Solubilization of naphthoquinones by complexation with hydroxypropyl-β-cyclodextrin

The effects of the hydroxypropyl-β-cyclodextrin (HPCD) on the solubility of 2-hydroxy-N-(5-methyl-3-isoxazolyl)-1,4-naphthoquinone-4-imine (I) were investigated. I is an experimental drug for the treatment of cancer which exhibits low water solubility and it is therefore difficult to prepare the solutions for biological tests. The presence of an ionizable hydroxyl moiety (pK_a=5.80) increases the solubility via pH adjustment, but only a solubility of 0.124 mg/ml was obtained at pH 8.00. I was found to form inclusion complexes in either its neutral or its anionic form with HPCD. Although the stability constant of the I complex is larger in the neutral form, a greater overall solubility is obtained when I is in its ionized form. A 270-fold solubility enhancement is possible by using a combined approach of pH adjustment and complexation with HPCD.     

Improvement of Solubility and Oral Bioavailability of Rutin by Complexation with 2-Hydroxypropyl-β-cyclodextrin

The object of this study was to enhance the solubility, dissolution rate, and oral bioavailability of rutin by complexation with 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD). The interaction of rutin with cyclodextrins (CyDs) was evaluated by the solubility, and ultraviolet (UV) and circular dichroism (CD) spectrophotometries. The chemical and enzymatic stability of rutin was examined in an alkaline buffer solution and in rat small intestinal homogenates, respectively. Dissolution rates of rutin and its CyD complexes were measured by the dispersed amount method. In vivo absorption studies of rutin after oral administration via conventional tablet containing rutin alone or its β-CyD complexes was performed on beagle dogs. The stability constants calculated from the phase solubility method increased in the order of HP-γ-CyD < G₂-β-CyD < β-CyD < HP-β-CyD. Spectroscopic studies also revealed that HP-β-CyD and β-CyD formed a relatively more stable inclusion complex with rutin. The dissolution rates of rutin increased by the complexation with CyDs in the order of rutin alone < HP-β-CyD ≤ β-CyD. HP-β-CyD inhibited the hydrolysis of rutin in the alkaline buffer solution and the small intestinal homogenates of rats, suggesting that HP-β-CyD may stabilize rutin in a gastrointestinal tract after oral administration. When the tablet containing rutin or its β-CyD complexes was administered to beagle dogs, the plasma levels of homovanillic acid (HVA) (a major stable metabolite of rutin) after oral administration of HP-β-CyD complex were much higher than in either that of rutin alone or in its β-CyD complex. The in vivo absorption study suggests that HP-β-CyD increased the oral bioavailability of rutin from the gastrointestinal tracts of beagle dogs because of the increase in solubility, faster dissolution rate, and gastrointestinal stability. HP-β-CyD has a significant advantage with respect to providing high aqueous solubility while maintaining a lack of toxicity in oral pharmaceutical preparations of rutin.     

Enhancement of norfloxacin solubility via inclusion complexation with β-cyclodextrin and its derivative hydroxypropyl-β-cyclodextrin

The objectives of the study were to investigate the effects of β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD) on the solubility and dissolution rate of norfloxacin prepared using three different methods, at drug to cyclodextrin weight ratios of 1:1, 1:2, 1:4 and 1:8. All the methods increased the solubility and dissolution rate of norfloxacin via inclusion complexation with βCD and HPβCD. Norfloxacin was converted from crystalline to amorphous form through inclusion complexation. Solvent evaporation method was the most effective method in terms of norfloxacin solubilisation, while inclusion complex of HPβCD has higher solubility than βCD complex when prepared using the same procedure.     

Improvement of water solubility and dissolution rate of ursodeoxycholic acid and chenodeoxycholic acid by complexation with natural and modified β-cyclodextrins

The inclusion complexes of ursodeoxycholic and chenodeoxycholic acid with β-cyclodextrin, heptakis-(2,6-di-O-methyl)-β-cyclodextrin and soluble polymerized β-cyclodextrin were investigated in solution (¹H-NMR spectrometry) and solid state (FT-IR spectroscopy and differential scanning calorimetry). Stability constants were determined at pH 7.4 and different temperatures and consequently thermodynamic parameters were obtained. All cyclodextrins are able to increase water solubility of the bile acids, particularly polymerized β-cyclodextrin. All complexes show high dissolution rate at 37°C and pH 1.1 and in particular freeze-dried complexes.     

Solubilization and Stabilization of a Benzylpenicillin Chemical Delivery System by 2-Hydroxypropyl-β-cyclodextrin

A dihydropyridine pyridinium salt redox carrier-based chemical delivery system for benzylpenicillin (1) was complexed with 2-hydroxypropyl--cyclodextrin (HPCD). The solubility of the lipophilic 1, which is incompatible with aqueous formulations, was dramatically increased and showed a linear dependency on the HPCD concentration. The degree of incorporation was 20 mg of 1 per g of complex. The stability study of 1 in various pH buffers indicated the base-catalyzed hydrolysis of the acyloxyalkyl linkage and the hydration of the 5,6 double bond of the dihydropyridine as the main degradation processes. The overall loss of 1, which follows first-order kinetics, was not influenced by changes in ionic strength and elimination of oxygen from the reaction medium. The HPCD complex of 1, which has a stability constant of 720–940 M ^–1, stabilized the chemical delivery system. The influence of the temperature on the stability of 1 is also discussed.     

Effect of 2-Hydroxypropyl-β-cyclodextrin on the Ocular Absorption of Dexamethasone and Dexamethasone Acetate

Complexation of dexamethasone (DX) and dexamethasone acetate (DXA) with 2-hydroxypropyl--cyclodextrin (HPCD) was investigated with an ultimate goal of formulating a topical ophthalmic solution of DXA. Aqueous solubility of DX and DXA was markedly increased due to formation of soluble inclusion complexes with HPCD. Based on characterization of complex formation by phase solubility and UV-spectroscopy methods, a stoichiometry of 1:1 and 1:1, 1:2 was assumed for DX-HPCD and DXA-HPCD complexes, respectively. The stability constants for complex formation estimated by phase solubility and UV-spectroscopy methods, respectively, were as follows: for DX-HPCD complex, K_{l :l} = 2193 and 2221 M^–1; and for DXA-HPCD complex, K _1:1 = 2240 and 2445 M ^–l and K _l:2 = 3 and 17 M ^–1. K _{l :l} of 2266 M ^–l and K _{l :2} of 20 M ^–l were also estimated for the DXA-HPCD complex by kinetics. The kinetics of DXA degradation in pH 7 phosphate buffer at 25°C followed pseudo first order. The addition of HPCD decreased the rate but the order of reaction remained unchanged. Free DXA degraded at a faster rate than complexed DXA. Ocular bioavailability in conjunctiva, cornea, iris, and aqueous humor postadministration of a 25-µl dose of formulations containing an equivalent of 0.1% (w/v) DX followed a rank-order of DXA-HPCD solution > DXA suspension > DX-HPCD solution > DX suspension.     

Use of 2-Hydroxypropyl-β-cyclodextrin as a Solubilizing and Stabilizing Excipient for Protein Drugs

A chemically modified, amorphous -cyclodextrin, namely, 2-hydroxypropyl--cyclodextrin (HPCD), was examined as a solubilizing and stabilizing agent for protein drugs. The aqueous solubility of ovine growth hormone at pH 7.4 was increased through the use of HPCD. This effect was manifested by higher UV transparency at 600 nm. Interleukin-2 (IL-2) is rendered insoluble upon lyophilization in the absence of stabilizers. Use of aqueous HPCD provides a clear solution, as indicated by fluorometric light scattering, and inhibits aggregate formation, as shown by ultracentrifugation and Western blot analyses. In addition, there were no major conformational changes of IL-2 in HPCD formulation as indicated by fourth-derivative ultraviolet spectroscopy. Finally, IL-2 retained 100% of its biopotency when prepared in HPCD solutions. Aggregation of insulin was also suppressed by HPCD. These data, as well as the i.v. safety of HPCD and its well-characterized chemical composition, suggest that this starch derivative may be a potentially useful excipient for protein drugs intended for parenteral use.     

Halogenation effects of pheniramines on the complexation with β-cyclodextrin

This study investigated the inclusion complexes of β-cyclodextrin with pheniramine and its halogenated derivatives chlorpheniramine and brompheniramine both experimentally and theoretically to characterize the effects of a halogenated phenyl ring on the intermolecular interactions. Fourier transform infrared and nuclear magnetic resonance (NMR) experiments provided evidence of the formation of inclusion complexes and NMR were conducted to evaluate the apparent binding constants. The two-layered hybrid ONIOM method, ONIOM(B3LYP/6-31G(d):PM3), was adopted to optimize the geometry. The linear relationships between the calculated and experimental values for frequencies (with a scaling factor of 0.96) and for magnetic properties (with a scaling factor of 1.05) demonstrate that the quantum chemical calculations were consistent with the experimental spectra. Additionally, the calculated binding energies were consistent with the experimental results: the stability order of the complexes and the trend of the binding energy is: brompheniramine > chlorpheniramine > pheniramine; S-enantiomer > R-enantiomer. Natural Bond Orbital analysis further demonstrated three major electronic delocalizations—from the substituent on the phenyl moiety of pheniramine to β-CD and from β-CD to the phenyl and amine moieties in pheniramine—which were the dominant intermolecular forces that were responsible for the substantially different binding strengths. Geometrical data and the partial charge distribution obtained by NBO analysis are provided as supplementary data.     

Improvement of water solubility and in vitro dissolution rate of aceclofenac by complexation with β-cyclodextrin and hydroxypropyl-β-cyclodextrin

The present study deals with the inclusion complexation of aceclofenac with β-cyclodextrin by grinding, microwave and spray-drying techniques. A derivative of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, was also subjected to the complexation process with aceclofenac by spray-drying technique. The samples were subjected to in-vitro dissolution studies, fourier transform infra-red spectroscopy, differential scanning calorimetry, nuclear magnetic resonance spectroscopy and x-ray diffraction studies. The in-vitro dissolution of aceclofenac-hydroxypropyl-β-cyclodextrin complex was faster as compared to the aceclofenac- β-cyclodextrin complex and aceclofenac alone. Spray-dried aceclofenac-β-cyclodextrin complex were subjected to anti-inflammatory and analgesic activity and showed significant anti-inflammatory and analgesic activity.     

Effect of 2-Hydroxypropyl-β-cyclodextrin on Crystallization and Polymorphic Transition of Nifedipine in Solid State

The glassy state of nifedipine (NP) was prepared in the absence and presence of 2-hydroxypropyl--cyclodextrin (HP--CyD), and its crystallization and polymorphic transition behavior was investigated by differential scanning calorimetry (DSC) and powder X-ray diffractometry. In DSC thermograms, the glassy NP exhibited an en-dothermic peak at 48°C representing the glass transition of NP, an exothermic peak at 105°C for the crystallization to a metastable form of NP (Form B), an exothermic peak at 125°C for the polymorphic transition of Form B to a stable form of NP (Form A), and an endothermic peak at 171°C for the melting of Form A. The powder X-ray diffractogram of Form B was apparently different from that of Form A. In the presence of HP--CyD, the exothermic peak at 125°C for the Form B to A transition disappeared and a new en-dothermic peak appeared at 163°C. This new peak was ascribed to the melting of Form B, and the conversion of Form B to Form A was significantly suppressed in HP--CyD matrix. Upon storage at 60°C, the glassy NP was converted to Form A with an activation energy of 18 kcal/mol. The apparent dissolution rate of the NP/HP--CyD (molar ratio 1:1) increased in the order of glassy NP < Form A < Form B, because the glassy NP was readily converted to Form A upon contact with water, resulting in a lower dissolution rate. The present data suggest that HP--CyD is useful for the preparation of a fast dissolving form of metastable NP through glassy NP.     

Development of machine learning models of β-cyclodextrin and sulfobutylether-β-cyclodextrin complexation free energies

A new set of 142 experimentally determined complexation constants between sulfobutylether-β-cyclodextrin and diverse organic guest molecules, and 78 observations reported in literature, were used for the development of the QSPR models by the two machine learning regression methods - Cubist and Random Forest. Similar models were built for β-cyclodextrin using the 233-compound dataset available in the literature. These results demonstrate that the machine learning regression methods can successfully describe the complex formation between organic molecules and β-cyclodextrin or sulfobutylether-β-cyclodextrin. In particular, the root mean square errors for the test sets predictions by the best models are low, 1.9 and 2.7 kJ/mol, respectively. The developed QSPR models can be used to predict the solubilizing effect of cyclodextrins and to help prioritizing experimental work in drug discovery.     

Study of the dissolution characteristics of oxazepam via complexation with β-cyclodextrin

Complex formation of oxazepam and β-cyclodextrin in solution was studied by phase solubility and spectral shift methods. The value of the apparent stability constant, K_c, calculated using these techniques, was 205 and 498 M⁻¹, respectively. Solid complexes of oxazepam and β-CD were prepared using the kneading and spray-drying methods. These complexes led to an improvement in the dissolution rate over free oxazepam, spray-drying being the most efficient technique. These complexes were characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray diffraction.     

Solubilization of Thiazolobenzimidazole Using a Combination of pH Adjustment and Complexation with 2-Hydroxypropyl-β-Cyclodextrin

The thiazolobenzimidazole l-(2,6-difluorophenyl)-lH,3H-thiazolo[3,4-a]benzimidazole, TBI, is an experimental drug for the treatment of AIDS which exhibits a low water solubility (11 µg/mL) and is therefore difficult to administer in an injectable solution dosage form at a target solution concentration of 10 mg/mL. The compound has a single ionizable functional group and exhibits an increase in solubility with decreasing pH consistent with a pK _a of 3.55, but the maximum solubility attainable by pH adjustment has been shown to be only 0.4 mg/mL (at pH 2). TBI has been found to form inclusion complexes in either its neutral or its protonated form with 2-hydroxypropyl--cyclodextrin (HPCD). The equilibrium constants for 1:1 complex formation were found to be 81 and 1033 M ^–l for the protonated and neutral species, respectively. Although the formation of protonated complex is less favored in comparison to the neutral complex, the contribution of this species to the overall solubility of TBI predominates at low pH. Thus, using a combined approach of pH adjustment and complexation with HPCD, a solubility enhancement of 3 orders of magnitude is possible. NMR proton spectroscopy and molecular modeling studies, conducted to understand the orientation of TBI in the complex and the effect of protonation, are described.     

Improved dissolution and bioavailability of phenytoin by sulfobutylether-β-cyclodextrin ((SBE)7m-β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) complexation

The inclusion complexation of phenytoin with charged and neutral water-soluble cyclodextrins (CDs), (SBE)_7m-β-CD and HP-β-CD, was studied in order to improve the low aqueous solubility and incomplete oral bioavailability of phenytoin. Effects of CDs on the aqueous solubility of phenytoin were determined by phase-solubility method at pH 7.4 and 11.0. Solubility of phenytoin increased as a function of CD concentration, showing A_L type diagrams for both (SBE)_7m-β-CD and HP-β-CD which indicate a formation of 1:1-complexes. Solid inclusion complexes of phenytoin with (SBE)_7m-β-CD and HP-β-CD were prepared by freeze-drying. Dissolution rate of phenytoin was increased with inclusion complexes as well as with phenytoin/HP-β-CD physical mixture in vitro. Also the freeze-drying of phenytoin tended to enhance the dissolution of phenytoin in vitro. However, plain phenytoin (300.0 mg) pharmacokinetics after oral administration as a crystal form and as a freeze-dried form were comparable in dogs. CD-based formulations of phenytoin increased peak plasma concentration of phenytoin about 1.6-fold and bioavailability (AUC_{0–24 h}) of phenytoin about 2-fold compared to plain phenytoin. Oral pharmacokinetics were not statistically different among various CD formulations. This study indicates that increased bioavailability of phenytoin in the presence of CDs was due to an increased extent of drug dissolution.     

Interaction of some anticancer drugs with carboxymethyl-β-cyclodextrin

The interaction between 23 anticancer drugs and carboxymethyl-β-cyclodextrin (CM-β-CD) was studied by reversed-phase charge-transfer thin-layer chromatography and the relative strength of interaction was calculated. CM-β-CD formed inclusion complexes with 13 compounds, the complex always being less hydrophobic than the uncomplexed drug. The inclusion-forming capacity of drugs differed considerably depending on their chemical structures. Principal component analysis indicated that the hydrophilic parameters (hydrophobicity, specific hydrophobic surface area) of drugs exert the greatest influence on the stability of CM-β-CD-drug inclusion complexes.     

Spectroscopic and computational insights into theophylline/β-cyclodextrin complexation: inclusion accomplished by diverse methods

Abstract

Current scenario in asthmatic prevalence worldwide calls for a facile, cost-effective, and energy efficient methodology to formulate the potent bronchodilator, theophylline (THP), into an effective dosage forms. Since the uses of THP are severely impeded by its poor aqueous solubility and low bioavailability, solid inclusion complexes (ICs) of THP in β-cyclodextrin (β-CD) were prepared to overcome the limitations. The ICs were developed by conventional methods and also by microwave irradiation method, which is environmentally more benign and requires lesser reaction time. The complexation phenomenon was effectual by the co-precipitation, freeze-drying, and microwave methods as affirmed from various spectroscopic analyses. ¹H NMR and molecular docking studies illustrated the total inclusion of THP into β-CD cavity. Better efficacy of the microwaved product was witnessed in terms of drug content, dissolution, and anti-biofilm activities. Thus microwave irradiation can be utilised as a naive and economical methodology to design β-CD–THP dosage formulations.     

Study of the complexation behaviour of gliclazide with partially methylated β-cyclodextrin in solution and solid state

The complexation of Gliclazide (GL) with a partially methylated β-cyclodextrin was studied. Phase-solubility and ¹H NMR spectroscopy were employed to investigate the complexation behaviour in solution and to demonstrate the complexation in liquid medium with the participation of both azabicyclooctyl and tolyl moieties of GL in the inclusion process. Solid systems prepared by kneading, co-grinding and spray drying have also been checked, using DSC and HSM, for assessing the formation of the inclusion compound. Experimental evidence of the complexation between drug and cyclodextrin was reported for the co-ground and spray-dried systems.     

In vitro and in vivo evaluation of novel immediate release carbamazepine tablets: complexation with hydroxypropyl-β-cyclodextrin in the presence of HPMC

Carbamazepine (CBZ)-hydroxypropyl-β-cyclodextrin (HP-β-CD) complex in the presence of HPMC was prepared and characterized by differential scanning calorimetry (DSC) and X-ray diffractometer intended for improving the dissolution rate of CBZ. The phase-solubility method was used to investigate the effect of HP-β-CD and HPMC on the solubility of CBZ. Tablets of the resulting complex were prepared using direct compression method and the bioavailability was evaluated in beagle dogs using a UPLC/MS/MS method. The results showed solubility of CBZ was increased up to 95 times by complexation with HP-β-CD in the presence of 0.1% HPMC. The results of DSC and X-ray diffraction proved a formation of complex between CBZ and HP-β-CD. Dissolution rate of CBZ was notably improved from complex tablets with more than 97.39% released within 10 min; whereas for the commercial tablets, around 60% was released within 30 min. Using commercial tablets as the reference formulation, the bioavailability of complex tablets was considerably increased by 1.5-fold (P<0.05) and T(max) was reduced to 0.88 h compared with 1.25 h for commercial tablets. Furthermore, a lower inter-subject variability (49.9%) was observed compared with that of the commercial tablets (39.7%). It is evident from the results herein that complexation with HP-β-CD in the presence of HPMC is a feasible way to prepare a rapidly acting and better absorbed CBZ oral product.     

Effects of β-cyclodextrin and di-O-methyl-β-cyclodextrin on the percutaneous absorption of butylparaben,indomethacin and sulfanilic acid

The effects of β-cyclodextrin (β-CD) and di-O-methyl-β-cyclodextrin (DM-β-CD) on the percutaneous absorption of butylparaben (BP), indomethacin (IM), and sulfanilic acid (SA) were investigated. The flow-through type diffusion cell was used for in vitro penetration experiments. All of the recorded data were fitted to the diffusion equation describing the drug penetration through a homogeneous plane membrane by the non-linear least-squares computer program, and two parameters corresponding to diffusion constant of drug and partition coefficient of that between skin and vehicle were obtained. Both cyclodextrins (CDs) decreased the penetration of BP depending on their concentrations. The decrease in BP penetration was explained by that in calculated apparent partition coefficient of BP and good correlation was observed between the partition coefficient and free BP fraction estimated based on the complex formation stoichiometry. IM penetration was also decreased by complex formation but some additional effects, somewhat different between β-CD and DM-β-CD, were observed. On the contrary, the penetration of SA which scarcely formed complex with either CD was significantly enhanced by DM-β-CD. This was attributed to the effect of DM-β-CD on the skin to reduce its barrier function.