) bigger particles are present. The PCS particle size analysis of unfractionated hydrogenated egg PC/cholesterol-liposomes (2:1, mole/mole) by PCS did not yield any significant results. On fractionation, however, a particle size range of 40 nm to 120 nm was determined in a reproducible manner. Our results indicate that the combination of size exclusion fractionation with subsequent photon correlation spectroscopic particle size analysis and enzymatic PC assay can give both more detailed and more reliable insight into the particle size distribution of small liposomes than PCS alone.
TL;DR: It can be inferred from the above results that MGK, an economical carrier, could be used for the dissolution enhancement of NM.
Abstract: This work examines the influence of modified gum karaya (MGK) on the oral bioavailability of a poorly water-soluble drug, nimodipine (NM), in comparison with that of gum karaya (GK). A cogrinding method was selected to prepare mixtures of NM and GK or MGK in a 1:9 ratio (NM:GK/MGK). Differential scanning calorimetry (DSC), Fourier transmission infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), solubility studies, and in vitro release studies were performed to characterize the properties of the cogrinding mixtures. No drug-carrier interactions were found, as confirmed by DSC and FT-IR studies. The XRD study revealed that the crystallinity of NM was identical in both the cogrinding mixtures and was decreased when compared to that of physical mixtures or pure NM. The in vitro release rate of NM from both cogrinding mixtures was significantly higher than that of physical mixtures or pure NM. The in vivo study revealed that the bioavailability of NM from pure drug was significantly lower when compared to the cogrinding mixtures. The oral bioavailability was found to be NM powder < cogrinding mixtures of NM and GK < cogrinding mixtures of NM and MGK < NM solution. It can be inferred from the above results that MGK, an economical carrier, could be used for the dissolution enhancement of NM.
TL;DR: This release was compared with those observed from solid drug particles as well as with dialysis experiments, and the efficacy of DSC was confirmed in studying the release from polymeric nanoparticulate systems compared with the “classical” release test by dialysis.
Abstract: The present work investigated the release of Flurbiprofen (FLU) from Eudragit RS100® (RS) and Eudragit RL100® (RL) nanosuspensions to a biological model membrane consisting of Dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV). This release was compared with those observed from solid drug particles as well as with dialysis experiments. Nanosuspensions were prepared by a modification of Quasi-Emulsion Solvent Diffusion technique. Drug release was monitored by the Differential Scanning Calorimetry (DSC). FLU dispersed in MLV affects the transition temperature (Tm) of DMPC liposomes, causing a shift towards lower values. The temperature shift is modulated by the drug fraction present in the aqueous lipid bilayer suspension. DSC was also performed, after increasing incubation periods at 37°C, on suspensions of blank liposomes added to fixed amounts of unloaded and FLU-loaded nanosuspensions, as well as to powdered free drug. Tm shifts, caused by the drug released from the polymeric system or by free-drug dissolution during incubation cycles, were compared with those caused by free drug increasing molar fractions dispersed directly in the membrane during their preparation. These results were compared with the drug release and were followed by a classical dialysis technique. Comparing the suitability of the 2 different techniques in order to follow the drug release as well as the differences between the 2 RL and RS polymer systems, it is possible to confirm the efficacy of DSC in studying the release from polymeric nanoparticulate systems compared with the “classical” release test by dialysis. The different rate of kinetic release could be due to void liposomes, which represent a better uptaking system than aqueous solution in dialysis experiments.
TL;DR: In this paper, the authors compared the behavior of some drug/carrageenan complexes having different solubility in water, in a controlled release formulation, and the results were related to their performance in controlled release formulations.
Abstract: The purpose of the present work was to compare the behavior of some drug/carrageenan complexes having different solubility in water, in a controlled release formulation. Diltiazem HCl, bupropion HCl, metoprolol tartrate, and tramadol HCl were used as model drugs. The complexes were characterized by means of solubility measurements, release test at constant surface area, and water uptake measurements, and the results were related to their performance in controlled release formulations. For the more soluble complexes (involving metoprolol and tramadol) the occurrence of gelation after hydration was observed, while diltiazem complex apparently did not gellify; bupropion behavior was intermediate. A correspondence was found between the observed differences in complex solubility and hydration-gelation behavior and the drug release profiles. For all the drugs considered, the release was completed in about 10 to 12 hours, but different kinetics were observed depending on the solubility of the complexes. All the considered complexes seem suitable for controlled release purposes, although the data obtained show the relevance of the complex solubility to drug release profiles.
TL;DR: Ibuprofen spheres with very good physical characteristics were developed using the rotor disk fluid-bed technology, a 1-step closed process that did not require additional unit processes, and to scale up the batch spheronization process.
Abstract: The aim of this study was to develop spheronized microparticulates as a drug delivery system using the 1-step closed rotor disk fluid-bed technology, and to scale up the batch spheronization process. Ibuprofen was used as the model drug and microcrystalline cellulose/sodium carboxymethyl cellulose hydrocolloid (Avicel® RC-581 or CL-611) was present as the diluent/binder. The mixture, in 1∶1 ratio, was blended with and without 1% sodium lauryl sulfate (SLS) and spheronized with the rotor disk insert, using either water or hydroxypropylmethyl cellulose (HPMC) as binder. Fluid-bed machines (Vector/Freund Flo-Coater model) FLM-1 (with 9-inch rotor insert for 0.75 kg) and FLM-15 (with a 12-inch and 19-inch rotor inserts for 1 kg and 5, 10 kg, respectively) were used. The critical process parameters included inlet air temperature, rotor disk speed and configuration, air flow, and rate of binder application. The 1 kg batch containing SLS that was made with 12-inch smooth stainless, steel or waffle teflon plates rotating at 500 rpm had desirable characteristics. The sphericity values were 0.88 and 0.91, with percent yield of 85.4 and 91.2 and drug content values of 94.47% and 91.44%, respectively. The spheroids showed good flow properties with respective rapid drug release (Q20=83.27 and 91.75). No difference was seen in the Avicel RC-581 and CL-611. Based on the 1 kg data, Avicel RC-581 and smooth stainless steel and waffle teflon plates (12 inch and 19 inch), the batch was scaled up to 5 and 10 kg. The scale-up parameters included rotor speed (124–300 rpm) and spray rate (90–140 g/min). The scale-up batches had similar flow characteristics, release rate, and size distribution. The geometric mean diameter increased as batch size increased, and slightly bigger spheroids were obtained using the waffle teflon plate. Ibuprofen spheres with very good physical characteristics were developed using the rotor disk fluid-bed technology, a 1-step closed process that did not require additional unit processes.