Mechanism of adsorption of actives onto microporous functionalised calcium carbonate (FCC)

Microporous ‘functionalised’ calcium carbonate (FCC) has potential for use as a carrier for the controlled release of ‘actives’, by permeation and diffusion. We have investigated the nature of the FCC surface and the mechanism of adsorption of two typical actives, namely the anti-inflammatory drug aspirin and the flavour compound vanillin, from chloroform and aqueous ethanolic solutions. There is indirect evidence from the quantitative perturbation of Tóth isotherms that their adsorption is hindered by a stagnant diffusion layer of water trapped in the micro-porosity of the FCC. To complement previous studies of the surface of FCC, it was also tested with the cationic probe benzyltrimethylammonium bromide and the anionic probe sodium 2-naphthalenesulphonate. Experimental procedures were validated by comparison with adsorption onto ground calcium carbonate and high surface area talc

Improved Interpretation of Mercury Intrusion and Soil Water Retention Percolation Characteristics by Inverse Modelling and Void Cluster Analysis

This work addresses two continuing fallacies in the interpretation of percolation characteristics of porous solids. The first is that the first derivative (slope) of the intrusion characteristic of the non-wetting fluid or drainage characteristic of the wetting fluid corresponds to the void size distribution, and the second is that the sizes of all voids can be measured. The fallacies are illustrated with the aid of the PoreXpert® inversemodelling package.Anewvoid analysis method is then described, which is an add-on to the inverse modelling package and addresses the second fallacy. It is applied to three widely contrasting and challenging porous media. The first comprises two fine-grain graphites for use in the next-generation nuclear reactors. Their larger void sizes were measured by mercury intrusion, and the smallest by using a grand canonical Monte Carlo interpretation of surface area measurement down to nanometre scale. The second application is to the mercury intrusion of a series of mixtures of ground calcium carbonate with powdered microporous calcium carbonate known as functionalised calcium carbonate (FCC). The third is the water retention/drainage characteristic of a soil sample which undergoes naturally occurring hydrophilic/hydrophobic transitions. The first-derivative approximation is shown to be reasonable in the interpretation of the mercury intrusion porosimetry of the two graphites, which differ only at low mercury intrusion pressures, but false for FCC and the transiently hydrophobic soil. The findings are supported by other experimental characterisations, in particular electron and atomic force microscopy

Evaluation of the potential of functionalised calcium carbonate as carrier for essential oils with regard to antimicrobial packaging applications

Functionalised calcium carbonates (FCCs) are inorganic mineral-based particles with a high porosity and extended surface area consisting of hydroxyapatite and calcium carbonate crystal structures. Therefore, FCCs have a high potential to be used as a carrier for active substances such as essential oils (EOs), which are well known for their antimicrobial activities, and control their release in antimicrobial packaging applications. In this study, different EOs were loaded on FCCs, and their antimicrobial activities were studied against Listeria innocua in in vitro tests and in food tests using sliced cooked chicken breast. FCCs loaded with thyme or oregano EO (10 wt%) showed the highest reduction in microbial load in in vitro tests at 37°C (≥8.6 log cfu/filter) as well as at 7°C after 6 days (≥7.0 log cfu/filter for thyme EO and 6.5 log cfu/filter for oregano EO). However, in food tests, FCC loaded with either EO did not show any significant antimicrobial activity. FCCs loaded with cinnamon or rosemary EO (10 wt%) did not show any significant antimicrobial activity in in vitro tests. On the other hand, they showed a significant reduction in microbial load (1.7 log cfu/g for cinnamon and 2 log cfu/g for rosemary) in food tests. Differences in antimicrobial activities in in vitro and food tests are probably due to the interaction of the components of the EOs and the components of the food such as fat and proteins

Investigating the influence of a powder compact's geometry on its pore structure and optical properties using terahertz spectroscopy

In this study, terahertz time domain spectroscopy (THz-TDS) is used to analyze how the geometry of a compact affects its pore structure (pore shape and orientation). By using flat-faced and biconvex compacts, it was evident from our analysis that pores tend to assume specific shapes and orientations based on the compact's geometry and this was found to significantly affect the extracted optical properties of samples prepared by mixing a material with polyethylene (PE) as diluent and subsequent compaction. However, such sensitivity to the pore properties opens a number of industrial applications such as for quality testing of pharmaceutical tablets. A comparison made between the PE based compacts and a set of pharmaceutical tablets prepared from the same formulation has revealed that flatfaced and biconvex compacts possess different pore geometries and hence different optical properties

Insights into the Control of Drug Release from Complex Immediate Release Formulations.

The kinetics of water transport into tablets, and how it can be controlled by the formulation as well as the tablet microstructure, are of central importance in order to design and control the dissolution and drug release process, especially for immediate release tablets. This research employed terahertz pulsed imaging to measure the process of water penetrating through tablets using a flow cell. Tablets were prepared over a range of porosity between 10% to 20%. The formulations consist of two drugs (MK-8408: ruzasvir as a spray dried intermediate, and MK-3682: uprifosbuvir as a crystalline drug substance) and NaCl (0% to 20%) at varying levels of concentrations as well as other excipients. A power-law model is found to fit the liquid penetration exceptionally well (average R2>0.995). For each formulation, the rate of water penetration, extent of swelling and the USP dissolution rate were compared. A factorial analysis then revealed that the tablet porosity was the dominating factor for both liquid penetration and dissolution. NaCl more significantly influenced liquid penetration due to osmotic driving force as well as gelling suppression, but there appears to be little difference when NaCl loading in the formulation increases from 5% to 10%. The level of spray dried intermediate was observed to further limit the release of API in dissolution

Simultaneous investigation of the liquid transport and swelling performance during tablet disintegration.

Fast disintegrating tablets have commonly been used for fast oral drug delivery to patients with swallowing difficulties. The different characteristics of the pore structure of such formulations influence the liquid transport through the tablet and hence affect the disintegration time and the release of the drug in the body. In this work, terahertz time-domain spectroscopy and terahertz pulsed imaging were used as promising analytical techniques to quantitatively analyse the impact of the structural properties on the liquid uptake and swelling rates upon contact with the dissolution medium. Both the impact of porosity and formulation were investigated for theophylline and paracetamol based tablets. The drug substances were either formulated with functionalised calcium carbonate (FCC) with porosities of 45% and 60% or with microcrystalline cellulose (MCC) with porosities of 10% and 25%. The terahertz results reveal that the rate of liquid uptake is clearly influenced by the porosity of the tablets with a faster liquid transport observed for tablets with higher porosity, indicating that the samples exhibit structural similarity in respect to pore connectivity and pore size distribution characteristics in respect to permeability. The swelling of the FCC based tablets is fully controlled by the amount of disintegrant, whereas the liquid uptake is driven by the FCC material and the interparticle pores created during compaction. The MCC based formulations are more complex as the MCC significantly contributes to the overall tablet swelling. An increase in swelling with increasing porosity is observed in these tablets, which indicates that such formulations are performance-limited by their ability to take up liquid. Investigating the effect of the microstructure characteristics on the liquid transport and swelling kinetics is of great importance for reaching the next level of understanding of the drug delivery, and, depending on the surface nature of the pore carrier function, in turn controlling the performance of the drug mainly in respect to dissolution in the body

Towards the next generation of drug administration: evaluation of drug delivery systems in vitro, in vivo, and in clinical settings

Currently, many promising therapeutic compounds suffer from substantial drawbacks such as rapid clearance from circulation, poor bioavailability, or severe toxicity in patients. One option to face these challenges might be the usage of nanoparticles as drug delivery systems. There are different classes of formulations, so called nanomedicines, including drug-protein conjugates, drug-polymer conjugates, liposomes, micelles, and polymersomes. In general, main therapeutic fields for engineered nanomaterials are oncology, cardiovascular medicine, neurology, anti-inflammatory drugs, and anti-infectious treatment. Herein (chapter 2.1), polymersomes prepared of the diblock copolymer PDMS b PMOXA are described. These were synthesised and modified to achieve targeting to the asialoglycoprotein receptor of hepatocytes. Conjugation of asialofetuin to the polymersomes’ surface increased uptake of these polymersomes into hepatocytes, when compared to unmodified polymersomes. Moreover, a model compound was successfully encapsulated into the polymersomes and sustained release was achieved. Biocompatibility of the various polymersomes was assessed in vitro, and zebrafish embryos were utilised as a first vertebrate model to evaluate in vivo toxicity. In conclusion, the targeted drug delivery system was safe and well tolerated in vitro as well as in vivo. Successful drug encapsulation and release make it a promising tool for clinical applications in the field of hepatology. Further comprehensive investigations, especially regarding scalability of production process and in vivo characterisation would be needed before stepping forward to the clinics. In addition to nanoparticles, polymers can also be used to synthesise hydrogels. Hydrogels are crosslinked networks formed by a hydrophilic macromolecular polymer. Their mesh like structure and physicochemical properties allow hydrogels to imbibe large amounts of water and to be used as drug delivery systems. Therefore, hydrogels are of special interest in the fields of drug delivery, biosensing, and tissue engineering. In this work (chapter 2.2), a self-assembling chitosan hydrogel based on chemically modified chitosan (a natural polymer) was prepared. Chitosan is known to be biocompatible, biodegradable, bio-renewable, and non-toxic. In addition, it is tissue-regenerating, haemostatic, and immune-stimulating, making it a very promising hydrogel scaffold for wound dressing. The obtained self-assembling chitosan hydrogel had a porous structure enabling loading it with proteins and releasing them in a sustained manner. Moreover, the hydrogel was biodegradable and could be lyophilised. These characteristics make it a promising scaffold for application of therapeutic proteins in the treatment of chronic wounds. It remains to be elucidated how this chitosan hydrogel loaded with therapeutic proteins would behave in vitro as well as in vivo before clinical applications could be considered. Another application for polymers are buccal films (BFs). BFs can be loaded with drugs and enable oral absorption of these drugs upon placing the BFs into the oral cavity, either sublingual, buccal, or palatal. Besides fast onset of action and reduced first pass metabolism, BFs are easy to be administered, even to vulnerable patient populations such as geriatric or paediatric patients who have difficulties with swallowing liquid or solid oral dosage formulations. This makes BFs – amongst other potential applications – highly valuable for phenotyping purposes, especially for these patient groups. Phenotyping is particularly important for drugs with a narrow therapeutic window that need to be carefully dosed, based on the patient’s individual metabolic capacity. One main metabolising enzyme is cytochrome P450 3A (CYP3A). It is assumed that CYP3A is involved in the metabolism of more than 50% of the marketed drugs. Consequently, such an essential metabolism pathway will be frequently affected by various drug-drug interactions including either inhibition of CYP3A enzymes or increase of CYP3A expression. Enzyme activity can vary up to 400-fold and thus, plasma concentrations of co administered drugs can change tremendously resulting in either reduced drug activity or toxic side effects. To phenotype CYP3A, the benzodiazepine midazolam is a well-accepted probe drug, but suffering from the drawback that patients are sedated during phenotyping with pharmacologically active midazolam doses. Therefore, a microdosing approach for phenotyping was recently developed. One elegant option to formulate and administer microdoses are BFs. Herein (chapter 2.3), a clinical study investigating the usability of a microdosed midazolam BF for phenotyping is described. According to the outcomes, such a film can be considered an interesting novel diagnostic tool in the field of personalised medicine. Before making its step into clinical daily practice, it remains to be evaluated how the microdosed midazolam BF reflects increased or inhibited CP3A activity. Moreover, it would be necessary to test the film again in a greater variety of volunteers (e.g. different age or weight) to be able to generalise the results obtained from the former study. As mentioned above, paediatric patients are a vulnerable population with the need for oral formulations that are easy and safe to administer. A medication’s taste and the ability of children to swallow their medicine may greatly influence the selection of a drug, therefore therapy and prescribing practice. The medication palatability is essential for patient acceptance, therapeutic compliance and successful outcome of a therapy. Not only BFs but also oral disintegrating tablets (ODTs) offer great options for this purpose. To test the palatability of a placebo ODT based on Functionalised Calcium Carbonate, a clinical study with 40 children from 2 to 10 years was conducted, in a setup that considered the specific communication challenges with this target group – obviously children cannot be expected to give quantified feedback on likeability, taste, etc. (chapter 2.4). The tablet was highly accepted by children as well as by their parents. Such palatable, inert carrier ODTs could be formulated to contain a wide range of active pharmaceutical ingredients for oral delivery that are currently unavailable as child friendly formulations or exist only as bad tasting liquids. This includes frequently used and highly relevant drugs, such as antibiotics and steroids. Therefore, the tested ODT or similar child-appropriate solid oral dosage forms could improve world-wide access to high quality medicines and adherence for children in future. In summary, a broad variety of innovative, mostly polymer-based application forms for drug ingredients have been preclinically and clinically evaluated and led to relevant insights on how drug availability could be further optimised

Investigating elastic relaxation effects on the optical properties of functionalised calcium carbonate compacts using optics-based Heckel analysis

Heckel analysis is a widely used method for the characterisation of the compression behaviour of pharmaceutical samples during the preparation of solid dosage formulations. The present study introduces an optical version of the Heckel equation that is based on a combination of the conventional Heckel equation together with the linear relationship defined between the effective terahertz (THz) refractive index and the porosity of pharmaceutical tablets. The proposed optical Heckel equation allows us to, firstly, calculate the zero-porosity refractive index, and, secondly, predict the in-die development of the effective refractive index as a function of the compressive pressure during tablet compression. This was demonstrated for five batches of highly porous functionalised calcium carbonate (FCC) excipient compacts. The close match observed between the estimated in-die effective refractive index and the measured/out-of-die effective THz refractive index supports the validity of the proposed form of the equation. By comparing the measured and estimated in-die tablet properties, a clear change in the porosity and hence, the effective refractive index, due to post-compression elastic relaxation of the FCC compacts, has been observed. We have, therefore, proposed a THz-based compaction setup that will permit in-line monitoring of processes during tablet compression. We envisage that this new approach in tracking powder properties introduced in this preliminary study will lead to the onset of further extensive and detailed future studies

Optics-based compressibility parameter for pharmaceutical tablets obtained with the aid of the terahertz refractive index

The objective of this study is to propose a novel optical compressibility parameter for porous pharmaceutical tablets. This parameter is defined with the aid of the effective refractive index of a tablet that is obtained from non-destructive and contactless terahertz (THz) time-delay transmission measurement. The optical compressibility parameter of two training sets of pharmaceutical tablets with $\textit{a priori}$ known porosity and mass fraction of a drug was investigated. Both pharmaceutical sets were compressed with one of the most commonly used excipients, namely microcrystalline cellulose (MCC) and drug Indomethacin. The optical compressibility clearly correlates with the skeletal bulk modulus determined by mercury porosimetry and the recently proposed terahertz lumped structural parameter calculated from terahertz measurements. This lumped structural parameter can be used to analyse the pattern of arrangement of excipient and drug particles in porous pharmaceutical tablets. Therefore, we propose that the optical compressibility can serve as a quality parameter of a pharmaceutical tablet corresponding with the skeletal bulk modulus of the porous tablet, which is related to structural arrangement of the powder particles in the tablet

Characterisation of pore structures of pharmaceutical tablets : a review

Traditionally, the development of a new solid dosage form is formulation-driven and less focus is put on the design of a specific microstructure for the drug delivery system. However, the compaction process particularly impacts the microstructure, or more precisely, the pore architecture in a pharmaceutical tablet. Besides the formulation, the pore structure is a major contributor to the overall performance of oral solid dosage forms as it directly affects the liquid uptake rate, which is the very first step of the dissolution process. In future, additive manufacturing is a potential game changer to design the inner structures and realise a tailor-made pore structure. In pharmaceutical development the pore structure is most commonly only described by the total porosity of the tablet matrix. Yet it is of great importance to consider other parameters to fully resolve the interplay between microstructure and dosage form performance. Specifically, tortuosity, connectivity, as well as pore shape, size and orientation all impact the flow paths and play an important role in describing the fluid flow in a pharmaceutical tablet. This review presents the key properties of the pore structures in solid dosage forms and it discusses how to measure these properties. In particular, the principles, advantages and limitations of helium pycnometry, mercury porosimetry, terahertz time-domain spectroscopy, nuclear magnetic resonance and X-ray computed microtomography are discussed