Liquid Lipids Act as Polymorphic Modifiers of Tristearin-Based Formulations Produced by Melting Technologies

Abstract

Despite the growing interest in lipid-based formulations, their polymorphism is still a challenge in the pharmaceutical industry. Understanding and controlling the polymorphic behavior of lipids is a key element for achieving the quality and preventing stability issues. This study aims to evaluate the impact of different oral-approved liquid lipids (LL) on the polymorphism, phase transitions and structure of solid lipid-based formulations and explore their influence on drug release. The LL investigated were isopropyl myristate, ethyl oleate, oleic acid, medium chain trigycerides, vitamin E acetate, glyceryl monooleate, lecithin and sorbitane monooleate. Spray-congealing was selected as an example of a melting-based solvent-free manufacturing method to produce microparticles (MPs) of tristearin (Dynasan®118). During the production process, tristearin MPs crystallized in the metastable α-form. Stability studied evidenced a slow phase transition to the stable β-polymorph overtime, with the presence of the α-form still detected after 60 days of storage at 25 °C. The addition of 10% w/w of LL promoted the transition of tristearin from the α-form to the stable β-form with a kinetic varying from few minutes to days, depending on the specific LL. The combination of various techniques (DSC, X-ray diffraction analysis, Hot-stage polarized light microscopy, SEM) showed that the addition of LL significantly modified the crystal structure of tristearin-based formulations at different length scales. Both the polymorphic form and the LL addition had a strong influence on the release behavior of a model hydrophilic drug (caffeine). Overall, the addition of LL can be considered an interesting approach to control triglyceride crystallization in the β-form. From the industrial viewpoint, this approach might be advantageous as any polymorphic change will be complete before storage, hence enabling the production of stable lipid formulations.

Solvent-Free Fabrication of Biphasic Lipid-Based Microparticles with Tunable Structure

“…In the case of DPCl2, after 6 months of storage at room temperature, the main thermal event detected was related to the melting of the β-polymorph, indicating that the conversion into the stable crystalline form. The conversion of the α-form of Dynasan 118-based MPs to the stable one is reported to be extremely slow and to take several months [33]. The presence of cetylstearyl alcohol, PEG and Cremophor EL might have accelerated the polymorphic transformation, as previously observed in other studies focused on the addition of liquid lipids [33] and some solid emulsifiers [38] to tristearin.…”

“…The conversion of the α-form of Dynasan 118-based MPs to the stable one is reported to be extremely slow and to take several months [33]. The presence of cetylstearyl alcohol, PEG and Cremophor EL might have accelerated the polymorphic transformation, as previously observed in other studies focused on the addition of liquid lipids [33] and some solid emulsifiers [38] to tristearin. In the case of CCPl1, the main endotherm at about 70 • C did not show significant differences after 6 months of storage.…”

“…The thermal profile of DCPl2 (Figure 5A) was characterized by three unresolved events: one endothermic peak at 59 • C, one exothermic event at 64 • C and a second endothermic peak at 72 • C. This profile was similar to those obtained from the second heating of the main lipid component, Dynasan 118, which showed an exothermic event (69 • C) placed between two endothermic peaks (65 and 76 • C). This behavior, typical of triglycerides, is related to the melting of the metastable α-polymorph, its solidification into the stable polymorph during the scan, followed by melting of the stable β-form [33]. Rapid crystallization has been reported to promote crystallization in the α-form [34].…”

“…Here, the addition of a hydrophobic surfactant (e.g., cetylstearyl alcohol) and the presence of liquid hydrophilic cores in the b-MPs can be responsible for the enhanced dye release with respect to the simple matrix systems. It has been previously observed that the introduction of lipid additives either solid (stearic acid, cetyl alcohol, or cetyl esters) [46] or liquid [33] lead to increased drug release from spray congealed microparticles. Moreover, results showed that the introduction of small amounts (5-10% w/w) of Cremophor EL in the hydrophilic phase led to a significant modification of the release profiles.…”

Phase Behavior of Drug–Lipid–Surfactant Ternary Systems toward Understanding the Annealing-Induced Change

“…The API diffusion from the Compritol matrix is mainly driven by time-dependent changes in the porous structure as a function of polymorphic transformation from high-to low-energy states. 13 A similar trend in lipids was also reported by Bertoni et al 14 The findings were also found to be in accordance with the published literature from our group. 15 Considerable information is available regarding the thermodynamics, polymorphism, and characterization of individual fat systems.…”