Elsevier

Chemistry and Physics of Lipids

Volume 183, October 2014, Pages 191-203
Chemistry and Physics of Lipids

Polymorphism of glyceryl behenates: From the individual compounds to the pharmaceutical excipient

https://doi.org/10.1016/j.chemphyslip.2014.07.005Get rights and content

Highlights

  • Glyceryl behenates are widely used in pharmaceutical formulations, from solid dosage forms to nanoparticles.

  • Solid state behavior of glyceryl behenates result from the presence of the three main constituents: mono, di and tri-behenin.

  • The monoglycerides content was shown to be essential to give its final structure to the glyceryl behenates excipient.

  • Special attention has to be required when mixing glyceryl behenates with other constituents that could trap monoglycerides.

Abstract

The present paper deals with the crystallization behavior of glyceryl behenate mixtures that are extensively used in the field of drug delivery. The aim of the study was to understand the structural and thermal behaviors of Compritol® by considering first the individual polymorphism of the main components constituting this excipient and then their mixtures. This excipient mainly contains dibehenin (∼50%), tribehenin (∼30%) and monobehenin (20%). It appeared clearly that the mixture polymorphism did not result from a simple addition of the individual behavior. Indeed, the solid state organization of this excipient strongly depended on the presence of the third main component, monobehenin, into the mixture. Furthermore, a threshold ratio of monobehenin, at least 10%, must be reach in order to obtain the typical structural organization (co-existence of α/sub-α subcells) and thermal behavior (solid–solid transition and melting) of Compritol®. This underlines that special attention is required when mixing Compritol® with other pharmaceutical ingredients that could trap monoglycerides and modify the equilibrium present in the pure excipient.

Introduction

Glycerol esters of fatty acids, also referred to as acylglycerols or glycerides, have been proven to be suitably meltable excipients able to sustain drug release from pharmaceutical oral dosage forms (Jannin et al., 2008). In this field, glyceryl behenate excipient presents special interest due to its pronounced hydrophobic character with a hydrophilic–lipophilic balance value of 2 and its moderate melting temperature with a drop point in the 64–74 °C range (European Pharmacopeia, 2007). Pharmaceutically approved glyceryl behenate is based on a mix of glycerol esters of 1-docosanoic or behenic acid with around one half by weight of glyceryl dibehenate. In the liquid phase, at temperature above its melting point, it shows ability to incorporate indifferently lipophilic or hydrophilic substances which can be efficiently trapped in the solid phase formed upon cooling. The mixture in its solid state is rigorously water-insoluble so that the release of the entrapped substances can be delayed through a diffusion mechanism mainly governed by the porosity of the matrix and the own solubility of the loaded host substances (Duclos et al., 1999, Li et al., 2006). It has been conveniently employed, with brand names of Compritol® 888 (named Compritol® in the following lines) or Speziol®GDB, as coating or core matrix agent for the preparation of sustained release dosage forms involving solvent-free processes, namely hot melt coating, melt granulation, melt extrusion, melt pelletization or direct compression methods. A number of studies focused on the use of glyceryl behenates in pharmaceutical formulations not only as tablet lubricant (Miller and York, 1988, Wang et al., 2010, Jannin et al., 2003, N'Diaye et al., 2003) but also and mainly as binders for matrix tablets (Li et al., 2006, Gambhire et al., 2007, ÖzyazIcI et al., 2006, Rao et al., 2009), capsules (Duclos et al., 1999), pellets (Hamdani et al., 2003, Krause et al., 2009, Barthelemy et al., 1999), microparticles (Passerini et al., 2010, Pivette et al., 2009, Long et al., 2006) or as components of nanoscale carrier systems (Jores et al., 2004, Rostami et al., 2014) for topical (Liu et al., 2007, Souto et al., 2006, Gupta and Vyas, 2012), pulmonary (Pilcer and Amighi, 2010), parenteral (Wissing et al., 2004) or oral (Runge et al., 1996, Jenning et al., 2000, Freitas and Müller, 1999, Elgart et al., 2012) administration of drugs. Comparatively little work has been undertaken so far to elucidate structural properties of Compritol® as a function of its thermal behavior. Most of solid lipids excipients, like Compritol®, that are manufactured using vegetable origin materials present a complex chemical composition of different glyceridic derivatives. The ability of each glyceridic compound to present different polymorphic form adds another source of complexity. This complexity in term of chemical composition and physical form can be deservedly suspected to influence loading efficiency and release kinetics of the drugs as well as stability of the formulations depending on the storage conditions (Windbergs et al., 2009, Reitz and Kleinebudde, 2007). The only one detailed investigation into of the solid state characteristics of Compritol® to date was performed by combining X-ray diffraction coupled to differential scanning calorimetry and infrared spectroscopy (Brubach et al., 2007). The cooling rate applied to the liquid phase was identified as one of the key factors for obtaining different crystalline organizations. It was thereby highlighted that slow cooling rates of a few degrees per minute lead to the coexistence of up to three lamellar phases of 2 L conformation differing in their long-range distances and interpreted as partial segregation between glyceryl di- and tri-behenates. Temperature quenching into liquid nitrogen similarly yields two lamellar phases while intermediate cooling rates like 10 °C/min apparently induce a single lamellar packing. Interestingly, all these phases were described as crystallizing in a pseudo-hexagonal lattice characterized by a sub-cell analogous to that of the sub-α form thoroughly described for long-chain mono- or diglycerides, especially 1-monobehenin (Lutton, 1971) and 1,2-dibehenin (Kodali et al., 1990).

The present study deals with further understanding of the thermotropic behavior of the ternary mixture of glyceryl mono-, di- and tri-behenates constituting Compritol® in relation with the preparation of multiparticulate dosage forms by a prilling process. This indeed consists of incorporating drugs in the molten exipient before extrusion through vibrating nozzles to produce calibrated liquid droplets which are then rapidly cooled during their fall in a temperature-controlled air column (Séquier et al., 2014). Such a process leads to monodisperse microgranules of perfectly spherical shape (Limousin, 1997). In a previous study (Pivette et al., 2009), we showed that under prilling conditions, Compritol® takes a lamellar organization characterized by a single long-range repeat distance and in which the hydrocarbon chains seem arrange in a sub-α pseudo-hexagonal sub-cell very similar to that found by Brubach et al. (Brubach et al., 2007). This structural state is preserved for long-time storage at room temperature and was demonstrated efficient to sustain the release of entrapped substances (Pivette et al., 2012). Here we aimed at deeper investigation of the formation of such a crystalline state and identify whether this actually corresponds to a totally miscible solid solution of the three glyceryl behenate derivatives or to the coexistence of more than one phase however with very close molecular packings. Indeed, each of the glycerol esters that constitute Compritol® taken separately exhibits a monotropic behavior, more or less complex depending on the number of grafted fatty acid units. Moreover, the temperature range in which the polymorphic transitions occur varies from one behenate derivative to the other. In this way, three distinct long-range lamellar organizations have been identified for tribehenin which differ by the lateral molecular packing and crystalline sub-cell: a hexagonal variety named α, an orthorhombic perpendicular one referred to as β′ and a thermodynamically stable form β corresponding to a triclinic parallel lattice (Lutton and Fehl, 1970). Similar crystalline structures can be observed for 1-monobehenin as well as a pseudo-hexagonal variety sub-α which forms reversibly from the hexagonal phase (Lutton, 1971, Vereecken et al., 2009). With respect to 1,2-dibehenin, α, β′ and sub-α varieties have been described (Kodali et al., 1990) while simpler behavior characterizes 1,3-dibehenin and 2-monobehenin isomers which mainly crystallize in triclinic parallel β form (Baur et al., 1949, Hagemann, 1988). The important question that arises from this current state of knowledge is to what extent each glyceryl behenate is implicated in the structural organization of Compritol® in its solid state under temperature-controlled crystallization process, especially the respective roles of the ester derivatives in the formation of a single sub-α phase. This approach was conducted in the present work by the thorough identification of the structures individually formed by each of the three behenates and by their reconstituted binary and ternary mixtures in proportions fitting with Compritol® composition. In the last case, the influence of monobehenin content was progressively incremented to determine the degree of freedom allowing unchanged solid-state characteristics. Differential scanning calorimetry (DSC) was used to determine the temperature and enthalpy variations associated with the solid-to-liquid phase transitions along melting or crystallization processes as well as those corresponding to the solid–solid phase transitions. X-ray diffraction (XRD) at small and wide angles was performed to characterize the different occurring structures and completed by experiments coupling DSC recording and temperature-controlled XRD analysis to study the polymorphic behavior of the systems in greater detail. Fourier transformed infrared (FTIR) spectroscopy was employed when necessary to strengthen some of the structural interpretations.

Section snippets

Materials

Compritol® 888 was provided by Gattefossé S.A.S. (Saint Priest, France). Monobehenin, dibehenin and tribehenin obtained by fractional crystallization in chlorinated solvent were purchased from Larodan Fine Chemicals (Malmö, Sweden). Chemical compositions, molecular masses and purities of all chemicals used in this work are indicated in Table 1.

Mixture preparation

The dibehenin/tribehenin (63:37 w/w%) mixture was prepared by weighing the two components (precision 0.01 mg) to obtain a 500 mg final sample. Before

Individual phase behavior of glyceryl behenates

Small- and wide-angle XRD patterns of individual compounds monobehenin, dibehenin and tribehenin in their solid states at 20 °C were recorded either as received from the supplier, i.e., having undergone a crystallization from chlorinated solvent (native compounds), or by cooling at 1 °C/min of the liquid phase obtained by melting at 90–110 °C (Fig. 1A). Long-range and short-range inter-reticular distances calculated from the q values at maximum of the SAXS and WAXS Bragg reflections are summarized

Conclusions

Phase behavior and solid state structural organization of Compritol® result from the association of the three main constituents: mono-, di- and tri-behenin. Indeed, the mono/di/tri mixture was clearly representative of the Compritol® behavior. We showed that monoglycerides and diglycerides pack together into a sub-α organization while tribehenin form a separate phase with a hexagonal symmetry (α).

Added to the good stability, sub-α phase is a pseudo-hexagonal packing which is less compact than

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