Interaction of Antimalarial Agent Artemisinin with Cyclodextrins

To obtain an effective solution of the poorly water soluble antimalarial agent artemisinin, the use of several kinds of cyclodextrins (CDs) as solubilizers was examined. The following CDs were used in this study: α-CD, β-CD, γ-CD as parent CDs, 2-hydroxypropyl-β-CD (HP-β-CD), sulfobutyl ether β-CD (SBE7-β-CD), heptakis (2,6-di-O-methyl)-β-CD (DM-β-CD), 2,3,6-partially methylated-β-CD (PM-β-CD) as modified CDs, and glucosyl-β-CD (G1-β-CD), and maltosyl-β-CD (G2-β-CD) as branched CDs. The solubility curves of artemisinin with CDs can all be classified as type A_L. The apparent stability constants for artemisinin-parent CD complexes increased in the order of α- < γ- ≤ β-CD. The constants for artemisinin-β-CD derivative (and β-CD) complexes increased in the order of G2-β-CD ? G1-β-CD cong; PM-β-CD ? β-CD < HP-β-CD < SBE7-β-CD < DM-β-CD. These results suggest that the addition of CDs enables the solubilization of artemisinin.     

Selectivity in capillary electrophoresis: application to chiral separations with cyclodextrins

In order to accurately evaluate the performances of any electrolyte medium, a clear concept of selectivity in capillary electrophoresis and related electroseparation techniques is proposed. Selectivity is defined as the ratio of the affinity factors of both analytes for a separating agent (phase, pseudophase, or complexing agent present in the background electrolyte). When in the presence of a complexing agent and if only 1:1 complexation occurs, selectivity corresponds to the ratio of the apparent binding constants and is independent of the concentration of the complexing agent. This concept is illustrated through the separations of neutral and anionic enantiomers in the presence of a cationic cyclodextrin, the mono(6-amino-6-deoxy)-β-cyclodextrin, as a chiral complexing agent. The values obtained for different pairs of enantiomers are discussed with regard to the functional groups that distinguish them. When the analytes have the same mobilities in free solution and in their complexed form, then the resolution equation developed in micellar electrokinetic chromatography may be applied and optimum conditions (affinity factors, chiral agent concentration) can be predicted.     

Molecular dynamics simulations of the interactions between β-cyclodextrin derivatives and single-walled carbon nanotubes

Since cyclodextrins (CDs) were discovered to be an excellent reagent to disperse carbon nanotubes (CNTs), they were used for the construction of CD/CNT based electrodes. Therefore, it is crucial to investigate the interactions between CDs and CNTs for their applications. Herein, β-cyclodextrin (β-CD) and their four derivatives, 2-O-(2-hydroxypropyl)-β-cyclodextrin (2-HP-β-CD), 6-O-(2-hydroxypropyl)-β-cyclodextrin (6-HP-β-CD), 2-O-(2-hydroxybutyl)-β-cyclodextrin (2-HB-β-CD) and 6-O-(2-hydroxybutyl)-β-cyclodextrin (6-HB-β-CD), were employed to investigate the interactions with single-walled carbon nanotubes (SWNTs) both in anhydrous and aqueous conditions by molecular dynamics simulation. The results showed that the interactions between SWNTs and CDs were strongly influenced by the structures of CDs such as substituted group and position. The attractive interactions between SWNTs and CDs monotonically increased with the radius of SWNT. Van der Waals attraction was the dominating force for CDs wrapped onto the surface of the nanotube ropes. Therefore, the results could provide a fundament for the choice of CDs in their further applications.     

Evaluation of a Sulfobutyl Ether β-Cyclodextrin as a Solubilizing/Stabilizing Agent for Several Drugs

Abstract

To evaluate the potential use of β-cyclodextrin sulfobutyl ether, 7 sodium salt (SBE7-β-CD) as a drug solubilizing and stabilizing agent, the solubilizing effects of SBE7-β-CD on 22 different poorly water-soluble drugs were compared with those of intact β-CD and heptakis-(2,6-di-O-melhyl)-β-CD (DMCD). SBE7-β-CD was generally a more effective solubilizer for poorly water-soluble drugs than was intact β-CD, but SBE7-β-CD was not as effective as DMCD. The effects of SBE7-β-CD on the acid hydrolysis rate of prostaglandin I₂, the alkaline hydrolysis rate of indomethacin, the dehydration of prostaglandin E₁, and the isomerization of prostaglandin A₁ were also investigated and compared to those for intact β-CD, DMCD, and 2,3,6 partially methylated-β-CD (PMCD). The stabilizing effects of SBE7-β-CD on chemically unstable drugs were generally higher than those of other CDs.     

A family of single-isomer, sulfated gamma-cyclodextrin chiral resolving agents for capillary electrophoresis. 1. Octakis(2,3-diacetyl-6-sulfato)-gamma-cyclodextrin

The first member of the single-isomer, sulfated gamma-cyclodextrin family, the sodium salt of octakis(2,3-diacetyl-6-sulfato)-gamma-cyclodextrin (ODAS-gamma CD) has been synthesized, analytically characterized, and used to separate, by capillary electrophoresis, a variety of neutral, acidic, basic, and amphoteric enantiomers in low pH background electrolytes. The anionic effective mobilities of the neutral and anionic analytes were found to increase with the concentration of ODAS-gamma CD. For weakly binding cationic analytes, the effective mobilities went from cationic high values, through zero, to increasingly larger anionic values as the concentration of ODAS-gamma CD was increased. For the strongly complexing cationic analytes, the effective mobilities became anionic even at very low ODAS-gamma CD concentrations and became smaller as the ionic strength of the background electrolyte increased with the increasing ODAS-gamma CD concentration. Separation selectivity followed the predictions of the charged resolving agent migration model: for neutral analytes it decreased as the concentration of ODAS-gamma CD was increased. For cationic analytes, selectivities were found to increase as the cationic effective mobilities approached zero, then decreased as the concentration of ODAS-gamma CD was increased further. The extent of peak resolution that could be realized with ODAS-gamma CD strongly depended on the magnitude of separation selectivity and the normalized electroosmotic flow mobility. ODAS-gamma CD proved to be a broadly applicable chiral resolving agent.     

Inclusion Complexation of Lorazepam with Different Cyclodextrins Suitable for Parenteral Use

The development of a parenteral lorazepam formulation, using cyclodextrins (CDs) as inclusion complexation agents, was investigated. CDs suitable for parenteral injection, i.e., hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxypropyl-γ-cyclodextrin (HP-γ-CD), sulfobutylether-7-β-cyclodextrin (SBE-7-β-CD), and maltosyl-β-cyclodextrin (malt-β-CD) were studied for the possibility to increase the solubility of lorazepam. Lorazepam interacted with all tested CD derivatives and 1:1 complexes are formed. HP-β-CD exerts the highest solubility improvement, reaching about 6 mg/ml lorazepam in 30% (w/v) CD solution. When using SBE-7-β-CD or malt-β-CD only half of that concentration can be dissolved. HP-γ-CD interacts much less with lorazepam. Parenteral solutions with 4 mg/ml in 30% (w/v) HP-β-CD solution, with 2 mg/ml in 30% (w/v) SBE-7-β-CD, and with 2 mg/ml lorazepam in 15% (w/v) HP-β-CD, were prepared. Sterile filtration of the formulation needs to be applied because of massive degradation of lorazepam during autoclaving. No precipitation is observed after dilution of the different formulations with (physiological) water or with 5% dextrose in water, which proves their suitability for administration with perfusions. The stability of the preparations was investigated in aqueous medium. During the first month, in all solutions more than 90% of lorazepam remained; after 3 months, less than 60% of lorazepam remained in the solutions with 15% (w/v) HP-β-CD and around 65–70% in the solutions with 30% (w/v) of CDs. Because of this short stability time, the preparations need to be lyophilized.     

Capillary electrophoresis with electrochemical detection for chiral separation of optical isomers

The enantiomers of two amine derivatives were directly separated by capillary electrophoresis (CE), employing β-cyclodxtrin (β-CD) as a chiral additive in strongly alkaline solutions. The analytes were detected by electrochemistry, using a copper disk electrode at +675 mV vs Ag/AgCl reference electrode. Both the free enantiomers and the enantiomer-cyclodxtrin inclusion complexes could be detected using this approach, although the complexed forms gave lower oxidation currents than the free forms. Factors affecting the chiral CE separation of the analytes, such as working potential, concentration of running buffer and β-CD, and applied voltage, were extensively investigated. Under the optimum conditions, baseline separation of the enantiomers could be accomplished in less than 18 min. In addition, a successful application of the method to the enantiomeric purity determination confirmed its validity and practicability.     

Chiral metabonomics: 1H NMR-based enantiospecific differentiation of metabolites in human urine via direct cosolvation with β-cyclodextrin

Differences in molecular chirality remain an important issue in drug metabolism and pharmacokinetics for the pharmaceutical industry and regulatory authorities, and chirality is an important feature of many endogenous metabolites. We present a method for the rapid, direct differentiation and identification of chiral drug enantiomers in human urine without pretreatment of any kind. Using the well-known anti-inflammatory chemical ibuprofen as one example, we demonstrate that the enantiomers of ibuprofen and the diastereoisomers of one of its main metabolites, the glucuronidated carboxylate derivative, can be resolved by (1)H NMR spectroscopy as a consequence of direct addition of the chiral cosolvating agent (CSA) β-cyclodextrin (βCD). This approach is simple, rapid, and robust, involves minimal sample manipulation, and does not require derivatization or purification of the sample. In addition, the method should allow the enantiodifferentiation of endogenous chiral metabolites, and this has potential value for differentiating metabolites from mammalian and microbial sources in biofluids. From these initial findings, we propose that more extensive and detailed enantiospecific metabolic profiling could be possible using CSA-NMR spectroscopy than has been previously reported.     

Inclusion complexes of fluorofenidone with β-cyclodextrin and hydroxypropyl-β-cyclodextrin

Background: Fluorofenidone is a novel antifibrotic drug and its aqueous solubility is low. Aim: This study was to prepare and characterize inclusion complexes of fluorofenidone (AKF-PD) with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD). Method: The AKF-PD/cyclodextrins (CDs) inclusion complexes were prepared by coprecipitation and freeze-drying, respectively. The solubility enhancement of AKF-PD was evaluated by phase solubility method. Inclusion complexation in solid phase was studied by X-ray diffraction (XRD) and differential thermal analysis (DTA). The dissolution profiles of AKF-PD/CDs inclusion complexes were investigated and compared with those of their physical mixtures and AKF-PD alone. Results: The phase solubility diagrams of AKF-PD with β-CD and HP-β-CD were of A_L-types, and the solubility of AKF-PD could be increased by 51.5% for β-CD at 0.014 M and 794.0% for HP-β-CD at 0.254 M. The results from XRD and DTA suggested that AKF-PD could form inclusion complex with β-CD or HP-β-CD. The dissolution rate of AKF-PD from the inclusion complexes was much more rapid than AKF-PD alone. Conclusions: The formulation of AKF-PD/CDs inclusion complexes showed superior performance in improving dissolution properties of AKF-PD.     

A Family of Single-Isomer Chiral Resolving Agents for Capillary Electrophoresis. 2. Hepta-6-sulfato-β-cyclodextrin

A new, hydrophilic, single-isomer charged cyclodextrin, the sodium salt of hepta-6-sulfato-β-cyclodextrin has been synthesized, characterized, and used for the capillary electrophoretic separation of the enantiomers of numerous noncharged, acidic, basic, and zwitterionic analytes. Hepta-6-sulfato-β-cyclodextrin proved to be a much stronger complexing agent for all the analytes tested, in both low-pH and high-pH background electrolytes, than the previously synthesized, moderately hydrophobic heptakis(2,3-diacetyl-6-sulfato)-β-cyclodextrin. The separation selectivities of the two single-isomer, differently functionalized charged cyclodextrins often proved to be complementary. In agreement with the predictions of the charged resolving agent migration model, separation selectivity for the noncharged analytes decreased as the concentration of hepta-6-sulfato-β-cyclodextrin was increased. For acidic, basic, and zwitterionic analytes, selectivity could increase, decrease, or pass a maximum, depending on the binding strength of the enantiomers and ionic mobilities of both the complexed and noncomplexed forms of the enantiomers.     

A Family of Single-Isomer Chiral Resolving Agents for Capillary Electrophoresis. 3. Heptakis(2,3-dimethyl-6-sulfato)-β-cyclodextrin

The third member of a new family of single-isomer charged cyclodextrins, the sodium salt of heptakis(2,3-dimethyl-6-sulfato)-β-cycldextrin, has been synthesized, characterized, and used for the capillary electrophoretic separation of the enantiomers of neutral, acidic, basic, and zwitterionic analytes. Though heptakis(2,3-dimethyl-6-sulfato)-β-cyclodextrin complexes much less strongly with any of the analytes tested here than the previously synthesized heptakis(2,3-diacetyl-6-sulfato)-β-cyclodextrin and heptakis-6-sulfato-β-cyclodextrin, it offers excellent enantioselectivities, complementary to those of the other two single-isomer, differently functionalized charged cyclodextrins. Confirming the predictions of the charged resolving agent migration model, heptakis(2,3-dimethyl-6-sulfato)-β-cyclodextrin allowed for the reversal of the migration order of the enantiomers of neutral analytes as the cyclodextrin concentration was increased. Just as with the previous two single-isomer charged resolving agents, separation selectivity for the acidic, basic, and zwitterionic analytes could increase, decrease, or pass a maximum as the cyclodextrin concentration was increased, depending on the respective binding strength of the enantiomers and the ionic mobilities of both the complexed and noncomplexed forms of the enantiomers.     

Effect of host-guest interactions on the cloud points of neutral thermosensitive homopolymers: poly(N-n-propylmethacrylamide) and polymers with similar structures

We investigated effect of cyclodextrins (CDs) on the cloud point of several thermosensitive polymers that are not ionizable. α-CD increased the cloud point of the poly(N-n-propylmethacrylamide) (PnPMAm) aqueous solution; by contrast, β-CD or γ-CD did not affect the cloud point of the PnPMAm solution. The cloud point of the PnPMAm solution increased gradually with an increase in the concentration of α-CD. Furthermore, we compared the effect of the CDs on the cloud points of four polymers with similar structures. As for poly(N-isopropylacrylamide) (PiPAAm), neither α-CD nor β-CD affected its cloud point. On the basis of the effect of the differently sized CDs on the cloud point of five polymers and the corresponding NOESY NMR data, we inferred that steric hindrance by the main chain of PiPAAm might be responsible for the bulky CD being unable to form a complex with the short isopropyl group.     

Cyclodextrin Inclusion Complexes of the Central Analgesic Drug Nefopam

ABSTRACT

Inclusion complexes of nefopam base (NEF) with various β‐cyclodextrins (βCDs) were investigated. All tested βCDs increased the apparent solubility of NEF according to a Higuchi A_L type plot (except βCD: A_N type plot), which indicates the formation of 1:1 stoichiometry inclusion complexes. ¹H-NMR and ¹³C-NMR experiments showed that complexation by CDs allowed an easy separation of the R and S enantiomers. Based on spectral data obtained from the two-dimensional rotating frame nuclear Overhauser effect spectroscopy (2D-ROESY), a reasonable geometry for the complexes could be proposed implicating the insertion of the benzoxazocine ring into the wide end of the torus cavity.     

Characterization,inclusion mode,phase-solubility and in vitro release studies of inclusion binary complexes with cyclodextrins and meglumine using sulfamerazine as model drug

In order to investigate the effect on the aqueous solubility and release rate of sulfamerazine (SMR) as model drug, inclusion complexes with β-cyclodextrin (βCD), methyl-β-cyclodextrin (MβCD) and hydroxypropyl-β-cyclodextrin (HPβCD) and a binary system with meglumine (MEG) were developed. The formation of 1:1 inclusion complexes of SMR with the CDs and a SMR:MEG binary system in solution and in solid state was revealed by phase solubility studies (PSS), nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), thermal analysis and X-Ray diffractometry (XRD) studies. The CDs solubilization of SMR could be improved by ionization of the drug molecule through pH adjustments. The higher apparent stability constants of SMR:CDs complexes were obtained in pH 2.00, demonstrating that CDs present more affinity for the unionized drug. The best approach for SMR solubility enhancement results from the combination of MEG and pH adjustment, with a 34-fold increment and a S_max of 54.8?mg/ml. The permeability of the drug was reduced due to the presence of βCD, MβCD, HPβCD and MEG when used as solubilizers. The study then suggests interesting applications of CD or MEG complexes for modulating the release rate of SMR through semipermeable membranes.     

Enantiomeric separation of sulfonium ions by capillary electrophoresis using neutral and charged cyclodextrins

Capillary zone electrophoresis was successfully applied, for the first time, to the chiral separation of structurally related sulfonium ions, using sodium phosphate buffer pH 2.5 with β-cyclodextrin (β-CD) or sulfated-β-cyclodextrin (S-β-CD) as the chiral selector with tetrabutylammonium bromide (TBA). For this study, a series of structurally related sulfonium ions in which one of the alkyl chains varied in length were synthesized from a common sulfide. The resolution of the ions was found to be dependent on the type of cyclodextrin used, the presence or absence of TBA, and the structure of the sulfonium ion. β-CD was found to be effective only for ions containing two aromatic groups, while the S-β-CD was effective only for ions containing one aromatic group. The chiral separation of thiophenium ions was also studied under the conditions established. Chiral separation of sulfonium ions in a binary buffer system containing methanol was explored as well. Separations were achieved for all but one sulfonium ion and one thiophenium ion. The data presented show the effectiveness of the enantiomeric separation using CZE with cyclodextrin-modified buffer for these types of ions.     

Fexofenadine/Cyclodextrin Inclusion Complexation: Phase Solubility,Thermodynamic, Physicochemical,and Computational Analysis

Interactions of fexofenadine (Fexo) with cyclodextrins (CDs: α- β-, γ-, and HP-β-CD) were investigated by several techniques including phase solubility, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), ¹H-nuclear magnetic resonance (¹H-NMR) and molecular mechanical modeling (MM⁺). The effects of CD type, pH, ionic strength, and temperature on complex stability were also explored. Fexo/CD complex formation follows the decreasing order: β-CD > HP-β-CD > γ-CD > α-CD (i.e., at pH 7.0 and 30°C, K₁₁ = 1139, 406, 130, and 104 M^?1, respectively). The linear correlation of the free energy of Fexo/β-CD complex formation (ΔG₁₁) with the free energy of inherent Fexo solubility (ΔG_So), obtained from the variation of K₁₁ with inherent Fexo solubility (S_o) at different pHs and ionic strengths, was used to measure the contribution of the hydrophobic character of Fexo to escape from water by including into the hydrophobic CD cavity. The hydrophobic effect (desolvation) contributes about 76% of the total driving force towards inclusion complex formation, while specific interactions contribute ?7.7 kJ/mol. Moreover, Zwitterionic Fexo/β-CD complex formation appears to be driven both by favorable enthalpy (ΔH°?=??23.2 kJ/mol) and entropy (ΔS°?=?15.2 J/mol.K) changes at pH 7.0. ¹H-NMR and MM⁺ studies indicate multimodal inclusion of the piperidine, carboxypropylphenyl, and phenyl moieties into the β-CD cavity. MM⁺ computations indicate that the dominant driving force for complexation is Van der Waals force with very little electrostatic contribution. ¹H-NMR, DSC, and XRPD studies indicate the formation of inclusion complex in aqueous solution and the solid state.     

Solubility and Dissolution Rate of Progesterone-Cyclodextrin-Polymer Systems

ABSTRACT

This contribution focused on the solubility improvement of the poorly water-soluble steroid hormone progesterone which, in its natural state, presents a reduced oral bioavailability. In the first part of this study, two simple, reproducible methods that were candidates for use in the preparation of inclusion complexes with cyclodextrins were investigated. Solubility capacities of the progesterone complex with hydroxypropyl-β-CD (HPβ-CD), hydoxypropyl-γ-CD (HPγ-CD), permethyl-β-CD (PMβ-CD), and sulfobutylether-β-CD (SBEβ-CD), prepared by the freeze-drying and precipitation methods, were evaluated by Higuchi phase solubility studies. The results showed that HPβ-CD and PMβ-CD were the most efficient among the four cyclodextrins for the solubilization of progesterone, with the highest apparent stability constants. Therefore, dissolution studies were conducted on these latest progesterone/cyclodextrin complexes and physical mixtures. Two additional natural cyclodextrins, β-CD and γ-CD, were taken as references. Hence, the influence of more highly soluble derivatives of β‐CD (HPβ-CD, PMβ-CD) on the progesterone dissolution rate, in comparison to pristine β-CD, alongside an increase in the cavity width for γ-CD versus β-CD, were investigated. The dissolution kinetics of progesterone dissolved from HPβ-CD, PMβ-CD, and γ-CD revealed higher constant rates in comparison to β-CD. Therefore, the aim of the second part of this study was to investigate the possibility of improving the dissolution rate of progesterone/β-CD binary systems upon formation of ternary complexes with the hydrophilic polymer, PEG 6000, as β-CD had the smallest progesterone solubility and dissolution capacity among the four cyclodextrins studied (β‐CD, HPβ-CD, HPγ-CD and PMβ-CD). The results indicated that dissolution constant rates were considerably enhanced for the 5% and 10% progesterone/β-CD complexes in PEG 6000.

The interaction of progesterone with the cyclodextrins of interest on the form of the binary physical mixtures, complexes, or ternary complexes were investigated by differential scanning calorimetry (DSC) and Fourier transformed-infrared spectroscopy (FT-IR). The results proved that progesterone was diffused into the cyclodextrin cavity, replacing the water molecules and, in case of ternary systems, that the progesterone β-cyclodextrin was well dispersed into PEG, thus improving progesterone bioavailability for subsequent oral delivery in the same way as derivatized cyclodextrins. The present work proves that ternary complexes are promising systems for drug encapsulation.     

Inclusion complexation of lorazepam with different cyclodextrins suitable for parenteral use

The development of a parenteral lorazepam formulation, using cyclodextrins (CDs) as inclusion complexation agents, was investigated. CDs suitable for parenteral injection, i.e., hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxypropyl-γ-cyclodextrin (HP-γ-CD), sulfobutylether-7-β-cyclodextrin (SBE-7-β-CD), and maltosyl-β-cyclodextrin (malt-β-CD) were studied for the possibility to increase the solubility of lorazepam. Lorazepam interacted with all tested CD derivatives and 1:1 complexes are formed. HP-β-CD exerts the highest solubility improvement, reaching about 6 mg/ml lorazepam in 30% (w/v) CD solution. When using SBE-7-β-CD or malt-β-CD only half of that concentration can be dissolved. HP-γ-CD interacts much less with lorazepam. Parenteral solutions with 4 mg/ml in 30% (w/v) HP-β-CD solution, with 2 mg/ml in 30% (w/v) SBE-7-β-CD, and with 2 mg/ml lorazepam in 15% (w/v) HP-β-CD, were prepared. Sterile filtration of the formulation needs to be applied because of massive degradation of lorazepam during autoclaving. No precipitation is observed after dilution of the different formulations with (physiological) water or with 5% dextrose in water, which proves their suitability for administration with perfusions. The stability of the preparations was investigated in aqueous medium. During the first month, in all solutions more than 90% of lorazepam remained; after 3 months, less than 60% of lorazepam remained in the solutions with 15% (w/v) HP-β-CD and around 65-70% in the solutions with 30% (w/v) of CDs. Because of this short stability time, the preparations need to be lyophilized.     

Interaction of Cyclomaltononaose (δ-CD) with Several Drugs

The effects of δ-cyclodextrin (δ-CD; cyclomaltononaose) on solubility of 14 drugs that are slightly soluble or insoluble in water were studied and compared with those of conventional cyclodextrins (CDs) such as α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), and γ-cyclodextrin (γ-CD). In general, δ-CD had a weak complex-forming ability with the drugs examined in comparison with β-CD and γ-CD. However, in the case of digitoxin, δ-CD enhanced solubility of the guest molecules. To determine the mechanism of inclusion complex formation of δ-CD with digitoxin, the interaction of both drugs was investigated by the solubility method and spectroscopic methods such as ultraviolet (UV) and ¹H-NMR (nuclear magnetic resonance). The changes in chemical shift (¹H) and hypsochromic shift of UV suggested that digitoxin was partially included in the cavity of δ-CD.     

Evaluation of Stereoselective Dissolution of Racemic Salbutamol Matrices Prepared with Commonly Used Excipients and 1H-NMR Study

The purpose of this work was to examine the in vitro enantioselective dissolution of salbutamol from matrix tablets containing various chiral excipients, such as γ-cyclodextrin (γ-CD), heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), sulfobutyl-β-cyclodextrin (SBE-β-CD), hydroxypropylmethylcellulose (HPMC), and egg albumin. In this study, two types of tablets were prepared; the coated tablet contained the complex of racemic salbutamol and cyclodextrin (γ-CD, DM-β-CD, and SBE-β-CD), and the uncoated tablet was composed of the drug with either HPMC or egg albumin. Subsequently, these formulations were evaluated for enantioselective release. The results revealed that the formulations containing either SBE-β-CD, HPMC, or egg albumin had no enantioselective release, while the formulation with DM-β-CD gave slightly different release of the two enantiomers at the end of the dissolution profile. The formulation containing γ-CD provided significant stereoselectivity throughout the dissolution profile. The release of the eutomer R-salbutamol was higher than that of the distomer S-salbutamol from the γ-CD tablet. In addition, the enantioselective interaction for the γ-CD inclusion complex was investigated by ¹H-NMR (nuclear magnetic resonance) spectroscopy and gave evidence to support the enantioselectivity obtained on dissolution.