Formulation study for lansoprazole fast-disintegrating tablet. II. Effect of triethyl citrate on the quality of the products

The purpose of this study was to develop enteric-coated microgranules for the lansoprazole fast-disintegrating tablet (LFDT), which is a rapidly disintegrating tablet containing enteric-coated microgranules. In our previous study, it was clarified that sufficient flexibility of the enteric layer was achieved by the optimized combined ratio of methacrylic acid copolymer dispersion to ethyl acrylate-methyl methacrylate copolymer dispersion and adding the optimized concentration of triethyl citrate to reduce the damage during the compression process. However, since triethyl citrate has an unpleasant bitter taste and is especially incompatible with lansoprazole, it adversely affects the taste and stability of lansoprazole in the enteric-coated microgranules. The enteric layer containing macrogol 6000 was proven useful to improve the unpleasant bitter taste and stability of lansoprazole, because macrogol 6000 does not have an unpleasant bitter taste and is more compatible than triethyl citerate. By covering the inner (first enteric layer) and outer side (third enteric layer) of the enteric layer containing triethyl citrate (second enteric layer) with the enteric layer containing macrogol 6000, we resolved the stability problem of lansoprazole and the unpleasant bitter taste. Finally, we developed enteric-coated microgranules comprising seven layers: 1) core, 2) active compound layer, 3) intermediate layer, 4) first enteric layer, 5) second enteric layer, 6) third enteric layer, and 7) over coating layer. The enteric-coated microgranules have the multiple functions of reducing the damage to the enteric layer during the compression process, improving the stability of lansoprazole, and masking the unpleasant bitter taste.     

Formulation study for lansoprazole fast-disintegrating tablet. III. Design of rapidly disintegrating tablets

Lansoprazole fast-disintegrating tablets (LFDT) are a patient-friendly formulation that rapidly disintegrates in the mouth. LFDT consist of enteric-coated microgranules (mean particle size, approximately 300 microm) and inactive granules. In the design of the inactive granules, mannitol was used as a basic excipient. Microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), and crospovidone were used as binders and disintegrants. A new grade of L-HPC (L-HPC-33), with a hydroxypropoxy group content of 5.0-6.9%, was developed and it has no rough texture due to a decrease in water absorption. It was clarified that L-HPC-33 could be useful as a binder and disintegrant in rapidly disintegrating tablets. LFDT contain enteric-coated microgranules in tablet form. The enteric-coated microgranule content in LFDT affect qualities such as tensile strength, disintegration time in the mouth, and dissolution behavior in the acid stage and in the buffer stage of LFDT. The 47.4% content of the enteric-coated microgranules was selected to give sufficient tensile strength (not less than 30 N/cm(2)), rapid disintegration time in the mouth (not more than 30 s), and dissolution behavior in the acid stage and buffer stage similar to current lansoprazole capsules. Compression force affected the tensile strength and the disintegration time in the mouth, but did not affect the dissolution behavior in the acid and buffer stages.     

All-dry synthesis and coating of methacrylic acid copolymers for controlled release

Initiated chemical vapor deposition (iCVD) is presented as an all-dry synthesis and coating method for applying methacrylic acid copolymers as pH-responsive controlled release layers. iCVD combines the strengths of liquid-phase chemical synthesis with a precision solvent-free chemical vapor deposition environment. Copolymers of methacrylic acid and ethyl acrylate were confirmed by a systematic shift in the carbonyl bond stretching mode with a shift in the comonomer ratio within the copolymer and by the ability to apply the Fineman-Ross copolymerization equation to describe copolymerization kinetics. Copolymers of methacrylic acid and ethylene dimethacrylate showed pH-dependent swelling behavior that was applied to the enteric release of fluorescein and ibuprofen.     

Characterization of layer-by-layer self-assembled multilayer films of diblock copolymer micelles

The in situ layer-by-layer (LbL) self-assembly of low Tg diblock copolymer micelles onto a flat silica substrate is reported. The copolymers used here were a cationic poly(2-(dimethylamino)ethyl methacrylate)-block-poly(2-(diethylamino)ethyl methacrylate) (50qPDMA-PDEA; 50q refers to a mean degree of quaternization of 50 mol % for the PDMA block) and zwitterionic poly(methacrylic acid)-block-poly(2-(diethylamino)ethyl methacrylate) (PMAA-PDEA), which has anionic character at pH 9. Alternate deposition of micelles formed by these two copolymers onto a silica substrate at pH 9 was examined. The in situ LbL buildup of the copolymer micelle films was monitored using zeta potential measurements, optical reflectometry, and a quartz crystal microbalance with dissipation monitoring (QCM-D). For a six layer deposition, complete charge reversal was observed after the addition of each layer. The OR data indicated clearly an increase in adsorbed mass with each additional micelle layer and suggest that some interdiffusion of copolymer chains between layers and/or an increase in the film roughness, and hence in the effective surface area of the micellar multilayers, must take place as the film is built up. QCM-D data indicated that the self-assembled micellar multilayers on a flat silica substrate undergo structural changes over a prolonged period. This is attributed to longer-term interdiffusion of the copolymer chains between the outer two layers after the initial adsorption of each layer is complete. The QCM-D data further suggest that the outer adsorbed layers adopt a progressively more extended conformation, particularly for the higher numbered layers. The morphology of each successive layer was characterized using in situ soft-contact atomic force microscopy, and micelle-like surface aggregates are clearly observed within each layer of the complex film, suggesting the persistence of aggregate structures throughout the multilayer structure.     

Asymmetric porous emulsion film

The formation mechanism of an “asymmetric” porous structure for the film cast from ethyl acrylate-methyl methacrylate copolymer emulsion prepared by emulsifire-free emulsion polymerization was investigated. The formation of this structure was affected by the emulsion stability which was varied by the postaddition of sodium sulfate or sodium dodecyl benzene sulfonate. It is concluded that it is derived from the production of porous skin film at the emulsion-air interface and the precipitation of flocculated particles at the bottom of emulsion during drying process.     

Formation of polyampholyte brushes via controlled radical polymerization and their assembly in solution

We describe the formation of polyampholytic block copolymer brushes and their assembly in solution. Specifically, we employ "surface-initiated" activators regenerated by electron transfer atom transfer radical polymerization (ARGET-ATRP) sequentially to form diblock copolymer grafts comprising blocks of poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) and poly(sodium methacrylate) (PNaMA) on flat impenetrable silica surfaces, i.e., SiO(x)/PNaMA-b-PDMAEMA and SiO(x)/PDMAEMA-b-PNaMA. Protonation of the PNaMA block results in formation of poly(methacrylic acid) (PMAA). We demonstrate that ARGET-ATRP of NaMA provides a convenient route to preparation of PMAA, which is an alternative method to the more traditional approach based on preparing PMAA by polymerizing tert-butyl methacrylate (tBMA) followed by cleavage of the tert-butyl group. We also discuss conformational changes of the individual polyelectrolyte blocks in solution as a function of solution pH by monitoring adsorption behavior of functionalized polystyrene spheres.     

Microstructural Characterization of Diblock Copolymers Formed by Styrene and Different Methacrylic Units

FT-IR, DSC, and NMR techniques allowed the structural characterization of four copolymers formed by styrene and methacrylic units (methacrylic acid (MAA), dimethylamine ethyl methacrylate (DMAEMA), sodium methacrylate (MANa), and 1-hydroxyethyl methacrylate (HEMA). The copolymer composition was studied by Fourier transform-infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR) spectroscopy. The thermal behavior of the block copolymers was analyzed by differential scanning calorimetry (DSC). Three of the four copolymers showed two transitions caused by changes in the polymer heat capacity (ΔCp) of each block. Diffusion-ordered spectroscopy (DOSY) experiments were used to distinguish copolymer from homopolymer mixtures. Finally, the triad-level stereosequences of styrene-methacrylic copolymers were obtained using ¹³C NMR. The results indicate that by increasing the alkyl-substituent length in the methacrylic block, the probability of syndiotactic polymerization increases.     

Emulsion co- and terpolymerization of styrene,methyl methacrylate,and methyl acrylate. I. Experimental determination and model prediction of composition drift and microstructure in batch reactions

In Part I of this series the reactivity ratios of the comonomer pair methyl acrylate-methyl methacrylate were determined with low-conversion bulk polymerizations. It was shown that the binary reactivity ratios of the systems styrene-methyl acrylate, styrene-methyl methacrylate, and methyl acrylate-methyl methacrylate describe composition drift in low-coversion bulk terpolymerizations with these monomers reasonably well. A computer model was developed to simulate the composition drift in emulsion co- and terpolymerizations. The composition drift in two batch emulsion copolymerization systems (styrene-methyl acrylate and methyl acrylate-methyl methacrylate) and one emulsion terpolymerization system (styrene-methyl acrylate-methyl methacrylate) was investigated both experimentally and with the model. Experimental results were compared with model calculations. The copolymer chemical composition distributions (CCD) were determined with gradient polymer elution chromatography (GPEC®). This technique was also used for the first time to obtain information about the extent of composition drift in emulsion terpolymerizations. Cumulative terpolymer compositions were determined with ³H-NMR as a function of conversion and with this information the three-dimensional CCD was obtained. The composition drift was analyzed with respect to free radical copolymerization kinetics (reactivity ratios) and monomer partitioning. It was shown that in most emulsion copolymerizations the composition drift is mainly determined by the reactivity of the monomers and to a lesser extent by monomer partitioning, except in systems where there is a large difference in water solubility. The model predictions for cumulative terpolymer composition as a function of conversion and the three-dimensional terpolymer CCD showed excellent agreement with the experiments. The GPEC® elution chromatogram of the terpolymer was found to be in accordance with the predicted CCD and the experimentally determined CCD. © 1996 John Wiley & Sons, Inc.     

Determination of Plasticizers Commonly Used In Pharmaceutical Dosage Forms by High Performance Liquid Chromatography

Abstract

A simple reversed-phase HPLC method was developed to identify and quantify plasticizers commonly used with polymers present in sustained or controlled release dosage forms. the plasticizers investigated included triethyl citrate, tributyl citrate, acetyl triethyl citrate, dibutyl sebacate, diethyl phthalate, dibutyl phthalate, and triacetin. the plasticizers were detected at 220 nm, the mobile phase being methanol:water (70:30 v/v%). the peak area response was linear over the studied concentration range of 0.5–5.0 mM/L for triethyl citrate, acetyl triethyl citrate, dibutyl sebacate, and triacetin, and 0.005 ? 0.05 mM/L for diethyl phthalate. the recovery from solvent-cast ethyl cellulose and Eudragit RS 100 films was complete. Two pharmaceutical applications of this assay included the quantitation of plasticizers in polymer-coated sugar beads and a leaching study of a water-soluble plasticizer, triethyl citrate, from polymeric films into simulated intestinal fluids.     

Effect of fluorinated groups on photooxidative stability of polymeric protectives applied on marble

Some new protective copolymers and a commercial one have been tested on Candoglia marble, a very low porosity stone. Two of the polymers contained a partially fluorinated methacrylic monomer, 2,2,2 trifluoro ethyl methacrylate (TFEMA), in combination with either an acrylic, methyl acrylate (MA) or a vinyl ether, n-butyl vinyl ether (n-BVE) unit. Two copolymers, ethyl methacrylate/n-butyl vinyl ether and ethyl methacrylate (EMA)/methyl acrylate (Paraloid B72), were non-fluorinated and similar in compositions and molar ratio. The aim of the work is to test the copolymers and compare the performances of fluorinated new polymers with the non fluorinated one and with the largely used commercial product. The results obtained demonstrate that the introduction, even in limited amounts, of fluorine atoms in the side ester groups of methacrylic type polymers really improves their protective effect and the durability of the stone treatments. The best results were obtained with the copolymer TFEM/MA which is the fluorinated homologous of Paraloid B72.     

Control of the Alternating Sequence for N‐Isopropylacrylamide (NIPAM) and Methacrylic Acid Units in a Copolymer by Cyclopolymerization and Transformation of the Cyclopendant Group

An alternating copolymer of methacrylic acid and N‐isopropyl acrylamide (NIPAM) was synthesized by selective cyclopolymerization of a special divinyl monomer and transformation of repeating cyclo‐units in the resultant cyclopolymer. Crucial to the breakthrough is the monomer design in view of two types of cleavable bonds (3° ester and activated ester) in the pendant group of the monomer and the lower reactivity ratio of the two double bonds (methacrylate and electron‐poor acrylate) for the polymerizable groups. The thus‐obtained cyclopolymer was transformed into the alternating copolymer by transformation of the activated ester into amide by isopropyl amine and cleavage of the 3° ester by trifluoroacetic acid. The resultant copolymer showed thermal and pH response in aqueous solution that was different from the 1:1 random copolymer as well as the homopolymers.     

Protein Delivery by Enteric Copolymer Nanoparticles

The release profiles of bovine serum albumin nanoencapsulated into an enteric copolymer (methacrylic acid/ethyl acrylate blended with poly (ethylene glycol)) show an effective protection for this protein from the stringent pH gastric environment. The nanoParticles (nP) yield of about 90% and encapsulation efficiency of 77–78% indicate a successful control of the process. The experimental evidence leads to physical entanglements between PEG and the copolymer be considered as the driving factor to modulate the release.     

在非水溶剂中聚甲基丙烯酸甲酯及其甲基丙烯酸共聚物与Rh6G的相互作用

本文用乙酸乙酯与不同比例乙醇配成混合溶剂, 考察在不同极性的介质中, Rh_6G对聚甲基丙烯酸甲酯及其与甲基丙烯酸共聚物分子形态的影响, 以及聚合物对Rh_6G荧光强度的影响, 发现Rh_6G与聚甲基丙烯酸甲酯没有特殊相互作用, 而与共聚物的相互作用受溶剂的极性影响很大, 随着极性增加, 从氢键作用过渡到静电作用。     

Development and evaluation of orally disintegrating tablets (ODTs) containing Ibuprofen granules prepared by hot melt extrusion

In the current study Ibuprofen was embedded in a methacrylate copolymer (Eudragit^® EPO) matrix to produce solid dispersions by hot-melt extrusion (HME) processing. The obtained granules were incorporated in orally disintegrating tablets (ODTs). The tablets were developed by varying the ratio of superdisintegrants such as sodium croscarmellose and crosslinked polyvinylpyrrolidone grades while a direct compression process was used to compress the ODTs under various compaction forces to optimize tablet robustness. The properties of the compressed tablets which included porosity, hardness, friability and dissolution profiles were further evaluated and compared with Nurofen^® Meltlet ODTs. The taste and sensory evaluation in human volunteers demonstrated excellence in masking the bitter active and improved tablet palatability.     

Preparation of novel alkaline pH‐responsive copolymers for the formation of recyclable aqueous two‐phase systems and their application in the extraction of lincomycin

Aqueous two‐phase systems have potential industrial application in bioseparation and biocatalysis engineering; however, their practical application is limited primarily because the copolymers involved in the formation of aqueous two‐phase systems cannot be recovered. In this study, two novel alkaline pH‐responsive copolymers were synthesized and examined for the extraction of lincomycin. The two copolymers could form a novel alkaline aqueous two‐phase systems when their concentrations were both 6% w/w and the pH was 8.4(±0.1)–8.7(±0.1). One copolymer was synthesized using acrylic acid, 2‐(dimethylamino)ethyl methacrylate, and butyl methacrylate as monomers. Moreover, 98.8% of the copolymer could be recovered by adjusting the solution pH to its isoelectric point (pH 6.29). The other copolymer was synthesized using the monomers methacrylic acid, 2‐(dimethylamino)ethyl methacrylate, and methyl methacrylate. In this case, 96.7% of the copolymer could be recovered by adjusting the solution pH to 7.19. The optimal partition coefficient of lincomycin was 0.17 at 30°C in the presence of 10 mM KBr and 5.5 at 40°C in the presence of 80 mM Ti(SO₄)₂ using the novel alkaline aqueous two‐phase systems.     

Polyacrylamide gels with electrostatic functional groups for the molecular imprinting of lysozyme

The system of polyacrylamide incorporated with methacrylic acid and 2-(dimethylamino)ethyl methacrylate was studied for the possibility of imprinting of lysozyme. The results show that approximately 27% (w/w) of the lysozyme template was not able to be extracted from the molecularly imprinted acrylamide polymers. The amount of the lysozyme template able to be extracted was increased by the addition of methacrylic acid. The molecularly imprinted polymer (MIP), which was prepared with 0.573 M acrylamide, 0.573 M methacrylic acid and 0.573 M 2-(dimethylamino)ethyl methacrylate at a total solution concentration of 20% (w/w), was able to adsorb 83% more lysozyme than the non-imprinted polymer. Selectivity of MIP was also studied.     

Effect of the chemical nature of metal oxide on adhesion to the polyacrylate matrix in filled nanocomposites

The morphology, particle size, and thermochemical properties of the surface of oxides Al₂O₃, NiO, TiO₂, ZnO, and ZrO₂ obtained by the wire electroexplosion method were studied. The nanoparticles are spherical, with a mean diameter of 54–86 nm depending on the nature of the oxide. The hydrophilicity of the surface of metal oxide nanopowders was found to change in the series NiO-ZrO₂-TiO₂-ZnO-Al₂O₃. Nanocomposites with widely varied compositions were obtained from butyl methacrylate copolymer with 5 wt % methacrylic acid and the oxides under study. The enthalpies of dissolution of the composites in chloroform were determined by Calvet calorimetry. The enthalpies of copolymer mixing with oxides were calculated using the thermochemical cycle. The limiting enthalpies of copolymer adhesion to the oxide surface were calculated from the thermochemical data. The limiting adhesion enthalpy was shown to be negative for all oxides under study; these values decreased in magnitude as the surface hydrophilicity increased. The results were analyzed from the viewpoint of balance between the specific and dispersion interactions at the interface.     

Characteristic changes of pH during the alkalization of latex dispersions of the ethyl acrylate — methacrylic acid copolymers

The titration curves of latex dispersions of ethyl acrylate — methacrylic acid copolymers have a rather complex shape which indicates a strong dependence of the apparent dissociation constant of carboxylic groups on the degree of neutralization and copolymer composition. These dependences seem to be related to changes in the macroscopic structure (swelling and disintegration) of dispersion particles during alkalization.     

Effects of altered reaction conditions on the synthesis of polyurethane-poly(2,2,2-trifluoroethyl methacrylate) triblock copolymer aqueous dispersion

Polyurethane-poly(2,2,2-trifluoroethyl methacrylate) (PU-PTFEMA) triblock copolymer aqueous dispersions were synthesized by three-step polymerization. In the first step, polyurethane prepolymers (PU) based on 2,4-toluene diisocyanate (TDI), polyether binary alcohol (N₂₂₀), α,α-dimethylol propionic acid (DMPA), hydroxypropyl acrylic acid (HPA), and butanediol (BDO) were prepared with butanediol as the chain extender and methylethylketon as solvent. The next step involved neutralization and dispersion in water, where prepolymers were neutralised by the addition of triethylamine (TEA). The last step was the seeded emulsion polymerization, where PU emulsion was used as seed, kalium persulfate (KPS) as initiator and 2,2,2-trifluoroethyl methacrylate (TFEMA) as comonomer. Factors influencing the synthesis of PU-PTFEMA copolymer aqueous dispersion were studied. Experimental data indicate that factors influencing the synthesis of PU-PTFEMA copolymer aqueous dispersion mainly involve reaction temperature, reaction time, the concentration of initiator, DMPA content, TFEMA content. Rotational viscometer and dynamic light scattering (DLS) were used to characterize the properties of copolymer aqueous dispersion.     

The copolymerisation of methyl and ethyl methacrylate in supercritical carbon dioxide

This paper reports the free radical dispersion copolymerisation of methyl and ethyl methacrylate in supercritical carbon dioxide. The polymerisation uses a poly(dimethyl siloxane) monomethacrylate macromonomer as the stabiliser. A range of different reaction times was investigated in order to probe the amount of each monomer incorporated in the copolymer. Analysis by ¹H NMR spectroscopy reveals that the monomers behave as in conventional solvents to form a random copolymer. The effect of varying the initiator concentration (initiator 2,2′‐azobisisobutyronitrile, AIBN) on the composition and molecular weights of the resultant copolymers has also been studied.