Influence of polymer molecular weight on the solid-state structure of PEG/monoolein mixtures

Abstract

The polar lipid monoolein (MO) and poly(ethylene glycol), PEG, of different molar mass (1500, 4000 and 8000) were melted, mixed and left to solidify at room temperature. Analysis of the solid mixtures by differential scanning calorimetry (DSC) and small angle X-ray scattering (SAXS) revealed that a phase separation occurs when MO is present in sufficient amounts. The molecular weight of the polymer determines the amount of MO that has to be added before a separate MO phase can be detected. To further understand this behaviour, the folding of the polymers and the thickness of the amorphous domains within the lamellar structure of PEG were determined by calculation of the one-dimensional correlation function from the experimental SAXS data. It revealed that the presence of MO makes the crystalline domains of PEG 1500, which crystallizes unfolded, increase at the expense of the amorphous domains. PEG 4000 and PEG 8000 obtain a higher degree of folding when the MO content in the mixtures increases. Furthermore, a second form of MO was detected when it phase separated from PEG 1500 and 4000. This behaviour was argued to be due to the secondary crystallization of the PEGs.

Introduction

Lipid-based drug formulations have the potential to serve as carriers both for poorly soluble drugs and compounds sensitive to enzymatic and chemical degradation. Therefore, there has been a considerable amount of scientific interest in these type of systems for delivery of lipophilic drugs and peptides [1], [2], [3], [4]. The properties of the lipid as a drug carrier can in many cases be improved by formation of dispersions, e.g. solid lipid nanoparticles (SLN) [5], emulsions [6] or microemulsions [7].

Solid dosage forms are generally preferred to liquid ones, primarily owing to their better storage stability. Combining the benefits of dispersed lipid with the properties of formulations in the solid-state is, therefore, an attractive prospect. Several methods of producing such systems have been presented. The ‘dry emulsion’ method, where the liquid is removed from an emulsion by spray drying [6] or lyophilization [8] is the most common concept. These drying techniques have been used to remove the water from SLN dispersions [9] and spray-drying has been applied to dry a liquid dispersion of a cubic phase [10]. Common for all these systems is that the liquid dispersion reconstitutes when they are added to water.

In a recent study, another type of solid lipid system was characterized: a solid mixture of the polar lipid monoolein (1-glyceryl monooleate, MO) and poly(ethylene glycol) (PEG) of average molecular weight 4000 g/mol (PEG 4000) [11], [12]. The idea was to create a pre-dispersed lipid system similar to a dry emulsion. It was found that MO and PEG 4000 phase separate when the mixture contains more than 5 wt% MO. In addition, MO induced a partial stabilization of the folded form of PEG 4000 and was partially intercalated into its amorphous lamellae.

Monoolein, a polar lipid formed during digestion of triglycerides, is non-toxic and has been approved for pharmaceutical use. It has been utilized in many areas, such as drug delivery [13], [14], [15] and protein crystallization [16].

PEG is a hydrophilic straight chain polymer available in a large number of molecular weights. Those of average molecular weights over ∼1000 g/mol are solid at room temperature. PEG in the solid-state is semi-crystalline and forms a lamellar structure. The degree of folding is determined by the chain length. The primary crystallization, where crystals of higher chain folding are commonly formed, is followed by a gradual extension of the polymer chains to more stable conformations [17]. Solid (PEGs) are common carriers in drug dispersions, one example being the dispersion of the drug griseofulvin in PEG 6000 [18], [19].

In the present study, we have expanded the scope and examined solid-state mixtures of MO and PEGs of lower (PEG 1500) and higher (PEG 8000) molecular weights, as well as the intermediate PEG 4000. The solid mixtures were prepared by co-melting and were characterized using differential scanning calorimetry (DSC) and small angle X-ray scattering (SAXS).

The effect of additives in solid PEGs and other semi-crystalline polymers has recently been investigated in different contexts. Solid-state mixtures of PEG and various surfactants have been studied [19], [20], [21] as has the melting of mixtures of PEGs and fatty acids [22]. Several studies have examined the solid-state structure of semi-crystalline polymers, including the influence of an added second component [23], [24], [25], [26]. However, to our knowledge, no such structure analysis of semi-crystalline polymers when mixed with a lipid component has been performed.