María Cristina Martínez-Ohárriz

Solid Dispersions of Diflunisal–PVP: Polymorphic and Amorphous States of the Drug

ABSTRACT Coprecipitates of diflunisal and polyvinylpyrrolidone (PVP K15, K30, and K90) and physical mixtures were studied using x-ray diffraction analysis, infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and hot-stage microscopy. X-ray diffraction results revealed an almost amorphous state, even in coprecipitates with a high content of drug, next to 70%, which was independent of the polymer molecular weight. The IR spectra of 70:30 drug–PVP solid dispersions suggest the formation of diflunisal–PVP hydrogen bonds. For 70:30 drug–polymer ratio, the physical mixture showed linear dissolution kinetics of free crystals, but the corresponding coprecipitates exhibit two different dissolution processes. When the 25:75 drug–polymer dispersion is analyzed by hot-stage microscopy, only solid plates of PVP are observed; the absence of drug particles may be due to a molecular dispersion of the drug into the polymer. Moreover, polymorphic changes of diflunisal were detected in the solid dispersions in comparison with the corresponding physical mixtures, which are always formed by polymorph II. At high concentrations of drug (75:25 and 80:20), x-ray diffraction patterns of solid dispersions showed the partial recrystallization of the drug, displaying the main diffraction peaks of polymorph I when ethanol was used as coprecipitation solvent, whereas diflunisal form IV was obtained in chloroform.

Solubilization and Interaction of Sulindac with Polyvinylpyrrolidone K30 in the Solid State and in Aqueous Solution

In this report the interactions of sulindac with polyvinylpyrrolidone K30 (PVP K30), both in the solid state and in aqueous solution, have been investigated. Solid dispersions of sulindac with PVP K30 were prepared by the solvent method in ethanol from various drug-to-polymer weight ratios. X-ray powder diffraction and differential scanning calorimetry have shown that PVP inhibits the crystallization of sulindac. The stabilization of the noncrystalline state of sulindac was shown by x-ray diffractometry after a 1-year storage. There was a considerable increase in the release rate of the drug when the polymer content was increased and the intrinsic dissolution rate values of these systems were calculated. From the UV spectra a bathochromic shift and a well-defined isosbestic point were observed at pH 2 and 6, which confirmed an interaction between the drug and the polymer in solution. Moreover, the apparent solubility of sulindac has been modified as a function of the polymer concentrations. The binding process between the drug and PVP was exothermic from the stability constant values at 25, 30, and 37 degrees C at pH 2.

Interactions of naproxen with vinylpyrrolidone and β-cyclodextrin: a fluorimetric study1

Abstract A spectrofluorimetric method to study the interactions of naproxen with 1-vinyl-2-pyrrolidone and β -cyclodextrin in aqueous solution has been proposed. As complexation causes appreciable spectral changes, this method enables the determination of the stability constants. Complexation with β -cyclodextrin results in an enhancement of the fluorescence of naproxen whereas 1-vinyl-2-pyrrolidone involves a quenching of fluorescence. It has been supposed 1:1 complex formation. Specifically, formation constants, enthalpy and entropy values have been obtained for the aforementioned complexes at different temperatures and pH values; their associated errors are given.

Influence of polyethylene glycol 4000 on the polymorphic forms of diflunisal.

The present study was carried out to investigate the physico-chemical characteristics of diflunisal-PEG 4000 solid dispersions prepared by melting, solvent and melting-solvent methods. The solvents chosen were chloroform, methanol and ethanol-water due to the fact that the drug presents different polymorphic forms in these solvents. The characterization of solid dispersions was performed by X-ray powder diffraction because this technique has the advantage over other identification methods that it can detect both drug and ligand simultaneously. The X-ray diffraction patterns of the diflunisal-PEG systems suggested that the drug/polymer ratio and the solvent nature play an important role in the crystallization of the drug. In this regard, diflunisal crystallizes in form I at high concentrations of the drug (drug/polymer 2:1) in the solidified melt dispersions, however, polymorph III is mainly obtained as the polymer content increases (1:1 and 2:3). Likewise, in solid systems obtained by the solvent and melting solvent methods the drug solidifies in form III in ethanol/water and methanol while polymorph IV crystallizes in chloroform. Finally, DSC thermograms and hot-stage microscopy data of solid dispersions prepared by the melting method have allowed to draw the diflunisal-PEG 4000 solid-liquid phase diagram.

Effect of PEG 4000 on the dissolution rate of naproxen

SummaryNaproxen is a nonsteroidal anti-inflammatory drug characterized by its low wettability and poor water solubility.Solid dispersions naproxen:PPEC 4000 have been prepared in order to improve the solubility and dissolution rate of the drug, since these factors can be the limiting steps for absorption and bioavailability of poorly soluble drugs. X-ray diffraction analysis, infrared spectroscopy and differential scanning calorimetry detected no physico-chemical interaction between the drug and the inert carrier PEG 4000. The phase diagram of the naproxen-PEG 4000 system produced by DSC and hot stage microscopy is reported.The intrinsic dissolution rate of naproxen is calculated. The dissolution kinetics of solid dispersions prepared by the solvent and melt methods are compared with those of free drug and physical mixture. The studies were carried out at 37°C and pH 1.2 according to the dispersed amount method.The dissolution profiles obtained indicate that a significant dissolution enhancement occurs with solid dispersions in comparison with the physical mixture. In addition, the physical mixture showed a dissolution rate higher than the free drug. Dissolution rate constants were determined by fitting the experimental data to the cube root function, to get straight line plots.

Influence of soluble and insoluble cyclodextrin polymers on drug release from hydroxypropyl methylcellulose tablets

Background: The influence of β-cyclodextrin (β-CD) polymers on drug release from hydroxypropyl methylcellulose (HPMC) matrices has not been reported in the literature. Aim: The influence of monomeric β-CD and both soluble and insoluble β‐CD polymers on drug release from tablets containing either 30% or 50% hydroxypropyl methylcellulose has been studied using diflunisal (DF) as model drug. Method: The DF-β-CD inclusion complex (1:1 M) was prepared by coevaporation and characterised using X-ray diffraction, differential thermal analysis, and IR spectroscopy. The dissolution assays were performed according to the USP paddle method. Results: The incorporation of β-CD in the complexed form increases drug release from hydroxypropyl methylcellulose tablets in comparison with the physical mixture because of the better solubilization of the drug. The soluble polymer promotes drug release to a higher extent than the physical mixture with monomeric β-CD, but the insoluble polymer, which is itself a hydrogel, gives rise to the most retarded release profile, probably by retention of the drug in its structure. The formulations containing physical mixtures with either β‐CD or the soluble polymer present an optimum adjustment to zero-order release kinetics, and the inclusion complex followed non-Fickian diffusion according to the Korsmeyer–Peppas model. Conclusion: The release profile of DF from a HPMC matrix can be modulated in different ways by the use of either monomeric or polymeric β-CD.

Solubilization and Interaction of Sulindac with β-Cyclodextrin in the Solid State and in Aqueous Solution

A sulindac-beta-cyclodextrin complex was obtained by the coprecipitation method. Kneaded solids and physical mixtures were also prepared. The complex was shown by x-ray powder diffraction to be noncrystalline whereas pure drug and any of the other sulindac-beta-CD system were crystalline. the endothermic peak of sulindac due to the fusion of drug disappeared in DSC thermograms for the coprecipitate product, which confirmed the interaction between sulindac and beta-CD in the solid state. After a 1-year storage drug crystals could not be observed by x-ray diffractometry, which indicated that the complex formed was stable. The complex showed the fastest dissolution rate which might be attributed to the high-energy noncrystalline state and the inclusion complex formation in solution. UV spectra were modified and the apparent solubility of the drug increased with the addition of beta-CD, which confirmed the interaction between sulindac and the ligand in solution. The apparent stability constant, K1:1, for the complex at pH 2 and 25, 30, and 37 degrees C was 340, 220, and 160 M-1, respectively, which confirmed the influence of temperature on the complex stability. The value of K1:1 at pH 6 and 25 degrees C was 139 M-1, which indicated that the complex is formed easier with the non-ionized sulindac. The enthalpy change, delta H degree, showed that the binding process is exothermic.

The Role of Cyclodextrins in ORAC-Fluorescence Assays. Antioxidant Capacity of Tyrosol and Caffeic Acid with Hydroxypropyl-β-Cyclodextrin

Tyrosol and caffeic acid are biophenols that contribute to the beneficial properties of virgin olive oil. The influence of hydroxypropyl-β-cyclodextrin (HPβ-CD) on their respective antioxidant capacities was analyzed. The ORAC antioxidant activity of tyrosol (expressed as μM Trolox equivalents/μM Tyrosol) was 0.83 ± 0.03 and it increased up to 1.20 ± 0.11 in the presence of 0.8 mM HPβ-CD. However, the ORAC antioxidant activity of caffeic acid experienced no change. The different effect of HPβ-CD on each compound was discussed. In addition, the effect of increasing concentrations of different cyclodextrins in the development of ORAC-fluorescence (ORAC-FL) assays was studied. The ORAC signal was higher for HPβ-CD, followed by Mβ-CD, β-CD, γ-CD and finally α-CD. These results could be explained by the formation of inclusion complexes with fluorescein.

Characterization of Complexes Between Naftifine and Cyclodextrins in Solution and in the Solid State

Naftifine (NF) is an antifungal drug poorly soluble in basic aqueous solutions. Complexation with cyclodextrins (CDs) improves the physicochemical characteristics of many drugs. The aim of this work is to characterize the interactions between NF and α-CD, β-CD, hydroxypropylβ-CD, methylβ-CD, and γ-CD. The studies have been developed in pH 12 aqueous solutions at 25°C and in the solid state. The apparent stability constants of the complexes have been determined from phase-solubility diagrams. In the solid state, crystalline and amorphous complexes have been characterized using X-ray diffraction patterns, thermal analysis, and Fourier transform infrared spectroscopy. The solubility of NF improves with all the CDs studied, with the exception of α-CD. Different types of diagrams have been found depending on the CD used. The interaction between NF and hydroxypropylβ-CD is stronger than that with β-CD due to the specific properties of the substituents. The coevaporation method can be said the best method in preparing the solid complexes, except for NF–α-CD; again, there is no evidence of complexation. Furthermore, the presence of different types of CD structures upon complexation (i.e., cage or channel) has been discussed. Dissolution rate studies have been performed, and a positive influence of complexation in the solid state has been observed.

Nanoaggregation of inclusion complexes of glibenclamide with cyclodextrins

Glibenclamide is a sulfonylurea used for the oral treatment of type II diabetes mellitus. This drug shows low bioavailability as consequence of its low solubility. In order to solve this problem, the interaction with cyclodextrin has been proposed. This study tries to provide an explanation about the processes involved in the formation of GB-βCDs complexes, which have been interpreted in different ways by several authors. Among native cyclodextrins, βCD presents the most appropriate cavity to host glibenclamide molecules showing AL solubility diagrams (K1:1≈1700M-1). However, [Formula: see text] solubility profiles were found for βCD derivatives, highlighting the coexistence of several phenomena involved in the drug solubility enhancement. At low CD concentration, the formation of inclusion complexes can be studied and the stability constants can be calculated (K1:1≈1400M-1). Whereas at high CD concentration, the enhancement of GB solubility would be mainly attributed to the formation of nanoaggregates of CD and GB-CD complexes (sizes between 100 and 300nm). The inclusion mode into βCD occurs through the cyclohexyl ring of GB, adopting a semi-folded conformation which maximizes the hydrogen bond network. As consequence of all these phenomena, a 150-fold enhancement of drug solubility has been achieved using β-cyclodextrin derivatives. Thus, its use has proven to be an interesting tool to improve the oral administration of glibenclamide in accordance with dosage bulk and dose/solubility ratio requirements.