Drug release profiles from and degradation of a novel biodegradable polymer, 2,2-bis(2-oxazoline) linked poly(-caprolactone)

In the present study, poly (epsilon -caprolactone) (PCL) was modified by introducing oxamide groups into PCL (PCL-O). The degradation (decrease in molecular weight) and erosion (weight loss) of PCL and PCL-O films were studied in PBS (pH 7.4, USP XXIV, 37 degrees C, 26 weeks incubation). The release rates of guaifenesin (M(w) 198.2), griseofulvin (M(w) 352.8), timolol (M(w) 332.4), sodium salicylate (M(w) 160.1) and FITC-dextran (M(w) 4400) from PCL and PCL-O preparations (solvent cast films, compression-molded plates, midi injection-molded rods and microparticles) were examined in PBS (pH 7.4, 37 degrees C). The degradation rate of PCL-O film was faster than that of PCL film while no erosion was observed for either film. When compared to the corresponding drug release from PCL films, the release rates of low molecular weight drugs (M(w)< or =352.8) from PCL-O films were comparable, their releases from both films following closely square-root-of-time kinetics. These results indicate that the oxamide groups had no substantial effect on the release of the low molecular weight drugs. The exception was sodium salicylate which was released faster from PCL-O film. However, FITC-dextran release was notably faster from PCL-O microparticles than from those made of PCL. FITC-dextran release was a combination of diffusion and polymer degradation and thus, the faster degradation of PCL-O enhanced the release of FITC-dextran. In conclusion, the effects of the oxamide groups on drug release profiles were dependent on the drug release mechanisms.     

Evaluation of electrophoretic method versus chromatographic, potentiometric and absorptiometric methodologies for determing pK(a) values of quinolones in hydroorganic mixtures

The advantages of using capillary electrophoresis (CE) over other methodologies for determining pK_a values of drugs in hydroorganic media are discussed. The focus of the discussion based upon the pK_a values of a series of quinolones determined in acetonitrile (MeCN)–water mixtures by CE, liquid chromatography, potentiometric, and spectrophotometric methods.     

Membrane permeability related physicochemical properties of a novel gamma-secretase inhibitor

Pharmaceutical profiling studies were conducted on a novel prototype γ-secretase inhibitor, to determine the potential of its oral absorption. Such compounds can be of use in the treatment of Alzheimer’s disease (AD). The studies included determination of solubility, dissociation constant (pK_a), octanol/water partition coefficient (log P) and the capacity factor (k_IAM′) on immobilized artificial membrane (IAM) chromatographic columns. The compound is very slightly solubility in water (120 ± 50 μg/mL) but the solubility increased considerably in basic medium (270 ± 60 μg/mL). The compound exhibited pK_a of (10.36 ± 0.11); and log P of (3.36 ± 0.16) determined by shake-flask method and (3.31 ± 0.01) determined by high performance liquid chromatography (HPLC). The experimentally determined log P values correlated well with the calculated one of 3.44. The observed log k_IAM′ value of (2.79 ± 0.04) indicates that the compound can reasonably be expected to have high membrane permeability, and therefore, good absorption profile if taken orally. This conclusion is also supported by other parameters determined.     

SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1-[2'methyl-4'-(5-methyl-1,2,3-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): a novel, potent and selective 5-HT1B receptor antagonist

SB-616234-A possesses high affinity for human 5-HT_1B receptors stably expressed in Chinese hamster ovary (CHO) cells (pK_i 8.3 ± 0.2), and is over 100-fold selective for a range of molecular targets except h5-HT_1D receptors (pK_i 6.6 ± 0.1). Similarly, affinity (pK_i) for rat and guinea pig striatal 5-HT_1B receptors is 9.2 ± 0.1. In [³⁵S]-GTPγS binding studies in the human recombinant cell line, SB-616234-A acted as a high affinity antagonist with a pA₂ value of 8.6 ± 0.2 whilst providing no evidence of agonist activity in this system. In [³⁵S]-GTPγS binding studies in rat striatal membranes, SB-616234-A acted as a high affinity antagonist with an apparent pK_B of 8.4 ± 0.5, again whilst providing no evidence of agonist activity in this system. SB-616234-A (1 μM) potentiated electrically stimulated [³H]-5-HT release from guinea pig and rat cortical slices (S₂/S₁ ratios of 1.8 and 1.6, respectively). SB-616234-A (0.3–30 mg kg⁻¹ p.o.) caused a dose-dependent inhibition of ex vivo [³H]-GR125743 binding to rat striatal 5-HT_1B receptors with an ED₅₀ of 2.83 ± 0.39 mg kg⁻¹ p.o. Taken together these data suggest that SB-616234-A is a potent and selective 5-HT_1B autoreceptor antagonist that occupies central 5-HT_1B receptors in vivo following oral administration.     

Determination of the ionization constants of 4-iodo-2,6-dimethylphenylcarbamoylmethyl iminodiacetic acid

In order to develop a radiopharmaceutical for hepatobiliary scintigraphy with better hepatobiliary properties new ligand for complexation of ^99mTc, 4-iodo-2,6-dimethylphenylcarbamoylmethyl iminodiacetic acid (METHYLIODIDA), was synthesized. Acid–base equilibria of METHYLIODIDA were studied potentiometrically, because these data are important for determination of complex formation conditions. It was established that METHYLIODIDA undergoes a complex acid–base equilibrium due to its zwitterionic nature and four proton-binding sites. The stoichiometric ionization constants were determined at 25 °C and constant ionic strength 0.1 M (NaClO₄): pK₁=1.7±0.1; pK₂=2.44±0.07; pK₃=6.29±0.02 and pK₄=10.91±0.06, respectively.     

pH-sensitive nanoparticles of poly(amino acid) dodecanoate complexes

Nanoparticles were formed by the complexation of poly( -arginine) (PLA), poly( -histidine) (PLH) and poly( -lysine) (PLL) with dodecanoic acid (C12). Dynamic light scattering, ζ potential measurements, atomic force microscopy, fluorescence, and circular dichroism spectroscopy were used for their characterization. It was found that the diameters of the poly( -arginine) dodecanoate (PLA-C12), poly( -histidine) dodecanoate (PLH-C12), and poly( -lysine) dodecanoate (PLL-C12) complex nanoparticles were in the range 120–200 nm. Furthermore, the pH-sensitive dissolution and the surface charges can be adjusted by choosing PLA, PLH and PLL. The particle stability against basic pH values increases with increasing pK_a value of the poly(amino acid) in the series PLH-C12, PLL-C12 and PLA-C12. The particles as such show a core-shell morphology. Their cores are formed by stoichiometric poly(amino acid) dodecanoate complexes while the shells stabilizing the particles are formed by cationic poly(amino acid) chains in an uncomplexed state. The particles were tested as containers for hydrophobic molecules such as pyrene, which served as a fluorescence probe for measuring the polarity within the particles, and Q₁₀ which functioned as a model drug. The maximum uptake of Q₁₀ into the nanoparticles is about 13% (w/w), thereby making the complexes attractive as simple drug carriers for controlled release purposes. Circular dichroism measurements revealed that the poly(amino acid) chains of PLA-C12 and PLL-C12 adopt predominantly an -helix and that of PLH-C12 a β-sheet.     

Potent antagonism of 5-HT(3) and 5-HT(6) receptors by olanzapine.

The interaction of the psychotropic agent olanzapine with serotonin 5-HT₃ and 5-HT₆ receptors was investigated. Olanzapine did not contract the isolated guinea pig ileum, but blocked contractions induced by the 5-HT₃ receptor agonist 2-methyl serotonin (2-CH₃ 5-HT) with a pK_B value of 6.38±0.03, close to the affinity of the 5-HT₃ receptor antagonist ondansetron. The atypical antipsychotic risperidone (1 μM) did not significantly inhibit 2-CH₃ 5-HT-induced contractions. Olanzapine had high affinity (pK_i=8.30±0.06) for human 5-HT₆ receptors in radioligand binding studies. Olanzapine did not stimulate [³⁵S]guanosine-5′-O-(3-thio)triphosphate ([³⁵S]GTPγS) binding to the G protein G_s in cells containing human 5-HT₆ receptors, but inhibited 5-HT-stimulated [³⁵S]GTPγS binding (pK_B=7.38±0.16). Among other antipsychotics investigated, clozapine antagonized 5-HT₆ receptors with a pK_B=7.42±0.15, ziprasidone was three-fold less potent, and risperidone, quetiapine and haloperidol were weak antagonists. Thus, olanzapine was not an agonist, but was a potent antagonist at 5-HT₆ receptors and had marked antagonism at 5-HT₃ receptors.     

PAMPA—a drug absorption in vitro model: 5. Unstirred water layer in iso-pH mapping assays and pKa—optimized design (pOD-PAMPA)

Iso-pH mapping unstirred parallel artificial membrane permeability assay (PAMPA) was used to measure the effective permeability, P_e, as a function of pH from 3 to 10, of five weak monoprotic acids (ibuprofen, naproxen, ketoprofen, salicylic acid, benzoic acid), an ampholyte (piroxicam), five monoprotic weak bases (imipramine, verapamil, propranolol, phenazopyridine, metoprolol), and a diprotic weak base (quinine). The intrinsic permeability, P_o, the unstirred water layer (UWL) permeability, P_u, and the apparent pK_a (pK_a^flux) were determined from the pH dependence of log P_e. The underlying permeability-pH equations were derived for multiprotic weak acids, weak bases and ampholytes. The average thickness of the unstirred water layer on each side of the membrane was estimated to be nearly 2000 μm, somewhat larger than that found in Caco-2 permeability assays (unstirred). Since the UWL thickness in the human intestine is believed to be about forty times smaller, it is critical to correct the in vitro permeability data for the effect of the UWL. Without such correction, the in vitro permeability coefficient of lipophilic molecules would be indicative only of the property of water. In single-pH PAMPA (e.g. pH 7.4), the uncertainty of the UWL contribution can be minimized if a specially-selected pH (possibly different from 7.4) were used in the assay. From the analysis of the shapes of the log P_e—pH plots, a method to improve the selection of the assay pH, called pK_a^flux—optimized design (pOD-PAMPA), was described and tested. From an optimally-selected assay pH, it is possible to estimate P_o, as well as the entire membrane permeability—pH profile.     

Degradation kinetics of vincristine sulphate and vindesine sulphate in aqueous solutions

The degradation kinetics of the antineoplastic drugs, vincristine and vindesine, have been studied in the pH range from − 2 up to 11 at 80°C. A stability-indicating HPLC system with UV detection was utilized for the analysis of vincristine and vindesine in the reaction solutions. The influences of external factors (e.g. pH, buffer concentrations, ionic strength and temperature) on the degradation rate have been studied systematically. The relationship between pH and log k_obs was modelled by using a non-linear least-squares curve-fitting computer program. From this plot thepK_a values of vindesine have been calculated. This plot also showed that vincristine was most stable at pH 4.8 and vindesine at pH 1.9.     

Trace enrichment on a metal-loaded thiol stationary phase in liquid chromatography: effect of analyte structure and pH value on the (de)sorption behaviour

In order to obtain more information on the (de)sorption processes on a metal-loaded thiol phase, various compounds containing heterocyclic nitrogen atoms have been studied. Adenine and adenosine, which contain no carbonyl groups in a position ortho to the ring nitrogen, were chosen to study the role of the binding donor atoms and, therefore, of the ‘minimum’ structure required for efficient pH-dependent (de)sorption. The results indicate that a single heterocyclic nitrogen atom, preferably with a high pK_a value, is sufficient to provide pH-dependent (de)sorption on chelating phases loaded with soft metal ions, such as Ag(I) or Hg(II), which can profitably be used in an on-line combination with column liquid chromatography. Barbiturates were chosen on the basis of their structural similarity with the earlier studied (halogenated) uracil derivatives. The (de)sorption behaviour of the barbiturates was studied as a function of the pH, the metal ion [Cu(II), Ag(I), Hg(II), Pd(II)] bound to the stationary phase and the type of stationary phase. The combined data show that the pK_a value of an analyte and the stability constant of the complex formed with the metal ion sorbed on the stationary phase give a reliable indication of the optimum (de)sorption pH. Application of this principle is demonstrated by the determination of four barbiturates in plasma.     

Measurement of pKa values of newly synthesized heteroarylaminoethanols by CZE

Heteroarylaminoethanol derivates are drugs which affect sympathetic nervous system and are used for medications of hypertensis. In solutions they behave like weak bases and their pK_a values represent important information on their potential biological uptake, pharmacological activity and in vivo biodisponsibility. This article brings the measurement of pK_a values of the series of seven new important heteroarylaminoethanols, compounds with potential vasodilating, β-adrenolytic and antioxidant activity, by capillary zone electrophoresis (CZE) with diode-array detection. It has been shown that capillary zone electrophoresis measurements of pK_a can be easily performed with very small quantities of studied substances, and, due to CZE separation power, the purity of samples is not of key importance. Moreover, the CZE method is fast and reliable, providing that suitable operational conditions are selected. The method is based on the measurement of the effective mobility curves within a suitable pH range and related regression analysis where pK_BH⁺ and electrophoretic mobility of BH⁺ are explicitly involved. The selection of sufficient operational buffers is of key importance for accurate and reproducible results, and, this article brings step by step the consideration procedure involved in this process. Further, this paper brings principles of least square regression analysis of non-linear function corresponding to exact explicit formula for mobility curve of monovalent weak base.     

Pluronic-g-poly(acrylic acid) copolymers as novel excipients for site specific, sustained release tablets

Potential utility of copolymers comprising Pluronic^® (PEO–PPO–PEO) surfactants covalently conjugated with poly(acrylic acid) (PAA) as excipients for sustained-release tablets was explored. Apparent particle density, particle size distribution, Carr index, thermal stability, and compression behavior of the Pluronic–PAA copolymers were characterized. Tablets prepared by direct compression of blends of Pluronic–PAA copolymers were evaluated on the basis of their thermomechanical profile, crushing strength, friability, and drug release properties. Small molecular weight drugs of aqueous solubility decreasing in the order theophylline > hydrochlorothiazide > nitrofurantoin were incorporated to the tablets. For comparison purposes, tablets were also prepared from PAA of Carbopol^® 71G (C71G), and mixtures of C71G and Pluronic^® F127, with each of the above three drugs. The Pluronic–PAA aggregates are stabilized by hydrophobic associations between poly(propylene oxide) (PPO) segments in aqueous solutions, and thus require higher ionization of the carboxylic groups to overcome the associations and swell. The swelling pattern of the Pluronic–PAA copolymers is more dramatically pH-dependent than that of Carbopol lacking any hydrophobic associations. The drug retention in and release from the Pluronic–PAA based tablets is profoundly pH-dependent and hence specific to the pH exceeding that of the pK_a > 5 of these copolymers. Theophylline- and hydrochlorotiazide-containing tablets made with Pluronic–PAA copolymers showed a reduced release rate under acidic conditions compared to the neutral or alkaline conditions, while the opposite pattern was observed with the Carbopol-based tablets due to the different pH-dependent swelling behavior of the polymers. Nitrofurantoin-containing tablets showed a remarkably low drug release rate owing to the strong hydrophobic character of nitrofurantoin and of its complexes with the copolymers. Integrity of the nitrofurantoin-containing tablets was maintained during the 24 h release test. Zero-order kinetics of the cumulative release profile of all drugs under study was observed with the Pluronic–PAA as a tablet excipient. Adequate mechanical properties, the self-assembling behavior, and the pH-sensitiveness of the Pluronic–PAA copolymers make them promising excipients for tablets with preferential delivery into a neutral to alkaline pH environment.     

The pharmacokinetics of pulmonary insulin in the in vitro isolated perfused rat lung: Implications of metabolism and regional deposition

The pharmacokinetics of several lung disposition pathways for pulmonary insulin were studied and modeled in the isolated perfused rat lung (IPRL). Insulin solution was administered by forced instillation into the airways of the IPRL as 0.1 or 0.02 ml doses of coarse spray, with or without bacitracin (BAC), N-ethylmaleimide (NEM) and atrial natriuretic peptide (ANP). Each insulin absorption profile was fitted to a kinetic model that incorporated the distribution fraction of the dose reaching the lobar region (DF) and the rate constants for absorption into perfusate (k_a) and non-absorptive loss (k_nal); k_nal was shown to be due to the sum of mucociliary clearance and metabolism. Insulin absorption occurred largely by passive diffusion with values for k_a = 0.39–0.50 h⁻¹. With DF = 0.91 following 0.1 ml doses, 11.9 ± 3.4% of bioavailabilities were observed in 1 h. In contrast, derived values for k_nal = 2.34–3.45 h⁻¹ were significantly larger than the rate constant for mucociliary clearance determined previously in this IPRL (0.96–1.74 h⁻¹) due to lung metabolism. Indeed, BAC, but neither NEM nor ANP, was found to decrease the value of k_nal, which suggested that BAC-inhibitable lung ectopeptidases, and not insulin degrading enzyme (IDE), were responsible for this pulmonary metabolism. Shallower lung distribution with DF = 0.73 following 0.02 ml doses resulted in reduced values for k_a = 0.27 h⁻¹ and k_nal = 2.79 h⁻¹, indicating that these kinetic processes may be lung-region dependent, even within this model and emphasizing the likely importance of reliable lung deposition in vivo.     

Caco-2 Cell Culture as a Model for Famotidine Absorption

The aim of the study was to determine penetration properties of Famotidine fro the formulations through colon adenocarcinoma (Caco)-2 cell monolayers and to compare in vitro with in vivo test results. It also aimed to determine the effect of particle size on the penetration properties of Famotidine when microsphere formulations were used. Famotidine was chosen as a model drug and Caco-2 cell culture model was used. Biodegradable Famotidine microspheres of poly(lactide-co-glycolide)(PLGA) polymer (50:50) were prepared by using multiple emulsion technique. Microspheres were coded according to their particle size and polymer[LHIV:60 μm Famotidine-PLGA(high viscosity), SHIV:6 μm Famotidine PLGA(high viscosity), LLIV:60 μm Famotidine-PLGA (low viscosity), SLIV:6 μm Famotidine-PLGA (low viscosity)]. Famotidine solution(5 mg/ml) and microsphere formulations were administered orally to mice and blood drug levels were determined and compared with the Caco-2 cell experiments. Permeability values of Famotidine through Caco-2 cells from various formulations were determined (log k_solution = 7, 274 ± 0, 010, log k_SHIV = -3, 884 ± 0, 033, log k_LHIV = -2, 300 ± 0, 009, log k_SLIV = -4, 076 ± 0, 208, log k_LLIV = 3, 525 ± 0, 045). Our results showed that H₂ receptor antagonists alter the barrier properties of the Caco-2 cell monolayer by causing an increment in the tightness of the tight junctions. Therefore, amount of the H₂ receptor antagonist-like drug at the site of action was found to be important as well as polymer type and particle size of microspheres for drug permeation. Permeation of the drug was lower when higher amounts of Famotidine were present at the diffusion site. A controlled release dosage form of H₂ receptor antagonist-like drugs may be beneficial for long-term treatments.     

Potentiometric investigation of the stability of palladium(II) complex of pralidoxime chloride in aqueous solution

The formation of a complex between palladium(II) chloride and pralidoxime chloride (PAM-2Cl) has been studied by means of potentiometric pH measurements. The real stability constant of the complex in aqueous medium of ionic strength 0.3 M (KCl) at 25.0°C was log K_s = 7.29. This value was close to that (log K_s = 7.02) obtained previously by spectrophotometric methods after appropriate correction with respect to the corresponding value of the acidic constant of PAM-2Cl (pK^c_a = 8.05), which was also determined under the same experimental conditions.     

Bioreversible quaternary N-acyloxymethyl derivatives of the tertiary amines bupivacaine and lidocaine—synthesis, aqueous solubility and stability in buffer, human plasma and simulated intestinal fluid

Design of water-soluble prodrugs may constitute a means to improve the oral bioavailability of drugs suffering from dissolution rate-limited absorption. The model drug bupivacaine containing a tertiary amine function has been converted into bioreversible quaternary N-acyloxymethyl derivatives. The pH-independent solubility of the N-butanoyloxymethyl derivate exceeded 1000 mg ml⁻¹ corresponding approximately to a 10,000-fold increase in water solubility compared to that of bupivacaine base. The kinetics of hydrolysis of the prodrugs was studied in the pH range 0.1–9.8 (37 °C). Decomposition was found to follow first-order kinetics and U-shaped pH-rate profiles were constructed. The observed differences between the hydrolytic lability of the derivatives might most likely be ascribed to steric effects. In most cases, the prodrugs were quantitatively converted into bupivacaine. However, for the hydrolysis of the N-butanoyloxymethyl derivative at neutral to slightly alkaline pH parallel formation of bupivacaine (80%) and an unknown compound X (20%) was observed. LC–MS analysis of the latter compound suggests that an aromatic imide structure has been formed from an intramolecular acyl transfer reaction involving a nucleophilic attack of the amide nitrogen atom on the ester carbonyl carbon atom. Whereas the derivatives were poor substrates for plasma enzymes; they were hydrolyzed rapidly to parent bupivacaine in the presence of pancreatic enzymes (simulated intestinal fluid) at 37 °C. The data indicate that such prodrugs possess sufficient stability in the acidic environment of the stomach to reach the small intestine in intact form where they can be cleaved efficiently by action of pancreatic enzymes prior to drug absorption. Thus, the N-acyloxymethyl approach might be of potential utility to enhance oral bioavailability of tertiary amines exhibiting pK_a values below approximately 6 and intrinsic solubilities in the low μM range.     

A modification of the Hammett equation for predicting ionisation constants of p-vinyl phenols

Currently there are several compounds used as drugs or studied as new chemical entities, which have an electron withdrawing group connected to a vinylic double bond in a phenolic or catecholic core structure. These compounds share a common feature – current computational methods utilizing the Hammett type equation for the prediction of ionisation constants fail to give accurate prediction of pK_a's for compounds containing the vinylic moiety. The hypothesis was that the effect of electron-withdrawing substituents on the pK_a of p-vinyl phenols is due to the delocalized electronic structure of these compounds. Thus, this effect should be additive for multiple substituents attached to the vinylic double bond and quantifiable by LFER-based methods. The aim of this study was to produce an improved equation with a reduced tendency to underestimate the effect of the double bond on the ionisation of the phenolic hydroxyl. To this end a set of 19 para-substituted vinyl phenols was used. The ionisation constants were measured potentiometrically, and a training set of 10 compounds was selected to build a regression model (r² = 0.987 and S.E. = 0.09). The average error with an external test set of six compounds was 0.19 for our model and 1.27 for the ACD-labs 7.0. Thus, we have been able to significantly improve the existing model for prediction of the ionisation constants of substituted p-vinyl phenols.     

Chemical and statistical considerations in the determination of partition coefficients of weakly ionizable drugs and poisons

Equations have been developed that relate the concentration (or a parameter directly proportional to concentration, such as optical absorbance) of a weakly ionizable solute in a water-immiscible phase, in equilibrium with an aqueous phase, to the pH of the aqueous phase, the partition coefficient of the unionized solute and the phase volume ratio. These relationships have been used in the design of experimental methods for determining partition coefficients, which require measurement of solute concentration in only one phase. Data obtained in this way permit ready recognition of deviations from assumptions made in the development of the model; these assumptions include insolubility of the ionized solute in the water-immiscible phase and lack of interaction between buffer components and solute. Conditions for optimal liquid—liquid extraction of weakly ionizable solutes are more easily recognized. With these techniques, the negative logarithm of the acid dissociation constant (pK′_a) and the logarithm of the octanol—water partition coefficient (log P) have been measured for warfarin (pK′_a = 5.15 ± 0.04; log P = 2.82 ± 0.06), strychnine (pK′_a = 8.29 ± 0.02; log P = 2.23 ± 0.04), phenol (pK′_a = 9.88 ± 0.02; log P = 1.75 ± 0.05), procaine (pK′_a = 8.11 ± 0.04; log P = 1.10 ± 0.08), and ephedrine (pK′_a = 9.92 ± 0.01; log P = 1.65 ± 0.04) at 21°C.     

Drug release responses of zinc ion crosslinked poly(methyl vinyl ether-co-maleic acid) matrix towards microwave

The drug release characteristics of beads made of poly(methyl vinyl ether-co-maleic acid) using Zn²⁺ as the crosslinking agent were investigated with respect to the influence of microwave irradiation. The beads were prepared by an extrusion method with sodium diclofenac as a model water-soluble drug. They were subjected to microwave irradiation at 80 W for 5 and 20 min, and at 300 W for 1 min 20 s and 5 min 20 s. The profiles of drug dissolution, drug content, drug–polymer interaction and polymer–polymer interaction were determined by dissolution testing, drug content assay, differential scanning calorimetry and Fourier transform infrared spectroscopy. Treatment of beads by microwave at varying intensities of irradiation can aid to retard the drug release with a greater reduction extent through treating the beads for a longer duration of irradiation. The treatment of beads by microwave induced the formation of multiple polymeric domains of great strength and extent of polymer–polymer and drug–polymer interaction. The release of drug from beads was retarded via the interplay of OH, NH, CH, (CH₂)_n and CO functional groups of these domains, and was mainly governed by the state of polymer relaxation of the matrix unlike that of the untreated beads of which the release of drug was effected via drug diffusion and polymer relaxation. In comparison to Ca²⁺ crosslinked matrix which exhibited inconsistent drug release retardation behavior under the influence of microwave, the extent and rate of drug released from the Zn²⁺ crosslinked beads were greatly reduced by microwave and the release of drug from these beads was consistently retarded in response to both high and low intensity microwaves.     

Poly(ethylene-co-methyl acrylate) membranes as rate-controlling barriers for drug delivery systems: characterization, mechanical properties and permeability

Poly(ethylene-co-methyl acrylate) (EMA) membranes with different amounts of methyl acrylate (MA) content were studied in terms of the thermal and mechanical properties, swelling and drug permeation. The increase in MA content in the copolymer significantly increased the percentage of elongation and decreased the tensile strength and modulus of elasticity of the membranes. The degree of swelling of the EMA membranes increased with the ethanol composition and MA content. The contact angle of a sessile drop (10 μL of ethanol/water solution) decreased with an increase in the ethanol fraction suggesting that the membrane wettibility increased with the ethanol content. The flux of diltiazem hydrochloride increased from 0.012 to 0.018 mg cm⁻² h⁻¹ with an increase in the MA content from 16.5 to 29.0%. By increasing the ethanol fraction from 0.4 to 1.0, the flux of diltiazem hydrochloride into the membranes with 29.0% MA, increased from 2.56 (±0.09)×10⁻³ to 18.38 (±0.62)×10⁻³ mg cm⁻² h⁻¹. The permeability coefficient increased from 5.85×10⁻⁶ to 3.53×10⁻⁴ cm h⁻¹ with an increase in the ethanol fraction. The flux can also be correlated with the drug solubility in the membrane and ethanol. For example, the solubilities of diltiazem hydrochloride, paracetamol and ibuprofen were 0.64, 6.68 and 504.48 mg cm⁻³ in the membrane, respectively. Under the same conditions, the flux for the above mentioned drugs was 0.08 (±0.01), 0.53 (±0.01) and 45.11 (±2.00) mg cm⁻² h⁻¹.