EDTMP Research Articles

A preclinical investigation of the saturation and dosimetry of 153Sm-DOTMP as a bone-seeking radiopharmaceutical

The therapeutic potential of the bone-seeking radiopharmaceutical 153Sm-labeled 1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid (153Sm-DOTMP) was assessed by measuring its dosage-dependent skeletal uptake at two chelant-to-metal ratios and its source organ residence times at a chelant-to-metal ratio of 1.5:1. A similar agent, 153Sm-labeled ethylenediaminetetramethylenephosphonic acid (153Sm-EDTMP), has been reported to exhibit dosage-limiting skeletal saturation. Sm-DOTMP was prepared with tracer activity of 153Sm and sufficient stable, unenriched Sm to simulate different activities. Cohorts of seven 280-g Sprague-Dawley rats were administered the equivalent of 296, 592, 888, 1184 and 1480 MBq (8, 16, 24, 32 and 40 mCi) at a fixed chelant-to-metal ratio of 1.5:1 and euthanized 3 h after administration. Cohorts of three 128-g Sprague-Dawley rats were administered equivalent dosages of 10.4, 592 and 888 (0.28, 16 and 32 mCi) at a fixed chelant-to-metal ratio of 270:1 and euthanized 2 h after administration. A simulated activity of 1480 MBq (40 mCi) at a chelant-to-metal ratio of 1.5:1 was administered to cohorts of seven rats that were euthanized at 2, 4, 24 or 48 h postadministration. The heart, lungs, liver, spleen, kidneys, small intestine, large intestine, urinary bladder, muscle and a femur were excised, weighed and counted. The data were analyzed to determine skeletal uptake and source organ residence times. No statistically significant skeletal saturation was observed up to human-equivalent dosages of 370 GBq (10 Ci) at a chelant-to-metal ratio of 1.5:1, but the skeletal uptake dropped by 40% over the range of dosages at a chelant-to-metal ratio of 270:1. At a chelant-to-metal ratio of 1.5:1, the preferred ratio, the skeletal uptake fraction in rats was 0.408 (95% confidence interval 0.396-0.419) with an effective half-life of 47.3 h (95% confidence interval 42.3-53.7; the physical half-life of 153Sm is 46.3 h). Extrapolating to an adult human model, 52.9 GBq (1.43 Ci) of 153Sm-DOTMP would deliver 40 Gy to the red marrow. 153Sm-DOTMP has dosimetry equivalent to that of 153Sm-EDTMP at low dosages, yet with no skeletal saturation at higher administered activities.

Improvement of electrocatalytic performance of carbon supported Pd anodic catalyst in direct formic acid fuel cell by ethylenediamine-tetramethylene phosphonic acid

The direct formic acid fuel cell (DFAFC) has two major shortcomings that limit its lifespan and performance: (i) the poor electrocatalytic stability of the carbon supported Pd (Pd/C) catalyst for the oxidation of formic acid and (ii) rapid decomposition of formic acid over the Pd/C catalyst. To solve the problems, the Pd/C catalyst is modified with ethylenediamine-tetramethylene phosphonic acid (EDTMP). The resulting catalyst is designated as Pd/C-E catalyst. It is found that the Pd/C-E catalyst can inhibit the decomposition of formic acid and promote the oxidation of formic acid through the direct pathway. Consistently, the Pd/C-E catalyst is significantly protected from CO poisoning. As compared to the Pd/C catalyst, the electrocatalytic performance of the Pd/C-E catalyst is significantly superior. These results provide the first proof of the concept that DFAFC can be significantly improved by Pd/C-E catalyst.

Production, Quality Control and Pharmacokinetic Studies of (177)Lu-EDTMP for Human Bone Pain Palliation Therapy Trials.

Developing new bone pain palliation agents is a mandate in handling end-stage cancer patients around the world. Possibly, Lu-177 ethylenediaminetetramethylene phosphonic acid ((177)Lu-EDTMP) is a therapeutic agent which can be widely used in bone palliation therapy. In this study, (177)Lu-EDTMP complex was prepared successfully using synthesized EDTMP ligand and (177)LuCl3. Lu-177 chloride was obtained by thermal neutron irradiation (4 × 10(13) n.cm(-2)s(-1)) of natural Lu2O3 samples. Radiochemical purity of (177)Lu-EDTMP was determined by ITLC (more than 99%). Stability studies of the final preparations in the presence of human serum were performed. The biodistribution of (177)Lu-EDTMP and (177)LuCl3 in wild-type rats was studied by SPECT imaging. A comparative accumulation study for (177)Lu-EDTMP and (177)LuCl3 was performed for vital organs up to 7 days. The complex was obtained in high radiochemical purity (more than 99%). The complex was stable in vitro in presence of human serum as well as final formulation. Significant bone uptake (> 70%) was observed for the radiopharmaceutical. Due to better physical properties of Lu-177 compared to Sm-153 and acceptable biodistribution results of the compound, (177)Lu-EDTMP seemed to be an interesting new candidate for clinical trials for bone pain palliation therapy.

Ethanol electrooxidation on carbon-supported Pt nanoparticles catalyst prepared using complexing self-reduction method

A novel self-reduction of Pt-complex method is used to prepare Vulcan XC-72 carbon-supported Pt nanoparticles (Pt/C) catalysts by employing ethylenediamine-tetramethylene phosphonic acid (EDTMP) as a complexing reagent. During the preparation of Pt/C catalysts, the particle size of Pt nanoparticles (Pt–NPs) can be controlled effectively in the range of 1.7–13.5 nm by adjusting reaction solution pH values. TEM images demonstrate that the Pt–NPs well disperse on the Vulcan XC-72 carbon support with a relatively narrow particle size distribution by using the complex self-reduction method. Therefore, the Pt/C catalysts prepared by the same method are suitable for evaluating the size effect of the Pt–NPs on electrocatalytic performance for ethanol electrooxidation. A correlation between the electrocatalytic activity of ethanol oxidation and particle size of the Pt/C catalysts indicates that Pt–NPs with mean particle size of ca. 2.5 nm possesses the highest electrocatalytic performance for ethanol electrooxidation.

Ethylene Diamine Tetramethylene Phosphonic Acid Labeled with Various β−-Emitting Radiometals: Labeling Optimization and Animal Biodistribution

Skeletal uptake of β(-)-emitting radionuclides may be used for bone pain palliation or myeloablation. The physical characteristics of the β(-) particles required for the two conditions are, however, different, that is, higher energies are favorable for destruction of bone marrow. In this study, the labeling conditions of ethylene diamine tetramethylene phosphonic acid (EDTMP) with three rare earth metals (90Y, 166Ho, and 177Lu) having β(-) particles of diverse physical characteristics were optimized, and their animal biodistributions were studied and compared with 153Sm-EDTMP. All the four radiometals (X = 90Y, 166Ho, 177Lu, and 153Sm) were produced from n,γ reactions of their respective precursors (89Y, 165Ho, 176Lu, and 152Sm). They were labeled with EDTMP at varying degrees of pH and molar ratios, and labeling yields were determined by paper chromatography at each data point. The complexes with optimal labeling yields and their chloride forms (XCl3) were then studied for biodistributions in 66 Sprague-Dawley male rats at 30 minutes, 2 hours, and 24 hours after injection. All the radiopharmaceuticals gave ∼98% complex yields at pH 8. At optimum pH level, good labeling was achieved at X:EDTMP molar ratios of 1:5, 1:8, and 1:20 for 90Y, 166Ho, and 177Lu complexes, respectively. 177Lu-EDTMP showed the best biodistribution results among all the complexes, with a total skeletal uptake of 70.2% ± 2.4% at 24 hours ((153)Sm-EDTMP = 59.1% ± 2.6%). 90Y-EDTMP had skeletal accumulation significantly higher than (166)Ho-EDTMP (45.5% ± 2.9% and 27.4% ± 3.6%, respectively). Blood activity of all the agents disappeared promptly through the kidneys. This study demonstrates higher localization of 177Lu-EDTMP in skeleton than 153Sm-EDTMP and shows that the localization of 90Y-EDTMP is better among the high-energy radiometals studied.

Preparation of highly dispersed and ultrafine Pd/C catalyst and its electrocatalytic performance for hydrazine electrooxidation

The highly dispersed and ultrafine carbon supported Pd nanoparticles (Pd/C) catalyst was synthesized by NaBH4 reduction method in the presence of ethylenediamine-tetramethylene phosphonic acid (EDTMP) ligand. The formation of the ultrafine Pd nanoparticles can be attributed to the avoidance of Pd(OH)2 precipitation and the decrease in the reduction potential of PdII species in EDTMP–PdII complex during the preparation of Pd/C catalyst. Electrochemical measurements indicated the resulting Pd/C catalyst possessed a significant electrocatalytic performance for hydrazine oxidation under the strong acidic conditions, indicating that the Pd/C catalyst has potential application in fabrication of acidic direct hydrazine fuel cell.

ChemInform Abstract: Kinetics of Dissolution of Calcium Fluoride Crystals in Sodium Chloride Solutions: Influence of Additives.

The kinetics of dissolution of calcium fluoride crystals in sodium chloride solutions has been investigated at 25 o C by using a constant composition method in which the undersaturation and ionic strength were maintained constant. Over a range of relative undersaturation, 0.075-0.40, the dissolution reaction appears to be controlled by a surface mechanism. The crystal dissolution rates are markedly inhibited by the addition of inorganic orthophosphate and organic polyphosphonates. The action of additives can be interpreted in terms of a Langmuir-type adsorption isotherm. Direct adsorption experiments have also been made by using ethylenediaminetetramethylenephosphonic acid

Facile controlled preparation of phosphonic acid-functionalized gold nanoparticles

In the preparation and storage of gold nanoparticles (Au-NPs) in colloidal form, the stability of the colloid is of utmost importance. We report a novel strategy for the synthesis of the phosphonic acid-functionalized gold nanoparticles (Au-NPs) with the high colloid stability by using ethylenediamine-tetramethylene phosphonic acid (EDTMP) as the reducing agent and its oxidation product as the stabilizing agent. The resultant phosphonic acid-functionalized Au-NPs show a remarkable colloidal stability, which likely arises from strong electrostatic effect of negatively charged phosphonate groups and the extremely hydrophilic property of phosphonate groups. Through the present method, the scope of reducing and stabilizing agents for preparation of phosphonic acid-functionalized Au-NPs extend from the -PO(3)H(2)-terminated thiols to the aminopolyphosphonates.

Electrochemical behavior of dopamine in the presence of phosphonate and the determination of dopamine at phosphonate modified zirconia films electrode with highly antifouling capability

Electrochemical oxidation of dopamine (DA) generally leads to electrode passivation due to accumulation of reaction products. Addition of ethylenediamine-tetramethylene phosphonic acid (EDTMP) to the supporting electrolyte can decrease the formal potential ( E 0 ′ ) of DA oxidation and enhance the antifouling capability of bare Au electrode due to the strong interaction between EDTMP and DA. Subsequently, an EDTMP modified zirconia films electrode is synthesized by using self-assembly method. The electrochemical measurements reveal the modified electrode possesses the excellent antifouling capability for DA oxidation and long-termed stability. In addition, the EDTMP modified zirconia films electrode can be used as a functional interface to sensitively and selectively detect DA in the presence of highly concentrated ascorbic acid (AA) due to the electrostatic interactions between the negatively charged phosphonic acid groups with DA.

Dose‐finding study of 153Sm‐EDTMP in patients with poor‐prognosis osteosarcoma

Samarium-153 ethylenediaminetetramethylene phosphonic acid ((153)Sm-EDTMP) has been used to treat patients with high-risk osteosarcoma. The purpose of the current study was to determine the maximally tolerated dose of (153)Sm-EDTMP that permits hematopoietic recovery within 6 weeks. Patients with recurrent or refractory osteosarcoma with bone metastases were enrolled in this study. Subjects were treated with increasing doses of (153)Sm-EDTMP, beginning with 1.0 millicuries (mCi)/kg and followed initially with 40% increment dose level escalations, using a continual reassessment method for dose escalation and de-escalation with a target dose-limiting toxicity (DLT) rate of 30%. Complete blood counts were monitored weekly, and the primary DLT was defined as failure to achieve an absolute neutrophil count >750/mm(3) and a platelet count >75,000/mm(3) within 6 weeks of treatment. In addition to assessing toxicity, dosimetry measurements were made to estimate the radiation dose delivered to target lesions. The maximally tolerated dose of (153)Sm-EDTMP was 44.8 megabecquerel (MBq)/kg (1.21 mCi/kg). DLTs were confined to hematologic toxicities, particularly delayed platelet recovery in 2 patients treated at a dose of 51.8 MBq/kg (1.4 mCi/kg). Grade 2 and 3 pulmonary toxicity (graded according to the National Cancer Institute Common Toxicity Criteria [version 3.0]) as reported in 2 patients (at administered activities of 44.8 MBq/kg and 51.8 MBq/kg) was attributable to progressive pulmonary disease. No other significant nonhematologic toxicities were observed. Patients with osteosarcoma who have previously been heavily treated with chemotherapy can be safely administered (153)Sm-EDTMP with rapid hematologic recovery. The data from the current study support the development of a future trial to assess the efficacy of combining targeted radiotherapy with cytotoxic chemotherapy as a treatment option for patients with high-risk osteosarcoma.

Percutaneous tumor curettage and interstitial delivery of samarium-153 coupled with kyphoplasty for treatment of vertebral metastases

The object of this study was to investigate the use of a minimally invasive technique for treating metastatic tumors of the vertebral body, aimed at relieving pain, preventing further tumor growth, and minimizing the adverse effects of systemic use of samarium-153 ((153)Sm). The procedure is performed in the same fashion as a kyphoplasty, using a unilateral extrapedicular approach under local anesthesia/mild general sedation, with the patient in the lateral decubitus position. The tumor is accessed as in a standard kyphoplasty. The side is chosen according to the location of the metastasis. Prior to inflation of the balloon the tumor is debulked by percutaneous curettage. Balloon inflation is carried out as per standard kyphoplasty in an attempt to create a larger space and reduce a possible kyphotic deformity. Three mCi of (153)Sm-EDTMP (ethylenediaminetetramethylenephosphonic acid) is then mixed with bone cement (polymethylmethacrylate) and injected into the void created by the balloon tamp. Twenty-four procedures were performed in 19 patients. There was reliable and reproducible delivery of the radiolabeled (153)Sm-EDTMP to the metastatic site, without spillage. The procedure was safe. There were no procedure-related complications. There was no hematological toxicity with the low doses of (153)Sm used. Pain improved in all patients. The long-term results related to tumor control continue to be investigated. Combined percutaneous debulking of confined vertebral metastases and administration of local (153)Sm is feasible and safe. Furthermore, this technique leads to immediate relief of cancer-related pain and may help prevent or slow down the progression of vertebral metastatic tumors.

Effects of Organic Additives on Calcium Sulfate Scaling in Pipes

A comprehensive study of the effects of nine organic additives on the formation of calcium sulfate scale in a pipe system was conducted using a multiple pipe flow system. Several factors that influence the inhibitory capability of phosphonic and carboxylic additives such as their chemical structure, their concentration, and the run time were closely scrutinized. Results showed that the organic additives influence the deposition of calcium sulfate on the walls of a pipe flow system at various levels. The superiority of the phosphonic additives, especially N,N,N′,N′-ethylenediaminetetramethylenephosphonic acid (EDTP) and nitrilotrimethylenephosphonic acid (NTMP), to other organic compounds with respect to scale prevention is discussed thoroughly. For the first time, it was demonstrated that a solution with a given concentration of inhibitor that is continuously refreshed in a pipe reactor becomes less effective over time. The morphology of the scales formed in the presence of different additives is also studied, using scanning electron microscopy.

177Lu-EDTMP: A Viable Bone Pain Palliative in Skeletal Metastasis

Designing ideal radiopharmaceuticals for use as bone pain palliatives require the use of a moderate energy beta() emitter as a radionuclide and a suitable polyaminophosphonic acid as a carrier molecule. Owing to its suitable decay characteristics [T(1/2) = 6.73 d, E((max)) = 497 keV, E() = 113 keV (6.4%), 208 keV (11%)] as well as the feasibility of large-scale production in adequate specific activity and radionuclidic purity using a moderate flux reactor, 177Lu could be considered as a promising radionuclide for palliative care in painful bone metastasis. The present study was therefore, oriented toward the preparation and biologic evaluation of 177Lu complex of ethylenediaminetetramethylene phosphonic acid (EDTMP) in various animal models, with an aim to prepare a viable radiopharmaceutical for bone pain palliation. 177Lu was produced with a specific activity of approximately 12 GBq/mg (approximately 324 mCi/mg) and radionuclidic purity of 99.98% by irradiation of natural Lu2O3 targeted at a thermal neutron flux of approximately 6 x 10(13) n/cm(2).s for 21 days. 177Lu-EDTMP complex was prepared in high-yield and excellent radiochemical purity (>99%), using EDTMP synthesized and characterized in-house. The complex exhibited excellent in vitro stability at room temperature. Biodistribution studies in Wistar rats showed a rapid skeletal accumulation of injected activity [(1.74 +/- 0.30)% per gram in femur at 3 hours postinjection] with a fast clearance from blood and minimal uptake in any of the major organs. Scintigraphic imaging studies carried out in normal Wistar rats, New Zealand white rabbits, as well as in Beagle dogs also demonstrated significant accumulation of the agent in the skeleton and almost no retention of activity in any other vital organs.

Comparative studies of 177Lu–EDTMP and 177Lu–DOTMP as potential agents for palliative radiotherapy of bone metastasis

177Lu is presently considered as an excellent radionuclide for developing bone pain palliation agents owing to its suitable nuclear decay characteristics [ T 1/2=6.73 d, E β (max)=497 keV, E γ =113 keV (6.4%) and 208 keV (11%)] and large-scale production feasibility with adequate specific activity using moderate flux research reactors. Multidentate polyaminophosphonic acids have already been proven as the carrier molecule of choice for radiolanthanides and similar +3 metal ions in designing agents for palliative radiotherapy of bone pain due to skeletal metastases. The present paper describes a comparison between 177Lu complexes of two potential polyaminophosphonic acid ligands, namely Ethylenediaminetetramethylene phosphonic acid (EDTMP) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP) with respect to their radiochemical and in-vivo biological characteristics. Although both the agents have exhibited promising features, the study reveals that 177Lu–EDTMP has marginally higher skeletal accumulation in comparison to that of 177Lu–DOTMP, while the latter has slightly faster blood clearance along with lower retention in liver and kidneys in animal models.

Metal–ligand solution equilibria studied by electrospray ionization mass spectrometry: correlation between ion intensity and acid–base equilibria in solution

Electrospray ionization mass spectrometry (ESI-MS) is increasingly used in the study of metal-ligand equilibria in aqueous solutions. However, the correlation between conditions in solution and mass spectra in the gas phase is far from being completely established. In the present work the equation i = kC(0)f was used to correlate relative ion intensity (i) in an ESI mass spectrum, the stoichiometric concentration (C(0)) in solution of the complex which produced this ion, and the fraction (f) of complex having the same protonation state as that of the ion detected in the spectrum. This equation takes into account that metal-ligand complexes have acid-base properties, and that these properties affect the efficiency by which the ions are brought from the solution to the gas phase. The equation was experimentally checked by electrospraying solutions containing aluminium(III) and any of the four ligands 3,4-dihydroxybenzoic acid, 3-hydroxy-2-(1H)pyridinone, citric acid, and ethylenediaminetetramethylenephosphonic acid at different pH values. ESI-MS experimental i values and C(0)f values calculated from literature data were plotted versus the solution pH. Values are correlated in the majority of cases, thus confirming the validity of the approach proposed. Correlation is lost, as expected, for low f or C(0) values, and when extensive gas-phase reactions occur. The equation i = kC(0)f can be used to estimate quantitative data for unknown metal-ligand solutions analyzed by ESI-MS.

Analysis of Multiple Factors Related to Hematologic Toxicity Following 153Sm-EDTMP Therapy

The aim of this study was to investigate the clinical factors related to hematologic toxicity caused by treatment with samarium-153 ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP). A total of 206 secondary bone neoplasm patients treated with 153Sm-EDTMP were analyzed retrospectively. Logistic regression (SPSS 10.0 for Windows; Chicago, IL) and correlation analysis were used to evaluate the factors concerned. Age, number of bone metastatic lesions, chemotherapy before treatment with 153Sm-EDTMP, concurrence of radiotherapy, and times of repeated treatments with 153Sm-EDTMP were determined by single factor analysis to be related to hematologic toxicity. Chemotherapy before treatment with 153Sm-EDTMP, concurrence of radiotherapy, drug use to maintain normal white blood cell counts, and times of repeated treatments with 153Sm-EDTMP were determined by multiple factor analysis to be related to hematologic toxicity. Chemotherapy before treatment with 153Sm-EDTMP, concurrence of radiotherapy, drug use to maintain normal white blood cell counts, and times of repeated treatments with 153Sm-EDTMP are the main clinical factors related to hematologic toxicity caused by 153Sm-EDTMP therapy. In patients with such factors, more attention might be paid to the change of blood cell counts after 153Sm-EDTMP therapy.

Speciation Studies of Iron (III) with (Poly)phosphonate Ligands: The Case of EDTMP (EthylenediamineTetramethylene Phosphonic Acid)

The complex formation equilibrium of ethylenediaminetetramethylenephosphonic acid (EDTMP, H8L) with iron (III) has been studied potentiometrically at 25°C and an ionic strength of 0.2 M (NaCl). The successive protonation constants of ligand EDTMP and the complex formation constants were determined with the PSEQUAD program. Keeping in view the biological studies, the speciation in the system Fe (III)—EDTMP was calculated and drawn with the HySS computer program, and pFe values are compared.

Preparation of Single-crystalline Selenium Nanowires in the Presence of Ethylenediaminetetramethylenephosphonic Acid

Abstract Selenium nanowires have been synthesized by using 2-mercaptoethylamine-depleted CdSe nanoparticles as selenium source and ethylenediaminetetramethylenephosphonic acid as chelating agent. The products were characterized by X-ray diffraction, scanning electron microscopy, high-resolution transmission electron microscopy, and UV–vis spectrophotometry. The result shows that the selenium nanowires are single crystals grown along the [001] direction of hexagonal lattice. The optical measurement shows a blue shift relative to the bulk hexagonal selenium, and the optical bandedge might be attributed to the interchain interactions within a hexagonal selenium crystal.

A Comparative Study of Monoclonal Antibodies (Mabs) Purified from Cell Culture Supernatant on EDTPA‐Modified Zirconia Beads and Protein A‐Hyper D Support

Abstract Colloidal zirconia was spray dried to yield zirconia particles, which were further modified with N, N, N′, N′‐ Ethylenediamine tetra methylenephosphonic acid (EDTPA) to yield a support for use in bioseparations. EDTPA modified zirconia particles will be further referred to as, r_PEZ. Cell culture supernatants rich in monoclonal antibody (Mab) subtypes IgG1, IgG2a, IgG2b, and IgG3 were chromatographed on a r_PEZ column, and on a protein A‐hyper D column that was purchased commercially. All Mab subtypes bound to r_PEZ and process yields in the range of 88 to 99% were obtained. The purity of the Mab products were ascertained by gel electrophoretic analysis and were estimated to be greater than 95%. The purified Mab products obtained from r_PEZ and protein A columns were compared to the reference Mab standard in biological and enzymatic assays. The value of the dissociation constant (Kd) was found to be comparable and was in the range to that obtained with reference Mab standard (0.231±0.03 M). In ad...

Identification of the mass transfer mechanisms involved in the transport of human immunoglobulin-G in N, N, N′, N′-ethylenediaminetetramethylenephosphonic acid-modified zirconia

Zirconia particles modified with N, N, N′, N′-ethylenediaminetetramethylenephosphonic acid (EDTPA), further referred to as r_PEZ, were studied as a support material for use in chromatography. Our previous studies have demonstrated the utility of r_PEZ in the separation of immunoglobulins from biological fluids. In the present study we sought to understand the underlying factors and identify the rate-limiting mechanisms that govern the transport of biomolecules in r_PEZ. Pulse injection techniques were used to elucidate the individual mass transfer parameters. Elution profiles obtained under retained and unretained conditions were approximated by the Gaussian equation and the corresponding HETP contributions were estimated. The dependence of the HETP values on incremental salt concentration in the mobile phase was determined. Resulting data in conjunction with the equations outlined in literature were used to estimate the theoretical number of transfer units for the chromatographic separation process. Our results indicate that surface diffusion probably plays a minor role; however pore diffusion was established to be the rate limiting mechanism for immunoglobulin G adsorption to r_PEZ. The HETP based methodology may be used to estimate the rate limiting mechanisms of mass transfer for any given chromatographic system under appropriate conditions.