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by Krisanin Chansanroj and Gabriele Betz

A number of natural compounds need to be applied when concerning toxicity and biocompatibility of excipients exploited in pharmaceutical formulations. Lipid materials, commonly used in food products, have not only gained increased interest due to their attractive low cost and toxicity, but also their derivative abilities in a wide range of hydrophilicity-lipophilic properties. The latter is perfectly suited for diverse applications, ranging from enhanced absorption to sustained release purposes. Furthermore, with respect to their relatively low melting points, a number of manufacturing techniques can be supported, examples being, fluid bed granulation/coating, high shear granulation, spray drying and spray congealing.

Hot melt coating techniques are developed in an attempt to reduce both processing time and production costs. In this process, coating materials are melted and directly sprayed to particulates in a fluid bed chamber, avoiding the aid of any solvents. Lipid materials, in a group of triglycerides and their derivatives, are excipients of choice due to their low melting points and appropriate melting behaviors. There are several reports demonstrating where successful hot melt coated granules and pellets for taste masking [1], improving tablet lubricating property [2], and controlling drug release [3-5] have been achieved.

Nevertheless, there are many cases where instability of triglyceride-based formulations caused by polymorphic change of lipid bases upon storage [6-8] are reported. To overcome these stability problems, a tempering treatment, where lipid bases are subjected to the transformation towards the stable form under appropriate conditions, is proposed [7, 8]. This article provides a background to polymorphism in triglyceride bases and demonstrates an example of inevitable changes in hot melt coated pellets after tempering treatment.

Polymorphism of triglycerides

As triglycerides (TGs) are composed of esters of glycerol with three fatty acid molecules, an arrangement of long aliphatic chains of fatty acids in different sub-cell structures reflect polymorphism. Three main polymorphs, so called, α, β' and β, are classified based upon sub-cell structures in hexagonal, orthorhombic and triclinic packing, respectively; see Fig. 1 [9].

Figure 1: Polymorphism of TGs (A) and correlation between polymorphic forms and Gib's free energy (B) [9].

Generally, rapid cooling of molten lipid leads to a formation of an unstable α-form which gradually transforms towards a stable β-form by time with or without intervention of an intermediate β’-form [10]. Therefore, processes containing a rapid cooling step, e.g., hot melt coating, spray drying, spray congealing, undoubtedly generate a proportion of the unstable α-form which eventually transforms towards the β-form on storage [6, 8, 11].

Tempering treatment

Tempering treatment is well-known in both the food and dairy process, to achieve desired polymorphic states of lipid ingredients. The product is held at around melting point temperature of the less stable form until completion of the transformation towards the stable form [9].

There is some controversy over the influence of tempering conditions on polymorphic change of TGs bases. Hamdani et al. [12] reported that increasing tempering temperature form 40 °C to 50 °C shortens the crystallization of Precirol from 2 weeks to 24 h. On the contrary, Sutananta et al. [13] found that the amount of lower melting fraction of Gelucire 43/01 is larger after increasing tempering temperature form 29 °C to 36 °C. In particular, each TG base has its own polymorphic characteristic. Therefore, it is necessary to examine polymorphic behavior of lipid bases especially under manufacturing condition, in order to estimate the property of the final product and decide an appropriate tempering performance.

Case study: Hot melt coated pellets

Preparation of hot melt coated pellets

In this study, hot melt coated pellets were prepared, and the effect of tempering treatment on physical properties of coated pellets, including drug release were studied. Hot melt coating was performed in a fluid bed coater (UniGlatt, Glatt) with the aid of heating systems for atomization air and pipeline insulation material. A 10% w/w of a model drug, metoprolol tartrate, was dispersed in hydrogenated soybean oil (HSO), melted at 100 °C, and sprayed to 500 µm microcrystalline cellulose seeds (Cellets® 500, Pharmatrans Sanaq) with an aim to sustain drug release by lipid matrix. Coating amount was 30% weight gain.

After coating, the pellets continued fluidizing until the product temperature dropped to 30 °C before stopping the operation. The cooling rate was 2-5 °C/min. Then coated pellets were kept in a glass bottle at room temperature (20-23 °C) and 4 °C for 2 days as a control study. Tempering treatment was performed by curing coated pellets in a hot air oven at 50 °C.

Polymorphic characterization of HSO

Three types of HSO, i.e., raw material, HSO after fast heating and cooling, and HSO after hot melt coating, were examined for their polymorphic behavior by Differential Scanning Calorimetry (DSC). Then their crystallinity was determined by Powder X-Ray Diffraction (XRD) in order to confirm the polymorphic characteristic.

HSO raw material possessed two endothermic peaks of β’- (64 °C) and β-forms (69 °C), corresponding to their X-Ray diffraction peaks, see Fig. 2. After melting and cooling, an endotherm of the α-form (56 °C) appeared which consequently recrystallized to the β’-form when heated. However after hot melt coating the HSO presented all three polymorphic forms, showing the acceleration of polymorphic transformation towards the stable form by the coating condition.

Figure 2: DSC thermograms, performed at a heat rate of 5 °C/min, (A) and XRD patterns (B) of HSO [8].

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