Annette Bauer-Brandl

• Chair at University of Southern Denmark

The in-person workshop “Drug Dissolution in Oral Drug Absorption” was held on May 23–24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict...

Amorphous solid dispersions (ASD) represent a viable formulation strategy to improve dissolution and bioavailability of poorly soluble drugs. Our study aimed to evaluate the feasibility and potential role of hydrogenated phospholipid (HPL) as a matrix material and solubilizing additive for binary (alone) or ternary (in combination with polymers) so...

Many novel small drug molecules are poorly water-soluble and thus, enabling drug formulations may be required to ensure sufficient absorption upon oral administration. Biopharmaceutical assessment and absorption prediction of enabling formulations, however, remains challenging. Combined in vitro dissolution/permeation (D/P) assays have gained incre...

Along with the increasing demand for candidate-enabling formulations comes the need for appropriate in vitro bioavailability forecasting. Dissolution/permeation (D/P) systems employing cell-free permeation barriers are increasingly gaining interest, due to their low cost and easy application as passive diffusion bio-predictive profiling in drug pro...

Along with the increasing demand for complex formulations comes the need for appropriate in vitro methodologies capable of predicting their corresponding in vivo performance and the mechanisms controlling the drug release which can impact on in vivo drug absorption. In vitro dissolution-permeation (D/P) methodologies that can account for the effect...

Due to the strong tendency towards poorly soluble drugs in modern development pipelines, enabling drug formulations such as amorphous solid dispersions, cyclodextrins, co-crystals and lipid-based formulations are frequently applied to solubilize or generate supersaturation in gastrointestinal fluids, thus enhancing oral drug absorption. Although ma...

The pharmacopoeial test method "Intrinsic Dissolution" (Ph.Eur. 2.9.29) is used to study the rate of dissolution for powders of active pharmaceutical ingredients normalized by the surface area. Therefore, powders are compacted into a special metal die holder, which is immersed into a dissolution vessel of the dissolution test apparatus (described i...

As numerous new drug candidates are poorly water soluble, enabling formulations are needed to increase their bioavailability for oral administration. Nanoparticles are a conceptually simple, yet resource consuming strategy for increasing drug dissolution rate, as predicting in vivo oral absorption using in vitro dissolution remains difficult. The o...

The development of multicomponent crystal forms, such as cocrystals, represents a means to enhance the dissolution and absorption properties of poorly water-soluble drug compounds. However, the successful discovery of new pharmaceutical cocrystals remains a time- and resource-consuming process. This study proposes the use of a combined computationa...

The marketed oral solution of itraconazole (Sporanox®) contains 40% (259.2 mM) of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The obvious role of HP-β-CD is to solubilize itraconazole and to overcome its poor aqueous solubility that restricts its absorption. In this study, we investigated the biorelevance of in vitro experiments by the influence of b...

Fosamprenavir is a phosphate ester prodrug that, upon dissolution, is cleaved to the poorly soluble yet readily absorbable parent drug amprenavir. In this study, a novel cell-free in vitro setup with quasi-continuous monitoring of the dynamic dissolution/bio-conversion/permeation of fosamprenavir was designed and tested. It consists of side-by-side...

The objective of this work was to optimize a thermosensitive in situ gelling formulation to improve intranasal and nose-to-brain delivery of the antiepileptic drug carbamazepine (CBZ). A preliminary procedure of vehicles obtained just mixing different fractions of poloxamer 407 (P407) and poloxamer 188 (P188) revealed preparations with phase transi...

The majority of new drug entities exhibits poor water solubility and therefore enabling formulations are often needed to ensure sufficient in vivo bioavailability upon oral administration. Several in vitro tools have been proposed for biopredictive screening of such drug formulations to facilitate formulation development. Among these, combined diss...

Various types of artificial biomimetic barriers are widely utilized as in vitro tools to predict the passive “transcellular” transport of drug compounds. The current study investigated if the sandwich barrier PermeaPad®, which is composed of tightly packed phospholipid vesicles enclosed between two support sheets, contributes to a transport mechani...

Many new drug entities are poorly water- soluble and thus require solubility- enhancing formulations to ensure sufficient bioavailability. On the other hand, it is more and more accepted that not all “dissolved” states of a drug contribute equally to enhanced absorption, i.e. an increase in apparent solubility does not necessarily go in parallel wi...

Extruded medicated chewing gum is a convenient but complex drug delivery system. Description of gum ingredient distribution and interactions in literature is sparse, but fundamental in product characterization and stability prediction. Although Raman spectroscopy has been used for such characterization of numerous dosage forms, its applicability to...

We aimed to understand the impact of the interplay between bile salts and cyclodextrins on the dissolution-permeation of poorly soluble drug compounds with a moderate-strong binding constant to cyclodextrin. Phase diagrams were prepared on the chosen model compound albendazole in phosphate buffer, fasted state simulated intestinal fluid (FaSSIF), a...

An important goal of the European Cooperation in Science and Technology (COST) Action UNGAP (UNderstanding Gastrointestinal Absorption-related Processes, www.ungap.eu) is to improve standardization of methods relating to the study of oral drug absorption. Solubility is a general term that refers to the maximum achievable concentration of a compound...

Background: To investigate the potential synergistic effects of olive oil releasing 2-oleoylglycerol and hydrolyzed pine nut oil containing 20% pinolenic acid on GLP-1 secretion, glucose tolerance, insulin secretion and appetite in healthy individuals, when delivered to the small intestine as potential agonists of GPR119, FFA1 and FFA4. Methods:...

A deep eutectic solvent (DES) is a eutectic system consisting of hydrogen bond donor and acceptor has been suggested as a promising formulation strategy for poorly soluble drugs. A DES consisting of choline chloride and levulinic acid in a 1:2 M ratio was used to formulate a liquid solution of the model drug aprepitant. This formulation was tested...

In order to achieve a high sample throughput, permeation experiments are often carried out using 96-well sandwich plates. Even though agitation is regarded as important, permeation studies in 96-well format are often carried out without agitation since orbital shaking, the most common agitation method for 96-well plates, has been reported to create...

Bacground & aim Pinolenic acid, a major component (~20%) of pine nut oil, is a dual agonist of the free fatty acid receptors, FFA1 and FFA4, which may regulate release of incretins and ghrelin from the gut. Here, we investigated the acute effects of hydrolyzed pine nut oil (PNO-FFA), delivered to the small intestine by delayed-release capsules, on...

Phospholipids are amphiphilic lipids with versatile properties making them promising excipients for enabling formulations for oral drug delivery. Unfortunately, systematic studies on how phospholipid type and content affect oral absorption are rare. Often, only one phospholipid type is used for the formulation development and only one formulation,...

It is our hypothesis that the presence of an absorptive sink for in-vitro dissolution experiments is decisive to predict extent and duration of super-saturation of low soluble drugs in formulations expected to increase oral absorption, often called enabling formulations. Combined dissolution-/permeation-testing may provide such absorptive sink. Com...

Supersaturated lipid-based drug delivery systems have recently been investigated for oral administration for a variety of lipophilic drugs and have shown either equivalent or superior oral bioavailability compared to conventional non-supersaturated lipid-based drug delivery systems. The aim of the present work was to explore supersaturated versus n...

PurposeHere, first experiences with a prototype tool for high throughput (passive) permeability profiling, a 96-well plate comprising the Permeapad® membrane, are reported. The permeabilities of a set of drugs were determined and compared to published measures of oral absorption, such as human fraction absorbed (Fa) and in vitro permeability values...

The aim of this rat study was to investigate the effect of liquid intake on the oral bioavailability of an amorphous solid dispersion (ASD) containing the poorly water-soluble compound ABT-869. To this end, an ASD was prepared by hot-melt extrusion and administered in form of powder in an open gelatin capsule. The study consisted of three arms: (1)...

Poorly water-soluble drugs continue to be a problematic, yet important class of pharmaceutical compounds for treatment of a wide range of diseases. Their prevalence in discovery is still high, and their development is usually limited by our lack of a complete understanding of how the complex chemical, physiological and biochemical processes that oc...

Early formulation screening can alleviate development of advanced oral drug formulations, such as amorphous solid dispersions (ASDs). Traditionally, dissolution is used to predict ASD performance. Here, a high-throughput approach is described that simultaneously screens drug dissolution and permeation employing a two-compartment 96-well plate. Free...

We investigated the ultrastructural pattern of colloidal phases in human duodenal fluids. Aspirates were collected from three volunteers in both fasted and fed nutritional states. Analysis methods comprised the combination of asymmetric flow field-flow fractionation (AF4) and multi-angle laser light scattering (MALLS). Furthermore, dynamic light sc...

The current study documents enhanced apparent solubility of the BCS class II drug celecoxib (CXB) when formulated as solid phospholipid dispersion (SPD) with either mono- or diacyl-phospholipids by freeze drying from hydro-alcoholic solvent. The enhanced solubility upon dispersion in buffer or fasted state simulated intestinal fluid (FaSSIF) is int...

Development of buccal application forms is gaining increasing interest in recent years, mostly driven by the insight that enabling formulations may help to overcome limitations as well as the need for patient-oriented medicines. A key characteristic of dosage forms is whether they can grant absorption of therapeutically relevant doses across the li...

Cell-free permeation systems are gaining interest in drug discovery and development as tools to obtain a reliable prediction of passive intestinal absorption without the disadvantages associated with cell- or tissue-based permeability profiling. Depending on the composition of the barrier, cell-free permeation systems are classified into two classe...

Colloidal phases (self-assemblies) in aqueous dispersions of selected binary bile salt/phospholipid blends were studied utilizing the combined analytical approach of asymmetrical flow field-flow fractionation (AF4) and multi-angle laser light scattering (MALLS) in order to resolve the co-existence of different colloidal assemblies. The binary blend...

Here we report first experiences with the novel in vitro dissolution/permeation setup PermeaLoop™. It was designed to overcome current limitations of in vivo predictive dissolution testing of enabling formulations, such as lack of relevant absorptive drag to allow for meaningful interplay between dissolution and permeation, as it is occurring in vi...

Aim of this project was to investigate the applicability of a recently developed in vitro microdialysis-sampling approach in connection with a dissolution-/permeation (D/P) system, especially the impact of surfactants within the perfusion fluid. The D/P-system is based on side-by-side chambers, separated by a barrier that simulates the intestinal b...

The simultaneous processes of lipid digestion and absorption together determine the oral bioavailability of drugs incorporated into lipid based drug delivery systems (LBDDS). A number of slightly different protocols for in vitro lipolysis are widely accepted; however, the permeation process has so far not been included into the models due to the ha...

Combined dissolution/permeation testing is gaining increasing attention as an in vitro tool for predictive performance ranking of enabling oral formulations. The current aim was to study how in vitro drug permeation evolves under conditions, where the donor concentration is changing (non-steady state). To this end, a model case was construed: compa...

Novel 1,2,4-thiadiazole derivatives as potent neuroprotectors were synthesized and identified. Their ability to inhibit the glutamate stimulated Ca²⁺ uptake was investigated. The solubility of thiadiazoles was measured in a buffer solution (pH 7.4) at 298 K. The distribution coefficients in 1-octanol/buffer (pH 7.4) and 1-hexane/buffer (pH 7.4) imm...

The aim of the current study was to evaluate a dynamic dissolution-/permeation-system for prediction of gastrointestinal and absorption-behavior of two commercial fenofibrate formulations. To this end, both dissolution and barrier-flux were followed simultaneously for fenofibrate powder, a microparticle formulation (Lipidil® 200mg) and a nanopartic...

A novel microdialysis-dissolution/permeation (M-D/P) system was developed for the biopharmaceutical assessment of oral drug formulations. This system consists of a side-by-side diffusion chamber, a microdialysis unit fixed within the dissolution chamber for continuous sampling, and a biomimetic Permeapad® as the intestinal barrier. In the M-D/P sys...

The present work explores the usefulness of Permeapad® for prediction of buccal absorption. Permeability studies with the model drug metoprolol were carried out using the Permeapad® barrier at pH values 7.4; 8.5; 9.0, and 9.5. It was confirmed that Permeapad® can withstand these conditions, and as expected, a clear increase in permeability was foun...

Liposomes represent a versatile drug formulation approach e.g. for improving the water-solubility of poorly soluble drugs but also to achieve drug targeting and controlled release. For the latter applications it is essential that the drug remains associated with the liposomal carrier during transit in the vascular bed. A range of in vitro test meth...

Celecoxib (CXB) is a Biopharmaceutical Classification System class II drug in which its oral bioavailability is limited by poor aqueous solubility. Although a range of formulations aiming to increase the solubility of CXB have been developed, it is not completely understood, whether (1) an increase in CXB solubility leads to a subsequent increase i...

Two new cocrystals of the non-steroidal anti-androgen drug bicalutamide (Bic) are reported with benzamide (BZA) and salicylamide (2OHBZA), both in a 1:1 molar ratio. X-ray crystal structure analysis shows that both cocrystals contain a folded molecular conformation of bicalutamide, similar to that seen in polymorph II of the pure drug. Calculations...

The poor aqueous solubility of BCS Class II drugs represents a major challenge for oral dosage form development. Using celecoxib (CXB) as model drug, the current study adopted a novel solid phospholipid nanoparticle (SPLN) approach and compared the effect of two commonly used industrial manufacturing methods, spray- and freeze-drying, on the solubi...

Low bioavailability nowadays often represents a challenge in oral dosage form development. Solid formulations composed of drug and phospholipid (PL), which, upon contact with water, eventually form multilamellar liposomes (i.e. ‘proliposomes’), are an emerging approach to solve such issue. Regarded as an ‘improved’ version of liposomes concerning s...

The aim of the present work was to investigate the potential of the new and innovative artificial barrier, Permeapad(TM), when exposed to surfactants and co-solvents, often employed for poorly water soluble compounds. The barrier was in addition also exposed to Fasted and Fed state simulated intestinal fluids versions 1 and 2 (FaSSIF and FeSSIF), a...

Solvates of the calcium-channel blocking agent felodipine with three structurally related common organic solvents, acetone (ATN), dimethyl sulfoxide (DMSO) and acetophenone (APN), are described. A relationship between the felodipine packing arrangement in all known solvates and the van der Waals volume of the solvent molecule is established. Interm...

In this work the suitability of a newly invented physical patch comprising a biomimetic barrier (named Permeapad(TM)) for drug permeability tests has been investigated. Exemplars of Permeapad(TM) were adapted to Franz diffusion cells and apparent permeability (Papp) of a series of drugs were measured and compared with calculated partition coefficie...

The aim of this work was to prepare chitosan (CH) based particulate formulations for colon delivery of vancomycin (VM). Chitosan microparticles (MPs) and nanoparticles (NPs) loaded with VM were prepared using different CH/tripolyphosphate (TPP) molar ratios and different technological processes. In particular, nanoparticles were prepared by ionic g...

The main problem occurring at the early stages of cocrystal search is the choice of an effective screening technique. Among the most popular techniques of obtaining cocrystals are crystallization from solution, crystallization from melt and solvent-drop grinding. This paper represents a comparative analysis of the following screening techniques: DS...

The calcium-channel blocking agent felodipine (Fel) forms co-crystals with 4,4′-bipyridine (BP) with 1:1 and 2:1 molar ratios. The [Fel + BP] (1:1) co-crystal exists in two polymorphic forms. Differential scanning calorimetry and solution calorimetry show that form I of the [Fel + BP] (1:1) co-crystal is the most thermodynamically stable phase. The...

Solid phospholipid (PL) nanoparticles with griseofulvin (GRIS) as a model drug were prepared by co-spray drying. Their dissolution properties were compared with formulations containing the physical blends of the native crystalline drug and excipient materials, and physical blends of the spray dried materials. Co-spray drying was performed from etha...

Porcelain mortars and pestles are frequently used to comminute drug substances on a small scale and (in some cases) in the production of liquid and semisolid suspensions. Although it is generally accepted that removal of a drug substance from a rough surface by rinsing may be difficult and may lead to cross-contamination, no hard data support that...

Solvates of the calcium-channel blocking agent felodipine with three structurally related high-boiling point solvents, dimethylacetamide (DMAA), dimethylethyleneurea (DMEU) and tetramethylurea (TMU), are described. The solvates can be formed either by solution crystallisation or solvent-drop mechanical grinding. In all of the crystal structures, th...

Context: The particularity of the Nano Spray Dryer B-90 is the nozzle containing a mesh vibrating at ultrasonic frequency. Objective: To study process parameters and processability of crude phospholipid dispersions, in particular the effect of concentration and mesh aperture on both particle size of the dry solid phospholipid nano-particles and...

The H2 antagonist cimetidine forms many polymorphs, several of which have resisted structural analysis thus far. Using single-crystal X-ray measurements obtained from synchrotron radiation, the crystal structure of cimetidine form C has been solved. This layered structure crystallizes in space group C2/c with an unusually large lattice parameter, a...

An efficient method for modelling a polytypic family is presented with the example of cimetidine in the form C polymorph. The method exploits the (3 + 1)-dimensional superspace model, which is a powerful tool for the description, prediction and understanding of polytype modifications in small-molecule crystallography, as illustrated with this pharm...

The title compound, C18H19Cl2NO4·C6H12N2·H2O, is a co­crystal hydrate containing the active pharmaceutical ingredient felodipine and diaza­bicyclo­[2.2.2]octane (DABCO). The DABCO and water mol­ecules are linked through O—H⋯N hydrogen bonds into chains around 21 screw axes, while the felodipine mol­ecules form N—H⋯O hydrogen bonds to the water mol­...

We report a (31)P NMR assay for quantification of aqueous phospholipid samples. Using a capillary with trimethylphosphate as internal standard, the limit of quantification is 1.30mM. Comparison of the (31)P NMR quantification method in aqueous buffer and in organic solvent revealed that the two methods are equal within experimental error. Changing...

Two previously known polymorphs (forms I and II) and two new polymorphs (forms III and IV) of the calcium-channel blocker felodipine were obtained during attempts to cocrystallize the compound with a variety of potential cocrystal formers. A correlation was observed between the polymorphic outcome and the effective pH value in the presence of the c...

Pectin has lately gained much attention for colon cancer treatment (1–3): it reduces the severity of colon cancer (3), and it is selectively digested by colonic microflora, which can be exploited as a trigger for drug release. Therefore, a pectin matrix potentially serves dual purposes in treatment of colon cancer as drug carrier and/or therapeutic...

This study examines the contribution of a 3-D model in an early development of pectin tablets. The aim of this work was to extract as much information of the compression behavior from as few tablets as possible. Pectins with various degrees of methoxylation (DM) were studied (4%-72%). The compressibility was evaluated using classic "in-die" Heckel...

Introduction: Although tableting is one of the most commonly used processes in drug manufacturing, the tablet formation process is still not fully understood, nor can it be fully controlled. Areas covered: In this paper, recent approaches to correlate tablet mechanical properties with process parameters are discussed, covering (mainly) the last...

The pharmaceutical use of some 3-hydroxyquinolinone derivatives with high cytotoxic and cytostatic activities (under in vitro conditions) as well as potential immunosuppressive properties is seriously limited by their low solubility in water accompanied by instability in oxidative environment, like physiological fluids. In an attempt to improve the...

In this work a new, accurate and convenient technique for the measurement of distribution coefficients and membrane permeabilities based on nuclear magnetic resonance (NMR) is described. This method is a novel implementation of localized NMR spectroscopy and enables the simultaneous analysis of the drug content in the octanol and in the water phase...

Four new 3-hydroxy-quinolinone derivatives with promising anticancer activity could be solubilized using liposomes as vehicle to an extent that allows their in vitro and in vivo testing without use of toxic solvent(s). A screening method to identify the maximum incorporation capacity of hydrophobic drugs within liposomes was successfully applied. T...

The aim of this work was to investigate the complexation of ibuprofen as model drug with various β-cyclodextrins (native β-cyclodextrin, hydroxypropyl-β-cyclodextrin with two different molar degrees of substitution, and methyl-β-cyclodextrin). Solutions of the commercially available β-cyclodextrins were prepared in phosphate buffer (73mM). The pH v...

This study examines the effect of the degree of methoxylation (DM) and particle size on compression properties and compactibility of pectin powders. A powder classification system based on sequential handling of compression parameters was applied. A single size fraction (90-125 μm) of pectin powders with DM values ranging from 5-72% was studied. Fo...

The present work evaluates the usefulness of “in die” elastic recovery descriptors as an indicator of tabletability. Tablet elastic recovery (“in die” and “out-of-die”) with respect to applied compression speed and dwell time were evaluated by applying 22-full factorial design with one centre point. Flat tablets of constant true volume were compres...

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The objective of this study was to evaluate possible usefulness of pectins for direct compression of tablets. The deformation behavior of pectin grades of different degree of methoxylation (DM), namely, 5%, 10%, 25%, 35%, 40%, 50%, and 60% were, examined in terms of yield pressures (YP) derived from Heckel profiles for both compression and decompre...

The present work describes an approach to quantify relationships between the material properties of various alpha-lactose monohydrate grades (alphaLM), process parameters (punch velocity, lubricant fraction) and the tablet tensile strength (TS). Milled, sieved, agglomerated and spray-dried alphaLMs were studied. Each material was tableted (11 mm fl...

The present work challenges a newly developed approach to tablet formulation development by using chemically identical materials (grades and brands of microcrystalline cellulose). Tablet properties with respect to process and formulation parameters (e.g. compression speed, added lubricant and Emcompress fractions) were evaluated by 2(3)-factorial d...

The exchange reaction between sulfopropyl-dextran (Sephadex C-25) and propranolol hydrochloride (prop-HCl) as a model drug was studied. Binding experiments were carried out using a dissolution tester and photometric quantification of the amount of drug bound. The thermodynamic parameters of the binding reaction were derived by isothermal titration...

Crystal lattice characteristics from the literature for different polymorphic forms of some nonsteroidal anti-inflammatory drugs (diclofenac, niflumic, flufenamic, tolfenamic, mefenamic acid) and structural relative compounds (N-phenylanthranilic acid and diphenylamine) were summarized and compared. Molecular conformational states in the crystal la...

The model system propranolol hydrochloride (PROP-HCl)/Amberlite™ was studied in terms of equilibrium concentrations and amount drug bound to the ion exchanger, and compared to the system potassium chloride (KCl)/Amberlite™. It was found that both the affinity and exchange capacity of Amberlite™ for PROP-H+ ions is higher than for K+. Specific heat...

The model system propranolol hydrochloride (PROP-HCl)/Amberlite™ was studied in terms of equilibrium concentrations and amount drug bound to the ion exchanger, and compared to the system potassium chloride (KCl)/Amberlite™. It was found that both the affinity and exchange capacity of Amberlite™ for PROP-H + ions is higher than for K + . Specific he...

The present study is an approach to describe and predict compaction and tablet properties by a combination of a set of commonly used mathematical descriptors and multivariate methods based on continuous compression profiles. Effects of formulation and process parameters (e.g. composition, powder properties, compression speed) of well-known direct c...

The relationship between the natural logarithm of the tablet porosity and the applied pressure is used to describe the compression behavior of a powder. Such a relationship, here referred to as a Shapiro-Konopicky-Heckel (SKH) profile, is usually divided into three regions, of which the first often is non-linear. The objective of this work was to a...

Abstract Suitability of a Quadro Comil™ for screening of direct compression tablet masses was evaluated with respect to alteration of particle size distribution and blending efficiency. Air jet sieving was qualijied for determination of a particle size of spraydried lactose and microcrystalline cellulose. Using a full 31 × 23 factorial design not o...

The purpose of this study was to design a 'Traveller Friendly Drug Delivery System' for PM-HCl. Conventional promethazine (PM-HCl) tablets are bitter, need to be taken 1 h before symptoms and water is also needed. Taste-masked granules were produced with Eudragit E100 by extrusion, and analyzed with FTIR, DSC, and XRD. Tablets formulated from granu...

Temperature dependency of saturated vapour pressure and thermochemical characteristics of fusion processes for 2-, 3- and 4-methoxybenzoic acids (anisic acids) were measured and thermodynamic functions of sublimation, fusion, and evaporation calculated. A new approach to split specific and nonspecific energetic terms in the crystal lattice was deve...

This article deals with the passive transport of electrolytes, water, and small organic molecules across biologic membranes (cell membranes and membranes that confine cellular compartments). Passive transport may be classified into diffusion, facilitated diffusion, and bulk flow. The focus in the current article is on simple diffusion, a process de...