Novel approach for overcoming the stability challenges of lipid-based excipients. Part 1: Screening of solid-state and physical properties of polyglycerol esters of fatty acids as advanced pharmaceutical excipients.

The major challenge of conventional lipid-based excipients (LBE) for drug delivery is their unstable solid state, affecting the stability of pharmaceutical product. Polyglycerol esters of fatty acids (PGFAs) are oligomeric hydroxyethers of glycerol fully or partially esterified with fatty acids. Tuning the number of polyglycerol moieties, fatty acids chain length and free hydroxyl groups per molecule results in diverse physicochemical properties, e.g. HLB, melting point, and wettability, which makes these molecules attractive candidates as novel LBE for different pharmaceutical applications. In this first part of our studies the solid state of PGFAs and the stability thereof were profiled on molecular, nano, and microstructural level and the resulting properties as LBE. DSC analysis confirmed the single phase system of PGFAs without phase separation. WAXS patterns revealed the absence of polymorphism and the direct crystallization into a stable α-form; without transition to more dense configurations. SAXS patterns exposed the lamellar arrangement. The lamellae stacks were characterized by the crystallite thickness and growth. The nano, microstructure and physicochemical properties of PGFAs remained stable during storage. The stable solid state and the broad functionality of PGFAs offer a novel approach to overcome the challenges faced by conventional LBE for advanced pharmaceutical applications. Examples for such applications are presented in the next parts of this study.

Microphase separation in solid lipid dosage forms as the cause of drug release instability.

Although lipid excipients are of increasing interest for development of taste-masked and modified release formulations, the drug release instability and the lack of mechanistic understanding in that regard still prevent their larger-scale application. In this work, we investigated the physical stability of a binary (tripalmitin/polysorbate 65) lipid coating formulation with a known stable polymorphism. The coating composition was characterized using DSC to construct the phase diagram of binary system and polarized light microscopy to display the microstructure organization. The water uptake and the erosion of slabs cast from the coating formulations were investigated post-production and after storage. Subsequently, N-acetylcysteine particles were coated with the selected formulations and the drug release stability was investigated. Additionally, microstructure characterization was performed via SEM and X-ray diffraction. The drug release instability was explained by polysorbate 65 and tripalmitin phase growth during storage, especially at 40°C, suggesting that polysorbate 65 can leak out of tripalmitin spherulitic structures, creating lipophilic and impermeable tripalmitin regions. The growth of polysorbate 65 phase leads to larger hydrophilic channels with reduced tortuosity. This work indicates that for obtaining stable drug release profiles from advanced lipid formulations, microphase separation should be prevented during storage.

Improving the granule strength of roller-compacted ibuprofen sodium for hot-melt coating processing.

Solvent-free hot-melt coating processing is a novel and cost-efficient approach to manufacturing taste-masked multiparticulate systems. However, most API powders are fine and cohesive and not processable by hot-melt coating. The aim of this study was to produce dense and abrasion-resistant granules with high drug content (>80%) via roller compaction for hot-melt coating process optimization. The selected API was ibuprofen sodium dihydrate, a salt of ibuprofen with improved bioavailability and poor intrinsic compactibility. The formulation and roller compaction process were developed for the production of granules with 94%w/w of API and low friability (∼30%), using sorbitol and isomalt as excipients. The strong bonding mechanism relied on powder jamming prior to the rollers and was investigated via scanning electron microscopy, differential scanning calorimetry and small and wide angle X-ray scattering. It was shown that sorbitol crystals are solubilized during roller compaction and recrystallize as sorbitol hydrate, acting as strong solid bridges. The robustness of the roller compaction process and the re-compaction of fines were investigated. A statistical design of experiments was conducted to evaluate the hot-melt coating process for taste masking of ibuprofen sodium granules. Taste masking required coating ratios higher than 40%w/w of granule batch, emphasizing the need for high-drug-content and abrasion-resistant granules.

Advanced stable lipid-based formulations for a patient-centric product design.

Multiparticulate dosage forms are a recent strategy to meet the special needs of children, elderly people and patients suffering from dysphagia. Our study presents a novel and cost-efficient approach for the manufacturing of a taste-masked multiparticulate system with a stable immediate release profile by applying lipid-based excipients in a solvent-free hot melt coating process. The thermosensitive N-acetylcysteine (N-ac) was used as model drug and hot-melt coated with a mixture of tripalmitin and polysorbate 65. A predictive in vitro method for the evaluation of the taste masking efficiency was developed based on the deprotonation of the carboxyl group of N-ac and the decline of pH, responsible for the unpleasant sour taste of the compound. The method was confirmed using in vivo studies. Differential scanning calorimetry and X-ray scattering experiments revealed polymorphic transformation and its dependency on transformation time, temperature and emulsifier concentration. During the process, the coating was transformed almost completely into the stable ß-polymorph, leading to an unaltered dissolution profile during storage. A statistical design was conducted that revealed the critical process parameters affecting the taste masking efficiency and drug release. This study shows the successful application of solvent-free hot-melt coating in the development of a taste-masked and stable formulation.

Role of Lipid Blooming and Crystallite Size in the Performance of Highly Soluble Drug-Loaded Microcapsules.

Hot-melt coating is of growing interest, because it does not require solvents, resulting in reduced process times and costs. However, excipients for this technology are mainly triacylglycerides (TAGs) or their derivatives, which exhibit polymorphism, surface disruption, and complex crystallite networks, affecting the release profile of produced microcapsules. In this work, anhydrous citric acid crystals were coated with molten tristearin using conventional inlet air temperatures (microcapsules A) and temperatures above the melting point of α-form (microcapsules B). Additionally, microcapsules A were tempered to achieve polymorphic stability (microcapsules AB). The product yield and coating efficacy were above 90% and 97%, respectively, demonstrating the feasibility and efficacy of the process. Small angle X-ray scattering analysis confirmed that the tristearin shell of microcapsules B is in the ß-form with a larger average crystallite size than microcapsules A and AB. Scanning electron microscopy images revealed a nonbloomed surface of microcapsules B. We showed that blooming does not play a critical role in the drug release, but the apparent diffusion coefficient of drug is dramatically reduced by increasing TAGs crystallite size and resulting tortuosity. This work brings new insights on the micrometric properties of solid lipid dosage forms, being an important step to prevent the overuse of excipients with unknown toxicity.