Investigation of inclusion complex of cilnidipine with hydroxypropyl-β-cyclodextrin

The objective of this study was to improve the water-solubility and photostability of cilnidipine by complexing it with hydroxypropyl-β-cyclodextrin (HP-β-CD or HP-beta-CD). The interactions of cilnidipine and HP-β-CD were characterized by ultra violet-visible (UV/VIS) spectroscopy, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transformation-infrared (FT-IR) spectroscopy and (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy to verify the formation of cilnidipine-HP-β-CD complex inclusion. Moreover, the binding sites in the HP-β-CD structure were also tracked through (1)H NMR spectroscopy analysis. All the characterization information proved the formation of cilnidipine-HP-β-CD inclusion complex, and the results demonstrated the superiority of the inclusion complex in dissolution rates and photostability; in addition, the apparent solubility of cilnidipine was increased more than 10,000-fold in the presence of HP-β-CD. The stability constant (1:1) was found to be 50,116M(-1), suggesting a high tendency of the drug to enter the HP-β-CD cavity. These results identified the cilnidipine-HP-β-CD inclusion complex as an effective new approach to design a novel formulation for pharmaceutical application.     

Preparation and characterization of a novel polymorph of indiplon, Form α

A new polymorph α of indiplon was discovered, initially prepared by two methods, and further characterized by various means including single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), variable temperature powder X-ray diffraction (VT-PXRD), differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), Fourier transform Raman (FT-Raman) spectroscopy and solubility determination. The crystal structure of Form α as analyzed by SCXRD differ from the three previously reported polymorphs, Form I, II, and III. In addition, PXRD and solubility measurements could clearly distinguish between Form α and Form I. Slight differences between the two forms were also detected by FT-Raman. No differences between Form α and I were observed by DSC, which was explained by VT-PXRD results showing a solid-solid phase change from Form α to Form I during the heating process. Solubility measurements at various temperatures showed that the two polymorphs were mutually monotropic and that Form I was the relatively thermodynamically stable crystal form.     

Application of Carrier and Plasticizer to Improve the Dissolution and Bioavailability of Poorly Water-Soluble Baicalein by Hot Melt Extrusion

The objective of this study was to develop a suitable formulation for baicalein (a poorly water-soluble drug exhibiting high melting point) to prepare solid dispersions using hot melt extrusion (HME). Proper carriers and plasticizers were selected by calculating the Hansen solubility parameters, evaluating melting processing condition, and measuring the solubility of obtained melts. The characteristic of solid dispersions prepared by HME was evaluated. The dissolution performance of the extrudates was compared to the pure drug and the physical mixtures. Physicochemical properties of the extrudates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Relative bioavailability after oral administration in beagle dogs was assessed. As a result, Kollidon VA64 and Eudragit EPO were selected as two carriers; Cremophor RH was used as the plasticizer. The dissolution of all the extrudates was significantly improved. DSC and PXRD results suggested that baicalein in the extrudates was amorphous. FTIR spectroscopy revealed the interaction between drug and polymers. After oral administration, the relative bioavailability of solid dispersions with VA64 and EPO was comparative, about 2.4- and 2.9-fold greater compared to the pure drug, respectively.

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Open in a separate windowᅟKEY WORDS: baicalein, carrier, high melting point, hot melt extrusion, plasticizer, solid dispersion     

Influence of β-cyclodextrin on the Properties of Norfloxacin Form A

Cyclodextrins are able to form host–guest complexes with hydrophobic molecules to result in the formation of inclusion complexes. The complex formation between norfloxacin form A and β-cyclodextrin was studied by exploring its structure affinity relationship in an aqueous solution and in the solid state. Kneading, freeze-drying, and physical mixture methods were employed to prepare solid complexes of norfloxacin and β-cyclodextrin. The solubility of norfloxacin significantly increased upon complexation with β-cyclodextrin as demonstrated by a solubility isotherm of the A_L type along with the results of an intrinsic dissolution study. The complexes were also characterized in the solid stated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffractometry, scanning electron microscopy (SEM), and solid-state nuclear magnetic resonance (ssNMR) spectrometry. The thermal analysis showed that the thermal stability of the drug is enhanced in the presence of β-cyclodextrin. Finally, the microbiological studies showed that the complexes have better potency when compared with pure drug.KEY WORDS: bioassay, complexation, intrinsic dissolution, norfloxacin, β-cyclodextrin     

Studies on trimethoprim:hydroxypropyl-β-cyclodextrin: aggregate and complex formation

The present study is focused on the characterization of the interaction between trimethoprim, a dihydropteroate synthesase inhibitor, and hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous solution and solid state. The freeze-drying method was used to prepare solid complexes, while simple blending was employed to obtain physical mixtures. The phase solubility was AN type, and demonstrated that trimethoprim solubility was significantly increased upon complexation with HP-β-CD. Conductivity experiments showed the presence of aggregates that explains the type profile for the solubility isotherm. The critical concentration for the aggregate formation was determined to be 69.3 mg/ml for pure HP-β-CD and 117.7 mg/ml in the presence of trimethoprim. Nuclear magnetic resonance spectroscopy provided evidence of trimethoprim:HP-β-CD molecular interaction in solution. Moreover, the complex was characterized in solid stated using Fourier-transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). The use of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) showed that the thermal stability of the drug is enhanced in the presence of HP-β-CD.     

The Stabilization of Amorphous Zopiclone in an Amorphous Solid Dispersion

Zopiclone is a poorly soluble psychotherapeutic agent. The aim of this study was to prepare and characterize an amorphous form of zopiclone as well as the characterization and performance of a stable amorphous solid dispersion. The amorphous form was prepared by the well-known method of quench-cooling of the melt. The solid dispersion was prepared by a solvent evaporation method of zopiclone, polyvinylpyrrolidone-25 (PVP-25), and methanol, followed by freeze-drying. The physico-chemical properties and stability of amorphous zopiclone and the solid dispersion was studied using differential scanning calorimetry (DSC), infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), hot-stage microscopy (HSM), X-ray diffractometry (XRD), solubility, and dissolution studies. The zopiclone amorphous solid-state form was determined to be a fragile glass; it was concluded that the stability of the amorphous form is influenced by both temperature and water. Exposure of amorphous zopiclone to moisture results in rapid transformation of the amorphous form to the crystalline dihydrated form. In comparison, the amorphous solid dispersion proved to be more stable with increased aqueous solubility.KEY WORDS: amorphous, fragile, solid dispersion, stability, zopiclone     

Inclusion complexes of azadirachtin with native and methylated cyclodextrins: solubilization and binding ability

The inclusion complexation behavior of azadirachtin with several cyclodextrins and their methylated derivatives has been investigated in both solution and the solid state by means of XRD, TG-DTA, DSC, NMR, and UV-vis spectroscopy. The results show that the water solubility of azadirachtin was obviously increased after resulting inclusion complex with cyclodextrins. Typically, beta-cyclodextrin (beta-CD), dimethyl-beta-cyclodextrin (DMbetaCD), permethyl-beta-cyclodextrin (TMbetaCD), and hydroxypropyl-beta-cyclodextrin (HPbetaCD) are found to be able to solubilize azadirachtin to high levels up to 2.7, 1.3, 3.5, and 1.6 mg/mL (calculated as azadirachtin), respectively. This satisfactory water solubility and high thermal stability of the cyclodextrin-azadirachtin complexes, will be potentially useful for their application as herbal medicine or healthcare products.     

Graft copolymers of xyloglucan and methyl methacrylate

Xyloglucan, a water-soluble food grade polysaccharide, was reported as a substrate for graft copolymerization of methyl methacrylate (MMA). Grafting PMMA (polymethyl methacrylate) with xyloglucan (XG) makes a new material with improved thermal stability and shelf life without affecting its hydrophilicity. XG was isolated from tamarind seed mucilage by aqueous extraction. Grafting of MMA was initiated by ceric ion in aqueous medium under N₂ atmosphere and the progress of the reaction was monitored gravimetrically by varying different reaction parameters. Grafting of MMA onto XG was confirmed by FTIR spectroscopy, NMR spectroscopy, differential scanning calorimetric (DSC) studies, thermal gravimetric analysis (TGA) studies and scanning electron micrographs (SEMs). This material might find potential to be used in drug delivery systems.     

Characterization and <Emphasis Type="Italic">In Vitro</Emphasis> Evaluation of the Complexes of Posaconazole with β- and 2,6-di-<Emphasis Type="Italic">O</Emphasis>-methyl-β-cyclodextrin

Posaconazole is a triazole antifungal drug that with extremely poor aqueous solubility. Up to now, this drug can be administered via intravenous injection and oral suspension. However, its oral bioavailability is greatly limited by the dissolution rate of the drug. This study aimed to improve water solubility and dissolution of posaconazole through characterizing the inclusion complexes of posaconazole with β-cyclodextrin (β-CD) and 2,6-di-O-methyl-β-cyclodextrin (DM-β-CD). Phase solubility studies were performed to calculate the stability constants in solution. The results of FT-IR, PXRD, ¹H and ROESY 2D NMR, and DSC all verified the formation of the complexes in solid state. The complexes showed remarkably improved water solubility and dissolution rate than pure posaconazole. Especially, the aqueous solubility of the DM-β-CD complex is nine times higher than that of the β-CD complex. Preliminary in vitro antifungal susceptibility tests showed that the two inclusion complexes maintained high antifungal activities. These results indicated that the DM-β-CD complexes have great potential for application in the delivery of poorly water-soluble antifungal agents, such as posaconazole.     

SN-38-Cyclodextrin Complexation and Its Influence on the Solubility,Stability, and In Vitro Anticancer Activity Against Ovarian Cancer

SN-38, an active metabolite of irinotecan, is up to 1,000-fold more potent than irinotecan. But the clinical use of SN-38 is limited by its extreme hydrophobicity and instability at physiological pH. To enhance solubility and stability, SN-38 was complexed with different cyclodextrins (CDs), namely, sodium sulfobutylether β-cyclodextrin (SBEβCD), hydroxypropyl β-cyclodextrin, randomly methylated β-cyclodextrin, and methyl β-cyclodextrin, and their influence on SN-38 solubility, stability, and in vitro cytotoxicity was studied against ovarian cancer cell lines (A2780 and 2008). Phase solubility studies were conducted to understand the pattern of SN-38 solubilization. SN-38-βCD complexes were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction analysis (XRPD), and Fourier transform infrared (FTIR). Stability of SN-38-SBEβCD complex in pH 7.4 phosphate-buffered saline was evaluated and compared against free SN-38. Phase solubility studies revealed that SN-38 solubility increased linearly as a function of CD concentration and the linearity was characteristic of an A_P-type system. Aqueous solubility of SN-38 was enhanced by about 30–1,400 times by CD complexation. DSC, XRPD, and FTIR studies confirmed the formation of inclusion complexes, and stability studies revealed that cyclodextrin complexation significantly increased the hydrolytic stability of SN-38 at physiological pH 7.4. Cytotoxicity of SN-38-SBEβCD complex was significantly higher than SN-38 and irinotecan in both A2780 and 2008 cell lines. Results suggest that SBEβCD encapsulated SN-38 deep into the cavity forming stable inclusion complex and as a result increased the solubility, stability, and cytotoxicity of SN-38. It may be concluded that preparation of inclusion complexes with SBEβCD is a suitable approach to overcome the solubility and stability problems of SN-38 for future clinical applications.     

Diclofenac-β-cyclodextrin binary systems: Physicochemical characterization and in vitro dissolution and diffusion studies

The aim of this work was to study the influence of β-cyclodextrin (β-CD) on the biopharmaceutic properties of diclofenac (DCF). To this purpose the physicochemical characterization of diclofenac-β-cyclodextrin binary systems was performed both in solution and solid state. Solid phase characterization was performed using differential scanning calorimetry (DSC), powder x-ray diffractometry (XRD), and Fourier transform infrared spectroscopy (FTIR). Phase solubility analyses, and in vitro permeation experiments through a synthetic membrane were performed in solution. Moreover, DCF/β-CD interactions were studied in DMSO by¹H nuclear magnetic resonance (NMR) spectroscopy. The effects of different preparation methods and drug-to-β-CD molar ratios were also evaluated. Phase solubility studies revealed 1∶1 M complexation of DCF when the freeze-drying method was used for the preparation of the binary system. The true inclusion for the freeze-dried binary system was confirmed by¹H NMR spectroscopy, DSC, powder XRD, and IR studies. The dissolution study revealed that the drug dissolution rate was improved by the presence of CDs and the highest and promptest release was obtained with the freeze-dried binary system. Diffusion experiments through a silicone membrane showed that DCF diffusion was higher from the saturated drug solution (control) than the freeze-dried inclusion complexes, prepared using different DCF-β-CD molar ratios. However, the presence of the inclusion complex was able to stabilize the system giving rise to a more regular diffusion profile. Published: October 22, 2005     

Enhancement of Oral Bioavailability of Curcumin by a Novel Solid Dispersion System

The objective of this study was to improve the solubility and bioavailability of curcumin by a new curcumin dripping pills (Cur-DPs) formulation using melt mixing methods. The optimal formulation consisted of Polyethoxylated 40 hydrogenated castor oil (Cremophor RH40), Poloxamer 188, and Polyethylene glycol 4000 (PEG 4000). Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier-transform infrared spectroscopy (FT-IR) were used to verify the forming of Cur-DPs. All the physical characterization information proved the formation of Cur-DPs, and the results demonstrated the superiority of the dripping pills in dissolution rates. The pharmacokinetic study of Cur-DPs was performed in rats compared to the pure curcumin suspension. The oral bioavailability of poorly water-soluble curcumin was successfully improved by CUR-DPs. And the stability of prepared Cur-DP was also in a good state in 3 months. These results identified the Cur-DPs was an effective new approach for pharmaceutical application.KEY WORDS: curcumin, dripping pills, oral bioavailability, physicochemical properties, stability     

Investigation of the solid state properties of amoxicillin trihydrate and the effect of powder pH

The purpose of this research was to investigate some physicochemical and solid-state properties of amoxicillin trihydrate (AMT) with different powder pH within the pharmacopoeia-specified range. AMT batches prepared using Dane salt method with the pH values from 4.39 to 4.97 were subjected to further characterization studies. Optical and scanning electron microscopy showed that different batches of AMT powders were similar in crystal habit, but the length of the crystals increased as the pH increased. Further solid-state investigations using powder x-ray diffraction (PXRD) demonstrated the same PXRD pattern, but the intensity of the peaks raised by the powder pH, indicated increased crystallinity. Differential scanning calorimetry (DSC) studies further confirmed that as the powder pH increased, the crystallinity and, hence, thermal stability of AMT powders increased. Searching for the possible cause of the variations in the solid state properties, HPLC analysis showed that despite possessing the requirements of the United States Pharmacopoeia (USP) for purity/impurity profile, there was a direct relationship between the increase of the powder pH and the purity of AMT, and also decrease in the impurity I (alpha-Hydroxyphenylglycine) concentration in AMT powder. Recrystallization studies confirmed that the powder pH could be controlled by adjusting the pH of the crystallization.     

Rapid assignment of solution 31P NMR spectra of large proteins by solid-state spectroscopy

The application of the (31)P NMR spectroscopy to large proteins or protein complexes in solution is hampered by a relatively low intrinsic sensitivity coupled with large line widths. Therefore, the assignment of the phosphorus signals by two-dimensional NMR methods in solution is often extremely time consuming. In contrast, the quality of solid-state NMR spectra is not dependent on the molecular mass and the solubility of the protein. For the complex of Ras with the GTP-analogue GppCH(2)p we show solid-state (31)P NMR methods to be more sensitive by almost one order of magnitude than liquid-state NMR. Thus, solid-state NMR seems to be the method of choice for obtaining the resonance assignment of the phosphorus signals of protein complexes in solution. Experiments on Ras.GDP complexes show that the microcrystalline sample can be substituted by a precipitate of the sample and that unexpectedly the two structural states observed earlier in solution are present in crystals as well.     

Acyclovir-Polyethylene Glycol 6000 Binary Dispersions: Mechanistic Insights

The dissolution and subsequent oral bioavailability of acyclovir (ACY) is limited by its poor aqueous solubility. An attempt has been made in this work to provide mechanistic insights into the solubility enhancement and dissolution of ACY by using the water-soluble carrier polyethylene glycol 6000 (PEG6000). Solid dispersions with varying ratios of the drug (ACY) and carrier (PEG6000) were prepared and evaluated by phase solubility, in vitro release studies, kinetic analysis, in situ perfusion, and in vitro permeation studies. Solid state characterization was done by powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR) analysis, and surface morphology was assessed by polarizing microscopic image analysis, scanning electron microscopy, atomic force microscopy, and nuclear magnetic resonance analysis. Thermodynamic parameters indicated the solubilization effect of the carrier. The aqueous solubility and dissolution of ACY was found to be higher in all samples. The findings of XRD, DSC, FTIR and NMR analysis confirmed the formation of solid solution, crystallinity reduction, and the absence of interaction between the drug and carrier. SEM and AFM analysis reports ratified the particle size reduction and change in the surface morphology in samples. The permeation coefficient and amount of ACY diffused were higher in samples in comparison to pure ACY. Stability was found to be higher in dispersions. The results suggest that the study findings provided clear mechanical insights into the solubility and dissolution enhancement of ACY in PEG6000, and such findings could lay the platform for resolving the poor aqueous solubility issues in formulation development.     

Synthesis, characterization and thermal sensitivity of chitosan-based graft copolymers

Novel chitosan-based graft copolymers (CECTS-g-PDMA) were synthesized through homogeneous graft copolymerization of (N,N-dimethylamino)ethyl methacrylate (DMA) onto N-carboxyethylchitosan (CECTS) in aqueous solution by using ammonium persulfate (APS) as the initiator. The effect of polymerization variables, including initiator concentration, monomer concentration, reaction time and temperature, on grafting percentage was studied. XRD, FTIR, DSC and TGA were used to characterize the graft copolymers. Surface-tension measurements, turbidity measurements and temperature-variable (1)H NMR analysis were combined to investigate the thermal sensitivity of CECTS-g-PDMAs in aqueous solution.     

Diblock copolymers based on dihydroxyacetone and ethylene glycol: synthesis, characterization, and nanoparticle formulation

Polymeric biomaterials have played an integral role in tissue engineering, biomedical devices, and targeted drug delivery. Block copolymers are especially important because their physical and chemical properties can be controlled by adjusting the ratio, size, and type of constituting blocks. Herein, the synthesis and characterization of diblock copolymers composed of poly(ethylene glycol) and a polycarbonate based on the metabolic intermediate, dihydroxyacetone, are reported. The length of the dihydroxyacetone-based block was controlled by adjusting the reactant feed ratios and initiator injection conditions. Intermediates and final products were characterized via (1)H NMR, GPC, DSC, TGA, and diffusion-ordered NMR spectroscopy. The dihydroxyacetone-based hompolymer is insoluble in water and most organic solvents, but is hydrophilic in nature. This, coupled with poly(ethylene glycol)'s solubility characteristics, allows the block copolymer to form nanoparticles in aqueous and organic anti-solvents. Dynamic light scattering and TEM results indicated the formation of spherical nanoparticles.     

Polyhydroxyalkanoate copolyesters produced by Ralstonia eutropha PHB−4 harboring a low-substrate-specificity PHA synthase PhaC2Ps from Pseudomonas stutzeri 1317

Polyhydroxyalkanoate (PHA) copolymers consisting of short-chain-length (SCL) and medium-chain-length (MCL) 3-hydroxyalkanoates (3HA) were produced by recombinant Ralstonia eutropha PHB⁻4 harboring a low-substrate-specificity PHA synthase PhaC2_Ps from Pseudomonas stutzeri 1317. These polyesters, containing a wide range of chain length, were purified and characterized by acetone fractionation, nuclear magnetic resonance (NMR), gel-permeation chromatography (GPC), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and mechanical property studies. The physical properties of the copolymers are dependent largely with 3-hydroxyoctanoate (3HO) content in all PHA.     

Preparation and characterization of nano-cellulose with new shape from different precursor

Three different precursor materials – 1. China cotton, 2. South African cotton, 3. Waste tissue papers were used to produce nano-cellulose by acid hydrolysis route. No chemical pretreatment has been done for the production of nano-cellulose from these precursors. Prepared nano-cellulose and their corresponding precursor materials were characterized by transmission electron microscopy (TEM), particle size analysis, X-ray diffraction (XRD) study, thermo gravimetric analysis (TGA), differential scanning calorimetric (DSC) analysis and Fourier transformed infra red (FTIR) spectroscopy. A comparative study of the characteristics was done with the properties of raw materials and with that of nano-cellulose. Shape and size of the nano cellulose generally depends on nature of the precursor and hydrolysis condition. Morphology study of nano-cellulose from different sources revealed range of length from 50 to 200 nm and diameter from 10 to 90 nm. Higher thermal stability and crystallinity of nano-cellulose were observed compared to that of precursor from TGA/DSC study.     

Synthesis and evaluation of a star amphiphilic block copolymer from poly(epsilon-caprolactone) and poly(ethylene glycol) as a potential drug delivery carrier

A star polymer composed of amphiphilic block copolymer arms has been synthesized and characterized. The core of the star polymer is polyamidoamine (PAMAM) dendrimer, the inner block in the arm is lipophilic poly(epsilon-caprolactone) (PCL), and the outer block in the arm is hydrophilic poly(ethylene glycol) (PEG). The star-PCL polymer was synthesized first by ring-opening polymerization of epsilon-caprolactone with a PAMAM-OH dendrimer as initiator. The PEG polymer was then attached to the PCL terminus by an ester-forming reaction. Characterization with SEC, (1)H NMR, FTIR, TGA, and DSC confirmed the star structure of the polymers. The micelle formation of the star copolymer (star-PCL-PEG) was studied by fluorescence spectroscopy. Hydrophobic dyes and drugs can be encapsulated in the micelles. A loading capacity of up to 22% (w/w) was achieved with etoposide, a hydrophobic anticancer drug. A cytotoxicity assay demonstrated that the star-PCL-PEG copolymer is nontoxic in cell culture. This type of block copolymer can be used as a drug delivery carrier.