Single quadrupole mass spectrometry for pre-clinical pharmacokinetic analysis: quantitation of carvedilol in dog plasma.

The pharmaceutical industry standard for bioanalysis is LC/MS/MS. There are, however, many instances where a single quadrupole detector could successfully be used to provide adequate sensitivity and selectivity for quantitation of drug substances in biological matrices. This paper presents one example of how a single quadrupole detector can be employed in a sensitive and selective analytical method for quantitation of carvedilol. A Synergi Hydro-RP (50 mm x 2 mm i.d.; 4 microm) column was used with acetonitile:water:formic acid mobile phase (32:68:0.01, v/v) at a flow rate of 200 microL/min into a single quadrupole mass spectrometer with an electrospray interface in the positive SIM mode. Using a 300 microL plasma aliquot and a liquid-liquid extraction procedure the limit of quantitation for the assay was 1 ng/mL. The assay utility was demonstrated in the analysis of carvedilol pharmacokinetic profiles in beagle dogs following oral carvedilol administration.

Ongoing in vivo studies with cytoskeletal drugs in tau transgenic mice.

Most drug discovery efforts for Alzheimer's disease (AD) have focused on prevention or clearance of beta-amyloid (Abeta) fibrils or oligomers, with far less attention to prevention of tau abnormalities that lead to neurofibrillary tangles (NFTs). Much evidence now indicates that Abeta multimers can trigger neurodegenerative changes that involve formation of dystrophic neurites and cytoskeletal collapse, possibly due loss of microtubule (MT) stabilization by the tau protein. We have found that several MT-stabilizing agents such as Taxol significantly enhanced neuronal survival in the presence of Abeta and identified agents that enter the brain, a necessity for in vivo testing in animal models of tau pathology. Studies were designed to test two agents in the tau mutant (JNPL3) mouse that develops severe motor deficits at about seven months of age, accompanied by neuropathological markers of tau pathology. In addition to using motor performance tests through the planned period of drug administration, we designed a simple appetitive memory test that required a reduction in ad lib food intake. Although the neurochemical data are still being analyzed, we were surprised to find that all of the JNPL3 mice, whether receiving the drug or not, developed no signs of motor impairment up to 10 months of age. This is considerably beyond the age at which free-fed mice survived and suggests that the food restriction alone may have delayed the pathological process. A study is ongoing with free-fed mice to determine if the drug interventions do have any beneficial effects in these mutant mice.

Effect of cyclodextrin charge on complexation of neutral and charged substrates: comparison of (SBE)7M-beta-CD to HP-beta-CD.

PURPOSE: To understand the role of charge in substrate/cyclodextrin complexation by comparing the binding of neutral and charged substrates to a neutral cyclodextrin, such as hydroxypropyl beta-CD (HP-beta-CD) with 3.5 degrees of substitution, and an anionically charged cyclodextrin, such as sulfobutyl ether beta-CD ((SBE)7M-beta-CD) with 6.8 degrees of substitution. METHOD: HP-beta-CD and (SBE)7M-beta-CD were evaluated in their ability to form inclusion complexes with neutral compounds, as well as to cationic and anionic substrates in their charged and uncharged forms. The complexation constants (Kc) were determined via a UV spectrophotometric technique, by monitoring the change in substrate absorbance upon incremental addition of a concentrated cyclodextrin solution. The role of electrostatic interaction was probed by observing Kc as a function of solution ionic strength. RESULTS: Neutral molecules displayed a stronger interaction with (SBE)7M-beta-CD compared to HP-beta-CD. In those cases where the guest possessed a charge (positive or negative), HP-beta-CD/substrate complexes exhibited a decrease in complexation strength (2 to 31 times lower) compared to the neutral forms of the same substrate. The same was true (but to a larger extent, 41 times lower) for negatively charged molecules binding to (SBE)7M-beta-CD due to charge-charge repulsion. However, positively charged molecules interacting with the negatively charged (SBE)7M-beta-CD displayed a similar binding capability as their neutral counterpart, due to charge-charge attraction. Further evaluation through manipulation of solution ionic strength revealed strong electrostatic interactions between substrate and cyclodextrin charges. In addition, the studies suggested that on average two sulfonates out of seven may be involved in forming ionic attraction or repulsion effects with the positive charges on prazosin and papaverine, or negative charges of ionized naproxen and warfarin. CONCLUSIONS: Presence of charge on the cyclodextrin structure provides an additional site of interaction compared to neutral cyclodextrins, which may be modified using solution ionic strength.

A simple and efficient high-performance liquid chromatographic assay for etomidate in plasma.

The development and validation of an effective and simplified LC assay for the quantitation of etomidate in beagle plasma is described. The methodology employs a rapid and simple protein precipitation procedure in combination with previously reported chromatographic conditions. Using a 0.3 ml aliquot of plasma, the assay is linear in the concentration range of 50 to 5000 ng/ml, with an extraction efficiency between 97 to 104% and accuracy between 98 and 105%.

Thermodynamics of binding of neutral molecules to sulfobutyl ether beta-cyclodextrins (SBE-beta-CDs): the effect of total degree of substitution.

PURPOSE: To understand the role of degree of substitution on binding of molecules to beta-Cyclodextrins (beta-CDs) with varying degrees of sulfobutyl ether (SBE) substitution. METHODS: Using UV spectroscopy, complexation constants of molecules to SBE-beta-CDs were estimated as a function of temperature, allowing for calculation of thermodynamic parameters, including the enthalpy and entropy of binding. RESULTS: Binding constants of various molecules to SBE-beta-CDs did not show a uniform trend to total degree of SBE substitution. However, a distinct pattern was observed with the enthalpy and entropy of complexation. The results showed the complexation of substrates to SBE-beta-CDs to be more entropy-favored as the number of SBE groups increased. This favorable entropy of interaction was compensated by a less favorable enthalpy of interaction. CONCLUSIONS: Enthalpy and entropy of complexation provided additional insight into the role that the alkylsulfonate groups may play in the complexation of molecules with SBE-beta-CDs.

Comparative effects of (SBE)7m-beta-CD and HP-beta-CD on the stability of two anti-neoplastic agents, melphalan and carmustine.

The purpose of this study was to evaluate and compare the potential use of two parenterally safe beta-cyclodextrins derivatives, (SBE)7m-beta-CD and HP-beta-CD, as solubilizers and stabilizers for melphalan and carmustine, two very unstable antineoplastic agents. Phase solubility and chemical stability of the compounds in the presence of the cyclodextrins were studied. UV, fluorescence, and several NMR techniques were used to probe the potential causes for the differences observed. The phase solubility method was found to provide only qualitative data on the binding of melphalan to the cyclodextrins since rapid degradation and the presence of products of degradation complicated the interpretation of the results. Qualitatively, however, the solubilizing potential was similar for the two cyclodextrins. The chemical stability studies indicate that both of the drugs had similar binding constants for both cyclodextrins; however, the intrinsic reactivities in the complexes were significantly lower with (SBE)7m-beta-CD than for HP-beta-CD. The main cause for this distinct difference appeared to correlate with differences in the site of binding and the polarity of the binding site.

New injectable melphalan formulations utilizing (SBE)(7m)-beta-CD or HP-beta-CD.

The objective of this work was to evaluate the potential of using (SBE)(7m)-beta-CD and HP-beta-CD as enabling excipients to improve on the current melphalan injectable formulation. Melphalan is an anti-neoplastic agent formulated for parenteral use as a sterile, non-pyrogenic, freeze-dried powder. It is marketed by Glaxo-Wellcome as ALKERAN((R)) for Injection (Alkeran). A major concern with melphalan therapy, other than its intrinsic cytotoxicity and biocompatibility, arises from its marginal aqueous solubility and chemical stability; thus, co-solvents are used in the current two-vial formulation. Because of the two-vial system, the product is also inconvenient to use. Two approaches to improve melphalan's formulation utilizing cyclodextrins, including the use of aqueous (SBE)(7m)-beta-CD or HP-beta-CD solutions as the reconstitution diluents, and/or the use of (SBE)(7m)-beta-CD as a freeze-drying excipient in a melphalan formulation, are presented. Results showed that, when the cyclodextrins were used as diluents, the use of organic co-solvents can be eliminated and the shelf-life of the reconstituted melphalan greatly enhanced. When the freeze-dried melphalan/(SBE)(7m)-beta-CD formulation was prepared, the formulation was found to be stable; and a simplified one-vial delivery system was achieved. In conclusion, the parenterally safe beta-cyclodextrins derivatives can provide promising alternatives and improved formulations for melphalan injectable and perhaps similar problematic drugs.

Factors affecting membrane-controlled drug release for an osmotic pump tablet (OPT) utilizing (SBE)(7m)-beta-CD as both a solubilizer and osmotic agent.

PURPOSE: The purpose of this study was to define membrane controlling factors responsible for drug release from a controlled-porosity osmotic pump tablet (OPT) that utilizes a sulfobutyl ether-beta-cyclodextrin, (SBE)(7m)-beta-CD, as both a solubilizing and osmotic agent. METHOD: The OPT was spray coated with cellulose acetate solutions varying the amount and size of micronized lactose, the amount of triethyl citrate (TEC) and the composition ratio of dichlormethane to ethanol. Chlorpromazine (CLP) was used as a model drug. The release of CLP from the OPTs was studied using the Japanese Pharmacopoeia dissolution method. The membrane surface area of the OPTs were measured with multi-point analysis by the gas absorption method. RESULTS: The release rate of CLP from OPTs containing (SBE)(7m)-beta-CD increased with increasing amounts of micronized lactose and decreasing amounts of TEC and lactose particle size in the membrane. Also, the CLP release rates from the spray-coated OPTs using mixtures of varying ratios of dichlormethane to ethanol were almost identical. The membrane surface area of the OPTs following release of membrane components had a linear relationship to CLP release rates from the OPTs. CONCLUSION: The present results confirmed that the membrane controlling factors responsible for the drug release were the amount and size of micronized lactose and the amount of TEC in the membrane.

Design and evaluation of an osmotic pump tablet (OPT) for chlorpromazine using (SBE)7m-beta-CD.

PURPOSE: The purpose of this study was to develop a controlled-porosity osmotic pump tablet (OPT) which exhibits pH-independent release profiles for a basic drug using a sulfobutyl ether-beta-cyclodextrin, (SBE)7m-beta-CD, which acts as both a solubilizer and as an osmotic agent. METHODS: Chlorpromazine free base (CLP) was chosen as a model drug for this study. The release of CLP from osmotic pump tablets was studied in vitro. In vivo absorption of CLP from the OPT was evaluated in male beagle dogs. RESULTS: The CLP release profile from an OPT prepared from a core tablet composed of a 1:10 molar ratio of CLP to (SBE)7m-beta-CD was pH-independent, and was controlled by modulating the membrane thickness of the OPT. Another cyclodextrin, hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and a sugar mixture of lactose and fructose resulted in pH-dependent release at the same molar ratio. An in vivo absorption study in dogs with an OPT containing (SBE)7m-beta-CD correlated very well with the in vitro release profiles using the Japanese Pharmacopoeia dissolution method. CONCLUSIONS: In addition to serving as a solubilizer and osmotic agent, (SBE)7m-beta-CD can also serve as the controlling agent for pH independent release of CLP from OPTs. This system successfully modified the in vivo input rate of CLP without compromising oral bioavailability.

Release of testosterone from an osmotic pump tablet utilizing (SBE)7m-beta-cyclodextrin as both a solubilizing and an osmotic pump agent.

A controlled porosity osmotic pump system for poorly water soluble drugs has been developed using sulfobutyl ether-beta-cyclodextrin sodium salt, (SBE)7m-beta-CD, which can act as both a solubilizing and an osmotic agent. The release of testosterone, a poorly water soluble drug (0.039 mg/ml at 37 degrees C), was evaluated using a new model device. The effect of (SBE)7m-beta-CD as the solubilizing and osmotic pump agent was compared with hydroxypropyl-beta-cyclodextrin (HP-beta-CD), a neutral cyclodextrin, and a sugar mixture (osmotic agent only). Testosterone release from the device was significantly faster with (SBE)7m-beta-CD than with HP-beta-CD or the sugar mixture. The solubility of testosterone in the device increased to 76.7 mg/ml through complexation with (SBE)7m-beta-CD in the imbibed water. It appears that testosterone release from the device in the presence of (SBE)7m-beta-CD was mainly due to osmotic pumping while for HP-beta-CD the major contribution appears to be due to diffusion. In the case of the sugar mixture, testosterone was poorly released, presumably due to the absence of a solubilizer. Therefore, it was concluded that (SBE)7m-beta-CD provides novel properties for the development of controlled- porosity osmotic pump tablets for poor solubility drugs.

Stability of rifabutin in two extemporaneously compounded oral liquids.

The stability of rifabutin 20 mg/mL in two oral liquids was studied. Powder from 100 150-mg rifabutin capsules was placed in a glass mortar. Cherry syrup (pH 2.9) or a 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories) was added to produce 750 mL of each formulation, which was then stored in 2-oz plastic prescription bottles. Three bottles of each formulation were stored at 4, 25, 30, and 40 degrees C. At 0, 1, 2, 4, 8, and 12 weeks, the bottles were collected and allowed to remain at room temperature for one hour; samples of about 1 mL were collected from each bottle, weighed, and assayed for rifabutin content by high-performance liquid chromatography. The rifabutin liquids prepared with cherry syrup and stored at 4, 25, and 30 degrees C lost a mean of < 8% of the initial drug concentration during the 12-week study; at 40 degrees C, the liquids lost > 10% of the initial drug concentration by 12 weeks. There was a mean loss of < 5% of the initial rifabutin concentration in all the liquids prepared with Ora-Sweet and Ora-Plus. The liquid prepared with cherry syrup, upon standing, showed a tendency for some of the ingredients to float. The suspension prepared with Ora-Sweet and Ora-Plus had a tendency to retain bubbles after it was shaken, but the ingredients did not settle upon standing. Rifabutin 20 mg/mL in two extemporaneously compounded oral liquids prepared from capsules and sweetened vehicles was stable for at least 12 weeks at 4, 25, 30, and 40 degrees C with the exception of rifabutin in cherry syrup, which was stable for only 8 weeks at 40 degrees C.

Design and evaluation of an osmotic pump tablet (OPT) for prednisolone, a poorly water soluble drug, using (SBE)7m-beta-CD.

PURPOSE: The purpose of this study was to develop a controlled-porosity osmotic pump tablet (OPT) for poorly water soluble drugs using a sulfobutyl ether-beta-cyclodextrin, (SBE)7m-beta-CD or Captisol, which acted as both a solubilizer and as an osmotic agent. METHODS: Prednisolone (PDL) was chosen as a model drug for this study. The release of PDL from osmotic pump devices and tablets was studied. In vivo absorption of PDL from OPT was evaluated in male beagle dogs. RESULTS: PDL release from the osmotic pump tablet with (SBE)7m-beta-CD was complete. Another cyclodextrin, hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and a sugar mixture of lactose and fructose resulted in incomplete release. Although PDL release from the OPT with (SBE)7m-beta-CD and the sugar formulation displayed mainly zero-order release characteristics, the tablet utilizing HP-beta-CD showed apparent first-order release characteristics. An in vivo absorption study in dogs correlated very well with the in vitro release profiles using the Japanese Pharmacopoeia dissolution method. CONCLUSIONS: The present results confirm that (SBE)7m-gamma-CD can serve as both the solubilizer and the osmotic agent for OPT of PDL, and modify the input rate of PDL without compromising oral bioavailability.

Pharmaceutical processing with supercritical carbon dioxide.

Replacement of traditional solvents with "environmentally benign" carbon dioxide is receiving increased attention in pharmaceutical processing. Among the reported applications, particle formation with dense carbon dioxide and the "clean" synthesis of drug compounds using carbon dioxide as a reaction medium hold immense potential for large-scale application in the pharmaceutical industry. This paper provides an overview of these rapidly emerging technologies along with examples of the wide variety of relatively contaminant-free pharmaceutical compounds that have been processed via these technologies on a laboratory scale. Challenges facing successful implementation in practice include demonstration of continuous production and harvesting of particles with desired and reproducible product characteristics. Mathematical models aimed at a better fundamental understanding of the underlying thermophysical phenomena are essential for rational design and scale-up of these technologies.

Cyclodextrins: their future in drug formulation and delivery.

Since their discovery, cyclodextrins and their ability to form inclusion complexes have fascinated chemists, formulators and recently, entrepreneurs. This mini-review has as its objective, a critical assessment of the current status of cyclodextrins in the formulation and delivery of pharmaceuticals and commentary on their potential future uses. The emphasis will be on answers to common questions often asked of pharmaceutical scientists working in this area. Why use cyclodextrins for drug solubilization and stabilization when alternative techniques are available? Why the greater interest in modified cyclodextrins and not the parent cyclodextrins? If a drug forms a strong cyclodextrin inclusion complex, how is the drug released in vivo? Dose the injection of a cyclodextrin/drug complex alter the pharmacokinetics of the drug? Are there drug products on the market which contain cyclodextrins? What is the regulatory status of cyclodextrins? Although definitive answers to all these questions are not possible at this time, many of these questions are answerable, and educated and informed responses are possible for the rest.

Fractionation and characterization of 4-sulfobutyl ether derivatives of cyclomaltoheptaose (beta-cyclodextrin).

4-Sulfobutyl ether derivatives of cyclomaltoheptaose (beta-cyclodextrin) (SBE-beta-CD) are being developed as parenterally safe solubilizing and stabilizing agents. SBE-beta-CDs are a mixture of positional and regional isomers containing from one to as many as twelve sulfobutyl ether (SBE) groups per cyclodextrin. Capillary electrophoretic (CE) analysis of these mixtures resolves these isomers based on the molar degree of SBE substitution (ds), and the electropherogram shows an almost symmetrical distribution of SBE incorporation centered around the band which represents the apparent average degree of substitution for the mixture. The objectives of this study were to isolate the different substitution bands for their characterization and to evaluate their mass contribution to the mixture. Mixtures of SBE-beta-CDs containing from mono- up to deca-SBE substitutions were fractionated by preparative anion-exchange chromatography with salt concentration gradient elution. The bands for each ds were well resolved as characterized by CE analysis with indirect UV detection. The isolated materials were desalted and lyophilized to obtain white solids, which were then characterized by nuclear magnetic resonance (1H NMR) spectroscopy, capillary electrophoresis (CE), and fast-atom-bombardment mass spectrometry (FABMS). The CE molar response factor of each ds was then determined, and the actual percent mass composition of a SBE-beta-CD mixture was calculated.

Isolation and characterization by NMR spectroscopy of three monosubstituted 4-sulfobutyl ether derivatives of cyclomaltoheptaose (beta-cyclodextrin).

The substitution profile of 4-sulfobutyl ether derivatives of cyclomaltoheptaose (beta-cyclodextrin) (SBE-beta-CD) prepared in our laboratories has been previously described. However, in those studies, no attempt was made to characterize the positional or regional isomers of this material. SBE-beta-CD derivatives with degrees of substitution of two or higher represent a large number of possible isomers dependent on this positional and regional substitution. The monosubstituted SBE derivative, however, cannot have regional isomers and, therefore, has only three possible substitution products related to the 2-, 3-, and 6-hydroxyl groups of a glucose unit. In this study the isomers were fractionated by preparative anion-exchange chromatography with the progress of the elution being followed by a capillary electrophoretic (CE) method that resolved these isomers. The eluent containing the isomers was processed, and the pure materials were characterized by nuclear magnetic resonance spectroscopy (1H NMR, DEPT, HETCOR, HOHAHA). Through this analysis the assignment of the positional isomers was made.

Effect of alkyl chain length and degree of substitution on the complexation of sulfoalkyl ether beta-cyclodextrins with steroids.

This study was designed to test how the sulfoalkyl ether (SAE) modification of beta-cyclodextrin (beta-CD) affects the binding capacity of testosterone and progesterone, thereby enhancing their solubility. The SAE-beta-CD derivatives contain either sulfopropyl ether (SPE) or sulfobutyl ether (SBE) groups on the 2-, 3-, and 6-hydroxyl positions of the dextrose moieties. SAE-beta-CDs are a mixture of positional and regional isomers containing from one to as many as 12 SAE groups per CD. The effect of chain length and the degree of substitution on complexation behavior was investigated by the phase-solubility method. The results were compared with those obtained with beta-CD, where possible, and with hydroxypropyl-beta-CD (HP-beta-CD). To determine the effect of degree of substitution (DS) on the binding, mixtures of SAE-beta-CDs with multiple substitution levels and varying average degrees of substitution were studied as well as mixtures of SAE-beta-CDs that contained the same degree of substitution. Mixtures that contained SAE-beta-CDs of the same degree of substitution were isolated from the multiple substitution level mixtures by ion-exchange chromatography and purified for investigation. Unlike the parent beta-CD, linear increases in the apparent solubilities of testosterone and progesterone were observed, and the binding potentials were comparable to those of beta-CD or better. The results demonstrate that the binding potentials of the SAE-beta-CD derivatives were dependent on the guest molecule, the degree of substitution, and the alkyl ether chain length. Our previous study showed the inhibition of complexation by direct sulfonation of the beta-CD. However, in the present work, interferences with the charged sulfonate groups were avoided by repositioning them away from the cavity. Increasing the degree of substitution assisted in complex formation; however, its effects were limited. Reduction of the alkyl chain length, as in the case of SPE-beta-CD compared with SBE-beta-CD, decreased the complexation potential. This decrease in complexation potential was further suppressed with an increase in the number of substituents placed on the CD torus. Generally, the binding potential of SAE-beta-CD derivatives increased with increasing alkyl chain length. However, placement of more than an optimum number of SAE groups on the CD torus resulted in inhibition of complexation.

Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery.

The objective of this Review is to summarize and critique recent findings and applications of both unmodified and modified cyclodextrins for in vivo drug delivery. This review focuses on the use of cyclodextrins for parenteral, oral, ophthalmic, and nasal drug delivery. Other routes including dermal, rectal, and pulmonary delivery are also briefly addressed. This Review primarily focuses on newer findings concerning cyclodextrin derivatives which are likely to receive regulatory acceptance due to improved aqueous solubility and safety profiles as compared to the unmodified cyclodextrins. Many of the applications reviewed involve the use of hydroxypropyl-beta-cyclodextrins (HP-beta-CDs) and sulfobutylether-beta-cyclodextrins (SBE-beta-CDs) which show promise of greater safety while maintaining the ability to form inclusion complexes. The advantages and limitations of HP-beta-CD, SBE-beta-CD, and other cyclodextrins are addressed.

Evaluation of the utility of capillary electrophoresis for the analysis of sulfobutyl ether beta-cyclodextrin mixtures.

A capillary electrophoresis (CE) method for the analysis of a sulfobutyl ether beta-cyclodextrin (SBE-beta-CD) mixture is described. The SBE-beta-CD has been prepared as a parenterally safe solubilizing agent and has historically been characterized by elemental analysis and nuclear magnetic resonance spectroscopy. While these methods provide gross values for the degree of substitution, the CE method described resolves the mixture of positional and regional isomers based on the degree of SBE substitution. The method uses benzoic acid in the running buffer and detects the CD by a decrease in background absorbance of the benzoic acid due to complexation. The necessity of a defined column was sequence between injections was evaluated. The reproducibility of migration times and peak areas/heights for 10 components of the mixture was determined. The modular CE system gave a relative standard deviation of 2.5% (n = 3) for six of the 10 peaks. Further refinements (pH buffer effects) were explored to improve the reproducibility with remaining components. The method was used to evaluate the reproducibility of the synthesis (21 different lots) and the effect of reaction variables (time, temperature and base) on the composition pattern of the modified CD.

The interaction of charged and uncharged drugs with neutral (HP-beta-CD) and anionically charged (SBE7-beta-CD) beta-cyclodextrins.

PURPOSE: The objective of this work was to determine the role that charge might play in the interaction of charged and uncharged drugs with neutral (2-hydroxypropyl-beta-cyclodextrin, HP-beta-CD) and anionically charged (SBE7-beta-CD) modified beta-cyclodextrins. SBE7-beta-CD is a sulfobutyl ether, sodium salt, derivative variably substituted on the 2-, 3- and the 6-positions of beta-cyclodextrin. The number seven refers to the average degree of substitution. METHODS: The binding of the acidic drugs, indomethacin, naproxen and warfarin and the basic drugs, papaverine, thiabendazole, miconazole and cinnarizine with the two cyclodextrins was determined at 25 degrees C as a function of pH and cyclodextrin concentration by the phase-solubility method. RESULTS: Except for miconazole and cinnarizine (Ap-type diagrams), all other materials studied displayed AL-type diagrams. By comparing the binding constants of both the charged and uncharged forms of the same drugs to both HP-beta-CD and SBE7-beta-CD, the following conclusions could be drawn. The binding constants for the neutral forms of the drugs were always greater with SBE7-beta-CD than with HP-beta-CD. For the anionic agents, the binding constants between SBE7-beta-CD and HP-beta-CD were similar while the binding constants for the cationic agents with SBE7-beta-CD were superior to those of HP-beta-CD, especially when compared with the neutral form of the same drug. CONCLUSIONS: A clear charge effect on complexation, attraction in the case of cationic drugs and perhaps inhibition in the case of anionic drugs, was seen with the SBE7-beta-CD.