Jasmine Musakhanian- Senior Scientific Director, Pharmaceutical Div., Gattefossé USA; Masumi Dave- Application Laboratory Manager, Pharmaceutical Div., Gattefossé USA; Elise Dauphin Chanard- Laboratory Manager, Pharmaceuticals, Gattefossé SAS, France.
Capsules are perceived as elegant, easy to swallow dosage forms, widely used for the delivery of nutraceutical and medicinal preparations. Advances in capsule technologies have hugely facilitated the incorporation of liquid, semi-solid, and solid ingredients into capsules. Improvements in shell composition provide choices ranging from softshell (one piece) to two-piece caps made up of gelatin or cellulosic polymers. Whereas the two[1]piece capsules are convenient for filling powders or granules, softshell gelatin remains the primary option for filing liquids and semi-solids.
Less developed in versatility perhaps is the nature of the “conventional” fill material which consists primarily of soybean oil, lecithin, and beeswax. Among the many limitations associated with this age-old approach is the requirement for heat and high energy mixing, viscosity build-up associated with loading of solid/powdered actives, and failed dissolution tests. To ensure homogeneity of the fill for example, the ingredients must be heated to temperatures >65°C for up to 72 hours before use, conditions that are not amenable to heat labile or oxidation prone molecules. Another drawback is the inconsistency and at times scarcity of supply for beeswax and lecithin. An innovative vehicle for suspending hydrophilic molecules or dissolving lipophilic actives without the drawbacks of the conventional mix is a product commercialized as Geloil™ SC (Geloil).
Designed for heat-free processing and filling into hard- and soft-shell capsules, Geloil is an optimized combination of three ingredients: soybean Oil (NF/EP/ GRAS), glyceryl distearate (NF/EP/FCC/E471/GRAS) and polyglyceryl-3 dioleate (NF/E475). It was developed by careful evaluation of each component and the impact of component ratios on the overall performance of the fill material. Geloil is produced under a tightly controlled manufacturing process, one that ensures high-quality and excellent batch-to-batch reproducibility. Strictly of vegetal origin, the product has an excellent safety profile, innocuity, and compatibility with all types of capsule shells.
The versatility of Geloil relates to its thixotropic nature, being gel-like under static undisturbed conditions, but which is readily fluidized when stirred or shaken. A plot of viscosity against shear rate for Geloil compared to the conventional mix (Figure 1) demonstrates that thixotropy is a reversible process i.e., the material gradually regains its viscosity towards equilibrium as shear force is reduced or removed. The plot also shows that relative to the conventional mix, it reverts much faster and closer to its initial viscosity when the shear rate is reduced to zero.
Figure 2 compares the viscosity of Geloil to that of the conventional mix when subjected to temperatures of 10°C to 50°C. As shown, rising temperature leads to a drop in viscosity for both systems. Comparatively, however, Geloil demonstrates significantly lower viscosity values especially at the ambient temperature range.
At ambient temperature Geloil has the appearance of a static liquid gel (Figure 3A) which becomes more fluid at 40°C (Figure 3B). A key advantage of Geloil is processing at ambient temperature. Warming up is optional and only relevant to exceptionally high solids loading, as discussed below. Higher processing temperatures are not needed nor recommended because the product becomes fully molten at 46°C.
To assess Geloil as a carrier for high levels of solids, calcium carbonate (CaCO3 ) was selected as model compound. CaCO3 is taken as mineral supplement for bone health and antacid for the symptomatic relief of heartburn. Varying amounts of CaCO3 , (30%, 35%, 40%, or 45%) were stirred into Geloil™ SC. The blends were homogenous and fluid in appearance. The viscosity measurements of these blends (Table nestled in Figure 4) are indicative of the ease with which up to 40 % solids may be incorporated at ambient temperature.
To investigate the feasibility of higher loading, Geloil was warmed to 40°C before adding 50% CaCO3 . This resulted in a blend with smooth, homogenous consistency (Figure 4). In a 600 mg capsule, this formulation would represent 300mg or about 25% of daily intake for calcium.
To assess the suitability of Geloil as carrier for hydrophilic and lipophilic molecules, vitamins C (ascorbic acid) , B6 (pyridoxine) and D3 (cholecalciferol) were used as model drugs. For the latter, based on hot stage microscopy under cross-polarized light (Figure 5), vitamin D3 solubility in Geloil exceeds ≥2500 IU/g. This level of solubility provides the potential for facile incorporation of the vitamin in small capsules. The U.S. recommended dietary allowance (RDA) for vitamin D3 is 600 IU per day.
The dissolution of various vitamins in the conventional mix capsules often fails the USP (II) release test. As shown in Figure 6, the USP release criteria of >75% in 45 minutes were not met with vitamins B6 and vitamin C in the conventional mix.
Meanwhile, the formulations with Geloil released >80% of vitamins, B6 in 45 minutes and vitamin C within 12 minutes. Lastly, a combination of Vitamins B2 and B6 in Geloil were subjected to stability testing. The samples stored for 9 months at ambient or 3 months under accelerated (ICH) conditions passed the USP test criteria.
These results merely underline the inert nature and versatility of Geloil for a wide range of applications without heat. The end user may need to make minor adjustments in the preparation, depending on the challenges unique to each molecule. Prior to stirring the active for example, it may be necessary to prepare a preconcentrate of antioxidants or the drug prior to stirring into Geloil.
Geloil is designed for pharmaceutical, over-the-counter (OTC), and nutraceutical preparations in capsules with minimal energy input. Avoiding heat completely or at least circumventing high temperatures in capsule manufacturing is too huge of a benefit to ignore. There is also the speed of formulation development with a vehicle that offers versatility for a wide range of molecules – simply add, mix, and fill into capsules. Lastly, it offers significant savings in product development, energy input, quality control, purchasing, and inventory management.