Physical and thermal characterisation of Precirol® and Compritol® as lipophilic glycerides used for the preparation of controlled-release matrix pellets

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Abstract

Physical and thermal properties of Compritol® and Precirol® as potential lipophilic binders in melt pelletisation process for the preparation of sustained-release matrix pellets were evaluated in this study. Experimental measurements were carried out using X-ray diffractometry, differential scanning calorimetry (DSC), hot-stage microscopy (HSM) and rheological measurements. These studies have shown that the lipophilic binders may present a relatively complex behaviour depending on the sample treatment (untreated, freshly solidified, aged samples). DSC and HSM methods have shown the presence of polymorphism for Precirol. Moreover, both untreated and fresh solidified Precirol and Compritol samples present partially amorphous layered structure which slowly crystallise in time. The rate of crystallisation was found to be more rapid for Precirol, and highly dependent on the ageing conditions (storage temperature). Finally, the evaluation of the thermal and rheological properties of Precirol and Compritol mixtures have shown that the use of such mixtures, presenting well distinct melting properties, could be a very interesting tool for the preparation of high fatty binder content prolonged-release pellets in high shear mixers if the product temperature is carefully controlled (between 45 and 50 °C) during the pelletisation process.

Introduction

Glycerides are a family of excipients which have generated considerable interest for the preparation of oral dosage forms. Gelucires represent a wide range of meltable excipients, which are composed of mixtures of glycerides and fatty acid esters of polyethylene glycol (PEG) (Sutananta et al., 1995a). The nature and the proportion of these components determine the hydrophilic–lipophilic characteristic (HLB value) of these excipients and the drug release properties from the corresponding dosage forms (Ratsimbazafy and Brossard, 1991; Craig, 1996).

In particular, Compritol® or glyceryl behenate and Precirol® or glyceryl palmito-stearate can be used as glyceride bases for the preparation of sustained-release dosage forms (Saraiya and Bolton, 1990). Indeed, the esterification of glycerol by long chain fatty acids and the absence of PEG esters give them a pronounced hydrophobic character expressed by the low HLB value of 2.

Several techniques have been used to obtain prolonged-release dosage forms from glyceride-based formulations, i.e. thermoplastic or melt granulation (Saraiya and Bolton, 1990), melt pelletisation (Hamdani et al., 2002), hot-melt extrusion (Liu et al., 2001) and hot-melt coating (Barthelemy et al., 1999).

As discussed in a previous work (Hamdani et al., 2002), phenylephrine hydrochloride, ciprofloxacine hydrochloride, ketoprofen and theophylline were used as model drugs, showing very different solubility characteristics, to prepare controlled-release pellets in high shear mixer by the melt pelletisation process. In summary, lipidic formulations based on the use of appropriate mixtures of lower (Precirol®) and higher (Compritol®) melting range fatty binders were proposed. Depending on the physico-chemical properties of the active ingredient, formulations containing different blends of lactose 450 mesh and relatively high amounts of lipidic binders (up to 80%, w/w) have been used in order to obtain appropriate prolonged-release properties.

Due to their chemical and physical complexity, the lipophilic binders may exhibit a complex behaviour (i.e. melting and crystallisation, physical modifications on storage). The aim of this study is to evaluate the physical, chemical and mechanical properties of these materials. This evaluation is particularly useful for the development of such controlled-release formulations as the melting and rheological characteristics of fatty binders are the most critical parameters to consider, specially when high amount of lipidic binder mixtures are used (Hamdani et al., 2002). Moreover, the physical ageing effects associated with glyceride-based dosage forms have also to be well understood in order to avoid any further drug release alteration during storage.

Many studies (Laine et al., 1988, Sutananta et al., 1994, Sutananta et al., 1995b) have shown the importance of considering the chemical composition and the physical structure of glyceride bases in order to understand the dissolution behaviour of drugs from these systems. However, the number of effective methods available for the study of the physical structure of complex solids is very limited (Craig, 1996). Four methods will be discussed in this paper, differential scanning calorimetry (DSC), X-ray diffraction, hot-stage microscopy (HSM) and rheological measurements (controlled stress capillary rheometer).

Section snippets

Materials and methods

Glyceryl palmito-stearate (Precirol® ATO 5, also known as Gelucire 54/02) and glyceryl behenate (Compritol® 888, also known as Gelucire 70/02) were supplied from Gattefossé (France). Compritol® and Precirol® occur as fine, white free flowing powders.

Results and discussion

Fig. 1 illustrates the DSC thermograms of untreated, freshly solidified and aged (1 week at 40 °C) Compritol® and Precirol® samples. It may be observed that, depending on the sample treatment, Precirol underwent changes as reflected by the shape of DSC curves. The presence of two melting endotherms, can only be detected only on the freshly solidified sample. However, the lowest melting endotherm lost during storage go with an increase in the height and sharpness of the higher melting endotherm.

Conclusion

Compritol and Precirol are very interesting materials which may present potential applications as lipidic binders in melt pelletisation process to develop prolonged-release dosage forms. This study has therefore highlighted the importance of considering the physical, thermal and rheological characteristics of glyceride bases in order to better control the properties of controlled-release formulations. Due to their chemical and physical complexity, the lipophilic binders may exhibit a relatively

Acknowledgements

Authors would like to acknowledge Mr. Szabo and Mrs. Segato from the department of Industrial Chemistry (Université Libre de Bruxelles) for their technical support for X-ray diffraction experiments.

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