Formulation of a Poorly Water-Soluble Drug Sirolimus in Solid Dispersions to Improve Dissolution

An attempt has been made to enhance solubility and dissolution of sirolimus by solid dispersion and complexation technique using various hydrophilic excipients. Sirolimus an immunosuppressant agent has low bioavailability due to its low aqueous solubility. Solid dispersion of sirolimus in PEG-6000, Poloxamer-188, and Mannitol were prepared by fusion and solvent evaporation method. Beta-CD complexation of sirolimus was prepared by kneading method. In vitro dissolution studies were carried out in 0.4% SLS in water, which showed that the solid dispersion containing PEG 6000 (1:1), which was prepared by solvent evaporation method, showed faster dissolution rate than the other formulations and β-cyclodextrin complex. Solid dispersions containing PEG 6000 was further investigated by x-ray powder diffraction, differential scanning calorimetry (DSC), and FTIR. X-ray powder diffraction and DSC patterns suggested that the drug state changed from crystalline to amorphous form in the formulation.     

Study of the interaction of clobazam with cyclodextrins in solution and in the solid state

Inclusion complexes of clobazam with alpha-, beta-, gamma-cyclodextrins (CyDs) and heptakis(2.6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) in aqueous solution and in the solid phase were studied by the solubility method, infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffractometry. In addition, inclusion complex of clobazam with heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin and the solid dispersion of clobazam with methyl cellulose (MC) in a ground mixture were investigated by IR, DSC and X-ray diffractometry. It was observed that DM-beta-CyD had the highest stability constant among the four CyDs in solution. Thermal and X-ray diffraction analyses showed that clobazam molecules existed in a molecularly dispersed state in the ground mixture of CyDs. Infrared spectra showed lower frequency shifts in the case of the ground mixtures of clobazam with natural CyDs, which can be attributed to the formation of hydrogen bonds between the two carbonyl groups of clobazam and hydroxyl groups of natural CyDs. In contrast, higher frequency shifts were observed in the case of the ground mixtures of clobazam with methylated CyDs and MC and these were considered to be due to the monomolecular dispersion of clobazam in a hydrophobic environment. The mode of interaction of clobazam with DM-beta-CyD was different from that with natural CyDs in the ground mixtures. Furthermore, the crystalline inclusion complex of clobazam with DM-beta-CyD was obtained by heating of the coprecipitate in vacuo at 120 degrees C for 1 h.     

Effect of grinding with hydroxypropyl cellulose on the dissolution and particle size of a poorly water-soluble drug.

A new benzofuroquinoline derivative, 3,9-bis(N,N-dimethylcarbamoyloxy)-5H-benzofuro[3,2-c]quinoli ne-6-one (KCA-098), shows poor oral absorption due to practical insolubility in water. In this study, a co-grinding technique employing a water-soluble polymer was used for improvement of the dissolution rate of KCA-098. Powder X-ray diffraction patterns and IR spectra of KCA-098 showed the conversion of the drug from a crystal state to an amorphous state by grinding with a polymer such as hydroxypropyl cellulose (HPC-SL) or polyvinylpyrrolidone (PVP K30). The particle size of KCA-098 was remarkably reduced to a submicron size by grinding with HPC-SL. The co-ground mixture with HPC-SL showed a rapid dissolution rate and maintained supersaturation for more than 1 h. On the other hand, the co-ground mixture with PVP K30 showed rapid dissolution and supersaturation for a shorter period. These data suggest that the rapid dissolution rate was obtained by the conversion of the drug particles from a crystal to amorphous state by grinding with water-soluble polymers and that a reduction in particle size to the submicron level led to the maintenance of supersaturation due to good dispersion.     

Spectrochemical Properties of Noncubical Transition Metal Complexes in Solutions. XIV. Angular Overlap Studies of bis(Salicylidene-2-aminothiazole)Copper(II) in Various Solvents

The copper(II) complex [Cu(sat)], where Hsat is salicylidene-2-aminothiazole (bidentate Schiff - base), was studied in variety of solvents. In the solid state, the complex is black. It has been characterized by elemental analysis, solubility in common solvents, molar conductivity, and ultraviolet (UV) and visible (Vis) spectroscopy. The complex is easily soluble in common solvents such as chloroform, dimethylformamide, dimethyl sulfoxide, and 1,4-dioxane. The known crystal structure of similar compounds shows planar coordination geometry for the copper center. Combined multitechnique experiments have been applied to confirm the structure of the complex in solutions. The molar conductivities indicate their nonelectrolyte properties in all these solvents. The spectroscopic measurements were used to study the coordination properties of donoratoms and their bonding abilities.     

乙酰基二茂铁呋喃甲酰腙与β-环糊精包结物的结构与特性

用饱和溶液法制备了二茂铁酰腙类化合物乙酰基二茂铁呋喃甲酰腙 (AFH)与β-环糊精的包结物 .元素分析及溶解常数测定结果证明两者形成了 1∶ 1包结物 .从溶解度曲线计算得出包合常数为2 2 7.3 L·mol-1.通过 UV,FTIR,X射线粉末衍射研究了包结特性 ,并用 NMR技术推断了包结物的结构     

Encapsulation of quercetin in β-cyclodextrin and (2-hydroxypropyl)-β-cyclodextrin cavity: In-vitro cytotoxic evaluation

The formation of host-guest inclusion complex of Quercetin (QRC) with β-Cyclodextrin (β-CD) and (2-Hydroxypropyl)-β-Cyclodextrin (HP-β-CD) is prepared by various methods such as physical method (PM), kneading method (KM) and co-precipitation method (CP). The solid inclusion complex is characterized by UV, Fluorescence, FT-IR, SEM, powder XRD and TG/DTA analysis. The cytotoxic activity of the solid complex is performed against breast cancer cell line and it is noticed that there is better activity than the QRC alone. Hence, the solid complex showed an improvement in the anticancer activity against MDA MB 231 cell line.     

Preparation and physicochemical characterization of carbamazepine (CBMZ): para-sulfonated calix[n]arene inclusion complexes

The formation of inclusion complexes with para-sulfonated calix[n]arene (PSC[n]A) was studied for carbamazepine (CBMZ), a poorly water soluble anticonvulsant drug. The effect of PSC[4]A and PSC[6]A on aqueous solubility of carbamazepine was studied extensively. The complete complexation of the drug was achieved after 48 h of shaking with PSC[n]A in water and evaporation of water to get solid complex. The interaction between PSC[n]A and CBMZ in solid state inclusion complexes was accomplished by aqueous phase solubility studies, HPLC, DSC, PXRD, FTIR, UV–Vis, and FT-Raman spectroscopy. The solubility of CBMZ increases as a function of PSC[n]A concentration. The results of the two phase solubility experiments are in good conformity to signify the formation of 1:1 (PSC[6]A:CBMZ) and 2:1 PSC[4]A:CBMZ complexes. The order of dissolution rate of CBMZ is inclusion complex > physical mixture > drug alone. The purpose of this study was to enhance solubility resulting in high dissolution rate and bioavailability of this essentially water insoluble drug.     

Study on the Supramolecular Inclusion Complex of β-Cyclodextrin/Lappaconitine

Lappaconitine (Lap) is a diterpenoid akaliamide, naturally occurring in roots and rhizomes of Aconitum and delphinium. Lap reveals bradycardic, hypotensive, antinocieptive activity. However, its application is restrained owing to its poor water solubility, toxicity and side effects on humans. In a number of pharmaceutical studies,CDs have been reported to interact with many drug molecules to form inclusion complexes. These inclusion complexes have been extensively used to improve water solubility of poorly soluble drugs, to reduce their toxicity, and to increase the dissolution rate [1]. In the present work, the β-CD/Lap complex was prepared by kneading method. The products have been characterized by the solubility measurement as well as UV, FTIR, NMR spectroscopy and X-ray powder diffractometry.     

Preparation of solid dispersion for ethenzamide-carbopol and theophylline-carbopol systems using a twin screw extruder

In the present study, we prepared solid dispersions of water-insoluble and soluble drugs (ethenzamide (ETZ) and theophylline (THEO)) by the twin screw extruder method, which made it possible to control both kneading and heating at the same time under the fusion point of each drug, using three types of the controlled-release high-molecular-weight substance Carbopol (CAR) as the carrier. The solid dispersions obtained were evaluated and compared with those prepared by the organic solvent method. These products showed significantly increased solubility of ETZ, but the solubility of THEO was reduced indicating that CAR slows the release of THEO. It is important not only to simply knead under high pressure but to select the optimal operation temperature to bring these drugs into a semi-fusion state. Solid dispersions obtained by this method showed X-ray diffraction and differential scanning calorimetry (DSC) patterns similar to those obtained by the organic solvent method indicating that the former can be used as a simple and effective method for preparation of solid dispersions.     

Physicochemical characterization and cytotoxic activity evaluation of hydroxymethylferrocene:β-cyclodextrin inclusion complex

An inclusion complex of hydroxymethylferrocene (FeMeOH) with β-cyclodextrin (β-CD) was prepared in the solid state by different techniques such as physical mixture, coprecipitation, kneading and freeze-drying. The formation of the inclusion complex was confirmed by X-ray Powder Diffractometry and Fourier Transform-Infrared spectroscopy. In aqueous solution, the 1:1 stoichiometry was established by a Job plot. The inclusion complex formation was also investigated by NMR and the stability constant (Kb) of the complex was determined to be 478 M?1, which is in agreement with that obtained with UV-Vis tritation (Kb = 541.3 M?1). The phase solubility study showed a diagram classified as Bs type and that the solubility of FeMeOH was slightly increased in the presence of β-CD. Furthermore, utilizing phase solubility diagram data, the Kb was estimated to be equal to 528.0 M?1. The cytotoxic activity of FeMeOH and its complexation product with β-CD was determined using the MTT-assay on MDA-MB-231 cell line, showing that the inclusion complex has a higher capability of inhibiting cell growth compared to that of pure FeMeOH.     

Preparation, characterization and in vitro dissolution studies of solid systems of valdecoxib with chitosan

In the present study, the solubilizing and amorphizing properties of Valdecoxib (a poorly water soluble anti inflammatory drug) with low molecular weight chitosan (a polymer), have been investigated. Binary systems of varying drug/polymer ratios were prepared using different techniques (physical mixing, co-grinding, kneading) and were tested for dissolution. Drug carrier interactions were investigated in both the liquid and solid state, by phase solubility analysis, differential scanning calorimetry, powder X-ray diffractrometry, FT-IR spectroscopy and scanning electron microscopy. The solubility of the drug increased with increasing polymer concentration showing A(N) type phase solubility diagram. Differential scanning calorimetry, powder X-ray diffractrometry and scanning electron microscopic studies of binary systems suggested generation of amorphous form of drug (in kneading and co ground mixtures). IR spectroscopy revealed the presence of hydrogen bonding in kneading and co ground mixtures. Drug dissolution was improved with increasing the polymer concentration in the mixture (Kneaded>co ground>physical mixture), which was attributed to the amorphonization and/or decreased drug crystallinity, size and polymer wetting effect. Enhanced dissolution combined with its direct compression feasibility and anti ulcerogenic action results in low molecular weight chitosan for developing fast release oral solid dosage forms of valdecoxib.     

2,4-D-α-Cyclodextrin Complexes

The aqueous solubility of the pesticide 2,4-D was improved by inclusion complexation with α-CD. The formation of such inclusion compounds was studied via the phase-solubility diagram (solution state) and by DSC and HSM (solid state). 2,4-D presented a typical B_s Higuchi solubility curve, coprecipitating a 1:2 pesticide-α-CD complex. In order to obtain solid complexes, three processing methods were checked: kneading, coprecipitation and spray-drying. DSC and HSM showed that only the last two of these yielded true inclusion compounds. Chemical analysis also revealed that the stoichiometry of such solid complexes corresponds to a 2,4-D-α-CD ratio of 1:2.     

Improvement of some pharmaceutical properties of mycophenolate mofetil (MMF) by para sulphonatocalix[4]resorcinarene inclusion complex

As a part of our investigations to unfold the chemistry of calixresorcinarene, we have focused on the formation of inclusion complex of a poorly soluble (43 μg ml^?1 at pH 7) drug mycophenolate mofetil (MMF) an immunosuppressive agent and an inosine monophosphate dehydrogenase (IMPDH) inhibitor with para sulphonatocalix[4]resorcinarene (PSC4R). The complete complexation of the drug was achieved after 48 h of stirring with para sulphonatocalix[4]resorcinarene(PSC[4]R) in water and evaporation of water yield the solid complex. The interaction between para sulphonatocalix[4]resorcinarene(PSC[4]R) and MMF in solid state inclusion complexes was accomplished by aqueous phase solubility studies, Thermal Analysis, HPLC, PXRD, FT-IR, and UV–Vis spectroscopy. The results of the phase solubility experiments are in good conformity to signify the formation of 2:1 PSC4R: MMF complexes. The purpose of this study was to enhance solubility and resulting in high dissolution rate and bioavailability of this essentially water insoluble drug. The results of the in vivo study shows that there is a remarkable change in the toxicity of the pure drug MMF and complex did not produce any mortality up to 2200 mg kg^?1.     

Interaction between Sulfaproxyline and β-Cyclodextrin in the Solution and Solid States

The 1 : 1 inclusion complex between sulfaproxyline (SP) and -cyclodextrin (-CD) was prepared by the freeze-drying and the kneading method. Complex formation was confirmed in the solid state by X-ray diffractometry and by infrared spectroscopy. The interaction between sulfaproxyline and -cyclodextrin in solution was studied by the solubility method and 13C-NMR spectroscopy. Phase solubility studies in water revealed a AN type diagram and a stability constant of 930 ± 120 M-1 for a 1 : 1 inclusion complex was derived. Complexation was found to improve the dissolution rate of sulfaproxyline.     

A Comparative Study of Naproxen – Beta Cyclodextrin Complexes Prepared by Conventional Methods and Using Supercritical Carbon Dioxide

Naproxen is a poorly soluble anti-inflammatorydrug, the solubility of which canbe enhanced by complexation withbeta-cyclodextrin. Besides that, the inclusioncomplex reduces the incidence of gastrointestinal side effects of the drug. The aim of this work was to compare the physicochemical characteristics of the solid complexes prepared by traditional methods (kneading, freeze-drying and spray-drying) and using a supercritical fluid technology. The unusual solvent properties of carbon dioxide above their critical temperature and pressure were exploited in order to prepare inclusion compounds. Complexes prepared using supercritical fluid technology showed similar properties to those of freeze-drying andspray-drying complexes as proved by DSC, FT-IRand UV.     

Preparation and Characterization of Biodegradable Polylactide（PLA） Microspheres Encapsulating Ginsenoside Rg3

In this study, the process of a biodegradable polylactide（PLA） microsphere encapsulating ginsenoside Rg3 was first studied by the emulsion solvent evaporation method, for enhancing solubility and stability of ginsenoside Rg3. Alabum was also first used as a modifier in this method. The mean diameter of the prepared PLA microspheres containing Rg3 was 40 μm. Ginsenoside Rg3 released from the microspheres was studied by HPLC and detected by UV. It was found that the drug release curve fitted the Model Heller-Baker best.     

Crystal growth and characterization of K[CS(NH2)2]4Br--A semiorganic non-linear optical crystal

This paper presents the synthesis and crystal growth of optically non-linear semi-organic crystal potassiumtetrakisthioureabromide (KTTB) using water and a mixture of acetone and water (1:1) by slow evaporation of aqueous solution at room temperature. The solubility has been determined in both the solvents at various temperatures. The compound crystallizes in non-centrosymmetric space group P41. The crystalline perfection of the grown crystals has been analysed by high-resolution X-ray diffraction measurements. The IR and polarized Raman spectra have been interpreted using both the factor group analysis. The results of the correlation field splitting of the thiourea internal vibrations are discussed. The optical characterization of the crystal shows the cut off wavelength near the UV region. Also the crystal shows good propensity to emit second harmonic generation of Nd:YAG laser.     

Quantitative wavelength-dependent photochemistry of the [CpFe(eta 6-ipb)]PF6 (ipb = isopropylbenzene) photoinitiator

The photochemically induced arene dissociation reaction of the widely used cationic photoinitiator complex [CpFe-(eta 6-isopropylbenzene)]PF6 has quantitatively been investigated in several different solvents at 293 K as a function of excitation wavelength at 355, 458, 488, 514, 633, and 683 nm. The complex was excited into the lowest-lying singlet ligand field manifold (355-514 nm) and directly into the corresponding lowest-lying triplet ligand field state (633, 683 nm). Absolute photochemical quantum efficiency (phi cr) results reveal that the system exhibits a strong excitation wavelength dependence in each investigated solvent and that the reaction is extremely efficient in the UV and visible regions. The wavelength dependence also reveals that the photochemistry does not occur solely from the lowest-lying ligand field triplet excited state. New insights in terms of both photophysical and mechanistic aspects of this system are obtained from the quantitative photochemical results.     

Improvement of dissolution properties of a new Helicobacter pylori eradicating agent (TG44) by inclusion complexation with beta-cyclodextrin

The interaction of a newly developed Helicobacter pylori eradicating agent (TG44, 4-methylbenzyl-4'-[trans-4-(guanidinomethyl)cyclohexylcarbonyloxy]biphenyl-4-carboxlylate monohydrochloride) with beta-cyclodextrin (beta-CyD) in aqueous solution and in solid state was studied to gain insight into the high in-vivo H. pylori eradicating activity of TG44/beta-CyD complex. The interaction was studied by the solubility method, spectroscopic methods, powder X-ray diffractometry and differential scanning colorimetry (DSC). TG44 gave A(L)-type phase solubility diagram with beta-CyD in water, showing a linear increase in solubility of the drug up to 8 mM beta-CyD concentration. The solubility of TG44 (0.04 mM in water at 25 degrees C) increased about 70-folds at 8 mM beta-CyD. Ultraviolet, circular dichroism, fluorescence and (1)H-nuclear magnetic resonance spectroscopic studies indicated that TG44 forms the inclusion complex with beta-CyD in a 1:1 stoichiometry and the biphenyl moiety of TG44 is preferably included in the beta-CyD cavity in water. The Giordano plot made by monitoring changes in the fusion enthalpy of TG44 (about 184 degrees C) suggested that TG44 forms the 1:1 complex with beta-CyD in the solid state. The TG44/beta-CyD solid complex in a 1:1 stoichiometry was prepared by the grinding and spray-drying methods and confirmed by powder X-ray diffractometry and DSC that the complex is in an amorphous state. The initial dissolution rate of TG44/beta-CyD complex was significantly faster than those of the drug alone and the physical mixture of both components, maintaining higher supersaturated concentrations of the drug for a long time. The results suggested that the higher eradicating activity of TG44/beta-CyD complex to Helicobacter pylori, compared with that of the drug alone, is attributable at least partly to the faster dissolving property of the complex and its ability to maintain the supersaturated state of the drug in the gastric fluid.     

Formulation and evaluation of gel containing nanostructured lipid carriers of tretinoin–Epi-β-CD binary complex for topical delivery

The objective of present research work was to formulate and evaluate topical gel containing tretinoin–cyclodextrin (CD) binary complex loaded into nanostructured lipid carriers (NLCs). Use of cyclodextrin and nanolipid carrier together in a system produced a synergistic effect by increasing the drug release and skin permeation, thus improving the overall therapeutic effect. Two different cyclodextrins i.e. β-CD and its water soluble polymeric derivative epichlorohydrin-β-cyclodextrin (EPI-β-CD) were used to obtain binary inclusion complex of drug-cyclodextrin (D-CD) systems by two different techniques (kneading and co-evaporation). The prepared solid complexes were characterized by FTIR, DSC, XRD etc. and the best system was selected for loading into nanolipid carriers. NLC comprising glyceryl mono stearate (GMS) and oleic acid were obtained by slightly modified emulsification evaporation method. Four different formulations of NLCs were suitability characterized for particle size, zeta potential, entrapment efficiency, drug loading and drug release. EPI-β-CD was found to be more effective than β-CD in enhancing solubility and dissolution properties of tretinoin. The most effective NLC formulation was incorporated into carbopol hydrogel which showed better permeation properties than that of the reference gel (0.1%).