Interaction between water and poly(vinylpyrrolidone) containing polyethylene glycol

Information on the interaction between water and polymers is indispensable for manufacturing solid dispersion of a drug by hot-melt extrusion because this interaction affects various properties of the water-polymer mixtures, such as their viscoelastic properties. In this study, poly(vinylpyrrolidone) K30 (PVP) containing 0%, 10%, and 20% poly(ethylene glycol) 400 (PEG) was used as model amorphous polymers. The interaction of water with these polymers was assessed by the evaluation of the glass transition temperature (Tg), the point on the isotherm corresponding to the weight of sorbed water required to form a complete monolayer on the solid surface (apparent Wm), and the maximal amount of nonfreezing water, which were measured by differential scanning calorimetry and water sorption isotherms. In all of the systems with a water content below a certain water fraction (0.1 for PVP, 0.12 for PVP-PEG 10%, and 0.16 for PVP-PEG 20%), the Tg values were successfully predicted using theoretical equations, whereas the experimental Tg values were higher than predicted for those with a water content above these water fraction levels. In addition, these values of water fraction are similar to the apparent W(m) values determined using the Guggenheim-Anderson-DeBoer (GAB) equation (0.110, 0.117, and 0.147 weight fraction of water for PVP, PVP-PEG 10%, and PVP-PEG 20%, respectively). Nonfreezing water is detected above 0.47, 0.49, and 0.51 weight fraction of water for PVP, PVP-PEG 10%, and PVP-PEG 20%, respectively. Miscibility between water and PVP or PVP-PEG seems to change according to the water content in the system. All parameters increase with the concentration of PEG in the sample. This may be explained by the fact that PEG has a larger number of polymer repeating units, which may therefore interact with water more than PVP.     

An investigation of the interfacial interaction between poly(acrylic acid) and glycoprotein

The swelling behaviour of poly(acrylic acid) microspheres, produced from poly(acrylic acid) crosslinked with maltose, was investigated as a function of time by using a laser diffraction spectrometer. Swelling was also studied in various pH glycoprotein solutions. Microscopy revealed confirmatory evidence of interfacial film formation when microsphere hydration occurred in a pH 5 glycoprotein solution. ATR-FTIR spectroscopy was used to determine the diffusion coefficient of water through the interfacial film existing at the poly(acrylic acid) glycoprotein solution interface. Both processes exhibited a pH dependency with rates decreasing in the sequence pH 7>6>5=4.     

Crystallization inhibition in solid dispersions of MK-0591 and poly(vinylpyrrolidone) polymers

The effects of poly(vinylpyrrolidone) (PVP) molecular weight, composition, and content on the crystallization of a model drug, MK-0591 (Form I), were investigated. Solid dispersions of crystalline MK-0591 with PVP homopolymers of different molecular weights (2500-1 x 10(6) g/mol) and with a copolymer containing poly(vinyl acetate) (PVA), (PVP/VA, 60:40, 5.8 x 10(4) g/mol) were prepared by the solvent method. MK-0591 in the solid dispersions was found to be X-ray amorphous. One glass transition temperature (T(g)) was observed suggesting drug-polymer miscibility. The T(g) values were higher than predicted by the Gordon-Taylor equation, indicating drug-polymer interactions. The extent of crystallization inhibition increased with PVP molecular weight and, for a comparable PVP molecular weight, the homopolymer was more effective in the crystallization inhibition of the drug than the copolymer. The first onset temperature of crystallization (T(c)(obs)) increased with polymer content. The T(c)(obs) values (normalized to polymer content) were a function of the difference between the T(g) of the polymer and drug. For PVP K-90, K-30, and K-17 dispersions, the T(c)(obs) values increased proportionally to the T(g) of the dispersions. However, for PVP K-12 and PVP/VA, the increase in T(c)(obs) values corresponded to a small decrease in the T(g) values of the dispersions. This result suggests that additional factors other than the reduction in mobility affect the crystallization behavior of MK-0591 in the solid dispersions, such as specific interactions. By Fourier transform-infrared spectroscopy, changes in the carbonyl-stretching band of PVP in the solid dispersions were observed. The existence of an ion-dipole interaction between COO(-)Na(+) of the drug and the cyclic amide group of PVP was postulated.     

Molecular interaction between riboflavin and salicylic acid derivatives in nonpolar solvents

The interaction of riboflavin-2',3',4',5'-tetrabutyrate (I) with salicylic acid (II), aspirin (acetylsalicylic acid, III), and salicylamide (IV) has been spectroscopically investigated to determine the binding mechanism. NMR and absorption spectra were measured in nonpolar solvents. The association constant K of the formation of complex was calculated from the absorption spectra. Compounds I and II form a 1:1 cyclic hydrogen-bonded dimer through the N-3 proton and the C-2 carbonyl oxygen of the isoalloxazine ring, and the carboxylic hydroxyl proton and carbonyl oxygen of II. Compounds I and III form a 1:1 cyclic hydrogen-bonded dimer by the same mode. Compound IV forms a 1:1 cyclic hydrogen-bonded dimer with I through the N-3 proton and the C-2 carbonyl oxygen of the isoalloxazine ring, and the amino proton and the carbonyl oxygen of IV. Salicylates produce marked changes in the absorption spectra of I. These spectral changes are attributed to the formation of the hydrogen-bonded dimer. It appeared that the strongest complex was formed with salicylic acid, a weaker one with aspirin, and an even weaker one with salicylamide.     

Interactions between bioadhesive poly(acrylic acid) and calciumions

Polycarbophil (PC) is a weakly crosslinked poly(acrylic acid) used for bioadhesive delivery systems. Complexation of calcium ions by this polymer depends on the accessability of carboxylate functions in the polymer. Therefore, the calcium binding capacity increased linearly with the degree of neutralisation. Crosslinking rendered 20% of the carboxyl inaccessable to calcium whereas in water-soluble non-crosslinked poly(acrylic acid) (PAA), all carboxylate groups bound calcium. Addition of ionic substances reduced the fraction of calcium ions bound due to a dehydration of the polymer and a competition between the ions for binding. In a physiological buffer, PC chelated maximally 80% of the total calcium concentration, and water-soluble PAA bound 95%. In comparison to calcium chloride solution, the binding constant decreased from 51400 I/mol to 1800 1/mol in Tyrode's solution, moreover, the number of binding sites in the polymer was reduced.A dispersion of PC in water yielded swollen particles with a size of ca. 2.5 μm, depending on the degree of neutralisation and on the concentration of electrolytes, especially calcium ions. Addition of electrolytes caused a decrease of the particle size due to dehydration of the polymer. The reduction was more pronounced with calcium.Chelation of calcium by PC could be an explanation for the increase in bioavailability of drugs observed with bioadhesive PC delivery systems. The function and structure of epithelial tissue could be affected by chelation of extracellular calcium.     

A novel approach to prepare insulin-loaded poly(lactic-co-glycolic acid) microcapsules and the protein stability study

The purpose of this study was to propose a new preparation method to fabricate insulin-loaded poly(lactic-coglycolic acid) (PLGA) microparticles satisfying protein loading, release profiles, burst release, and particularly stability of the encapsulated protein. Insulin-loaded microcapsules were produced by a single phase o/o solvent evaporation method. The characteristics of the microcapsules were determined by various methods: the surface morphology and size of microparticles by atomic force microscopy and scanning electron microscopy, insulin crystalinity and drug-polymer interactions by XRD, DSC, and FTIR, chemical integrity and aggregation of insulin using HPLC and SDS-PAGE, the protein secondary structure by far ultraviolet-circular dichroism (CD), the antigenicity activity of insulin with ELISA techniques. PLGA microparticles showed smooth surfaces with microcapsule. Encapsulation efficiency of 51% and constant insulin release rate with initial insulin burst release of 24% was obtained. Encapsulated and released insulin was in the intact form and it was dispersed in crystalline state in the polymer matrix. Ease of manufacturing under mild preparation conditions, high level of drug entrapment, desirable release pattern with relatively low initial burst effect and an ability to preserve protein structure are the advantages which are offered by the developed protein encapsulation method.     

Section 2 Comparative clinical trial of three propionic acid derivatives(ibuprofen,ketoprofen and naproxen) in rheumatic diseases

Summary

A comparative study was carried out in 30 patients with rheumatic disease to assess the effectiveness and tolerance of 1200?mg. ibuprofen, 300?mg. ketoprofen, and 1000?mg. naproxen daily. The trial lasted 2 months, ibuprofen and ketoprofen being given in alternating 15-day periods to 15 of the patients, and ibuprofen and naproxen given similarly to the other 15 patients. The results, as assessed by patients and physician, showed similar efficacy against pain for all three drugs, with a slight tendency in favour of ibuprofen. Ibuprofen was much better tolerated and even allowed a return to normal in some patients with gastric intolerance of the other drugs. Overall assessment of treatment showed a clear patient preference for ibuprofen.     

A molecular dynamics simulation of reactant mobility in an amorphous formulation of a peptide in poly(vinylpyrrolidone)

The reaction pathways available for chemical decomposition in amorphous solids are determined in part by the relative mobilities of the potential reactants. In this study, molecular dynamics simulations of amorphous glasses of polyvinylpyrrolidone (PVP) containing small amounts of water, ammonia, and a small peptide, Phe-Asn-Gly, have been performed over periods of up to 100 ns to monitor the aging processes and associated structural and dynamic properties of the PVP segments and embedded solutes. Glass transition temperatures, Tg, were detected by changes in slopes of the volume-temperature profiles and the internal energy-temperature profiles for the inherent structures upon cooling at different rates. Analyses of the molecular trajectories below Tg reveal both temporal and spatial heterogeneity in polymer and solute mobility, with each molecule or part of a molecule displaying quite different relaxation behaviors for translational, rotational, and/or conformational motions. Rotations of individual polymer segments on the time scale up to 100 ns, though far from complete, are described by the Kohlrausch-Williams-Watts stretched exponential function with relaxation times tau on the order of 10-2.8 x 10(4) micros at an averaged stretching parameter beta of 0.39. The rotation rates are, on the average, faster for the side chains and for segments near the ends of the chains than for the backbones and segments near the middle of the chains. In contrast to their behavior in water, solute diffusive motions in the glassy polymer exhibit non-Einsteinian behavior over the time scale of the simulations characterized by two types of motion: (1) entrapments within relatively fluid microdomains surrounded by a matrix of relatively immobile polymer chains; and (2) jumps between microdomains with greater probability of hopping back to the solute's previous location. The average jump length and frequency are highly dependent on solute size, being much smaller for the tripeptide, Phe-Asn-Gly, than for water and ammonia. The diffusivities of water and ammonia, solutes capable of forming hydrogen bonds with the lactam residues within the polymer segments, are significantly reduced by strong electrostatic interactions. The conformational preferences of Phe-Asn-Gly were compared in the amorphous polymer and water to detect differences in the degree to which the tripeptide may be predisposed toward deamidation of the asparagine side chain in these environments. Although only minor differences are evident in peptide conformation, the conformational dynamics for the peptide embedded in the glassy polymer are characterized by a higher energy barrier between conformational states and 2.5-44-fold larger relaxation times for the dihedral angles of interest than in water. However, in the context of peptide deamidation, these differences may be of secondary importance in comparison to the more than two to three orders of magnitude reduction in the diffusivities of water, ammonia, and the tripeptide in PVP.     

Conjugation of poly(styrene-co-maleic acid) derivatives to the antitumor protein neocarzinostatin: pronounced improvements in pharmacological properties

An anticancer agent of intermediate molecular weight and having both a hydrophilic and hydrophobic nature was developed by utilizing the antitumor protein neocarzinostatin (NCS; Mr = 12000) as a prototype drug. The modification was achieved by reacting the two amino groups on NCS with an anhydride group of partially half-esterified (p-E-) or partially hydrolyzed (p-H-) poly(styrene-co-maleic anhydride) (SMA) in 0.8 M NaHCO3. The SMA samples with narrow molecular weights distributions (Mw = ca. 2000) were prepared by copolymerizing styrene and maleic anhydride in cumene followed by fractionation by means of a column-elution method. The derivatives p-E- or p-H-SMA were then formed by using the appropriate monoalcohols or H2O, respectively. These SMA derivatives contain about 2 mol of anhydride residues/mol of SMA. The reaction product, SMA-conjugated NCS (designated as SMANCS), was purified by dialysis followed by gel filtration with Sephadex G-75. The complete reaction yielded essentially a single product, biantennary SMANCS. The molecular weight of the pure SMAMCS was estimated by various methods, including polyacrylamide gel electrophoresis with NaDodSO4, HPLC in the gel permeation mode, fluorescence polarization, and a decrease in both nitrogen and protein contents. These results agree with the apparent molecular weight of about 16000. Characters of SMANCS was considerably altered from that of parental NCS: solubility characteristics in both organic and aqueous solvents were changed, the biological half-life in blood was prolonged 10 times, and antitumor activity became more pronounced, but the toxicity was reduced to one-fourth of the parental NCS. Thus, the present study has provided a method of improving biologically active substances by polymer conjugation.     

Influence of various drugs on the glass transition temperature of poly(vinylpyrrolidone): a thermodynamic and spectroscopic investigation

PURPOSE: To determine the influence of hydrogen bonding and solubility parameter on the glass transition temperature (T(g)) of various drug-poly(vinylpyrrolidone) blends. METHODS: The T(g) of PVP films containing either acetaminophen, naproxen, salicylamide, carbamazepine, griseofulvin or propranolol hydrochloride were measured using differential scanning calorimetry. Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction was used to characterize the specific interactions between the drug-PVP blends and the physical state of the films, respectively. The total solubility parameter and its individual components were calculated using the method of Van Krevelen. RESULTS: Salicylamide displayed the greatest plasticizing effect, depressing the T(g) to the minimum. This was consistent with the FTIR data, which indicated the presence of hydrogen bonding with PVP. Griseofulvin showed the least plasticizing effect due to lack of interaction with PVP. All the drugs except griseofulvin were amorphous within the film up to 30% (w/w) drug composition. The correlation between the various components of the solubility parameters and the plasticizing effect of drugs was very poor. CONCLUSIONS: Spectroscopic investigation for the presence of interaction between the drugs and PVP proved to be extremely predictive of the plasticizing effect of various drugs. In contrast, solubility parameters appeared to be far less sensitive indicators of drug-PVP miscibility.     

Surface pressure measurements in particle interaction and stability studies of poly(lactic acid) nanoparticles

Stability of nanoparticle dispersion in different environments is one key issue in determining the performance and safety of the drug delivery system in question. In this study, aggregation tendency and particle-particle interactions of poly(lactic acid) nanoparticles were evaluated by their interfacial behavior upon compression. Surface pressure versus trough area (pi vs. A) isotherms of the nanoparticles were registered on different subphases (pH, electrolyte concentration). The compressed particle populations were transferred to silica plates by Langmuir-Schaefer deposition and analyzed with scanning electron microscope. Aggregation of the electrostatically stabilized surfactant-free nanoparticles due to subphase alterations was clearly detected from the isotherms even though zeta potential value of the nanoparticles (-35mV) suggested a stable system. When steric stabilization, provided by a surfactant (Poloxamer 188) in this study, was involved besides the electrostatic stabilization, the nanoparticles remained non-aggregated over a wider range of conditions. Steric stabilization together with electrostatic stabilization extended the repulsion to a longer distance.     

Effect of polymer size and cosolutes on phase separation of poly(vinylpyrrolidone) (PVP) and dextran in frozen solutions

The aim of this study was to elucidate the effect of the molecular weight of polymers on their miscibility in frozen solutions to model the physical properties of freeze-dried pharmaceutical formulations. Thermal analysis of frozen solutions containing poly(vinylpyrrolidone) (PVP) and dextran of various molecular weights was performed at polymer concentrations below the binodal curve at room temperature. Frozen solutions containing PVP 29,000 and dextran 10,200 showed two thermal transitions (glass transition temperature of maximally freeze-concentrated solution: Tg') representing two freeze-concentrated amorphous phases, each containing predominantly one of the polymers. A combination of smaller polymers (PVP 10,000 and dextran 1,060) was freeze-concentrated into an amorphous mixture phase across a wide range of concentration ratios. Combinations of intermediate size polymers separated into two freeze-concentrated phases only at certain concentration ratios. Addition of NaCl prevented the phase separation of PVP and dextran in the aqueous and frozen solutions. Higher concentrations of NaCl were required to retain the miscibility of larger polymer combinations in the freeze-concentrate. The molecular weights of the component polymers, polymer concentration ratio, and cosolute composition are the important factors that determine component miscibility in frozen solutions.     

Molecular mobility-based estimation of the crystallization rates of amorphous nifedipine and phenobarbital in poly(vinylpyrrolidone) solid dispersions

The overall crystallization rates and mean relaxation times of amorphous nifedipine and phenobarbital in the presence of poly(vinylpyrrolidone) (PVP) were determined at various temperatures to gain further insight into the effect of molecular mobility on the crystallization rates of amorphous drugs and the possibility of predicting stability from their molecular mobility. Nifedipine-PVP (9:1 w/w) and phenobarbital-PVP (95:5 w/w) solid dispersions were prepared by melting and rapidly cooling mixtures of each drug and PVP. The amount of amorphous nifedipine remaining in the solid dispersion was calculated from the heat of crystallization,which was obtained by differential scanning calorimetry. The amount of amorphous phenobarbital remaining in the solid dispersion was estimated from the change in the heat capacity at its glass transition temperature (T(g)). The time required for the amount of amorphous drug remaining to fall to 90% (t(90)) was calculated from the profile of time versus the amount of amorphous drug remaining. The t(90) values for the solid dispersions studied were 100-1000 times longer than those of pure amorphous drugs when compared at the same temperature. Enthalpy relaxation of the amorphous drugs in the solid dispersions was reduced compared with that in the pure amorphous drugs, indicating that the molecular mobility of the amorphous drugs is reduced in the presence of PVP. The temperature dependence of mean relaxation time (tau) for the nifedipine-PVP solid dispersion was calculated using the Adam-Gibbs-Vogel equation. Parameters D and T(0) in this equation were estimated from the heating rate dependence of T(g). Similar temperature dependence was observed for t(90) and tau values of the solid dispersion, indicating that the information on the temperature dependence of the molecular mobility, along with the crystallization data obtained at around the T(g), are useful for estimating the t(90) of overall crystallization at temperatures below T(g) in the presence of excipients.     

Examination of the flow rheological and textural properties of polymer gels composed of poly(methylvinylether-co-maleic anhydride) and poly(vinylpyrrolidone): rheological and mathematical interpretation of textural parameters

The purpose of this study was to mathematically characterize the effects of defined experimental parameters (probe speed and the ratio of the probe diameter to the diameter of sample container) on the textural/mechanical properties of model gel systems. In addition, this study examined the applicability of dimensional analysis for the rheological interpretation of textural data in terms of shear stress and rate of shear. Aqueous gels (pH 7) were prepared containing 15% w/w poly(methylvinylether-co-maleic anhydride) and poly(vinylpyrrolidone) (PVP) (0, 3, 6, or 9% w/w). Texture profile analysis (TPA) was performed using a Stable Micro Systems texture analyzer (model TA-XT 2; Surrey, UK) in which an analytical probe was twice compressed into each formulation to a defined depth (15 mm) and at defined rates (1, 3, 5, 8, and 10 mm s(-1)), allowing a delay period (15 s) between the end of the first and beginning of the second compressions. Flow rheograms were performed using a Carri-Med CSL(2)-100 rheometer (TA Instruments, Surrey, UK) with parallel plate geometry under controlled shearing stresses at 20.0 degrees +/- 0.1 degrees C. All formulations exhibited pseudoplastic flow with no thixotropy. Increasing concentrations of PVP significantly increased formulation hardness, compressibility, adhesiveness, and consistency. Increased hardness, compressibility, and consistency were ascribed to enhanced polymeric entanglements, thereby increasing the resistance to deformation. Increasing probe speed increased formulation hardness in a linear manner, because of the effects of probe speed on probe displacement and surface area. The relationship between formulation hardness and probe displacement was linear and was dependent on probe speed. Furthermore, the proportionality constant (gel strength) increased as a function of PVP concentration. The relationship between formulation hardness and diameter ratio was biphasic and was statistically defined by two linear relationships relating to diameter ratios from 0 to 0.4 and from 0.4 to 0.563. The dramatically increased hardness, associated with diameter ratios in excess of 0.4, was accredited to boundary effects, that is, the effect of the container wall on product flow. Using dimensional analysis, the hardness and probe displacement in TPA were mathematically transformed into corresponding rheological parameters, namely shearing stress and rate of shear, thereby allowing the application of the power law (eta = kgamma(n)) to textural data. Importantly, the consistencies (k) of the formulations, calculated using transformed textural data, were statistically similar to those obtained using flow rheometry. In conclusion, this study has, firstly, characterized the relationships between textural data and two key instrumental parameters in TPA and, secondly, described a method by which rheological information may be derived using this technique. This will enable a greater application of TPA for the rheological characterization of pharmaceutical gels and, in addition, will enable efficient interpretation of textural data under different experimental parameters.     

The mechanism of interaction between chlorhexidine digluconate and poly(2-hydroxyethyl methacrylate)

The extent of the interaction between chlorhexidine digluconate and poly(2-hydroxyethyl methacrylate), (PHEMA), is independent of temperature between 22-50 degrees C which is consistent with an ion-ion interaction mechanism. Different contact lens materials exhibit different affinities for chlorhexidine digluconate, the extent of uptake correlating in rank order with the number of free carboxylic acid sites in the polymers. Esterification of the carboxyl groups with diazomethane, resulted in a reduction in the affinity of the treated polymers for chlorhexidine to a near basal level. The uptake of chlorhexidine in soaking solution experiments involving lenses made from PHEMA and the more ionic material, poly(2-hydroxyethyl methacrylate-co-isobutyl methacrylate-co-methacrylic acid), was consistent with their carboxylate content. However, the fraction of bound disinfectant released was lower from the terpolymer, suggesting there are differences in bonding strengths between chlorhexidine and different contact lens hydrogels.