Research paper
Investigation of the release mechanism of a sparingly water-soluble drug from solid dispersions in hydrophilic carriers based on physical state of drug, particle size distribution and drug–polymer interactions

https://doi.org/10.1016/j.ejpb.2006.11.020Get rights and content

Abstract

In the present study the release mechanism of the sparingly water-soluble drug felodipine (FELO) from particulate solid dispersions in PVP or PEG was investigated. FT-IR data indicated that a N–H⋯O hydrogen bond is formed between FELO and polymers. The drug–polymer interaction was theoretically studied with the density functional theory with the B3LYP exchange correlation function. The interaction energies have been estimated at −31.8 kJ/mol for PVP and −18.8 kJ/mol for PEG. Also, detailed vibrational analysis of the complexes showed that the red shift of the N–H bond stretching in FELO molecule due to H-bonding was higher in the FELO–PVP complex than in the FELO–PEG complex. Both the experimental and theoretical data indicated that a stronger interaction of FELO with PVP than with PEG was developed. The interactions of FELO with the polymer appeared to control the physical state (amorphous or crystalline) and the particle size of FELO in the solid dispersions. In the FELO/PVP dispersions, the drug is found as amorphous nanoparticles whereas in FELO/PEG dispersions the drug is dispersed as crystalline microparticles. The size of drug particles in the dispersion was also influenced by drug proportion, with an increase in drug content of the dispersion resulting in increased drug particle size. The particle size of drug, the proportion of drug in the dispersion and the properties of the polymer (molecular weight) appeared to determine the mechanism of drug release from the solid dispersions, which was drug diffusion (through the polymer layer)-controlled at low drug contents and drug dissolution-controlled at high drug contents. In situ DLS measurements indicate that the large initial particles of FELO/PVP and FELO/PEG solid dispersions with low drug content (10–20 wt%) are very rapidly decreased to smaller particles (including nanoparticles) during dissolution, leading to the observed impressive enhancement of FELO release rate from these dispersions.

Introduction

The enhancement of the bioavailability of poorly water-soluble drugs is one of the greatest challenges of drug development and several pharmaceutical technologies have been investigated to this end. Amongst them is the dispersion of the drug into an inert, hydrophilic polymer matrix [1], [2]. Although a large number of studies have been published on the subject, the mechanisms underpinning the observed enhancement of the rate of drug release are not yet understood [3], [4]. The reason for this lies in the complexity of the release process and the multitude of factors that can affect it, including the properties of drug (solubility [5], physical state [6], particle size [7]), the properties of the polymer forming the matrix (dissolution rate [8], molecular weight [9] and the possible drug–polymer interaction [10], [11]). Craig proposed a simplified drug release model differentiating between carrier-controlled and drug-controlled dissolution, depending on drug solubility in the concentrated polymer layer that is formed on the dissolving surface [3]. The proposed model might help to identify the correct strategy to control (improve) the release rate of drug from the solid dispersion (the strategy will depend on release mechanism, i.e. if the release is carrier- or drug-controlled) and perhaps most importantly to understand the causes of possible formulation instability upon storage and select scientifically sound approaches to deal with it. Although useful as methodological approach in identifying possible dominant mechanisms of drug release from solid dispersions, the model is based on several assumptions that may not hold in many cases. For example, drug release by diffusion through the polymer layer is considered to be too slow to exert any significant effect on drug release. However, this may not be true especially in the case of low molecular weight polymers.

Our long-term aim is to develop an immediate-release formulation of felodipine (FELO), which could be useful as an emergency treatment in ischemic heart disease. In our previous work, we have shown that the interaction (hydrogen bonding) between PVP and FELO affected drug solubility and particle size distribution of drug in the polymer matrix and that through these effects drug–polymer interaction affected drug release [12]. In this report, we provide evidence that felodipine release from solid dispersions in PVP or PEG is significantly enhanced due to a rapid dissolution of initial particles of the dispersion into smaller particles, including nanoparticles, and that the release mechanism changes gradually from a diffusion-controlled to a dissolution-controlled one with increasing drug proportion in the solid dispersion. The felodipine–polymer interactions at the molecular level have been evaluated, based on experimental 1H NMR data (in solution), FT-IR data (in solid state) and theoretical quantum mechanical calculations, and their consequences with regard to the physical state of the drug in the dispersions and the drug release are discussed.

Section snippets

Materials

Felodipine (FELO) with an assay of 99.9% was obtained from PCAS (Longjumeau, France) with a melting point of 143–145 °C and solubility in water approximately 0.5 mg/L while it is freely soluble in ethanol. Poly(vinyl pyrrolidone) (PVP) type Kollidon K30 with a molecular weight Mw of 50,000–55,000 was obtained from BASF (Ludwigshafen, Germany), Tg = 167 °C (DSC), moisture content 1.95% (TGA) and bulk density 0.410 g/cm3. Poly(ethylene glycol) (PEG 4000) with a molecular weight of 3898 g/mol (calculated

Release profiles

As it can be seen in Fig. 1 an impressive enhancement of FELO dissolution rate is achieved with both types of dispersion (FELO/PVP and FELO/PEG) containing 10 or 20 wt% FELO. Drug release is almost complete after 30 min from the 10 wt% dispersions and after 60 min from the 20 wt% dispersions. As the drug content of the dispersion increased, the rate of release became lower for both types of dispersion. The FELO/PEG dispersions exhibited a little lower release rates compared to the FELO/PVP

Discussion

FELO exhibits high permeability through biological membranes, but its absorption after oral administration is limited by its low dissolution rate, due to its very low aqueous solubility (lower than 0.5 mg/lt). In order to increase the dissolution rate of FELO, several attempts have been made in the past. Since FELO is a crystalline compound, most of these attempts deal with preparation of the glassy state of the drug [24], [25], [26], [27]. From our previous studies, it was found that

Conclusions

The interactions at the molecular level of FELO with the polymer carrier (PVP and PEG) appeared to control the physical state (amorphous or crystalline) and the particle size of FELO in the solid dispersions of FELO in PVP or PEG. When these interactions are relatively strong, as in the case of FELO/PVP dispersions, the drug forms amorphous particles in the nano-range of sizes. If they are relatively weak, as in the case of FELO/PEG solid dispersions, the drug is dispersed as crystals having

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