Premix Membrane Emulsification: Preparation and Stability of Medium-Chain Triglyceride Emulsions with Droplet Sizes below 100 nm.

Premix membrane emulsification is a promising method for the production of colloidal oil-in-water emulsions as drug carrier systems for intravenous administration. The present study investigated the possibility of preparing medium-chain triglyceride emulsions with a mean particle size below 100 nm and a narrow particle size distribution using sucrose laurate as an emulsifier. To manufacture the emulsions, a coarse pre-emulsion was repeatedly extruded through alumina membranes (Anodisc™) of 200 nm, 100 nm and 20 nm nominal pore size. When Anodisc™ membranes with 20 nm pore size were employed, nanoemulsions with z-average diameters of about 50 nm to 90 nm and polydispersity indices smaller than 0.08 could be obtained. Particle growth due to Ostwald ripening was observed over 18 weeks of storage. The Ostwald ripening rate linearly depended on the emulsifier concentration and the concentration of free emulsifier, indicating that micelles in the aqueous phase accelerated the Ostwald ripening process. Long-term stability of the nanoemulsions could be achieved by using a minimised emulsifier concentration or by osmotic stabilisation with soybean oil added in a mass ratio of 1:1 to the lipid phase.

Formulation of Cannabidiol in Colloidal Lipid Carriers.

In this study, the general processability of cannabidiol (CBD) in colloidal lipid carriers was investigated. Due to its many pharmacological effects, the pharmaceutical use of this poorly water-soluble drug is currently under intensive research and colloidal lipid emulsions are a well-established formulation option for such lipophilic substances. To obtain a better understanding of the formulability of CBD in lipid emulsions, different aspects of CBD loading and its interaction with the emulsion droplets were investigated. Very high drug loads (>40% related to lipid content) could be achieved in emulsions of medium chain triglycerides, rapeseed oil, soybean oil and trimyristin. The maximum CBD load depended on the type of lipid matrix. CBD loading increased the particle size and the density of the lipid matrix. The loading capacity of a trimyristin emulsion for CBD was superior to that of a suspension of solid lipid nanoparticles based on trimyristin (69% vs. 30% related to the lipid matrix). In addition to its localization within the lipid core of the emulsion droplets, cannabidiol was associated with the droplet interface to a remarkable extent. According to a stress test, CBD destabilized the emulsions, with phospholipid-stabilized emulsions being more stable than poloxamer-stabilized ones. Furthermore, it was possible to produce emulsions with pure CBD as the dispersed phase, since CBD demonstrated such a pronounced supercooling tendency that it did not recrystallize, even if cooled to -60 °C.

Heat Treatment of Poloxamer-Stabilized Triglyceride Nanodispersions: Effects and Underlying Mechanism.

Lipid nanoemulsions are being investigated for the parenteral administration of poorly soluble drugs. A narrow particle size distribution in these formulations is a prerequisite for meaningful research and safe administration to patients. Autoclaving a poloxamer-stabilized trimyristin nanoemulsion resulted in moderate particle growth and a strong decrease in particle size distribution width ( Göke , K. ; Roese , E. ; Arnold , A. ; Kuntsche , J. ; Bunjes , H. Mol. Pharmaceutics 2016 , 13 , 3187 . ). In this work, the critical parameters for such a change upon autoclaving poloxamer 188-stabilized lipid nanodispersions were investigated to elucidate the underlying mechanism. Nanodispersions of triglycerides with esterified fatty acid chain lengths from C8 to C18 were treated at different temperatures and for varying durations. The influence of a decrease in poloxamer 188's cloud point was tested by adding potassium chloride to the dispersions prior to autoclaving. The influence of poloxamer 188 concentration and of the type of emulsifier was investigated. The change in particle size and particle size distribution width upon heat treatment was analyzed by dynamic or static light scattering or differential scanning calorimetry. A short esterified fatty acid chain length of the triglycerides, high temperatures, and the addition of potassium chloride were key factors for particle growth up to emulsion break up, whereas the cloud point of poloxamer 188 was irrelevant. Sodium dodecyl sulfate and sucrose laurate had negative effects on emulsion stability during autoclaving. It was concluded that the increase in particle size and the decrease in particle size distribution widths upon heat treatment resulted from heat-accelerated Ostwald ripening and not from a coalescence-based process.

Control over Particle Size Distribution by Autoclaving Poloxamer-Stabilized Trimyristin Nanodispersions.

Lipid nanoparticles are under investigation as delivery systems for poorly water-soluble drugs. The particle size in these dispersions strongly influences important pharmaceutical properties like biodistribution and drug loading capacity; it should be below 500 nm for direct injection into the bloodstream. Consequently, small particles with a narrow particle size distribution are desired. Hitherto, there are, however, only limited possibilities for the preparation of monodisperse, pharmaceutically relevant dispersions. In this work, the effect of autoclaving at 121 °C on the particle size distribution of lipid nanoemulsions and -suspensions consisting of the pharmaceutically relevant components trimyristin and poloxamer 188 was studied. Additionally, the amount of emulsifier needed to stabilize both untreated and autoclaved particles was assessed. In our study, four dispersions of mean particle sizes from 45 to 150 nm were prepared by high-pressure melt homogenization. The particle size distribution before and after autoclaving was characterized using static and dynamic light scattering, differential scanning calorimetry, and transmission electron microscopy. Asymmetrical flow field-flow fractionation was used for particle size distribution analyses and for the determination of free poloxamer 188. Upon autoclaving, the mean particle size increased to up to 200 nm, but not proportionally to the initial size. At the same time, the particle size distribution width decreased remarkably. Heat treatment thus seems to be a promising approach to achieve the desired narrow particle size distribution of such dispersions. Related to the lipid content, suspension particles needed more emulsifier for stabilization than emulsion droplets, and smaller particles more than larger ones.

Stability of the Metastable α-Polymorph in Solid Triglyceride Drug-Carrier Nanoparticles.

Colloidal dispersions of crystalline nonpolar lipids are under intensive investigation as carrier systems in pharmaceutics and nutrition. In this context, the controlled preparation of particles in a metastable polymorphic state is of some interest for the delivery of active substances. In the present study, tristearin particles stabilized with three α-polymorph-preserving emulsifier regimes ((I) sodium glycocholate/saturated long-chain phospholipids, (II) sodium glycocholate, and (III) poly(vinyl alcohol) (PVA)) were investigated concerning the stability of the metastable α-polymorph after controlled crystallization of the particles from the melt. Upon long-term storage, the α-polymorph was preserved best in PVA-stabilized dispersions, followed by those stabilized with the glycocholate/phospholipid mixture and finally those stabilized solely with the bile salt. In particular for rapidly crystallized nanoparticles, the formation of an α-polymorph with highly reduced lamellarity was observed. According to time-/temperature-resolved synchrotron X-ray diffraction analysis with simultaneous DSC (differential scanning calorimetry) studies, this less-ordered α-polymorph transformed into the common, lamellar α-form upon heating. Although the presence of the less-ordered form is probably related to the extraordinarily high stability of the metastable α-polymorph observed in some of the dispersions, it could not completely prevent the transition into the stable ß-polymorph. The higher the transition temperature of the less-ordered α-form to the ordered one, the slower was the polymorphic transition to the stable ß-polymorph. To estimate the polymorphic stability of the differently stabilized particles upon isothermal long-term storage, standard DSC measurements on samples stored at 23 °C for 4 weeks seem to be of predictive value.

Solubility of Poorly Soluble Drugs in Phosphatidylcholine-Based Drug Delivery Systems: Comparison of the Loading Capacity in the Bulk Formulation and Its Dispersed State.

The aim of this study was to determine the drug loading capacity of phosphatidylcholine-based formulations for four poorly water-soluble drug substances (clofazimine, fenofibrate, artemether, cannabidiol). Two self-dispersing lipid formulations were investigated, which consisted of soybean phospholipids, medium-chain triglycerides and ethanol with a different phospholipid-oil ratio. The direct loading of the bulk formulation was conducted with dual centrifugation, which proved to be a suitable method for screening experiments with the highly viscous formulations. To estimate possible precipitation after dispersion in the gastrointestinal fluids, the solubility of the drugs was investigated in the dispersed formulations. For this purpose, nanodispersions were prepared from the bulk formulations via high pressure homogenization and subsequently subjected to passive loading. A newly developed HPLC method with Charged Aerosol Detection allowed a simultaneous evaluation of the content of soybean lecithin and medium-chain triglycerides in the nanodispersions. When comparing the two phosphatidylcholine-based formulations, a high content of oil was advantageous with regard to a high loading capacity. Drug substances with melting points below 150 °C exhibited a high solubility in the phospholipid-based formulations. A surprisingly high solubility was observed for artemether and cannabidiol with up to 13.0% and 33.3% drug loaded to the formulations, respectively. In the dispersions, a similar solubility as in the bulk formulations was obtained for fenofibrate and cannabidiol. Clofazimine yielded a higher loading result in the nanodispersions than in the bulk formulation.

Release of TGF-ß3 from Surface-Modified PCL Fiber Mats Triggers a Dose-Dependent Chondrogenic Differentiation of Human Mesenchymal Stromal Cells.

The design of implants for tissue transitions remains a major scientific challenge. This is due to gradients in characteristics that need to be restored. The rotator cuff in the shoulder, with its direct osteo-tendinous junction (enthesis), is a prime example of such a transition. Our approach towards an optimized implant for entheses is based on electrospun fiber mats of poly(ε-caprolactone) (PCL) as biodegradable scaffold material, loaded with biologically active factors. Chitosan/tripolyphosphate (CS/TPP) nanoparticles were used to load transforming growth factor-ß3 (TGF-ß3) with increasing loading concentrations for the regeneration of the cartilage zone within direct entheses. Release experiments were performed, and the concentration of TGF-ß3 in the release medium was determined by ELISA. Chondrogenic differentiation of human mesenchymal stromal cells (MSCs) was analyzed in the presence of released TGF-ß3. The amount of released TGF-ß3 increased with the use of higher loading concentrations. This correlated with larger cell pellets and an increase in chondrogenic marker genes (SOX9, COL2A1, COMP). These data were further supported by an increase in the glycosaminoglycan (GAG)-to-DNA ratio of the cell pellets. The results demonstrate an increase in the total release of TGF-ß3 by loading higher concentrations to the implant, which led to the desired biological effect.

Processing of Lipid Nanodispersions into Solid Powders by Spray Drying.

Spray drying is a promising technology for drying lipid nanodispersions. These formulations can serve as carrier systems for poorly water-soluble active pharmaceutical ingredients (APIs) that are loaded into the lipid matrix to improve their bioavailability. Once the API-loaded nanocarriers have been further processed into solid dosage forms, they could be administered orally, which is usually preferred by patients. Various solid lipids as well as oils were used in this study to prepare lipid nanodispersions, and it was shown that their nanoparticulate properties could be maintained when lactose in combination with SDS was used as matrix material in the spray-drying process. In addition, for lipid nanoemulsions loaded with fenofibrate, a good redispersibility with particle sizes below 300 nm at a lipid content of 26.8 wt.% in the powders was observed. More detailed investigations on the influence of the drying temperature yielded good results when the inlet temperature of the drying air was set at 110 °C or above, enabling the lactose to form an amorphous matrix around the embedded lipid particles. A tristearin suspension was developed as a probe to measure the temperature exposure of the lipid particles during the drying process. The results with this approach indicate that the actual temperature the particles were exposed to during the drying process could be higher than the outlet temperature.

Horseshoe lamination mixer (HLM) sets new standards in the production of monodisperse lipid nanoparticles.

Microfluidic mixers promise unique conditions for the controlled and continuous preparation of nanoparticles by antisolvent precipitation. Nanoparticles may enable encapsulation of drug or mRNA molecules in the form of carrier nanoparticles or can provide higher bioavailability in the form of drug nanoparticles. The ultimate goal in microfluidic approaches is the production of nanoparticles with narrow size distributions while avoiding contaminations and achieving sufficiently high throughput. To achieve this, a novel microfluidic precipitation device was developed and realized by two-photon polymerization: mixing elements were designed in such a way that the liquids undergo a repeated Smale horseshoe transformation resulting in an increased interfacial area and mixing times of less than 10 ms. These elements and an additional 3D flow focusing ensure that no organic phase is exposed to the channel walls. The integration of a fluidic shield layer in the flow focusing proved to be useful to delay the precipitation process until reaching a sufficient distance to the injection nozzle. Lipid nanoparticle preparation with different concentrations of castor oil or the hard fat Softisan® 100 were performed at different flow rates and mixing ratios with and without a shield layer. Flow rates of up to 800 µl min-1 and organic phase mixing ratios of up to 20% resulted in particle sizes ranging from 42 nm to 166 nm with polydispersity indices from 0.04 to 0.11, indicating very narrowly distributed, and in most cases even monodisperse, nanoparticles. The occurrence of fouling can be completely suppressed with this new type of mixing elements, as long as Dean vortices are prevented. Moreover, this parameter range in the horseshoe lamination mixer provided a stable and continuous process, which enables a scalable production.

Tablet Disintegration and Dispersion under In Vivo-like Hydrodynamic Conditions.

Disintegration and dispersion are functional properties of tablets relevant for the desired API release. The standard disintegration test (SDT) described in different pharmacopoeias provides only limited information on these complex processes. It is considered not to be comparable to the biorelevant conditions due to the frequent occurrence of high hydrodynamic forces, among other reasons. In this study, 3D tomographic laser-induced fluorescence imaging (3D Tomo-LIF) is applied to analyse tablet disintegration and dispersion. Disintegration time (DT) and time-resolved particle size distribution in close proximity to the tablet are determined in a continuously operated flow channel, adjustable to very low fluid velocities. A case study on tablets of different porosity, which are composed of pharmaceutical polymers labelled with a fluorescent dye, a filler, and disintegrants, is presented to demonstrate the functionality and precision of the novel method. DT results from 3D Tomo-LIF are compared with results from the SDT, confirming the analytical limitations of the pharmacopoeial disintegration test. Results from the 3D Tomo-LIF method proved a strong impact of fluid velocity on disintegration and dispersion. Generally, shorter DTs were determined when cross-linked sodium carboxymethly cellulose (NaCMCXL) was used as disintegrant compared to polyvinyl polypyrrolidone (PVPP). Tablets containing Kollidon VA64 were found to disintegrate by surface erosion. The novel method provides an in-depth understanding of the functional behaviour of the tablet material, composition and structural properties under in vivo-like hydrodynamic forces regarding disintegration and the temporal progress of dispersion. We consider the 3D Tomo-LIF in vitro method to be of improved biorelevance in terms of hydrodynamic conditions in the human stomach.

Spatially and Temporally Controllable BMP-2 and TGF-ß3 Double Release From Polycaprolactone Fiber Scaffolds via Chitosan-Based Polyelectrolyte Coatings.

Temporally and spatially controlled growth factor release from a polycaprolactone fiber mat, which also provides a matrix for directional cell colonization and infiltration, could be a promising regenerative approach for degenerated tendon-bone junctions. For this purpose, polycaprolactone fiber mats were coated with tailored chitosan-based nanogels to bind and release the growth factors bone morphogenetic protein 2 (BMP-2) and transforming growth factor-ß3 (TGF-ß3), respectively. In this work we provide meaningful in vitro data for the understanding of the drug delivery performance and sterilizability of novel implant prototypes in order to lay the foundation for in vivo testing. ELISA-based in vitro release studies were used to investigate the spatial and temporal control of release, as well as the influence of radiation sterilization on protein activity and release behavior. Layer-by-layer coatings based on BMP-2-containing chitosan tripolyphosphate nanogel particles and negatively charged alginate showed a good sustainment of BMP-2 release from chemically modified polycaprolactone fiber mats. Release control improved with increasing layer numbers. The approach of controlling the release via a barrier of cross-linked chitosan azide proved less promising. By using a simple, partial immersion-based dip-coating process, it was possible to apply opposing gradients of the growth factors BMP-2 and TGF-ß3. Final radiation sterilization of the growth factor-loaded implant prototypes resulted in a radiation dose-correlated degradation of the growth factors, which could be prevented by lyophilization into protective matrices. For the manufacture of sterile implants, the growth factor loading step must probably be carried out under aseptic conditions. The layer-by-layer coated implant prototypes provided sustained release from opposing gradients of the growth factors BMP-2 and TGF-ß3 and thus represent a promising approach for the restoration of tendon-bone defects.

Evaluation of the Formulation Parameter-Dependent Redispersibility of API Nanoparticles from Fluid Bed Granules.

The production of nanosuspensions of poorly soluble active pharmaceutical ingredients (API) is a popular technique to counteract challenges regarding bioavailability of such active substances. A subsequent drying of the nanosuspensions is advantageous to improve the long-term stability and the further processing into solid oral dosage forms. However, associated drying operations are critical, especially with regard to nanoparticle growth, loss in redispersibility and associated compromised bioavailability. This work extends a previous study regarding the applicability of an API (itraconazole) nanosuspension as a granulation liquid in a fluidized bed process with focus on the influence of applied formulation parameters on the structure of obtained nanoparticle-loaded granules and their nanoparticle redispersibility. Generally, a higher dissolution rate of the carrier material (glass beads, lactose, mannitol or sucrose) and a higher content of a matrix former/hydrophilic polymer (PVP/VA or HPMC) in the granulation liquid resulted in the formation of coarser and more porous granules with improved nanoparticle redispersibility. HPMC was found to have advantages as a polymer compared with PVP/VA. In general, a better redispersibility of the nanoparticles from the granules could be associated with better dispersion of the API nanoparticles at the surface of the granules as deduced from the thickness of nanoparticle-loaded layers around the granules. The layer thickness on granules was assessed by means of confocal Raman microscopy. Finally, the dispersion of the nanoparticles in the granule layers was exemplarily described by calculation of theoretical mean nanoparticle distances in the granule layers and was correlated with data obtained from redispersibility studies.

Influence of process and formulation parameters on the preparation of solid lipid nanoparticles by dual centrifugation.

A promising strategy to formulate poorly water-soluble active pharmaceutical ingredients (APIs) is the application of these substances in solid lipid nanoparticles. These drug carrier systems are commonly prepared by high-pressure homogenization above the melting temperature of the utilized lipid. While being very useful for large-scale production this method is quite resource-consuming and does not allow simultaneous processing of multiple samples, e.g. for screening purposes. For this reason, an alternative manufacturing process, dual centrifugation, is introduced to prepare solid lipid nanoparticles. The ingredients of the dispersions were directly weighed into 2 mL vessels at room temperature without the need to prepare a pre-mix emulsion. Due to an additional rotation of the samples in the heated centrifuge as well as the addition of grinding media an intensive stressing of the samples was achieved. The emulsification process was finished within 10 min with sample temperatures of up to 90 °C being obtained. Dependent on the process set-up like grinding media size, filling ratio or process temperature and the composition of the lipid formulation, the achieved particles sizes were below 200 nm and had a narrow, monomodal size distribution.

Transfer Investigations of Lipophilic Drugs from Lipid Nanoemulsions to Lipophilic Acceptors: Contributing Effects of Cholesteryl Esters and Albumin as Acceptor Structures.

When studying the release of poorly water-soluble drugs from colloidal drug delivery systems designed for intravenous administration, the release media should preferentially contain lipophilic components that represent the physiological acceptors present in vivo. In this study, the effect of different acceptor structures was investigated by comparing the transfer of fenofibrate, retinyl acetate, and orlistat from trimyristin nanoemulsion droplets into lipid-containing hydrogel particles, as well as to bovine serum albumin (BSA). A nanodispersion based on trimyristin and cholesteryl nonanoate was incorporated into the hydrogel particles (mean diameter ~40 µm) in order to mimic the composition of lipoproteins. The course of transfer observed utilizing the lipid-containing hydrogel particles as an acceptor was in relation to the lipophilicity of the drugs: the higher the logP value, the slower the transfer. There was no detectable amount of the drugs transferred to BSA in liquid solution, demonstrating clearly that albumin alone does not contribute substantially as acceptor for the lipophilic drugs under investigation in this study. In contrast, cholesteryl nonanoate contributes to a much greater extent. However, in all cases, the partition equilibrium of the drugs under investigation was in favor of the trimyristin emulsion droplets.

Drug localization and its effect on the physical stability of poloxamer 188-stabilized colloidal lipid emulsions.

Colloidal lipid emulsions are a promising formulation option for poorly water-soluble drugs. Due to their complex composition, they provide different sites for the localization of drugs. Drug molecules can be situated in the lipid matrix, in the aqueous phase with its structures formed by an excess of emulsifier or at the droplet interface. The interface and the mechanism of stabilization is mainly characterized by the emulsifier. In this study, the main focus was on the influence of drug localization on the stability of emulsions sterically stabilized with poloxamer188. In addition to 5% of this non-ionic emulsifier, the emulsions contained 10% soybean oil. The localization of the drugs fenofibrate, curcumin, betamethasone valerate, cinnarizine, dibucaine and flufenamic acid within the emulsion system at a physiological pH of 7.4 as well as their influence on emulsion stability were examined. The results indicated that the stability of poloxamer 188-stabilized emulsions can be influenced in a positive or negative way by the localization of drug molecules in the interface of emulsion droplets. Applying cinnarizine as model substance at pH 5, 7.4 and 10, no pronounced change in the localization was detected as a result of alterations in the charge of the drug.

Transfer of Lipophilic Drugs from Nanoemulsions into Lipid-Containing Alginate Microspheres.

Knowledge about the release behavior and drug retention properties of colloidal carriers is of essential importance for quality control as well as to predict in vivo performance. When conducting release studies from such systems, the release media should preferentially contain lipophilic acceptor components in order to mimic physiological conditions. In this study, transfer from a trimyristin nanoemulsion into lipid-containing hydrogel beads was investigated for fenofibrate, cannabidiol, retinyl acetate, orlistat, and lumefantrine. To generate the acceptor system, a trimyristin nanoemulsion was incorporated into Ca-alginate microspheres (mean diameter ~40 µm) with a spraying method. Using this approach, the advantages of small lipophilic acceptor particles with a large interfacial area were combined with a single separation process from the donor via a filtration step. The method was applicable to distinguish between fast (fenofibrate) and slow drug transfer (lumefantrine) with good time resolution. Lipophilicity, estimated according to the calculated logP value of the respective drug, was a major factor influencing the transfer performance: the higher the logP value, the slower the transfer. This experimental setup is a promising technique to investigate the release of poorly water-soluble drugs from various types of nanocarriers under closer to physiological conditions than with many other methods currently applied.

Goodbye fouling: a unique coaxial lamination mixer (CLM) enabled by two-photon polymerization for the stable production of monodisperse drug carrier nanoparticles.

Poorly soluble drugs can be incorporated in lipid carrier nanoparticles to achieve sufficient bioavailability and open up diverse routes of administration. Preparation by antisolvent precipitation in microfluidic systems enables excellent control of lipid nanoparticle size. However, particle-containing flows bear the risk of material deposition on microchannel surfaces, limiting reproducibility, prolonged continuous processing and scale-up by parallelization as required for practical use. The coaxial lamination mixer (CLM) introduced in this study can fully eliminate contact of the organic phase with the channel walls while efficiently mixing organic and aqueous phases. This unique micromixer, including a nozzle for coaxial injection, a sequence of stretch-and-fold elements and inlet filters, cannot be realized by conventional 2.5D microfabrication but only by 3D two-photon polymerization. Hydrodynamic focusing of the organic phase and fast coaxial lamination were studied in simulations and flow visualization experiments. Different concentrations of castor oil or a hard fat and polysorbate 80 dissolved in ethanol were injected and combined with purified water. Total flow rates of 100 and 200 µL min-1 and flow rate ratios of 15% or less resulted in particle sizes between 67 and 153 nm and polydispersity indices of 0.04 to 0.10. Extended preparation time revealed stable particle sizes and displayed no fouling, indicating that CLMs will even allow high throughput parallelization. Stable castor oil nanoemulsions loaded with the poorly soluble drugs fenofibrate or cannabidiol were prepared. In conclusion, the unique 3D design of the CLM enables prolonged, stable and scalable production of small as well as very narrowly distributed, in most cases even monodisperse drug-loaded lipid nanoparticles.

Orodispersible Films: A Delivery Platform for Solid Lipid Nanoparticles?

To overcome the poor bioavailability observed for many newly developed active pharmaceutical ingredients (APIs), an appropriate formulation strategy is necessary. One approach is the formulation of these substances in solid lipid nanoparticles and their further processing into solid dosage forms. A promising and innovative oral delivery platform could be orodispersible films (ODFs). ODFs were already investigated more closely, e.g., for the administration of API nanoparticles, and proved their suitability for this formulation approach. The current study was aimed at investigating if the HPMC (hydroxypropyl methyl cellulose) film matrix is also suitable to serve as an appropriate delivery platform for solid lipid nanoparticles. Dependent on the type of triglyceride nanoparticles embedded in the film matrix and the formulation of the lipid particles, lipid contents of up to 54 wt.% could be realized in the film matrix without the loss of the nanoparticulate state. Good mechanical properties were confirmed for these films by determining the tensile strength as well as the elongation before breakage. Interestingly, processing of a lipid suspension into this solid dosage form led to a significantly reduced transformation of the lipid particles from the metastable α- into the stable ß-polymorph. This could prove very beneficial when the lipid particles are loaded with APIs.

An improved method for the simultaneous determination of water uptake and swelling of tablets.

Water uptake and swelling of tablets are processes occurring during active pharmaceutical ingredient (API) release. Thereby, disintegration is promoted and the enhanced exposure of API surface area to the release medium facilitates API dissolution. An experimental set-up for the simultaneous and time-resolved determination of water uptake and swelling of tablets has been developed. Water uptake was determined with a balance and swelling was determined with a camera. To validate the gravimetrical analysis, real-time water uptake measurements with inert test specimens were performed. The standard deviation of these measurements was considered to depict precision. A complementary gravimetrical analysis was employed to determine accuracy. For both, precision and accuracy, a maximum deviation of 6% was found. An algorithm for the symmetry-based 3D volume reconstruction was applied to obtain volumes of the tablets from 2D images. X-ray micro computed tomography was used to validate the accuracy and the determined volumes were in good accordance within 6% deviation. A case study with binary formulations of a filler and disintegrants confirmed reproducibility and demonstrated the ability of the method to discriminate formulation characteristics, such as disintegrant type, composition and porosity for water uptake and swelling with the necessary temporal resolution.

Tablet formulation development focusing on the functional behaviour of water uptake and swelling.

The functional behaviour of tablets is strongly influenced by their manufacturing process and the choice of excipients. Water uptake and swelling are prerequisites for tablet disintegration, dispersion and hence active pharmaceutical ingredient (API) dissolution. High proportions of polymeric excipients in tablets, which are typically used as API carriers in amorphous solid dispersions (ASDs), may be challenging due to the formation of a gelling polymer network (GPN). In this study, systematic investigations into the formulation development of tablets containing polymeric and other excipients are performed by water uptake and swelling analysis. The impact of tablet composition and porosity as well as pH of the test medium are investigated. The pH affects the analysis results for Eudragit L100-55 and Eudragit EPO. HPMC and Kollidon VA64 inhibit water uptake and swelling of tablets due to the formation of a GPN. High tablet porosity, coarse particle size of the polymer and the addition of fillers and disintegrants can reduce the negative impact of a GPN on tablet performance. The application of lubricants slows down the analysed processes. Water uptake and swelling data are fitted to an empirical model obtaining four characteristic parameters to facilitate the simple quantitative assessment of varying tablet formulations and structural properties.