Polymer Hydroxypropyl Methylcellulose Research Articles

Targeting enteral endocrinal L-cells with dietary carbohydrates, by increasing the availability of miglitol in the intestinal lumen, leads to multi-fold enhancement of plasma glucagon-like peptide-1 levels in non-diabetic canines

The principle aim of this study was to design a controlled release (CR), bioadhesive formulation of miglitol (in form of pellets) which would regulate the post-prandial glucose levels via reversible inhibition of α-glucosidase enzyme as well as by modulating the glucagon-like peptide-1 (GLP-1) pathway in non-diabetic canines. A multilayered pellet formulation which was both bioadhesive (because of hydroxy propyl methyl cellulose polymer) and CR (because of the ethyl cellulose layer) was formulated. We report a novel finding that the CR formulation of miglitol (S3) induced a 2.2-fold elevation in the Cmax as well as the overall AUC0–24 of GLP-1 values in comparison to the non-CR (immediate release (IR) formulation). The S3 formulation also resulted in better, steady, and prolonged control of glucose levels over a time period of 7 h in comparison to the IR formulation possibly due to combination of both, prolonged inhibition of the α-glucosidase enzyme and enhanced plasma GLP-1 levels. The S3 formulation was stable with no changes in the dissolution profiles at both of the stability conditions tested, 25°C/60% RH and 40°C/75% RH. Aqueous polymeric coating of the pellets (in contrast to coating using organic solvents) resulted morphologically in a uniform polymeric film and also releases profiles with lower burst effect. Curing played a significant role in determining release profile of the pellets, prepared by aqueous polymeric coating method.

Nasal in situ gel containing hydroxy propyl β-cyclodextrin inclusion complex of artemether: development and in vitro evaluation

The objective of the present investigation was to explore the formulation and evaluation of in situ gel for the nasal delivery of artemether (ARM), a poorly water-soluble antimalarial agent using temperature induced gelation technique using Pluronic with mucoadhesive polymer Hydroxy Propyl Methyl Cellulose (HPMC) K4M in different ratios. Initially, due to low water solubility, an inclusion complex of the antimalarial artemether (ARM) in hydroxypropyl-β-cyclodextrin (HPβCD) was prepared and characterized. The in situ gels so prepared were characterized for its gelation properties, viscosity, gel strength, mucoadhesion, drug content, drug release rate and for its histopathological studies. Pluronic and HPMC based in situ gel (PLH2) showed the effective gelation, viscosity, gel strength and drug release properties along with good mucoadhesive strength, it is further subjected for stability studies carried out at 30 ± 2 °C and 60 ± 5% RH for 90 days in order to know the influence of temperature and relative humidity on drug content and on drug release profile. Histological examination of formulations did not show any remarkable damage to nasal mucosa. The formulation also retained the good stability at accelerated conditions over the period of 90 days. Owing to these properties it can be used as an effective delivery system for the nasal route. These in situ gelling systems would be definitely useful for cerebral malaria.

Development of Sustained Release Capsules Containing “Coated Matrix Granules of Metoprolol Tartrate”

The objective of this investigation was to prepare sustained release capsule containing coated matrix granules of metoprolol tartrate and to study its in vitro release and in vivo absorption. The design of dosage form was performed by choosing hydrophilic hydroxypropyl methyl cellulose (HPMC K100M) and hydrophobic ethyl cellulose (EC) polymers as matrix builders and Eudragit® RL/RS as coating polymers. Granules were prepared by composing drug with HPMC K100M, EC, dicalcium phosphate by wet granulation method with subsequent coating. Optimized formulation of metoprolol tartrate was formed by using 30% HPMC K100M, 20% EC, and ratio of Eudragit® RS/RL as 97.5:2.5 at 25% coating level. Capsules were filled with free flowing optimized granules of uniform drug content. This extended the release period upto 12 h in vitro study. Similarity factor and mean dissolution time were also reported to compare various dissolution profiles. The network formed by HPMC and EC had been coupled satisfactorily with the controlled resistance offered by Eudragit® RS. The release mechanism of capsules followed Korsemeyer-Peppas model that indicated significant contribution of erosion effect of hydrophilic polymer. Biopharmaceutical study of this optimized dosage form in rabbit model showed 10 h prolonged drug release in vivo. A close correlation (R(2) = 0.9434) was established between the in vitro release and the in vivo absorption of drug. The results suggested that wet granulation with subsequent coating by fluidized bed technique, is a suitable method to formulate sustained release capsules of metoprolol tartrate and it can perform therapeutically better than conventional immediate release dosage form.

Phase Behavior of Nonionic Polymer Hydroxypropylmethyl Cellulose: Effect of Gemini and Single-Chain Surfactants on the Energetics at the Cloud Point

Nonionic cellulose ether−water systems have a characteristic feature of phase separation at certain temperatures, also termed the cloud point. The effect of various surfactants as additives on the phase behavior of nonionic cellulose ether, hydroxypropylmethyl cellulose (HPMC), has been studied. It was found that in the presence of ionic surfactants the cloud point (TCP) of HPMC decreased when small amounts of surfactant were added, and at higher concentration it increased. In the case of alkyltrimethylammonium bromides, surfactants with a longer alkyl chain (cetyltrimethylammonium bromide, CTAB, and tetradecyltrimethylammonium bromide, TTAB) influenced the TCP much more than that with a shorter alkyl chain (dodecyltrimethylammonium bromide, DTAB). Cetylpyridinium chloride (CPC) and cetylpyridinium bromide (CPB) were utilized to see the counterion effect on the TCP of polymer. Anionic surfactant sodium dodecyl sulfate (SDS) was found to be more effective as compared to its cationic counterpart with the sa...

Effect of microwave irradiation on the hydroxypropyl methylcellulose powder and its hydrogel studied by Magnetic Resonance Imaging

Proton Magnetic Resonance Imaging (MRI) has been used to study the physical changes of hydroxypropyl methylcellulose (HPMC) hydrogels due to microwave irradiation of the polymer. The proton one-dimensional images, derived from relaxation, spin density and diffusion-weighted spin-echo experiments, provide insights on the dynamics of water and the motional state of the polymer inside the hydrogels. The obtained results indicate that the microwave irradiation causes the breaking of the HPMC polymer–hydrogen bonding network in HPMC powder which influences the dynamics of water and polymer chains within its hydrogels. In order to explain the observed spin–spin relaxation time in hydrogels composed of irradiated polymers, we have to assume that in addition to a fast exchange between the free and bound state of water also a rapid proton exchange between the water protons and the hydrogen of hydroxyl groups of side chains of the monomeric units of HPMC polymer is a major transverse relaxation mechanism.

Determination of Water Penetration and Drug Concentration Profiles in HPMC-Based Matrix Tablets by Near Infrared Chemical Imaging

This work describes methodologies based on near infrared chemical imaging (NIR CI) and chemometric data analysis for studying hydration behaviors of prolonged release tablets, which contain a high solubility drug at high load and a hydrophilic polymer hydroxypropylmethylcellulose (HPMC). Hydration studies were performed by suspending the tablets in water at ambient temperature. The hydrated tablets were then dissected and scanned by NIR CI. Single wavelength images were obtained for accurately measuring radial dimension of the gel layer and size of the tablet core. By performing a principal component analysis (PCA), the phenomenon of polymer phase transition from the glassy state to rubbery state was detected and visualized. Partial least squares (PLS) models were created for quantitative analysis of the active pharmaceutical ingredient (API) and relative concentration of water in the hydrated tablets. The API concentration profiles are suitable for defining the swelling front in hydrated tablets. Because the NIR CI results are pixel-specific and each pixel has its unique coordinates, it is feasible to analyze and present the results according to spatial locations. The physical and chemical changes at the swelling/diffusion fronts can be demonstrated by overlaying the PCA and PLS results, which shed light on the release mechanism.

In-vitro and in-vivo erosion profiles of hydroxypropylmethylcellulose (HPMC) matrix tablets

The purpose of this study was to evaluate and compare the in-vitro and in-vivo erosion profiles of two tablet formulations primarily consisting of hydroxypropylmethylcellulose (HPMC) and lactose. HPMC was used at concentrations below and above the reported values for polymer percolation threshold in controlled release matrix formulations: 20 and 40% (w/w) HPMC. In-vitro erosion behaviour was studied using traditional gravimetric and scintigraphic methods, with radiolabelled charcoal used as a marker to quantify erosion profiles in scintigraphic studies. Six healthy male subjects participated in a randomised crossover scintigraphic erosion study. Both in-vitro and in-vivo erosion profiles determined using the gravimetric and/or scintigraphic method for matrix tablets were dependent upon the concentration of HPMC, and erosion was faster for tablets containing 20% (w/w) HPMC than those containing 40% (w/w) HPMC. Good correlation was found between in-vitro gravimetric and scintigraphic erosion profiles for both tablets. Tablets containing 40% (w/w) HPMC (polymer level above percolation threshold) demonstrated robust in-vivo performance and showed stronger correlation with in-vitro erosion profiles. The study demonstrated that a matrix formulation with a lower concentration of HPMC and higher lactose concentration is more likely to perform poorly in the in-vivo environment.

Predictable pulsatile release of tramadol hydrochloride for chronotherapeutics of arthritis

The present investigation deals with the development of a pH and time-dependent press-coated pulsatile drug delivery system for delivering drugs into the colon. The system consists of a drug containing core, coated by a combination of natural polymer Delonix regia gum (DRG) and hydroxypropyl methylcellulose (HPMC K4M) in various proportions, which controls the onset of release. The whole system was coated with methacrylic acid copolymers, which not only prevents the drug release in the stomach, but also prolongs the lag time. Tramadol HCl was used as a model drug and varying combinations of DRG and HPMC K4M were used to achieve the desired lag time before rapid and complete release of the drug in the colon. It was observed that the lag time depends on the coating ratio of DRG to HPMC and also on press coating weight. Drug release was found to be increased by 15–30% in the presence of colonic microbial flora. The results showed the capability of the system in achieving pulsatile release for a programmable period of time and pH-dependent release to attain colon-targeted delivery.

Gas permeation related to the moisture sorption in films of glassy hydrophilic polymers

AbstractThe purpose of this article is to elucidate the effect of integral sorption of moisture on gas permeation in glassy hydrophilic polymers. The oxygen and the simultaneous moisture sorption into various hydroxypropyl methylcellulose (HPMC) films were measured under a wide range of relative humidities using sorption analyzer equipment. Correspondingly, the oxygen permeability at different ambient conditions was measured using an oxygen detector. The solubility of oxygen in the HPMC film was found to be affected by the amount of water and therefore by the water state. At low moisture content, the water molecules are present as bound water, which promotes the sorption of oxygen in the HPMC films. At moisture content higher than 5%, water clusters are rapidly formed, which increase the affinity of HPMC polymer towards water rather than towards oxygen molecules, resulting in a decrease of oxygen solubility in the polymer. This was found to be the governing factor for the reduction in the oxygen permeability in glassy HPMC films at high water activity. This proposes a specific interaction between moisture sorption and oxygen transport in coating films like HPMC, which is of important aspect in the coating design and formulation. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

FORMULATION OF ORAL MUCOADHESIVE TABLETS OF TERBUTALINE SULPHATE USING SOME NATURAL MATERIALS AND IN VITRO-IN VIVO EVALUATION

Mucoadhesive polymers that bind to the gastric mucin or epithelial cell surface are useful in drug delivery for the purpose of increasing the intimacy and duration of contact of drug with the absorbing membrane. Several synthetic polymers are in use for this purpose. Since the biodegradability of the synthetic polymers are questionable, in this investigation an oral mucoadhesive controlled delivery system has been developed for terbutaline sulphate (TS) using natural mucoadhesive materials extracted from the edible fruits like Zizyphus mauritiana (ZM) and Aegle marmelos (Linn.) Cor. (AM) that have better mucoadhesive property than synthetic polymer hydroxypropylmethylcellulose K4M (HPMC K4M). The in vitro adhesive and mucoadhesive strength of mucoadhesive materials extracted from the fruits of ZM and AM were evaluated and compared with HPMCK4M using both Share Stress and Wilhelmy Plate. Different formulations of oral mucoadhesive coated TS tablets were prepared using these natural materials and compared with tablets prepared with HPMCK4M and hardness, thickness, friability, weight variation and drug content of tablets were tested. The in vitro release of TS was studied in buffer pH 7.2 at 370C 0.50C. Tablets were orally administered to rabbits and blood plasma concentration of TS was determined using HPLC. It was found that mucoadhesive materials extracted from the fruits of ZM and AM exhibited better adhesiveness and mucoadhesiveness as compared with the HPMC- K4M. The in vitro study of TS exhibited showed greater drug release profile for tablets prepared with natural materials than synthetic polymers and confirmed with in vivo study. In vitro and in vivo correlation showed the same release profile.

Design, In Vitro Evaluation and Release Rate Kinetics of Matrix Type Sustained Release Tablet Containing Aceclofenac

Enteric coated aceclofenac matrix tablets were formulated as sustained release tablets employing hydroxypropyl methylcellulose polymer and the sustained release behavior of the fabricated tablets were investigated. Sustained release matrix tablets containing 200 mg aceclofenac were developed using different drug polymer ratios of hydroxypropyl methylcellulose. Tablets were prepared by wet granulation technique. Formulation was optimized on the basis of acceptable tablet properties and in vitro drug release. The resulting formulations produced monolithic tablets with optimum hardness, uniform thickness, consistent weight uniformity and low friability. Aceclofenac release from tablets was extended from 16 to 24 h from formulated batches. The results of dissolution studies indicated that formulation F-V (drug to polymer 1:0.470), the most successful of the study, exhibited drug release pattern very close to theoretical release profile. Applying kinetic equation models to F-V batch it was found to be followed Higuchi model, as the plots showed high linearity, with correlation coefficient (R) value 0.9911.Therefore, the formulation F-V tablets showed diffusion dominated drug release. The accelerated stability study showed that the shelf life 40 months (batch F-V) and promising drug storage results.

Practical application to time indicator of a novel white film formed by interaction of calcium salts with hydroxypropyl methylcellulose

We have found that a cast film forms a white film when an aqueous solution comprising hydroxypropyl methylcellulose (HPMC) and calcium salts such as calcium lactate pentahydrate (CLP) and calcium chloride (CaCl 2) is used. In contrast, the obtained white film was transformed into a transparent film by the addition of purified water. The transformation time for the change from the white film to the transparent film was dependent on film thickness. The relationship between the transformation time and the film thickness was significantly correlated, and it was found that the white film could be adaptable as time indicator. The formation of a white film comprising HPMC and calcium salts was strongly dependent on temperature conditions. The objective of the present study is to investigate the mechanism of the formation of this white film because of the interaction between HPMC and calcium salts. The DSC and XRPD results indicate that the calcium salts affect the HPMC polymer phase in the cast film comprising HPMC and calcium salts. By carrying out attenuated total reflection Fourier transform infrared (ATR FT-IR) analysis, we found that the white film could be formed by the calcium salts affecting the region associated with the C–O–C, C–O, and CH 3 stretching of the HPMC polymer phase.

Transdermal Delivery of Ketorolac

A reservoir type transdermal patch for delivery of ketorolac, a potent analgesic agent was studied. The low permeability of skin is the rate-limiting step for delivery of most of the drugs. Studies were carried out to investigate the effect of permeation enhancers on the in vitro permeation of ketorolac across rat skin. The reservoir type transdermal patch was fabricated and the core was filled with gel system of a non ionic polymer HPMC (hydroxypropyl methyl cellulose) formulated in PBS (phosphate buffer saline) solution of pH of 5.4 along with isopropyl alcohol at 25% w/w concentration. Various permeation enhancers' viz. dimethyl sulphoxide, d-limonene, eucalyptus oil and transcutol (diethylene glycol monoethyl ether) were incorporated into the gel system. Permeation enhancement of ketorolac with different enhancers followed the order eucalyptus oil> transcutol> DMSO> d-limonene. Cyclic terpene containing eucalyptus oil was found to be the most promising chemical permeation enhancer for transdermal delivery of ketorolac. The increase in concentration of eucalyptus oil further enhanced drug permeation with maximum flux being achieved at 10% w/w of 66.38 microg/cm(2)/h. Further enhancement of permeation rate of ketorolac across skin was attained by application of abrading gel containing crushed apricot seed onto the skin. There was 5.16 times enhancement and flux of 93.10 microg/cm(2)/h was attained. A reservoir type transdermal patch for delivery of ketorolac thus appears to be feasible of delivering ketorolac across skin.

Thermal and morphological properties of SA/HPMC blends

AbstractSodium alginate (SA) was blended with varying amounts of hydroxypropyl methylcellulose (HPMC) viz., 10, 20, and 30 wt % by solution casting process. Thus, the obtained blends were characterized by using different analytical techniques such as differential scanning calorimetry (DSC), thermogravimetric analyzer (TGA), Fourier transform infrared spectroscopy (FTIR), and scanning electron microcopy (SEM). FTIR studies reveal the hydrogen bond formation between hydroxyl groups of SA and HPMC polymer chains. DSC analysis shows single glass transition temperature (Tg) for SA/HPMC blends indicating compatibility and physical interaction between SA and HPMC polymer chains. TGA analysis indicates variation of thermal stability of SA with change in compositions of HPMC. SEM studies reveal uniform distribution of second phase in the blends. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009

Entrapment of ketorolac tromethamine in polymeric vehicle for controlled drug delivery

The most common method for applying a drug in to the eye is to formulate the drug in the form of an eye drop, but this method is not considered ideal for ocular delivery of drug because of poor bioavailability arising from precorneal loss processes, this loss of drug from the precorneal area is a net effect of drainage, tear secretion and noncorneal absorption. Following the above lead we tried to improve the ocular bioavailability by increasing the corneal contact time and the feasible way was to formulate a drug with mucoadhesive/viscosity imparting agents. The adhesive strength of various polymers on corneal surface was studied with the help of self modified Franz diffusion cell and freshly excised goat/bovine cornea. The polymers hydroxypropylmethylcellulose, carboxymethylcellulose sodium, Eudragit type E/RL/RS, Carbopol ETD 2020 and Carbopol 934 National Formulary were formulated with drug, ketorolac tromethamine. The adhesive strength of polymers on corneal surface and permeation characteristics of drug through cornea were investigated by using above said formulations. Eudragit type E/RL/RS did not show any improvement in mucoadhesion, but the formulations containing Carbopol ETD 2020 and Carbopol 934 national formulary showed good mucoadhesion on corneal surface in the concentration as low as 0.75%. The mucoadhesive strength was also evaluated using the combination of Carbopol acrylates/C 10-30 alkylacrylate with allylpentaerithrital and preservative benzalkonium chloride, which also resulted in good mucoadhesion with improved corneal permeation. Observations made in this study indicate the potentiality of the ophthalmic formulations containing mucoadhesive/viscosity imparting agents.

A simple and sensitive transient ITP method for on‐chip analysis of PCR samples

We present a sensitive, simple and robust on-chip transient ITP (TITP) method for the analysis of polymerase chain reaction (PCR) samples. This TITP analysis was performed on a poly (methyl methacrylate) microchip with cross structure. The PCR sample was injected into a 4 mm free-solution buffer channel to increase sample loading. When applied separation voltage, the sample ions were stacked by TITP using chloride ions in the sample matrix as the leading ions and HEPES in the background electrolyte as the terminating ions. The stacked sample plug was then separated by zone electrophoresis (ZE) in hydroxypropylmethyl cellulose polymer. The whole operation was carried out in single background electrolyte. Sample injection, preconcentration / separation were performed continuously with the sequential switching of voltage. By injection of the sample into the free-solution buffer channel, sampling bias was avoided and the injection time was reduced. With this TITP method, the detection sensitivity was improved without loss of resolution, a 20-fold signal enhancement was achieved and the average limit of detection was estimated to be 0.24 pg/microL (S/N = 3). The TITP method is simple, fast and sensitive, thus is well suited to direct analysis of the highly saline PCR samples.

Co-solvent Evaporation Method for Enhancement of Solubility and Dissolution Rate of Poorly Aqueous Soluble Drug Simvastatin: In vitro–In vivo Evaluation

A number of synthesized chemical molecules suffer from low aqueous solubility problems. Enhancement of aqueous solubility, dissolution rate, and bioavailability of drug is a very challenging task in drug development. In the present study, solubility and dissolution of poorly aqueous soluble drug simvastatin (SIM) was enhanced using hydrophilic, low viscosity grade polymer hydroxypropyl methylcellulose (HPMC K(3)LV). The co-solvent evaporation method was developed for efficient encapsulation of hydrophobic drug in polymer micelles of HPMC K(3)LV. Spray drying and rotaevaporation method were applied for solvent evaporation. Co-solvent-evaporated mixture in solid state was determined by differential scanning calorimetry (DSC), X-ray diffraction studies (XRD), scanning electron microscopy, and Fourier-transform infrared spectroscopy. In vitro-in vivo studies were performed on co-solvent-evaporated mixture and compared with SIM. In vivo study was conducted on healthy albino rats (Wister strain), and formulations were administered by oral route. Results of the study show the conversion of crystalline form of SIM into amorphous form. The dissolution rate was remarkably increased in co-solvent-evaporated mixtures compared to SIM. co-solvent-evaporated mixtures showed better reduction in total cholesterol and triglyceride levels than the SIM. The low-viscosity grade HPMC acts as a surfactant, which enhances the wetting of drug and thus improves the solubility of drug. The co-solvent evaporation method provides good encapsulation efficiency and produces amorphous form of SIM, which gave better solubility and dissolution than the crystalline SIM.

Hydroxypropyl Methylcellulose Acetate Succinate-Based Spray-Dried Dispersions: An Overview

Spray-dried dispersions (SDDs) of low-solubility drugs have been prepared using the polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS). For a variety of drug structures, these SDDs provide supersaturation in in vitro dissolution determinations and large bioavailability increases in vivo. In bile-salt/lecithin in vitro solutions, these SDDs provide amorphous drug/polymer colloids and an increased concentration of free drug and drug in micelles relative to crystalline or amorphous drug. As dry powders, the SDDs are a single amorphous phase in which the drug remains amorphous and dispersed and does not crystallize over storage times relevant for practical drug products. A melting temperature (Tm)/glass-transition temperature (Tg) (K/K) versus log P map for 139 compounds formulated as SDDs provides a perspective on an appropriate formulation strategy for low-solubility drugs with various physical properties.

PH-Controlled drug release from mesoporous silica tablets coated with hydroxypropyl methylcellulose phthalate

A simple pH-controlled drug release system was successfully prepared by coating pH-sensitive polymer hydroxypropyl methylcellulose phthalate (HPMCP) on drug-loaded mesoporous SBA-15 tablet. Using famotidine (Famo) as a model drug, the effects of coating times and drying temperature on drug release were studied in detail to optimize the drug release system. In simulated gastric fluid (SGF, pH 1.2), it took only 2 h for Famo to be completely released from mesoporous silica tablet without HPMCP coating. Also in SGF, with the increase of coating times and drying temperature, the release of Famo was greatly delayed by HPMCP coating. For the tablet with twice coating of HPMCP and dried at 80 °C, only 4.0 wt.% of Famo could be released within 4 h. However, in simulated intestinal fluid (SIF, pH 7.4), HPMCP coating did not show obvious effect on the release of Famo.

Oral matrix tablet formulations for concomitant controlled release of anti-tubercular drugs: Design and in vitro evaluations

The aim of the present investigation was to develop controlled release (C.R.) matrix tablet formulations of rifampicin and isoniazid combination, to study the design parameters and to evaluate in vitro release characteristics. In the present study, a series of formulations were developed with different release rates and duration using hydrophilic polymers hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). The duration of rifampicin and isoniazid release could be tailored by varying the polymer type, polymer ratio and processing techniques. Further, Eudragit L100-55 was incorporated in the matrix tablets to compensate for the pH-dependent release of rifampicin. Rifampicin was found to follow linear release profile with time from HPMC formulations. In case of formulations with HPC, there was an initial higher release in simulated gastric fluid (SGF) followed by zero order release profiles in simulated intestinal fluid (SIFsp) for rifampicin. The release of isoniazid was found to be predominantly by diffusion mechanism in case of HPMC formulations, and with HPC formulations release was due to combination of diffusion and erosion. The initial release was sufficiently higher for rifampicin from HPC thus ruling out the need to incorporate a separate loading dose. The initial release was sufficiently higher for isoniazid in all formulations. Thus, with the use of suitable polymer or polymer combinations and with the proper optimization of the processing techniques it was possible to design the C.R. formulations of rifampicin and isoniazid combination that could provide the sufficient initial release and release extension up to 24 h for both the drugs despite of the wide variations in their physicochemical properties.