Search

Glaucoma, a leading cause of blindness due to elevated intraocular pressure (IOP), is managed with medications like latanoprost (LAT), a prostaglandin analogue, to enhance aqueous outflow. Despite the challenge posed by eye anatomy and tear dynamics, effective ocular bioavailability via topical administration remains elusive. This study aims to optimize self-assembled nanomicelles incorporating LAT, an anti-glaucoma drug, belonging to BCS Class II (low solubility and high permeability) via a two-level, two-factor full factorial design, the nanomicelles were formulated via direct dissolution method and validated using design of expert. The optimized nanomicelles exhibited a spherical morphology, with a size of 69 nm and encapsulation efficiency of 77.5%, demonstrating a sustained LAT release over 12 h. In normotensive rabbits, the nanomicelles elicited a substantial reduction in intraocular pressure (IOP) by up to 40% for a duration of three days, that was significantly longer than the IOP-lowering efficacy of XALATAN eye drops (24 h). These findings indicated that self-assembled nanomicelles hold promise for enhancing the ocular bioavailability and extending the therapeutic duration of LAT, while providing the physical stability., (© 2024. The Author(s).)

Nanoparticles have numerous applications as drug carriers in drug delivery. The aim of the study was to produce tamoxifen nanoparticles with a defined size and higher encapsulation for efficient tissue uptake with controlled drug release. The quality by design approach was utilized to produce tamoxifen-loaded Eudragit nanoparticles by identifying the significant process variables using the nanoprecipitation method. The process variables (amount of drug, polymer, and surfactant) were altered to analyze the influence on particle size (PS), % encapsulation efficiency (EE). The results showed that the drug and polymer individually as well as collectively have an impact on PS, while the surfactant has no impact on the PS. The %EE was influenced by the surfactant individually and in interaction with the drug. The linear regression model was endorsed to fit the data showing high R 2 values (PS, 0.9146, %EE, 0.9070) and low p values (PS, 0.0004, EE, 0.0005). The PS and EE were confirmed to be 178 nm and 90%, respectively. The nanoparticles were of spherical shape, as confirmed by SEM and TEM. The FTIR confirmed the absence of any incompatibility among the ingredients. The TGA confirmed that the NPs were thermally stable. The in vitro release predicted that the drug release followed Higuchi model.

A modified method to determine protein encapsulation efficiency in polymer matrices has been developed and applied to two proteins and two polymers to demonstrate its wide range of applicability. This study was pursued due to the wide variation in reported protein encapsulation efficiency of polymer-based microcapsules, even when the protein, the polymer, and the microcapsule manufacturing method were consistent. Hemoglobin (Hb) and bovine serum albumin (BSA) were chosen as model proteins and ethylcellulose and poly(lactic-co-glycolic acid) (PLGA) as model polymers. The polymer of the microcapsule was dissolved in dichloromethane/ethanol or dichloromethane/ethyl acetate for ethylcellulose or PLGA microcapsules, respectively. Liberated proteins were simultaneously precipitated, pelleted by centrifugation, isolated by decanting the polymer solution, redissolved in 10% w/v sodium dodecyl sulfate in 0.8 N sodium hydroxide, and quantified using a modified Lowry assay. Blank microcapsules and exogenously added proteins demonstrated ≥ 93.8% recovery of proteins. The mean encapsulation efficiency of ethylcellulose or PLGA microcapsules was 52.4 or 76.9% for Hb and 86.4 or 74.7% for BSA, respectively. This demonstrates the effective use of centrifugation and the importance of an appropriate cosolvent system in the measure of encapsulation efficiency where one solvent dissolves the polymer while the other solvent quantitatively precipitates the liberated protein. It is evident that an alkaline solution of sodium dodecyl sulfate is efficient at quantitatively dissolving precipitated proteins. Remediation of problems observed with current methods and high reproducibility suggest that this modified method is generally applicable to the measure of protein encapsulation efficiency of polymer microcapsules.

The objective was to use caffeine and Soluplus® to improve the dissolution rate and to maintain a concentration of BCS Class II rosuvastatin calcium that exceeds its solubility. Caffeine and Soluplus® together substantially improved the dissolution rate and the extent of rosuvastatin release. Formulations for direct compression tablets included Formulation F1, a control with drug but with neither caffeine nor Soluplus® present; F2 with drug-caffeine complex; F3 with drug and Soluplus® and F4 with drug-caffeine complex and Soluplus®. Each formulation blend provided satisfactory flow properties. Tablets were comparable in mass, hardness and friability. A marked decrease in disintegration time occurred when the hydrotropic or micellar agent was included in the formulation. Assay (98-100%) and content uniformity (99-100%) results met requirements. Release studies in pH 1.2, 6.6, and 6.8 buffers revealed the superiority of F4. At 45 min sampling time, F3 and F4 tablets each provided a cumulative drug release greater than 70% in each medium. F2 tablets exhibited compliance to official standards in pH 6.6 and 6.8 buffers but not in pH 1.2 buffer, whereas tablets based on F1 failed in each medium. Two-factor ANOVA of the release data revealed a statistical difference across the four formulations in each release medium. Pairwise comparison of release profiles demonstrated that, of the four formulations, F4 provided the most effectively enhanced dissolution rate, improvement to the extent of drug release and support of a concentration higher than the solubility of rosuvastatin calcium.

Objective: Fine particle ethylcellulose (FPEC) or poly(ethylene oxide) (PEO) addition to a Kollidon CL-SF was investigated to address low yield and poor sphericity in extruded-spheronized pellets., Significance: The success of crospovidone as a diluent in extrusion-spheronization was dependent on a small particle size of the polymer. FPEC aided production of rugged and spherical pellets using a large particle size grade, Polyplasdone ® XL. PEO acted as an extrusion-spheronization aid when ethylcellulose was the diluent. These extrusion-spheronization aids could serve in this role when Kollidon ® CL-SF (K CL-SF) is the diluent., Methods: The influence of formulation and process variables on pellet properties was investigated using design of experiments. A planetary mixer was used to prepare powder blends and the wetted mass after addition of water. An EXD 60 extruder produced extrudate that was spheronized in a Q230 marumerizer. Wet pellets were dried in a forced-air oven., Results: FPEC improved rounding up but reduced pellet yield. Poly(ethylene oxide) imparted desired characteristics to the wetted mass, the extrudate, and the spheronized pellets. Pellet average diameter, yield, sphericity, aspect ratio, friability, and dissolution profile were assessed. Equations for pellet characteristics facilitated discussion of the influences of factors and their interactions. Optimization was performed on pellets that included PEO., Conclusions: PEO proved to be an exceptional extrusion-spheronization aid in the preparation of pellets using K CL-SF. It facilitated wetted mass extrusion with minimal mass loss to the extruder, and markedly improved the sphericity of the pellets produced by marumerization. Immediate release pellets were obtained.

Certain issues with the use of particles of chitosan (Ch) cross-linked with tripolyphosphate (TPP) in sustained release formulations include inefficient drug loading, burst drug release, and incomplete drug release. Acetaminophen was added to Ch:TPP particles to test for advantages of drug addition extragranularly over drug addition made during cross-linking. The influences of Ch concentration, Ch:TPP ratio, temperature, ionic strength, and pH were assessed. Design of experiments allowed identification of factors and 2-factor interactions that have significant effects on average particle size and size distribution, yield, zeta potential, and true density of the particles, as well as drug release from the directly compressed tablets. Statistical model equations directed production of a control batch that minimized span, maximized yield, and targeted a t 50 of 90 min (sample A); sample B that differed by targeting a t 50 of 240-300 min to provide sustained release; and sample C that differed from sample B by maximizing span. Sample B maximized yield and provided its targeted t 50 and the smallest average particle size, with the higher zeta potential and the lower span of samples B and C. Extragranular addition of a drug to Ch:TPP particles achieved 100% drug loading, eliminated a burst drug release, and can accomplish complete drug release., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the physicochemical and in vitro characteristics of solid dispersions using BCS II model drugs with Soluplus® and one of its component homopolymers, PEG 6000., Methods: Nifedipine (NIF) and sulfamethoxazole (SMX) of 99.3% and 99.5% purity, respectively, were selected as BCS II model drugs, such that an improved dissolution rate and concentration in the gastrointestinal tract should increase oral bioavailability. Soluplus® is an amorphous, tri-block, graft co-polymer with polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol (PCL:PVAc:PEG6000) in the ratio 57:30:13. PEG 6000 (BASF) is a waxy material with melting point of about 60 °C. Solid dispersions were prepared using lyophilization or spray drying techniques. Dissolution study, crystallinity content, and analysis for new chemical bond formation have been used to evaluate the dispersed materials., Results: Although each polymer improved the drug dissolution rate, dissolution from Soluplus® was slower. Enhanced dissolution rates were observed with NIF solid dispersions, but the dissolution profiles were quite different due to the selected technique, polymer, and dissolution medium. For SMX, there was similarity across the dissolution profiles despite the medium, polymer, or applied technique. Each polymer was able to maintain an elevated drug concentration over the three hour duration of the dissolution profile, i.e., supersaturation was supported by the polymer. DSC thermograms revealed no melting endotherm, suggesting that the drug is amorphous or molecularly dispersed., Conclusion: NIF and SMX solid dispersions were successfully prepared by spray drying and lyophilization using Soluplus® or PEG 6000. Each polymer enhanced the drug dissolution rate; NIF dissolution rate was improved to a greater extent. Dispersions with PEG 6000 had a faster dissolution rate due to its hydrophilic nature. DSC analysis showed that no crystalline material exists in the dispersions.

The search for excipients to replace microcrystalline cellulose (MCC) in the production of pellets by extrusion-spheronization in cases of drug incompatibility or the lack of pellet matrix disintegration forms the basis of this study. A combination of к-carrageenan as a spheronization aid, chitosan as a diluent and Carbopol(®) 974P as a binder in the production of pellets containing no MCC has been investigated using acetaminophen as a model drug. Design of experiments allowed assessment of formulation and processing effects on pellet responses that included size, shape, fines, yield and friability. Statistical analysis revealed that the main factors and some of the two-factor interactions had a significant effect on pellet characteristics. Formulations containing high levels of к-carrageenan required more water to produce a wetted mass with good extrudability and extrudate capable of being spheronized. Although only a low level of Carbopol was used in the formulation, it imparted cohesiveness to the wetted mass as well as the extrudate. Furthermore, it was discovered that Carbopol could act as an extrusion aid, enabling the wetted mass to flow easily through the extruder screen holes without building up heat. Spherical and rugged pellets were produced that met the immediate release criterion.

Successful pellet production has been reported in literature with cross-linked poly(vinylpyrrolidone), Polyplasdone® XL-10 and INF-10. In the present study, a quality by experimental design approach was used to assess several formulation and process parameter effects on the characteristics of Polyplasdone® XL-10 pellets, including pellet size, shape, yield, usable yield, friability, and number of fines. The hypothesis is that design of experiments and appropriate data analysis allow optimization of the Polyplasdone product. High drug loading was achieved using caffeine, a moderately soluble drug to allow in vitro release studies. A five-factor, two-level, half-fractional factorial design (Resolution V) with center point batches allowed mathematical modeling of the influence of the factors and their two-factor interactions on five of the responses. The five factors were Polyplasdone® level in the powder blend, volume of water in the wet massing step, wet mixing time, spheronizer speed, and spheronization time. Each factor and/or its two-factor interaction with another factor influenced pellet characteristics. The behavior of these materials under various processing conditions and component levels during extrusion-spheronization have been assessed, discussed, and explained based on the results. Numerical optimization with a desirability of 0.974 was possible because curvature and lack of fit were not significant with any of the model equations. The values predicted by the optimization described well the observed responses. The hypothesis was thus supported.

Context: Drug dispersed in a polymer can improve bioavailability; dispersed amorphous drug undergoes recrystallization. Solid solutions eliminate amorphous regions, but require a measure of the solubility., Objective: Use the Flory-Huggins Theory to predict crystalline drugs solubility in the triblock, graft copolymer Soluplus® to provide a solid solution., Materials and Methods: Physical mixtures of the two drugs with similar melting points but different glass forming ability, sulfamethoxazole and nifedipine, were prepared with Soluplus® using a quick technique. Drug melting point depression (MPD) was measured using differential scanning calorimetry. The Flory-Huggins Theory allowed: (1) interaction parameter, χ, calculation using MPD data to provide a measure of drug-polymer interaction strength and (2) estimation of the free energy of mixing. A phase diagram was constructed with the MPD data and glass transition temperature (T g ) curves., Results: The interaction parameters with Soluplus® and the free energy of mixing were estimated. Drug solubility was calculated by the intersection of solubility equations and that of MPD and T g curves in the phase diagram., Discussion: Negative interaction parameters indicated strong drug-polymer interactions. The phase diagram and solubility equations provided comparable solubility estimates for each drug in Soluplus®. Results using the onset of melting rather than the end of melting support the use of the onset of melting., Conclusion: The Flory-Huggins Theory indicates that Soluplus® interacts effectively with each drug, making solid solution formation feasible. The predicted solubility of the drugs in Soluplus® compared favorably across the methods and supports the use of the onset of melting.

Context: Drug dispersed in a polymer can improve bioavailability; dispersed amorphous drug undergoes recrystallization. Solid solutions eliminate amorphous regions, but require a measure of the solubility., Objective: Use the Flory-Huggins Theory to predict crystalline drugs solubility in the triblock, graft copolymer Soluplus® to provide a solid solution., Materials and Methods: Physical mixtures of the two drugs with similar melting points but different glass forming ability, sulfamethoxazole and nifedipine, were prepared with Soluplus® using a quick technique. Drug melting point depression (MPD) was measured using differential scanning calorimetry. The Flory-Huggins Theory allowed: (1) interaction parameter, χ, calculation using MPD data to provide a measure of drug-polymer interaction strength and (2) estimation of the free energy of mixing. A phase diagram was constructed with the MPD data and glass transition temperature (Tg) curves., Results: The interaction parameters with Soluplus® and the free energy of mixing were estimated. Drug solubility was calculated by the intersection of solubility equations and that of MPD and Tg curves in the phase diagram., Discussion: Negative interaction parameters indicated strong drug-polymer interactions. The phase diagram and solubility equations provided comparable solubility estimates for each drug in Soluplus®. Results using the onset of melting rather than the end of melting support the use of the onset of melting., Conclusion: The Flory-Huggins Theory indicates that Soluplus® interacts effectively with each drug, making solid solution formation feasible. The predicted solubility of the drugs in Soluplus® compared favorably across the methods and supports the use of the onset of melting.

Polyplasdone of different particle size was used to study the sorption, desorption, and distribution of water, and to seek evidence that larger particles can internalize water. The three samples were Polyplasdone® XL, XL-10, and INF-10. Moisture sorption and desorption isotherms at 25 °C at 5% intervals from 0 to 95% relative humidity (RH) were generated by dynamic vapor sorption analysis. The three products provided similar data, judged to be Type III with a small hysteresis that appears when RH is below 65%. An absent rounded knee in the sorption curve suggests that multilayers form before the monolayer is completed. The hysteresis indicates that internally absorbed moisture is trapped as the water is desorbed and the polymer sample shrinks, thus requiring a lower level of RH to continue desorption. The fit of the Guggenheim-Anderson-de Boer (GAB) and the Young and Nelson equations was accomplished in the data analysis. The W(m), C(G), and K values from GAB analysis are similar across the three samples, revealing 0.962 water molecules per repeating unit in the monolayer. A small amount of absorbed water is identified, but this is consistent across the three particle sizes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The effect of small ethylcellulose particle size on the manufacture and properties of pellets produced by extrusion-spheronization was investigated. A factorial design revealed the effects of microcrystalline cellulose (MCC), polyethylene oxide (PEO), water, and spheronization speed and time on pellet properties. Response surface modeling allowed optimization of the responses with expansion to a central composite design. Pellet yield, size, shape, friability and drug release profile were studied, along with surface and interior morphology. Pellets were spherical irrespective of the formulation and process variables and exhibited physical and mechanical characteristics appropriate for further processing. Yield in the 12/20 mesh cut was lower with FPEC than observed with coarse particle ethylcellulose (CPEC), but FPEC-containing pellets were more rugged and the PEO to obtain optimal pellets was lower for FPEC compared to CPEC. Immediate release products were obtained and ethylcellulose particle size was of no consequence to drug release. Observed responses for the optimized product agreed with predicted values, demonstrating the success of the optimization procedure. These results suggest that FPEC is a good diluent for extrusion-spheronization.

The ability of crospovidone to take up and distribute water in the polymer samples was studied using differential scanning calorimetry (DSC). Polyplasdone(®) is an example of crospovidone that, although insoluble in water, serves as a superdisintegrant. Three samples of Polyplasdone(®) with different mean particle size were studied to see the effect of particle size on the water uptake and distribution characteristics. Water was shown to plasticize Polyplasdone(®) samples by a reduction in the glass transition temperature as the water content was increased. Although the particle sizes covered a wide range, there was essentially no difference in the ability to take up or distribute water. Three types of water were observed, namely water closely associated with the polymer, water built up as multilayers, and bulk water. Although the water closely associated with the polymer could not be detected by DSC, it could be calculated by mass balance and by extrapolation of the data to the x-axis in a plot of freezable water content as a function of the actual water content. A split in the melting endotherm of water that freezes supported the premise of two forms of freezable water. The number of water molecules per repeating unit could be calculated., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Hydralazine hydrochloride is an antihypertensive used alone or in combination with isosorbide nitrate for the treatment of congestive heart failure. Since control of blood pressure should be continuous, sustained release delivery of this drug is considered therapeutically beneficial. Core beads for oral administration of this drug were prepared by extrusion-spheronization. Using experimental design to define the coat that was applied, the core beads were coated using a fluid bed coater to different coat thickness with combinations of two commercially available products dissolved in a hydroalcoholic solvent. The coat is a film with a combination of ethylcellulose and hydroxypropylcellulose that can provide desirable release profiles. Visually spherical and rugged bead products were obtained. Two products were identified that exhibited essentially a zero order release profile following a 2-h lag time with release of greater than 70% of the drug over the next 10 h in simulated intestinal fluid.

A multiparticulate product for colon-specific delivery of a small molecule drug has been developed and characterized. Microcrystalline cellulose core beads containing 5-aminosalicylic acid produced by extrusion-spheronization were coated with chitosan and Aquacoat(®) ECD mixtures according to a factorial design. Coated beads were characterized in terms of drug release, shape, and friability. The optimum formulation was enteric coated and exposed to media simulating conditions in the stomach, small intestine, and colon. Release studies in simulated intestinal fluid revealed that the drug release rate from the coated beads, which were spherical and rugged, depended on the level of chitosan in the coat and the coat thickness. Enlarged pores observed on the surface of the coated beads exposed to the medium containing rat cecal and colonic enzymes are believed to have caused a significant enhancement of the drug release rate compared to the control exposed only to simulated gastric and intestinal fluids. The release mechanisms involved polymer relaxation and dissolved drug diffusion for simulated intestinal fluid and simulated colonic fluid, respectively. From the facilitated drug release in a colonic environment and the inhibition of drug release under gastric and intestinal conditions, it can be concluded that this multiparticulate system demonstrates the potential for colon-specific drug delivery., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The present research investigates the enhancement of the dissolution rate of celecoxib by using spray-drying to prepare a solid dispersion with various polymers, namely Kollicoat IR® (Kollicoat), polyvinyl alcohol (PVA) 22000, or polyethylene glycol 6000 (PEG). The investigated drug-to-polymer mass ratios were 1:1, 1:2, and 1:4 by weight. Hydroalcoholic or methylene chloride solvent systems were used. The obtained yields ranged from 65% to 78%, whereas the entrapment efficiencies were between 68% and 82%. The results revealed an increase in the dissolution rate of the prepared particles up to 200% within 20 min. The prepared particles were investigated using differential scanning calorimetry, scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The increased dissolution rate was attributed to hydrogen bond formation between celecoxib and each polymer together with the reduced size of the formed particles offering a greater overall surface area. It was concluded that spray-drying may be considered a successful one-step technique to improve the dissolution rate of celecoxib when using Kollicoat, PVA, or PEG as the carrier polymer.

Background: This study investigates a new means to achieve colon-specific drug delivery., Objective: This study assesses the use of chitosan and ethylcellulose in the coat of a compression-coated tablet to achieve colon-specific drug delivery. The effects of chitosan type and its level as well as the coat thickness were evaluated., Materials and Methods: Caffeine-containing core tablets were prepared by direct compression. Three chitosan samples with different molecular weight and degree of deacetylation were used. Direct compression produced the finished coated tablet. The product was tested for its potential in colon-specific drug delivery by conducting release studies in simulated gastric and intestinal fluids. Enzymes harvested from rat cecal and colonic contents contributed to a medium to study drug release under colonic conditions., Results: Essentially no drug was released until action on the tablet by either the acidic pH or the presence of enzymes in the release medium. Chitosan type had no effect on drug release as long as the coating level was the same. Lowering the chitosan level in the coat or increasing the coat thickness increased the lag time., Discussion: The type of chitosan can be changed and yet the product is still susceptible to enzyme or pH effects. This indicates that chitosan present in the coat is still available for such action by the release medium. One can control the chitosan level or the thickness of the coat to achieve a desired delivery profile., Conclusion: As colonic media can dramatically promote drug release, the potential for colon-specific drug delivery is confirmed.

Introduction: Developments in industrial pharmacy are often linked to the discovery of pharmaceutical excipients. Although recently introduced as a material for immediate release coatings, Kollicoat IR already has other applications., Areas Covered: In this review, the different properties and pharmaceutical applications of Kollicoat IR as an excipient are discussed. In the first part, the chemical structure and the physicochemical characteristics are examined. The second part is a presentation of the available Kollicoat IR products followed by a brief overview of the preclinical studies completed for its use as an instant release coating material., Expert Opinion: Although the polymer was intended as an immediate release coating material for tablets, grafting PEG with polyvinyl alcohol to form this polymer provides physicochemical properties that lead to ever-broadening applications. Understanding its properties can lead to the development of a new use for Kollicoat IR. The addition of Kollicoat IR to an ethylcellulose or polyvinyl acetate tablet coat was successful at modifying the drug release rate. Designing a successful controlled release coat simply requires acknowledgment of the drug release mechanism from the mixture of polymers that includes Kollicoat IR. Moreover, the interaction between Kollicoat IR and poorly soluble drugs produces fast-dissolving solid dispersions prepared using hot stage extrusion, spray drying, or freeze drying.

The aim of this study was to investigate human erythrocytes as a carrier for targeted drug delivery of primaquine (PQ). The process of PQ loading in human erythrocytes, as well as the effect of PQ loading on the oxidative status of erythrocytes, was also studied. At PQ concentrations of 2, 4, 6, and 8 mg/mL and an incubation time of 2 h, the ratios of the concentrations of PQ entrapped in erythrocytes to that in the incubation medium were 0.515, 0.688, 0.697 and 0.788, respectively. The maximal decline of erythrocyte reduced glutathione content was observed at 8 mg/mL of PQ compared with native erythrocytes p < 0.001. In contrast, malondialdehyde and protein carbonyl were significantly increased in cells loaded with PQ (p < 0.001). Furthermore, osmotic fragility of PQ carrier erythrocytes was increased in comparison with unloaded cells. Electron microscopy revealed spherocyte formation with PQ carrier erythrocytes. PQ-loaded cells showed sustained drug release over a 48 h period. Erythrocytes were loaded with PQ successfully, but there were some biochemical as well as physiological changes that resulted from the effect of PQ on the oxidative status of drug-loaded erythrocytes. These changes may result in favorable targeting of PQ-loaded cells to reticulo-endothelial organs. The relative impact of these changes remains to be explored in ongoing animal studies.

Poly(vinylpyrrolidone) (PVP) hydrogels were crosslinked by gamma irradiation to add structure and rigidity, and then rheological and mucoadhesive properties were evaluated. The effects of PVP concentration, radiation dose, and additives, such as poly(ethylene glycol) (PEG) and glycerol, on rheological properties were investigated. In an oscillatory analysis, an increase in polymer concentrations increased the storage modulus (G') and the loss modulus (G″) but decreased the loss tangent (tan δ < 1). The relationships between G'or G″ and the frequency levelled off at higher frequencies, which is indicative of polymer chain entanglement and network formation. Each of the 6% PVP hydrogels exhibited plastic flow with rheopectic behavior. PVP concentration, radiation dose, and the presence of PEG or glycerol influenced the rheological and mucoadhesive properties of the hydrogels. However, adding acyclovir to the formulation did not have a profound effect on the rheological behavior of the hydrogels. The results suggest that a 3% PVP hydrogel with 1% PEG crosslinked with 20 kGy is the most appropriate hydrogel. The results demonstrated the successful complementary application of oscillatory and flow rheometry to characterize and develop a hydrogel for mucosal drug administration.

The objectives were to characterize propranolol hydrochloride-loaded matrix tablets using guar gum, xanthan gum, and hydroxypropylmethylcellulose (HPMC) as rate-retarding polymers. Tablets were prepared by wet granulation using these polymers alone and in combination, and physical properties of the granules and tablets were studied. Drug release was evaluated in simulated gastric and intestinal media. Rugged tablets with appropriate physical properties were obtained. Empirical and semi-empirical models were fit to release data to elucidate release mechanisms. Guar gum alone was unable to control drug release until a 1:3 drug/gum ratio, where the release pattern matched a Higuchi profile. Matrix tablets incorporating HPMC provided near zero-order release over 12 h and erosion was a contributing mechanism. Combinations of HPMC with guar or xanthan gum resulted in a Higuchi release profile, revealing the dominance of the high viscosity gel formed by HPMC. As the single rate-retarding polymer, xanthan gum retarded release over 24 h and the Higuchi model best fit the data. When mixed with guar gum, at 10% or 20% xanthan levels, xanthan gum was unable to control release. However, tablets containing 30% guar gum and 30% xanthan gum behaved as if xanthan gum was the sole rate-retarding gum and drug was released by Fickian diffusion. Release profiles from certain tablets match 12-h literature profiles and the 24-h profile of Inderal(®) LA. The results confirm that guar gum, xanthan gum, and HPMC can be used for the successful preparation of sustained release oral propranolol hydrochoride tablets., (© 2010 American Association of Pharmaceutical Scientists)

The aim of this work was to study the ability of beta-cyclodextrin (beta-CD) or hydroxypropyl beta-cyclodextrin (HP-beta-CD) to ameliorate the induction of gastric ulcers by a nonsteroidal anti-inflammatory drug, indomethacin or piroxicam, in rats exposed to restraint and hypothermic stress at 4 degrees C. Using oral gavage, rats fasted for 72 h were administered the equivalent of a 100 mg/kg dose of the assigned drug, alone or with the designated cyclodextrin (CD). The rats were placed in suitable rodent restrainers and then placed inside a ventilated refrigerator maintained at a temperature of 4 degrees C. Six hours later, each animal was removed, anaesthetized with ether, and the abdomen opened. Each stomach was removed, opened along the greater curvature and gently rinsed with isotonic saline solution. The induced gastric ulcers were examined and assessed with the help of a 10x binocular magnifier. Pronounced and marked gastric ulceration with complete loss of the mucosa, extensive deposition of fibrin and dense neutrophilic infiltrate were observed in rats treated with each of the drugs alone. Treatment with indomethacin or piroxicam alone induced ulcer indices of 26 +/- 2.3 or 14 +/- 1.8, respectively. However, beta-CD and HP-beta-CD each significantly suppressed ulceration due to restraint and cold stress. Rats treated with indomethacin or piroxicam in the presence of either beta-CD or HP-beta-CD exhibited normal tissues. Therefore, beta-CD and HP-beta-CD act as protective agents against gastrointestinal disorders produced by restraint and cold stress, even with the added stress from administration of either indomethacin or piroxicam.

Itraconazole (ITZ) solid complex using hydroxypropyl-beta-cyclodextrin (ITZ-HP-beta-CD) with 20% polyvinylpyrrolidone was prepared by a co-evaporation method. The complex improved antifungal activity against C. parapasilosis and C. albicans. The complex demonstrated good flow and compressibility characteristics. The complex was formulated as a capsule dosage form and drug release was evaluated. Capsules containing ITZ-HP-beta-CD at a molar ratio of 1:3 with 20% polyvinylpyrrolidone have a faster dissolution rate than commercial capsules (Sporanox). About 88% of ITZ was released in less than 30 min and the initial dissolution rate exhibited a 3.5-fold increase compared to the commercial product. UV spectrophotometeric, HPLC, and antimicrobial methods were used to determine ITZ concentration in the release medium and the results obtained by these methods are reported. It was found that HPLC analysis is a suitable and reliable method for determination of the drug concentration with a coefficient of variation less than 10%. The intraday precision showed a coefficient of variation less than 3.96%, and that for interday was less than 4.99%. The HPLC method was more accurate and precise than the antimicrobial and UV-spectrophotometric methods for determination of ITZ concentration present in the release medium.

This study evaluated the potential of coarse ethylcellulose (CPEC) and high molecular weight polyethylene oxide (PEO) as excipients in the production of beads by extrusion-spheronization. CPEC was investigated as a diluent and PEO as an extrusion aid and a binder. Beads were manufactured with caffeine as a model drug. Release studies were conducted, and the bead size, shape, yield, and friability were determined. The effects of formulation and process variables and their interactions were studied by a sequential experimental design based on a response surface method. In the initial stage, a two level half fractional factorial design was employed as a screening design, which was subsequently augmented to a central composite design. Statistical analysis indicated that formulation variables including PEO content, microcrystalline cellulose (MCC) content, and water content, and two process variables, namely spheronizer speed and spheronization time, significantly affected the properties of the beads. Interactions between two factors have significant effects on several of the measured responses. Simultaneous optimization of the responses was conducted and validated by performing experiments at the optimal conditions. Overall, the results confirmed that immediate release, spherical beads with low friability and narrow size distribution could be produced with minimal amounts of MCC., (2009 Elsevier B.V. All rights reserved.)

Characteristics of Carbopol-containing pellets have been shown to be dependent on the form of the weakly basic drug, propranolol, when the drug forms are fixed as masses in the formulations. To further investigate the effect of the drug forms on pellet and drug release characteristics, the drug forms were incorporated as a fixed number of moles in the formulation. Forms of propranolol, viz. the free base and the hydrochloride and maleate salt forms, resulted in different yield, roundness, smoothness, and friability, but the average pellet diameter was not affected. The free base form was released more slowly than the other two forms. Mathematical analysis of the release data revealed that Fickian diffusion and polymer relaxation contributed to the release mechanism in each case, although polymer relaxation was more influential with the free base form.

Drug release rates from extruded-spheronized beads containing Carbopol have been shown to be dependent on the chemical nature of different types of drugs. To further clarify solubility, salt counterion, pH, and ionic strength effects on Carbopol bead characteristics, including but not limited to the drug release profile, the present study utilizes propranolol in its free base, hydrochloride, and maleate forms. Different forms of propranolol resulted in different bead average diameter, roundness, and smoothness, but the ruggedness was not affected. Release profiles for the two salt forms were nearly superimposable, but the free base form was released more slowly. Mathematical analysis of the release data revealed that Fickian diffusion and polymer relaxation were contributing factors to the release mechanism in each case, although polymer relaxation was more influential with the free base form. In light of these results, the choice of the form of a drug should be considered carefully when preparing Carbopol-containing beads produced by extrusion-spheronization.

The purpose of the study was to explore the utilization of Carbopol 974P, NF, resin in a bead dosage form manufactured by extrusion and spheronization. It was possible to prepare beads in this study by using calcium chloride to overcome the tack problem associated with wetted Carbopol 974P. The actives included both salts of weakly basic drugs (chlorpheniramine maleate and diphenhydramine hydrochloride) and nonelectrolytes (caffeine and dyphylline) which have a broad range of solubilities. Nonelectrolytes were released faster than the salts of weakly basic drugs. This is contrary to the behavior typically seen with a matrix system where the more soluble drug is released faster than a poorly soluble one. In the results of the present study, the solubility does not determine the drug release rate. Ionic interactions between the protonated amines of the salts and the carboxylates of the Carbopol resin are suggested to be the reason for the slower release of the salts of weakly basic drugs. Data from tack measurements confirm that this ionic interaction affects the behavior of the wetted Carbopol. In addition to the drug release profiles, bead average diameter, roundness, friability, and density were also determined.

A means to produce extruded-spheronized beads, devoid of microcrystalline cellulose (MCC) and with a high drug load (greater than 80%, w/w), is presented. Immediate release bead product with a high yield (greater than 60% of 1mm diameter beads) and low friability (mass loss less than 4.0%) that were spherical to the naked eye (roundness score less than 1.20) were obtained. The formulation consists only of water-soluble components, taking advantage of the properties of soluble polyethylene oxide (PEO) and methoxypolyethylene glycol (MPEG). This approach incorporates minimal processing aids, with wetted PEO providing the apparent plasticity and cohesiveness, and MPEG550 providing the apparent self-lubricating characteristics necessary for successful extrusion and subsequent spheronization into beads. The success of this approach has important implications in cases where high drug load beads are desired, but where MCC cannot be used due to chemical incompatibility or where complete release cannot be achieved with MCC-containing beads.

The objective of the study was to assess and compare the interaction and distribution of water within microcrystalline cellulose (MCC) and chitosan by differential scanning calorimetry (DSC) and dynamic vapor sorption analysis. The amounts of nonfreezing and freezing water in hydrated samples were determined from melting endotherms obtained by DSC. After accounting for the percent crystallinity of MCC and chitosan, no statistically significant difference was observed in their ability to bind water molecules per repeating unit at the minimum water content at which freezing water is evident. Exposure of chitosan to water for 30 min was sufficient to achieve equilibration at 61% w/w actual water content. The moisture sorption profiles were analyzed according to the GAB and Young and Nelson equations. The adsorbed monolayer, externally adsorbed moisture, and internally absorbed moisture were not statistically different for MCC and chitosan after accounting for the amorphous content of the polymers. These studies suggest that chitosan can act as a "molecular sponge," and thus aid in the production of beads by extrusion and spheronization., (Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93: 1766-1779, 2004)

The influences of the pH, tripolyphosphate (TPP) concentration, and ionic strength of the gelling medium on the entrapment efficiency, release, and activity of lipase in chitosan hydrogel beads were studied. A solution of Candida rugosa lipase was prepared in a 1.5% w/v chitosan and 1% (v/v) acetic acid medium, and dropped into a TPP solution. Release of lipase in pH 7.2 Tris buffer was monitored over 36 h using the micro BCA protein assay. The activity of the entrapped enzyme was assayed using the Sigma lipase activity method. Following preliminary studies, an experimental design was followed to develop mathematical models that describe bead characteristics as functions of the pH and the TPP concentration in the gelling medium. The pH and the TPP concentration each had an effect on the entrapment, retention, and activity of lipase. Entrapped lipase retained a high degree of activity in multiple reactions. The ionic strength, in the range studied, exerted a minimal effect on bead characteristics. Statistical analysis allowed optimization within the factor space with respect to maximizing the enzyme entrapment efficiency and activity, and also minimizing the amount released after 36 h in the Tris buffer.

The purposes of this study were to investigate the use of chitosan in the manufacture of beads by extrusion-spheronization without inclusion of microcrystalline cellulose, and to study the effect of formulation and process variables on the characteristics of the beads. Beads containing chitosan, fine particle ethylcellulose, hydroxypropyl methylcellulose (HPMC), and caffeine as the model drug were manufactured. Bead size, yield, shape, friability, density, porosity, and release studies were determined. Spherical beads with good mechanical properties could be manufactured without microcrystalline cellulose. Release studies showed that there was immediate release of drug from the beads. A five factor, half fraction screening design was employed to study the effect of formulation variables and process variables on the properties of the beads. Statistical analysis indicated that formulation variables such as the chitosan content, HPMC content, and water content, and process variables such as the spheronizer speed and extruder speed significantly affected the physical properties of the beads. The bead size decreased with an increase in chitosan content. Significant two-factor interactions exist between the variables for several of the measured responses. Beads with high percentage yield and high sphericity can be obtained at high chitosan content, and low HPMC content, water content, spheronizer speed, and extruder speed. Less friable beads can be obtained at high levels of studied formulation variables and low levels of studied process variables. Beads of high density and low porosity can be manufactured at high levels of the studied formulation and process variables. Regression equations were generated using Statgraphics Plus software that can be used to develop formulations with desired bead properties. Chitosan was useful to provide beads of acceptable physical properties using water as a granulating fluid in the extrusion-spheronization process.

The purpose of this research was to investigate the interaction of water with ethylcellulose samples and assess the effect of particle size on the interaction. The distribution of water within coarse particle ethylcellulose (CPEC; average particle size 310 micro m) and fine particle ethylcellulose (FPEC; average particle size 9.7 micro m) of 7 cps viscosity grade was assessed by differential scanning calorimetry (DSC) and dynamic vapor sorption analysis. The amounts of nonfreezing and freezing water in hydrated samples were determined from melting endotherms obtained by DSC. An increase in water content resulted in an increase in the enthalpy of fusion of water for the two particle size fractions of EC. The amount of nonfreezable water was not affected by the change in particle size at low water contents. Exposure of ethylcellulose to water for 30 minutes is sufficient to achieve equilibration within the hydrated polymer at 47% wt/wt water content. The moisture sorption profiles were analyzed according to the Guggenheim-Anderson-de Boer (GAB) and Young and Nelson equations, which can help to distinguish moisture distribution in different physical forms. The amount of externally adsorbed moisture was greater in the case of FPEC. Internally absorbed moisture was evident only with the CPEC. In light of these results, an explanation is offered for the success of FPEC in wet-granulation methods where CPEC was not successful.

In the present study, the applicability of fine particle ethylcellulose (FPEC) to produce matrix tablets by a wet granulation technique was evaluated. The effect of various formulation and process variables, such as FPEC content, hardness of the tablet, and solubility of the drug, on the release of drug from these tablets was examined. Tablets were prepared by wet granulation of drug and FPEC in an appropriate mass ratio. Theophylline, caffeine, and dyphylline were selected as nonionizable model drugs with solubilities from 8.3 to 330 mg/mL at 25 degrees C. Ibuprofen, phenylpropanolamine hydrochloride, and pseudoephedrine hydrochloride were selected as ionizable drugs with solubilities from 0.1 to 2000 mg/mL at 25 degrees C. Drug release studies were conducted in 37 degrees C water with UV detection. As the FPEC content and the hardness of the tablets increased, the release rate of the drug decreased. The drug release rate increased with an increase in the solubility of the drug. Model equations, intended to elucidate the drug release mechanism, were fitted to the release data. Parameters were generated and data presented by SAS software. The Akaike Information Criterion was also considered to ascertain the best-fit equation. Fickian diffusion and polymer relaxation were the release mechanisms for nonionizable and ionizable drugs.

The purpose of this study was to immobilize lipase (triacylglycerol ester hydrolase, E.C. 3.1.1.3) from Candida rugosa using various polymers in the form of beads, to evaluate enzyme loading, leaching, and activity; and to characterize the beads. Agarose, alginate, and chitosan were the polymers selected to immobilize lipase by entrapment. Agarose beads exhibited undesirable swelling in the leaching and activity medium and the polymer was not used further. Alginate or chitosan beads were prepared by ionic gelation using calcium chloride or sodium tripolyphosphate, respectively, as the cross-linking agent in the gelling solution. Some hatches of beads of each polymer were freeze dried. The results show that alginate beads leached substantially more enzyme than did chitosan beads. Entrapment efficiency, however, was the same for different chitosan levels as well as different alginate levels (43-50%). Activity in alginate was low at 240 +/- 33 and 220 +/- 26, compared to 1,110 +/- 51 and 1,150 +/- 11 units/ml in chitosan, for fresh and freeze-dried beads, respectively. The higher lipase activity in chitosan beads compared to that in alginate beads could be attributed to an alginate-enzyme interaction. It can be concluded that chitosan is a polymer worthy of pursuit to immobilize lipase.

The effects of the molecular weight (MW) and degree of deacetylation (DD) of chitosan on chitosan hydrogel beads were characterized, and the entrapment efficiency, release of entrapped lipase, and activity of immobilized Candida rugosa lipase were investigated. Fresh and freeze-dried beads were characterized. A solution of lipase was prepared in a 1.5% (w/v) chitosan and 1% (v/v) acetic acid medium, and then dropped into a tripolyphosphate solution to prepare the beads. The release studies were performed over 36 h. The enzyme activity was assayed using the Sigma lipase activity method. Chitosan with high MW and DD resulted in a higher loading. A lower activity was observed for beads produced with high DD chitosan. MW did not have a marked effect on the activity. The release study revealed that enzyme release increased to a maximum when the bead was manufactured with a low MW and a moderate to high DD chitosan sample. Freeze drying did not affect the release or the activity of the lipase. Chitosan with a high MW and DD can thus improve loading and reduce the release of lipase in these beads. The choice of chitosan can affect the activity normalized for lipase loading, and beads with desirable qualities can be produced.

The degradative activities of extracellular and cell-associated portions of rat cecal and colonic enzymes, whose activities are comparable to that in the human colon, against five chitosan samples were characterized. The effects of the molecular weight (MW) and degree of deacetylation (DD) of chitosan on its susceptibility to degradation were investigated. In addition, the degradation function of rat bacterial enzymes was compared to that of a commercially available almond emulsin beta-glucosidase that contains a chitinase. The results show that rat bacterial enzymes had the ability to degrade chitosan with extracellular enzymes exhibiting a more profound effect than did cell-associated enzymes. The reaction to bacterial enzymes degradation was dependent on both the MW and DD of the chitosan sample. Those samples with a lower MW and lower DD were more susceptible substrates. A similar degradation function of rat bacterial enzymes and of almond emulsin beta-glucosidase on chitosan was revealed, which indicates that almond emulsin beta-glucosidase might be able to be used as an in vitro enzyme system to predict the large intestinal degradation of chitosan.

A multiparticulate system of chitosan hydrogel beads has been investigated for colon-specific delivery of macromolecules using fluorescein isothiocyanate-labeled bovine serum albumin as a model protein. The hydrogel bead was formed by polyelectrolyte complexation of chitosan with its counterion, tripolyphosphate (TPP). The protein release experiments were carried out in vitro under different conditions to simulate the pH and times likely to be encountered during intestinal transit to the colon. The results show that the hydrogel beads were degraded by rat cecal and colonic enzymes, resulting in a marked acceleration in the release of protein. The ability of rat cecal and colonic enzymes to degrade chitosan hydrogel beads was independent of pretreatment conditions. A commercial beta-glucosidase preparation containing a chitinase did not have a similar effect on the chitosan bead, even though it has been found to mimic the degradation function of rat cecal and colonic enzymes in vitro for chitosan in solution. Degradation of the chitosan-TPP hydrogel beads in the presence of rat cecal and colonic enzymes indicates the potential of this multiparticulate system to serve as a carrier to deliver macromolecules specifically to the colon.

Ethylcellullose has traditionally been used in tablets as a binder in an alcohol solution form. In the present study, fine-particle ethylcellulose (FPEC) was used as a binder to manufacture immediate-release tablets by the direct compression technique. The binding potential of FPEC is compared to that of commercially available coarse-particle ethylcellulose at the same viscosity grade and to that of hydrophilic binders. The compression force setting was kept constant for all batches. The concentration of the binder was varied from 5% to 25%. Acetaminophen was used as a model drug because capping is a problem frequently observed during high-speed compaction and further processing of acetaminophen tablets. In this study, there would be an increase in the contact area with FPEC and hence greater bond formation. This greater bond formation should be able to reduce the problem of capping in tablets containing highly elastic materials such as acetaminophen. Tablets were evaluated based on the following tests: weight variation, extent of capping, hardness, friability, disintegration, and dissolution. Based on the results of these tests, FPEC proved to be an effective binder for directly compressed acetaminophen tablets. The 10% and 15% formulations of FPEC passed all the tests and also produced the hardest tablets.

A commercially available almond emulsin beta-glucosidase preparation has been reported to have chitobiose activity, and can hydrolyze chitin substrates due to a chitinase present in the enzyme preparation. This beta-glucosidase preparation was used to investigate hydrolytic activity on five chitosan samples with different molecular weight and degree of deacetylation. The degree of deacetylation and molecular weight of the chitosan samples were determined using a circular dichroism and a viscometric method, respectively. The hydrolytic activity of this beta-glucosidase preparation on chitosan was monitored viscometrically as the most convenient means of screening. Solutions of chitosan in pH 5.0 acetate buffer were prepared using the different viscosity grades of chitosan. The specific viscosity, measured after addition of beta-glucosidase to the above solutions, decreased dramatically over time in comparison to that of the respective control mixture without enzyme. Eadie-Hofstee plots established that hydrolysis of chitosan by this enzyme preparation obeyed Michaelis-Menten kinetics. Apparent Michaelis-Menten parameters and initial degradation rates were calculated and compared to determine the influences of the degree of deacetylation and molecular weight on the hydrolysis. The results show that higher molecular weight and higher degree of deacetylation chitosans possessed a lower affinity for the enzyme and a slower degradation rate. Faster degradation rates, then, are expected with lower molecular weight and low degree of deacetylation chitosans. Hydrolysis of these chitosan samples confirms the existence of a chitinase in the almond emulsin beta-glucosidase preparation, and further studies are warranted.

Lambda-carrageenan, a linear, high molecular weight sulfated polysaccharide, was successfully employed in both its native and sulfobutyl derivatized form as a chiral selector in capillary electrophoresis for the separation of enantiomers of basic pharmaceutical compounds. In order to characterize the chiral selectivity properties of this chiral selector, various structurally related racemic compounds were analyzed for enantiomeric interactions using capillary electrophoresis. The results of these studies were then rationalized and analyzed utilizing a general quantitative structure-property relationship (QSPR) evaluation in order to predict critical analyte structural requirements for successful enantiomeric separation. Important structural components of the analytes were found to include the aromatic content, the type of substitution on the aromatic ring, presence of a primary or secondary protonated amine, and an overall positive charge to the molecule., (Copyright 2000 Wiley-Liss, Inc.)

Lambda-carrageenan, a linear high molecular weight sulfated polysaccharide, was employed as a chiral selector in capillary electrophoresis for the separation of enantiomers of weakly basic pharmaceutical compounds. In order to improve the utility of the chiral selector, the purity and concentration of the lambda-carrageenan and other important capillary electrophoresis method parameters were investigated. The results indicated that the purity and concentration of the lambda-carrageenan, ionic strength of the buffer, and temperature were critical to successful enantioseparation. These new method conditions were then applied to previously investigated beta-blockers (such as propranolol HCl and pindolol) and racemic tryptophan derivatives. These studies were successful in identifying important method conditions for the improved enantioselectivity with lambda-carrageenan., (Copyright 2000 Wiley-Liss, Inc.)

Preliminary studies revealed that Carbopol 974P, NF resin could be incorporated into beads manufactured by extrusion and spheronization, and can slow the release of a highly water soluble drug if calcium chloride was included in the granulating fluid to reduce the tack of the wetted polymer. In this study, the same approach was used to produce high quality chlorpheniramine maleate beads with a prolonged release duration. Because of the complex nature of the extrusion and spheronization process and the various components in the bead formulations, a statistically sound factorial experiment was considered for this study. A one-half fraction of a two level factorial design with three center points was employed to estimate the effects of simultaneously modifying multiple process and formulation variables, including the Carbopol concentration, calcium chloride concentration, water content, and the spheronization speed and time. Product yield, average bead roundness, and the drug release profile were selected as responses. Increasing the Carbopol content across the experimental range resulted in a significant (P<0.05) reduction in the percentage drug released at 25, 40, and 60 min. Results suggest that combining the conditions of high Carbopol, high water, and low calcium chloride levels with low spheronization speeds at long spheronization times produce the highest quality bead with the longest drug release duration.

The purpose of this work was to determine any effects the presence of sodium carboxymethyl starch may have on the antimicrobial activity of vancomycin given a previously described interaction between vancomycin and sodium carboxymethyl starch. In particular, the in-vitro activity of vancomycin against two clinically relevant bacteria, Staphylococcus aureus and Enterococcus faecalis, was studied in the presence of varying concentrations of sodium carboxymethyl starch. From two independent studies conducted using an agar dilution method, it appeared that the binding of vancomycin to sodium carboxymethyl starch had no effect on the in-vitro antimicrobial activity of vancomycin. The minimum inhibitory concentration of vancomycin against S. aureus in the presence of as much as 1 mg mL(-1) sodium carboxymethyl starch was similar to that of the control where no sodium carboxymethyl starch was added (1-4 microg mL(-1) vs 1-2 microg mL(-1), respectively). Likewise, the minimum inhibitory concentration of vancomycin against E. faecalis in the presence of 1 mg mL(-1) sodium carboxymethyl starch was also similar to that of the control where no sodium carboxymethyl starch was added (1-4 microg mL(-1) vs 1-4 microg mL(-1), respectively). However, there may be factors in the in-vitro method, such as high ionic strength, that could disrupt the interaction between vancomycin and sodium carboxymethyl starch. Therefore, the possibility of diminished vancomycin activity in-vivo cannot be ruled out. A small percentage (8-10%) of vancomycin was determined to be bound to sodium carboxymethyl starch in broth media. Given these results, the impact of sodium carboxymethyl starch on the in-vitro antimicrobial activity of vancomycin is expected to be minimal. Binding studies could not be conducted with gelled agar due to its semi-solid state.

Release data from ethylcellulose (EC) matrix tablets was analyzed to determine which release equation provides the best fit to the data and to observe the effect of drug solubility on the release mechanism(s). Tablets were prepared by direct compression of drug, EC, and lubricant in an appropriate mass ratio to achieve a high and a low drug loading. Theophylline, caffeine, and dyphylline were selected as non-electrolyte xanthine derivatives with solubilities from 8.3 to 330 mg/ml at 25 degrees C. Drug release studies were conducted in 37 degrees C water with UV detection at 272 nm. Several equations to characterize release mechanisms were tested with respect to the release data. Drug diffusion, polymer relaxation, and tablet erosion were the mechanisms considered. Parameters were generated and ANOVA data presented by WinNonlin Pro(R) software. The Akaike Information Criterion was also considered to ascertain the best fit equation. At high drug loading, drug was released by a diffusion mechanism with a rate constant that increased with an increase in aqueous solubility. At low drug loading, polymer relaxation also became a component of the release mechanism. However, its contribution to drug release was less pronounced as solubility decreases, becoming negligible in the case of theophylline., (Copyright.)

Purpose: Calculation of the ideal solubility of a crystalline solute in a liquid solvent requires knowledge of the difference in the molar heat capacity at constant pressure of the solid and the supercooled liquid forms of the solute, delta Cp. Since this parameter is not usually known, two assumptions have been used to simplify the expression. The first is that delta Cp can be considered equal to zero; the alternate assumption is that the molar entropy of fusion, delta Sf, is an estimate of delta Cp. Reports claiming the superiority of one assumption over the other, on the basis of calculations done using experimentally determined parameters, have appeared in the literature. The validity of the assumptions in predicting the ideal solubility of five structurally unrelated compounds of pharmaceutical interest, with melting points in the range 420 to 470 K, was evaluated in this study., Methods: Solid and liquid heat capacities of each compound near its melting point were determined using differential scanning calorimetry. Linear equations describing the heat capacities were extrapolated to the melting point to generate the differential molar heat capacity., Results: Linear data were obtained for both crystal and liquid heat capacities of sample and test compounds. For each sample, ideal solubility at 298 K was calculated and compared to the two estimates generated using literature equations based on the differential molar heat capacity assumptions., Conclusions: For the compounds studied, delta Cp was not negligible and was closer to delta Sf than to zero. However, neither of the two assumptions was valid for accurately estimating the ideal solubility as given by the full equation.

This paper explores the utility of aqueous solubility of structurally similar drugs in predicting optimum conditions for extrusion and spheronization of pellets using response surface methodology. Pharmacologically active xanthine derivatives exhibiting widely varying aqueous solubility were used to determine optimum conditions for pelletization. The amount of water added to the formulation, wet mixing time, and spheronizing time were explored in a series of central composite experimental designs to exhaustively explore and mathematically model the response surfaces for each drug. Using a marketed microcrystalline cellulose excipient, optimum extrusion and spheronization conditions for less soluble drugs required more water, a longer wet mixing time, and prolonged spheronizing times. Results were similar when a new microcrystalline cellulose was substituted, except that more water was required. When comparing results for different drugs, a strong linear relationship was observed between the aqueous solubility of the drug and the water content required for optimum pellet production. The water content range over which quality pellets could be produced was much broader for poorly soluble drugs. Aqueous solubility of the active component appears to be a good predictor for the water requirements for optimum extrusion and spheronization of pellets for pharmaceutical applications.

Lambda-carrageenan, a linear high molecular weight sulfated polysaccharide, has been employed as a chiral selector in capillary electrophoresis for the separation of enantiomers of weakly basic pharmaceutical compounds. The racemic compounds that were enantioresolved included propranolol, pindolol, tryptophanol, laudanosine and laudanosoline. In addition, the diastereomeric pair of cinchonine and cinchonidine were also resolved. Method conditions such as buffer pH, electrolyte concentration, column temperature, and chiral selector concentration were found to be important for improvement of enantioselectivity.

A common method of assessing the quality of emulsions is to evaluate the size distribution of the globules of the internal phase. The primary aim of this work is to compare the sensitivity of this test to an alternative method. The sizes of the globules of two emulsions, an oral emulsion and a total parenteral nutrition (TPN) emulsion, were determined using a light microscope. Globule size analyses were performed upon preparation and during storage of the emulsions. Using a computer program specially developed for this study, the recorded diameters were placed into size groups and the volumes of each of the measured globules was determined. For each size group, the total volume of all the globules within the group and the volume percentage of the oil phase represented by the group were calculated. The volume distribution of the internal phase across the size groups was found to predict emulsion instability better than the globule number distribution and thus is a better determinant of emulsion quality. This technique may have general application in the evaluation of TPN emulsions and other spheres, such as liposomes.