Amorphous Cyclodextrin Research Articles

Amorphization of cyclodextrins by spray drying for producing encapsulated functional gas powders for agri-food applications

Cyclodextrin (CD) powders are the most suitable solid matrices to encapsulate gases to produce gas powders in agri-food industries, where gases have been widely used to ensure processability, quality, functionality, safety, and stability of many products. The use of gases in powder form is much easier and safer than conventional means of gas utilization from pressurized cylinders or tanks. Gas powders are typically produced by crystallization from aqueous CD solutions under gas pressure, which is time consuming and results in low product yield. In amorphous structure, CD powders enable a rapid and 100% yield method to produce stable gas powders. However, most commercial CD powders exist in crystalline structure. In this review, we describe the amorphization of CD powders by spray drying, the properties of amorphous CD powders in comparison with its crystalline counterparts, gas encapsulation using amorphous CD powders, and applications of gas-CD powders in food and agriculture production.

Granules of finasteride and cyclodextrin obtained by hot-melt extrusion to target the hair follicles

This study aimed to develop topical granules of finasteride (FIN) with a follicular targeting potential to treat androgenic alopecia. In this sense, FIN inclusion complexes with cyclodextrin produced by two different methods (nanospray-drying and rotary evaporation) were inserted into polymeric matrices by hot-melt extrusion (HME) and evaluated regarding their physicochemical properties, skin permeation, and follicular targeting capacities. While rotary evaporation produces complexes with low interaction between the components and a crystalline profile, nanospray-drying can generate almost completely amorphous systems with high drug-cyclodextrin interactions. Both provided slow drug release and limited drug skin permeation. A desirable follicular targeting was achieved (40%) by combining such amorphous cyclodextrin complex with the polymeric matrix by HME. In conclusion, the FIN inclusion complexes produced by HME represent promising topical formulations for the optimized alopecia treatment, targeting the drug directly at the action site. Furthermore, the developed formulation can be easily produced by a scalable industrial process.

Crystallisation properties of amorphous cyclodextrin powders and their complexation with fish oil.

Water-induced crystallisation of amorphous core-cyclodextrin (CD) complex is an essential step in a solid encapsulation process and removal of added water is a challenging. Ethanol addition is expected to shorten the complex dehydration time. This study investigated crystallisation of amorphous spray-dried α-, β- and γ-CD powders by direct mixing 15% (w/w) of ethanol:water mixture (0:100, 20:80, 40:60, 60:40, 80:20 and 100:0) over 72h period. The results showed α- and β-CD powders crystallised at all concentrations of ethanol solutions. Especially mixed with 0:100 and 20:80 ethanol:water solutions, the crystallisation behaviour of α- and β-CD powders was similar to that of commercial crystalline counterparts. γ-CD powders exhibited a crystallisation sign as mixed with 0:100 and 20:80 ethanol:water solutions only. In the study of fish oil encapsulation using the mixture of water and ethanol to induce the complex crystallisation, only γ-CD powder was able to form complex with fish oil.

Designing and evaluation of extended release matrix tablet containing altretamine–HP-β-CD inclusion complex

The aim of present study was to prepare sustained release tablets of a poorly soluble anticancer drug using cyclodextrin complexation as a potential approach. Altretamine is an alkylating agent practically insoluble in water and posses poor oral bioavailability. For this, the most suitable binary system of ALT-HP-β-CD was selected to improve the aqueous solubility and then embedding the complexed drug into a matrix tablet with fusion method. Tablets were prepared using glycerol monostearate (GMS) and polyethylene glycol 4000 (PEG4000). Complexes were prepared at different ratios and mixed with other excipients to achieve tablets with efficient dissolution profile complying with the requirements for sustained delivery of solid dosage forms. Results of Fourier Infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) proved that kneading was most efficient technique for preparation of amorphous cyclodextrin inclusion complex with ALT and entrapping this complex into tablet. Dissolution profile of ALT was enhanced significantly in pH 6.8 from the binary system and significant within the limits (t test Student p < 0.05). The release kinetics of the tablets showed that diffusion was responsible for controlling the release from the tablets.

Physico-chemical characterization in solution and in the solid state of clonazepam complexes with native and chemically-modified cyclodextrins

Clonazepam (CLZ) is a benzodiazepine derivative, whose bioavailability, limited by its very poor water-solubility, could be improved by cyclodextrin complexation. However, the choice of the most proper cyclodextrin to use to fully exploit its potential favourable effects on the drug, is a critical step. Therefore, in the present work, the performance of some amorphous cyclodextrin (CD) derivatives in terms of complexing, solubilizing and amorphizing power towards CLZ was carefully evaluated and compared with that of natural CDs. The role of CD cavity size, amorphous or crystalline nature, and presence and type of substituents on its ability in producing effective interactions with the drug has been investigated. Equimolar CLZ–CD solid systems were obtained by blending, kneading, co-grinding and coevaporation. Drug–CD interactions were investigated by phase-solubility analysis, differential scanning calorimetry and X-ray powder diffractometry. Among the natural CDs, β-CD showed the highest complexing ability, suggesting that its cavity size is the most proper to host the drug molecule. The presence of substituents had a negative effect on the performance of α-CD and γ-CD, while it improved the complexing and solubilizing power of β-CD, and the methylated derivative was more effective than the hydroxypropylated one. Solid-state studies revealed that amorphous CDs had highest amorphizing power than the corresponding natural crystalline ones, and methylated-β-CD (Me-β-CD) was the best carrier. As for the preparation method, co-grinding was the most powerful in promoting the formation of efficacious drug–CD solid-state interactions. Dissolution rate studies confirmed Me-β-CD as the best partner for CLZ and co-grinding as the best method for maximizing the drug dissolution properties. Therefore, co-ground products with Me-β-CD could be selected as the best system for future development of CLZ formulations with improved therapeutic efficacy.

Effect of storage on the dissolution rate of a fast-dissolving perphenazine/β-cyclodextrin complex

In general, the chemical and physical stability of amorphous cyclodextrin complexes and how storage affects their dissolution rate have not been widely reported. The aim of this study was to evaluate the solid-state stability of a fast-dissolving perphenazine/β-cyclodextrin (β-CD) complex, which has been found to be well absorbed after sublingual administration to rabbits. In addition, the dissolution rate of plain β-CD in crystalline and amorphous forms was determined. The amorphous perphenazine/β-CD complex powders were prepared by spray-drying and freeze-drying, and their stability was examined after storage at 40°C, 75% relative humidity (RH) or at room temperature, 60% RH for up to 82 days. Perphenazine was found to be chemically stable in all samples. The dissolution rate of perphenazine remained practically unchanged at both storage conditions, although partial crystallization was observed in both spray-dried and freeze-dried samples at 40°C, 75% RH. Interestingly, it was also observed that the dissolution rates of crystalline and amorphous β-CD were similar. The results suggest that CD complexation may represent a suitable alternative for preparing intraorally dissolving formulations because the fast dissolution rate of the drug was maintained even though changes in the crystal structure were observed during storage.

Designing an extended release waxy matrix tablet containing nicardipine–hydroxy propyl β cyclodextrin complex

Aim The current study aimed to prepare a sustained release tablet for a drug which has poor solubility in alkaline medium using complexation with cyclodextrin. Nicardipine hydrochloride (NC) a weak basic drug was chosen as a model drug for this study. Method Firstly the most suitable binary system NC-HPβCD was selected in order to improve drug solubility in the intestinal media and then embedding the complexed drug into a plastic matrix, by fusion method, consists of glycerol monostearate (GMS) as an inert waxy substance and polyethylene glycol 4000 (PEG4000) as a channeling agent, after that the final solid dispersion [(NC:HPβCD):GMS:PEG4000] which was prepared at different ratios was mixed with other excipients, avicel PH101, lactose, and talc, to get a tablet owning dissolution profile complying with the FDA and USP requirements for the extended release solid dosage forms. Results Infrared spectroscopy (IR), differential scanning colorimetry (DSC), polarized microscopy and X-ray diffractometry proved that the coevaporation technique was effective in preparing amorphous cyclodextrin complexes with NC and trapping of NC within the HPβCD cavity by dissolving both in ethanol and evaporate the solvent using a rotavapor at 65 °C. Dissolution profile of NC enhanced significantly in pH 6.8 from NC:HPβCD inclusion complex prepared by the rotavapor ( t-test Student p < 0.05). The release of NC from tablet containing [(NC:HPβCD):GMS:PEG4000] [(1):0.75:0.5] (w/w/w) solid dispersion (F8) was complying with the FDA dissolution requirements for extended release dosage forms, and studying the kinetics of the release showed that the diffusional contribution is the major factor controlling the drug release from that formula. Conclusion The prepared waxy matrix tablet containing NC complexes with CD shows promising results as extended release tablets.

Assessment of solid-state interactions of naproxen with amorphous cyclodextrin derivatives by DSC

A microcalorimetric method based on differential scanning calorimetry (DSC) of drug-additive binary systems to assess kneading-induced interactions was applied to naproxen (NAP) in combinations with amorphous hydroxypropyl β-cyclodextrin (HPβCd), β-cyclodextrin sulfobutyl ether, sodium salt ((SBE) 7m-βCd), acetyl β-cyclodextrin (AcβCd) and acetyl γ-cyclodextrin (AcγCd). Modifications of thermal parameters of NAP in DSC curves of physical mixtures indicate heating-induced interactions which resulted in a broadening of the NAP melting endotherm in the combinations with HPβCd, AcβCd and AcγCd. The effect of kneading on the interaction was particularly pronounced for the NAP–HPβCd and NAP–(SBE) 7m-βCd systems, which show a similar drug-to-carrier interaction ratio (1:2 by weight) as that of the other systems. Drug-to-carrier ratios, calculated considering the amount of NAP which recrystallizes from the melted mixtures equivalent to NAP not bound to the carrier, show a distinctly lower affinity in solid-state of the drug for the anionically charged (SBE) 7m-βCd with respect to other neutral carriers. The similar affinity of NAP for AcβCd and AcγCd demonstrates that the geometry of the cavity, which is a determinant factor for the inclusion complexation in liquid state, does not influence the interaction process in solid-state.

New Injectable Aqueous Carbamazepine Solution Through Complexing with 2‐Hydroxypropyl‐β‐Cyclodextrin: Tolerability and Pharmacokinetics After Intravenous Injection in Comparison to a Glycofurol‐Based Formulation

The poor water solubility of the antiepileptic drug (AED) carbamazepine (CBZ) is generally considered an absolute contraindication to parenteral administration in epileptic patients. However, the water solubility of CBZ can be largely enhanced through formation of an inclusion complex with an amorphous cyclodextrin derivative, 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). We studied tolerability and pharmacokinetics of an aqueous CBZ:HP beta CD solution after intravenous (i.v.) administration in dogs. For comparison, a conventional glycofurol-based solution of CBZ was used. We also administered a commercial liquid formulation of CBZ orally (p.o.). Infusion of CBZ:HP beta CD solutions or HP beta CD "placebo" formulations i.v. was well tolerated by the animals. In contrast, infusion of CBZ:glycofurol solutions and glycofurol placebo solutions induced marked behavioral and cardiovascular adverse effects. Pharmacokinetic studies indicated that glycofurol inhibited CBZ metabolism by decreasing formation of the major CBZ metabolite CBZ-10,11-epoxide (CBZ-E). With infusion of CBZ:HP beta CD 10 ml/min for 12-15 min, resulting in a CBZ dose of CBZ 5 mg/kg body weight, peak CBZ plasma levels of approximately 3.6 micrograms/ml were obtained. This relatively low peak concentration is primarily due to the rapid elimination of CBZ in dogs [half-life (t1/2) < 1 h]. Comparison of peak plasma levels determined after p.o. administration of CBZ to dogs with peak CBZ levels previously determined after p.o. administration in humans indicated that about four times higher doses are needed in dogs to attain the same peak plasma levels as in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclodextrin derivatives in the GC separation of racemic mixtures of volatile compounds, part V: Heptakis 2,6‐dimethyl‐3‐pentyl‐β‐cyclodextrins

AbstractThis paper describes an evaluation of the chromatographic performance of columns coated with amorphous cyclodextrin (CD) derivatives, in particular 2,3,6‐tripentyl‐β‐CD (2,3,6‐TriPe‐β‐CD), 2,6‐dipentyl‐3‐methyl‐β‐CD (2,6‐DiPe‐3‐Me‐β‐CD), and 2,6‐dimethyl‐3‐pentyl‐β‐CD (2,6‐DiMe‐3‐Pe‐β‐CD), all diluted in polysiloxane (OV‐1701 or OV‐1701‐OH), for the separation of the enantiomers of volatile compounds. 2,6‐DiMe‐3‐Pe‐β‐CD in OV‐1701 offers performance comparable with (or better than) that of the other two CDs, and without their drawbacks (inconsistency of results, as described previously).This article compares the separating ability of 2,6‐DiMe‐3‐Pe‐β‐CD and 2,3,6‐TriMe‐β‐CD, and describes the influence of the CD derivative to polysiloxane ratio, the minimum operating temperatures of the columns, and the reproducibility and consistency of performance of columns coated with the former CD derivative diluted in polysiloxane.

A non- surfactant formulation for alfaxalone based on an amorphous cyclodextrin: Activity studies in rats and dogs

The steroid anesthetic, alfaxalone, is commercially available for veterinary use in a formulation containing Cremophor-EL® and alfadalone acetate. The allergic sensitivity of some species to this formulation limits its veterinary application and also led to withdrawal of the product for human use. The present studies evaluated alfaxalone formulated as an inclusion complex with a mixture of 2-hydroxypropyl-β-cyclodextrin (HPCD) isomers for anesthetic properties in rats and dogs. Aqueous solutions of alfaxalone-HPCD showed identical anesthetic profiles in rats compared to the commercial formulation. In contrast, the anesthetic response to alfaxalone-HPCD in dogs was not accompanied with massive histamine release and pronounced decrease in respiration and blood pressure seen after the commercial preparation. Anesthesia induction and recovery phases were rapid and uncomplicated after alfaxalone-HPCD. An anaphylactoid-like response did occur in dogs after the same dose of alfaxalone as the commercial preparation. The favorable anesthetic profile of alfaxalone formulated as an HPCD complex together with previous toxicology and stability studies suggest that the steroid may be successfully formulated for intravenous dosing with modified cyclodextrins.

Drug solubilizers to aid pharmacologists: Amorphous cyclodextrin derivatives

Conversion of crystalline α-, β-, or γ-cyclodextrins into amorphous mixtures of water soluble derivatives yields non-toxic solubilizers which dissolve drugs through the formation of inclusion complexes. From these types of compounds 2-hydroxypropyl ethers of cyclodextrins have presently been investigated and the ranges for the safe use in working with (a) receptor binding assays on membrane preparations, (b) cells in vitro, and (c) parenteral use in mice were established for these compounds. The drugs which were investigated were dissolved in amounts linearly proportionate to the concentration of the solubilizers used and did not precipitate upon dilution by aqueous media. These solubilizers may considerably facilitate pharmacological evaluation of new, water insoluble potential drugs.