Development of fast-dissolving tablets of flurbiprofen-cyclodextrin complexes

The present study was aimed at developing a tablet formulation based on an effective flurbiprofen-cyclodextrin system, able to allow a rapid and complete dissolution of this practically insoluble drug. Three different cyclodextrins were evaluated: the parent β-cyclodextrin (previously found to be the best partner for the drug among the natural cyclodextrins), and two amorphous, highly soluble β-cyclodextrin derivatives, i.e., methyl-β-cyclodextrin and hydroxyethyl-β-cyclodextrin. Equimolar drug-cyclodextrin binary systems prepared according to five different techniques (physical mixing, kneading, sealed-heating, coevaporation, and colyophilization) were characterized by Differential Scanning Calorimetry, x-ray powder diffractometry, infrared spectroscopy, and optical microscopy and evaluated for solubility and dissolution rate properties. The drug solubility improvement obtained by the different binary systems varied from a minimum of 2.5 times up to a maximum of 120 times, depending on both the cyclodextrin type and the system preparation method. Selected binary systems were used for preparation of direct compression tablets with reduced drug dosage (50 mg). Chitosan and spray-dried lactose, alone or in mixture, were used as excipients. All formulations containing drug-cyclodextrin systems gave a higher drug dissolved amount than the corresponding ones with drug alone (also at a dose of 100 mg); however, the drug dissolution behavior was strongly influenced by formulation factors. For example, for the same drug-cyclodextrin product the time to dissolve 50% drug varied from less than 5 minutes to more than 60 minutes, depending on the excipient used for tableting. In particular, only tablets containing the drug kneaded with methyl-β-cyclodextrin or colyophilized with β-cyclodextrin and spray-dried lactose as the only excipient satisfied the requirements of the Food and Drug Administration (FDA) for rapid dissolving tablets, allowing more than 85% drug to be dissolved within 30 minutes. Finally, it can be reasonably expected that the obtained drug dissolution rate improvement will result in an increase of its bioavailability, with the possibility of reducing drug dosage and side effects.     

Effects of grinding with microcrystalline cellulose and cyclodextrins on the ketoprofen physicochemical properties

Ground mixtures of ketoprofen (KETO) with native crystalline β-cyclodextrin, amorphous statistically substituted methyl-β-cyclodextrin, and microcrystalline cellulose were investigated for both solid phase characterization (differential scanning calorimetry (DSC) powder X-ray diffractometry, and infrared (IR) spectrometry) and dissolution properties (dispersed amount and rotating disk methods) to evaluate the role of the carrier on the performance of the final product. The effects of different grinding conditions, partial sample dehydration, and 1 year storage at room temperature were also investigated. The results pointed out the importance of the carrier nature on the efficiency of the cogrinding process. Both cyclodextrins were much more effective than was microcrystalline cellulose, even though no true inclusion complex formation occurred by mechanochemical activation. The best results were obtained from ground mixtures with methyl-β-cyclodextrin, which showed the best amorphizing and solubilizing power toward the drug and permitted an increase of approximately 100 times its intrinsic dissolution rate constant, in comparison with the approximate 10 times increase obtained from ground mixtures with β-cyclodextrin.     

Influence of the substitution of β-cyclodextrins by cationic groups on the complexation of organic anions

The inclusion complexation of the organic anion, dansyl-acid, by cationic derivatives of β-cyclodextrin has been investigated. A series of cationic β-cyclodextrins with various positive charge has been synthesized by selective functionalization of the primary face of β-cyclodextrin with amino groups. The complexes were of the 1:1 stoichiometry; the stability constants (K₁₁) have been evaluated from UV–Vis measurements by application of the Benesi–Hildebrand equation. The presence of amino groups increased the complexation ability. β-cyclodextrin fully substituted at the primary face with amino groups showed the strongest inclusion binding ability towards the dansyl-acid guest. The enhanced complexation for anions was ascribed to the cationic amino groups. A simple thermodynamic model of the electrostatic contribution to the complexation is presented.     

Investigation and physicochemical characterization of clarithromycin-citric acid-cyclodextrins ternary complexes

The purpose of this study was to investigate the effect of citric acid (CA) on the complexation of clarithromycin (CLM) with β-cyclodextrin (βCD) in aqueous solutions and in the solid state. A phase solubility study revealed a positive effect of CA on the drug solubility. A B_s-type solubility with an apparent stability constant (K_c) of 102.4 M^-1 was obtained for CLM in βCD solution and 161.2 M^-1 for CLM in 6 mM βCD solution. Solid ternary complexes were prepared by coevaporation and lyophilization. CLM-βCD-CA interactions were studied in the solid state by differential scanning calorimetry (DSC), infrared spectroscopy, scanning electron microscopy and X-ray diffractometry. A part of the guest molecule was located in the βCD host cavity. The results obtained suggest that the lyophilization method yields a higher degree of amorphous entity than coevaporation.     

The influence of diluent on the release of theophylline from hydrophilic matrix tablets

The role of β-cyclodextrin (β-CD) on the apparent solubility of theophylline was investigated by the solubility method. Binary systems of theophylline and β-CD were prepared using the dry co-grinding method. Their characterization was performed by differential scanning calorimetry (DSC). The dissolution rate of theophylline and theophylline/β-CD and dissolution studies of matrix tablets prepared from mixtures containing theophylline and ground theophylline were carried out. It can be concluded that β-CD is related to an increase in the apparent solubility and dissolution rate of the drug, promoting improvement on the release of theophylline from matrices manufactured with hydroxypropylmethylcellulose (HPMC). This can be attributed to the amorphous state and the increased wettability of the drug.     

Solubility and dissolution rate of progesterone-cyclodextrin-polymer systems

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.     

The physicochemical characteristics of freeze-dried scutellarin-cyclodextrin tetracomponent complexes

In an effort to improve the solubility of the insoluble drug scutellarin, a novel complexation of scutellarin with β-cyclodextrin (β-CD) was studied. Tetracomponent freeze-dried complex was prepared with scutellarin, β-CD, Hydroxypropyl Methylcellulose (HPMC), and triethanolamine. To confirm complex formation, complex was characterized by Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction, and differential scanning calorimetry (DSC). Phase-solubility analysis suggested the soluble complexes having 1:1 stoichiometry. The β-CD solubilization of scutellarin could be improved significantly by combining water-soluble polymer and pH adjuster. Comparing the binary, ternary solid systems with tetrary systems, tetracomponent freeze-dried complex showed the best effect of solubilization. A maximal solubility of scutellarin (23.65 mg/ml) was achieved with tetracomponent freeze-dried complex, up to 148-fold increase over scutellarin solubility in water, and the solubility of scutellarin is 15.35 ug/ml (up to 6-fold) in simulated gastric fluid.     

Effect of hydroxypropyl-beta-cyclodextrin on the solubility of an antibacterial isoxazolyl-naphthoquinone

The complexation of 2-hydroxy-N-(3,4-dimethyl-5-isoxazolyl)-1,4-naphthoquinone-4-imine (I) with a highly soluble cyclodextrin, hydroxypropyl-β-cyclodextrin (HP-β-CD) was studied in aqueous media by solubility methods. I is an antibacterial and trypanocidal agent that is undergoing preclinical testing. Unfortunately, I exhibits low water solubility, and it is therefore difficult to prepare the solutions for biological tests. I inclusion took place with 1:1 stoichiometry. The stability constants of the I complexes calculated from the slope and the intercept of the phase solubility diagrams are larger in the less ionized form, whereas greater overall solubility is obtained in basic media.     

The effect of 2-hydroxypropyl-beta-cyclodextrin on in vitro drug release of steroids from suppository bases

The effects of 2-hydroxypropyl-β-cyclodextrin (HPCD) on drug solubility and drug release from suppository bases were studied for dexamethasone (DX), dexamethasone acetate (DXA), hydrocortisone (HC), hydrocortisone acetate (HCA), and prednisolone acetate (PNA). It was found that HPCD significantly increased the aqueous solubility of all five steroids, and the increased drug solubility significantly influenced the drug release from the polyethylene glycol (PEG) base but not from the cocoa butter base.     

Transdermal Iontophoresis and Skin Retention of Piroxicam from Gels Containing Piroxicam : Hydroxypropyl-β-cyclodextrin Complexes

Iontophoretic transport of piroxicam (Px) across porcine ear skin in vitro was investigated. Cathodal iontophoresis of negatively charged Px was carried out from gel formulations containing Px as an inclusion complex with hydroxypropyl-β-cyclodextrin (HP-β-CD). From the gels, following a 7 h application period at 0.4 mA/cm², iontophoresis delivered 3.4 times more drug than passive diffusion. The formation of Px : HP-β-CD complexes did not increase the iontophoretic Px flux through the skin. However, Px complexation with HP-β-CD allowed us to increase the drug concentration in the gel; because of that, the amount of Px transported across the skin increased considerably. After iontophoretic experiments, the amount of Px retained in skin seemed to be related to the flux values obtained in each case. Skin pretreatment with 20% HP-β-CD, tested passively and iontophoretically for 3 h, followed by the application of gel containing Px : HP-β-CD complexes, showed no enhancing capacity in any case. The amount of Px retained in the skin after pretreatment experiments was found to be very similar to that obtained without skin pretreatment and was observed to be related to the Px flux through the skin.     

Improvement of dissolution and bioavailability of nitrendipine by inclusion in hydroxypropyl-beta-cyclodextrin

A significant increase in solubility and dissolution rate of nitrendipine, a slightly soluble calcium channel blocker, was achieved by inclusion complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD). The inclusion complex was prepared by solvent evaporation method and characterized by phase solubility method, x-ray diffractometry, infrared spectroscopy, and differential scanning calorimetry. The solubility of nitrendipine increased linearly as a function of HP-β-CD concentration, resulting in A_L-type phase solubility diagram which revealed a formation of inclusion complex in a molar ratio of 1:1, with the apparent association constant of 108.3 M^-1. The in vitro dissolution rate of nitrendipine in pH 7.4 phosphate buffer was in the order of inclusion complex, physical mixture, and nitrendipine powder. These three different forms of nitrendipine were administered orally to rats with a dose of 10 mg/kg equivalent to nitrendipine. The AUC of inclusion complex was significantly larger than that of nitrendipine powder. T_max of inclusion complex was significantly shorter and C_max was significantly higher than those of nitrendipine powder. C_max of physical mixture was higher than that of nitrendipine powder. T_max of physical mixture, however, remained the same. The results indicated that the bioavailability of nitrendipine could be improved markedly by inclusion complexation, possibly due to an increased dissolution rate.     

Influence of hydroxypropyl-beta-cyclodextrin on the transdermal permeation and skin accumulation of oxybenzone

The objective of the present study was to determine the effects of hydroxypropyl-β-cyclodextrin (HPCD) concentration on the transdermal permeation and skin accumulation of a model ultraviolet (UV) absorber, oxybenzone. The concentration of oxybenzone was held constant at 2.67 mg/mL for all formulations, while the HPCD concentrations varied from 0 to 20% (w/w). Complexation of oxybenzone by HPCD was demonstrated by differential scanning calorimetry. A modified Franz cell apparatus was used in the transdermal experiments, with aliquots of the receptor fluid assayed for oxybenzone by high-performance liquid chromatography. From the permeation data, flux of the drug was calculated. Skins were removed from the diffusion cells at specified time points over a 24-hr period and the oxybenzone content in the skin determined. The aqueous solubility of oxybenzone increased linearly with increasing HPCD concentration, following a Higuchi A_L-type complexation. The stability constant of the reaction was calculated from the phase-solubility diagram and found to be 2047 M^-1. As the concentration of HPCD was increased from 0 to 10%, transdermal permeation and skin accumulation of oxybenzone increased. Maximum flux occurred at 10% HPCD, where sufficient cyclodextrin was added to completely solubilize all oxybenzone. When the concentration of HPCD was increased to 20%, both transdermal permeation and skin accumulation decreased. These data suggest the formation of a drug reservoir on the surface of the skin.     

Fatigue crack initiation and growth under mixed mode loading in aluminum alloys 2017-T3 and 7075-T6

Fatigue crack initiation and growth characteristics under mixed mode loading have been investigated on aluminum alloys 2017-T3 and 7075-T6, using a newly developed apparatus for mixed mode loading tests. In 2017-T3, the fatigue crack initiation and growth characteristics from a precrack under mixed mode loading are divided into three regions—shear mode growth, tensile mode growth and no growth—on the ΔK_I-ΔK_II plane. The shear mode growth is observed in the region expressed approximately by ΔK_II > 3MPa√m and ΔK_II/ΔK_I > 1.6. In 7075-T6, the condition of shear mode crack initiation is expressed by ΔK_II > 8 MPa√m and ΔK_II/ΔK_I > 1.6, and continuous crack growth in shear mode is observed only in the case of ΔK_I/ΔK_II, 0. The threshold condition of fatigue crack growth in tensile mode is described by the maximum tensile stress criterion, which is given by Δσ_θmax √2πr 1.6MPa√m, in both aluminum alloys. The direction of shear mode crack growth approaches the plane in which K_I decreases and K_II increases towards the maximum with crack growth. da/dN-ΔK_II relations of the curved cracks growing in shear mode under mixed mode loading agree well with the da/dN-ΔK_II relation of a straight crack under pure mode II loading.     

Multicomponent complexes of piroxicam with cyclodextrins and hydroxypropyl methylcellulose

The purpose of the study was to investigate the effect of hydroxypropyl methylcellulose (HPMC) on the complexation of piroxicam (PX) with β-cyclodextrin (β-CD) and dimethyl-β-cyclodextrin (DM-β-CD) in solution and in the solid state. Phase solubility study revealed a positive effect of the polymer on the drug complexation. Improvement in stability constants values, K_s, of ternary complexes clearly proves the benefit of the HPMC addition for promoting higher complexation efficiency. Solid binary and ternary complexes were prepared by spray drying. Drug-CD and drug-CD-polymer interactions were studied in the solid state by differential scanning calorimetry (DSC), zeta-potential measurements, and particle size distribution. A marked increase in the PX dissolution rate was observed even in binary and ternary complexes. The presence of HPMC in ternary complexes slightly retarded the release of PX. Cyclodextrin complexation increased the PX concentration gradient over the semipermeable membrane, resulting in an increased PX flux. The retarded diffusion of PX to the membrane interface decreased the PX flux values of the ternary complexes.     

Influence of cyclodextrin complexation on the in vivo photoprotective effects of oxybenzone

The objective of the current study was to investigate the influence of cyclodextrin complexation on the in vivo photoprotective effects of a model ultraviolet (UV) absorber, oxybenzone, and to compare these novel sunscreens to a commercial SPF 30 sunscreen product. Aqueous-based solutions and suspensions containing 2.7 mg/mL oxybenzone and up to 20% (w/w) hydroxypropyl-β-cyclodextrin (HPCD) were prepared. The sunscreens were applied to the dorsal skin of SKH-1 hairless mice and the animals were exposed to up to two minimal erythemal doses (MEDs) of UV radiation. Control animals received no sunscreen treatment. Lipid damage, as quantified by decreases in the lipid melting temperature of the epidermis, was determined using differential scanning calorimetry immediately after UV exposure. The number of sunburn cells (SBCs) and the extent of edema were measured 24 hours postexposure. Results showed that all oxybenzone-containing formulations decreased the number of SBCs formed, diminished swelling, and reduced the physical damage to the skin structure, in comparison to control. Thus, complexation did not prevent oxybenzone from reacting with light. The 20% HPCD formulation exhibited more substantial photoprotection at UV exposures of one or two MEDs, as evidenced by the formation of fewer SBCs. The 5% HPCD formulation also provided substantial protection against epidermal lipid damage. These studies demonstrate that inclusion of HPCD in sunscreen formulations may enhance the in vivo photoprotective effects of the UV absorbers. No single HPCD-containing sunscreen, however, was found to be equivalent to a commercially available sunscreen product for all biomarkers investigated.     

Inclusion Complexes of Tolnaftate with β-Cyclodextrin and Hydroxypropyl β-Cyclodextrin

Tolnaftate, an antifungal agent, was found to form inclusion complexes with both β-cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrins (HPBCDs) with two different degrees of substitution [HPBCD(A)-8% and HPBCD(B)-3%]. Complex formation in the solution state was studied using phase solubility and spectral shift methods. Solid complexes were prepared by the coprecipitation method. Solubilities and dissolution rates were determined for each solid complex, its corresponding physical mixture, and free drug. The increase in solubility of tolnaftate with added HPBCD was found to be significantly greater than with added β-CD. For both HPBCD(A) and HPBCD(B), over the concentration range 0-0.05 M. 1:1 complexes with stability constants of 1460 ± 139 M^-1 and 1860 ± 165 M^-1 were observed, respectively. Over the β-CD concentration range 0-0.02 M, a 1:1 complex with a stability constant of 1190 ± 105 M^-1 was observed. At higher HPBCD concentrations, the increase in solubility was observed to show a positive deviation from linearity (type A_p phase diagram). Using the spectral method, in a 2 5% v/v methanol in water system, the stability constants were determined to be 1020 ± 150 M^-1 1110 ± 120 M^-1 and 1100 ± 260 M^-1 for HPBCD(A), HPBCD(B) and β-CD, respectively. The solid complexes prepared showed improved dissolution over physical mixtures and free drug.     

Interaction of Iodine with 2-Hydroxypropyl-α-cyclodextrin and Its Bactericidal Activity

ABSTRACT

To obtain an effective iodine solution, the use of 2-hydroxypropyl-α-cyclodextrin (2-HP-α-CD) as solubilizer was examined in comparison with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), potassium iodide (KI), and polyvinylpyrrolidone (PVP). The stability constants for inclusion of iodine with cyclodextrin and KI were ascertained by the solubility method. The apparent stability constants increased in the following order: KI<β-CD<α-CD<2-HP-α-CD. This order was nearly in accordance with that of the stabilization ability. The largest volatile depression effect was exhibited by 2HP-α-CD. The measurement of the minimum inhibitory concentration (MC) using Escherichia coli NIH-J-2 and Staphylococcus aureus FDA209P suggested that the bactericidal activity of the iodine/2-HP-α-CD system was the same as that of the iodine/α-CD, iodine/β-CD, and iodine/PVP systems. The present results suggest that the combination of 2-HP-α-CD and iodine is useful for a stable and effective iodine solution.     

Interface structure at the large misfit, still common epitaxy β-FeSi2(101) or (110)//Si(111)

In this paper we compare the elastic energies obtained by tight-binding molecular dynamics simulations for several strained structures of β-FeSi₂, corresponding to the most frequent epitaxial relationships ‘on’ and ‘in’ silicon. Our results confirm that, for coherent interfaces, the very common β-FeSi₂(101) or (110)//Si(111) orientation generates a very large contribution to the elastic energy, due to the large misfit. Therefore, we suggest that the frequent nucleation of such epitaxial relationships in precipitates is provided by the correspondence of the two-dimensional crystal structure for the Si sites between Si(111) and β-FeSi₂(101) or (110). We show it to be maintained even after misfit relaxation in the silicon matrix, as simulated by a large-scale molecular dynamics run.     

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.     

An accurate redetermination of the Sn binding energy

The energy of well-known strong γ line from ¹⁹⁸Au, the “gold standard”, has been modified in the light of new adjustments in the fundamental constants and the value of 411.80176(12) keV was determined, which is 0.29 eV lower than the latest 1999 value. An energy calibration procedure for determining the neutron binding energy, B_n, from complicated (n, γ) spectra has been developed. A mathematically simple minimization function consisting only of terms having as parameters the coefficients of the energy calibration curve (polynomial) is used. A priori information about the relationships among the energies of different peaks on the spectrum is taken into account by a Monte-Carlo simulation. The procedure was used in obtaining B_n for ¹¹⁸Sn. The γ-ray spectrum from thermal neutron radiative capture by ¹¹⁷Sn has been measured on the IBR-2 pulsed reactor. γ-rays were detected by a 72 cm³ HPGe detector. For a better determination of B_n it was important to determine B_n for ⁶⁴Cu. This value was obtained from two γ-spectra. One spectrum was measured on the IBR-2 by the same detector. The other spectrum was measured with a pair spectrometer at the Brookhaven High Flux Beam Reactor. From these two spectra, B_n for ⁶⁴Cu was determined to be equal to 7915.52(8) keV. This result essentially differs from the previous value of 7915.96(11) keV. The mean value of the two most precise results of the B_n for ¹¹⁸Sn, was determined to be 9326.35(9) keV. The B_n for ⁵⁷Fe was determined to be 7646.08(9) keV.