Development of an Image-based Method for Tablet Microstructure Description and Its Correlation with API Release Rate.

The performance of a pharmaceutical formulation, such as the drug (API) release rate, is significantly influenced by the properties of the materials used, the composition of the final product and the tablet compression process parameters. However, in some cases, the knowledge of these input parameters does not necessarily provide a reliable description or prediction of tablet performance. Therefore, the knowledge of tablet microstructure is desirable to understand such formulations. Commonly used analytical techniques, such as X-ray tomography and intrusion mercury porosimetry, are not widely used in pharmaceutical companies due to their price and/or toxicity, and therefore, efforts are made to develop a tool for fast and easy microstructure description. In this work, we have developed an image-based method for microstructure description and applied it to a model system consisting of ibuprofen and CaHPO4∙2H2O (API and excipient with different deformability). The obtained parameter, the quadratic mean of the equivalent diameter of the non-deformable, brittle excipient CaHPO4∙2H2O, was correlated with tablet composition, compression pressure and API release rate. The obtained results demonstrate the possibility of describing the tablet dissolution performance in the presented model system based on the microstructural parameter, providing a possible model system for compressed solid dosage forms in which a plastic component is present and specific API release is required.

Serum and lymph pharmacokinetics of nilotinib delivered by yeast glucan particles per os.

Nilotinib is a selective tyrosine-kinase inhibitor approved for the treatment of chronic myeloid leukemia. It is poorly soluble in aqueous media and has a low oral bioavailability. Nilotinib encapsulation into yeast glucan particles (GPs) was investigated in this work as a means of increasing bioavailability. The amorphization of nilotinib in GPs resulted in an increased dissolution rate, which was confirmed by in vitro experiments using biorelevant dissolution media. Simultaneously, GPs containing nilotinib were effectively taken up by macrophages, which was quantified in vitro on cell cultures. The overall oral bioavailability in a rat model was approximately 39 % for nilotinib delivered in a reference formulation (Tasigna) and was almost doubled when delivered in GPs. The contribution of glucan particles to the lymphatic transport of nilotinib was quantified. When delivered by GPs, cumulative nilotinib absorption via the lymphatic system increased by a factor of 10.8 compared to the reference, but still represented arelative bioavailability of only 1.12 %. The cumulative uptake of GPs in the lymph was found to be 0.54 mg after a single dose of 50 mg. Yeast glucan particles can therefore serve as a drug delivery vehicle with a dual function: dissolution rate enhancement by amorphization, and, to asmaller extent, lymphatic delivery due to macrophage uptake.

Pharmaceutical Product Characterization and Manufacturability of Surfactant-Enriched Oil Marbles with Abiraterone Acetate.

The present study investigates the physicochemical properties and stability of a novel lipid-based formulation-surfactant-enriched oil marbles containing abiraterone acetate. While the biopharmaceutical performance of this formulation has been reported recently, this study aims to fill the gap between a promising in vivo performance and industrial applicability. A series of techniques were employed to assess the solid-state characteristics of oil marble cores along with their physicochemical properties upon stability testing. The chemical stability of abiraterone acetate in the formulation was also investigated. The core of the formulation was found to be stable both physically and chemically over 12 months of storage. The in vitro performance of stressed samples was evaluated using a dissolution experiment. The formulation has successfully self-emulsified upon incubation in bio-relevant media, resulting in a fast and complete API release. An important issue connected with the excipient used as a covering material of oil marbles has been identified. The seemingly insignificant water sorption caused agglomeration of the oil marbles and consequently compromised the dissolution rate in some of the stressed samples. Replacing HPMC with lactose as a covering material resulted in more favorable properties upon storage. Overall, it has been shown that oil marbles are an industrially applicable concept of the solidified lipid-based formulation.

Streamlining of the Powder Mixing Process based on a Segregation Test.

In direct compression of tablets, it is crucial to maintain content uniformity within acceptable margins, especially in formulations with low drug loading. To assure it, complex and multistep mixing processes are utilized in the industry. In this study, we suggest the use of a simple segregation test to evaluate mixing process performance and mixture segregation to produce tablets having satisfying content uniformity while keeping the process as simple and low cost as possible. Eventually, the formulation propensity to segregation can be evaluated using process analytical technology (PAT) to adjust the mixing process parameters to changing source drug properties. In this study, that approach was examined on a model drug with a broad batch-to-batch variability in particle size and shape. Excipients were chosen so that the resulting blend composition mimicked some marketed formulations. For each drug batch, two formulation blends were prepared through different preparation processes (one simple and one complex) and subsequently subjected to segregation tests. From those, segregation coefficients were obtained to compare segregation tendencies and homogeneity robustness between the drug batches and the blend preparation methods. The inter-particulate interactions were substantially influenced by the drug particle morphology and size and resulted in different segregation behavior. Based on these findings, a simple segregation test proved to be a useful tool for determining the suitability of different batches of the model drug to be used in a certain formulation. Moreover, for a particular batch A, the test revealed a potential for mixing process simplification and therefore process intensification and cost reduction.

Monitoring of particle sizes distribution during Valsartan precipitation in the presence of nonionic surfactant.

Particle size is a key parameter when dealing with drug particle formation, delivery or dissolution. The correct measurement of particle size depends on various factors, such as sample preparation or dilution, but also on the choice of method for its characterization. In this work, we study the process of precipitation of poorly water-soluble drug Valsartan from supersaturated solution in the presence of nonionic surfactant Tween 20. Several techniques including dynamic light scattering (DLS) operated in several measuring modes, optical microscope (OM) and static light scattering (SLS) were used to analyze the kinetics of particle formation. As concluded by the results, the increase in turbidity of the solution seriously limits the application of classical DLS to properly measure the particle size and polydispersity. One way to get around this restriction is by dilution, which however results in a decrease in the size of Valsartan particles in the studied population. In contrast, here we present for a first time technique based on modulated 3D cross correlation DLS equipped with the sample goniometer to determine size of submicron particles of the drug in highly turbid solutions. Additionally, a modified OM was used to measure micron-sized particles for samples without any dilution in a continuous mode. Measured particle sizes combined with measured Valsartan concentration allowed us to identify mechanism responsible for the particle formation from supersaturated solutions. The main mechanism, as it is shown in this work, is covering surface of precipitate particles by the amount of used Tween 20.

Bioavailability Enhancement and Food Effect Elimination of Abiraterone Acetate by Encapsulation in Surfactant-Enriched Oil Marbles.

Abiraterone acetate has limited bioavailability in the fasted state and exhibits a strong positive food effect. We present a novel formulation concept based on the so-called oil marbles (OMs) and show by in vitro and in vivo experiments that the food effect can be suppressed. OMs are spherical particles with a core-shell structure, formed by coating oil-based droplets that contain the dissolved drug by a layer of powder that prevents the cores from sticking and coalescence. OMs prepared in this work contained abiraterone acetate in the amorphous form and showed enhanced dissolution properties during in vitro experiments when compared with originally marketed formulation of abiraterone acetate (Zytiga®). Based on in vitro comparison of OMs containing different oil/surfactant combinations, the most promising formulation was chosen for in vivo studies. To ensure relevance, it was verified that the food effect previously reported for Zytiga® in humans was translated into the rat animal model. The bioavailability of abiraterone acetate formulated in OMs in the fasted state was then found to be enhanced by a factor of 2.7 in terms of AUC and by a factor of 4.0 in terms of Cmax. Crucially, the food effect reported in the literature for other abiraterone acetate formulations was successfully eliminated and OMs showed comparable extent of bioavailability in a fed-fasted study. Oil marbles therefore seem to be a promising formulation concept not only for abiraterone acetate but potentially also for other poorly soluble drugs that reveal a positive food effect.

Identification and Pharmaceutical Characterization of a New Itraconazole Terephthalic Acid Cocrystal.

The crystallization of poorly soluble drug molecules with an excipient into new solid phases called cocrystals has gained a considerable popularity in the pharmaceutical field. In this work, the cocrystal approach was explored for a very poorly water soluble antifungal active, itraconazole (ITR), which was, for the first time, successfully converted into this multicomponent solid using an aromatic coformer, terephthalic acid (TER). The new cocrystal was characterized in terms of its solid-state and structural properties, and a panel of pharmaceutical tests including wettability and dissolution were performed. Evidence of the cocrystal formation was obtained from liquid-assisted grinding, but not neat grinding. An efficient method of the ITR-TER cocrystal formation was ball milling. The stoichiometry of the ITR-TER phase was 2:1 and the structure was stabilized by H-bonds. When comparing ITR-TER with other cocrystals, the intrinsic dissolution rates and powder dissolution profiles correlated with the aqueous solubility of the coformers. The rank order of the dissolution rates of the active pharmaceutical ingredient (API) from the cocrystals was ITR-oxalic acid > ITR-succinic acid > ITR-TER. Additionally, the ITR-TER cocrystal was stable in aqueous conditions and did not transform to the parent drug. In summary, this work presents another cocrystal of ITR that might be of use in pharmaceutical formulations.

Investigation of tablet disintegration pathways by the combined use of magnetic resonance imaging, texture analysis and static light scattering.

Efficient tablet disintegration is a pre-requisite for fast and complete drug dissolution from immediate release formulations. While the overall tablet disintegration time is a routinely measured quality attribute of pharmaceutical products, little attention is usually paid to the analysis of disintegration fragments and the cascade of elementary steps that lead to their formation. In this work, we investigate the disintegration pathways of directly compressed tablets by a unique combination of three methods: (i) magnetic resonance imaging (MRI), to gain insight into structural changes of tablets during disintegration; (ii) texture analysis, to measure the disintegration kinetics; and (iii) static light scattering, to characterise the size distribution of disintegration fragments. By systematically varying the tablet composition (50-90% of ibuprofen as a model active ingredient, 0-4% of croscarmellose sodium disintegrant, 6-50% of lactose monohydrate filler), a relationship between the tablet formulation, the size distribution of the disintegration fragments and the dissolution rate of the active ingredient has been established. To interpret the experimental observations, we analyse the disintegration fragments by Raman mapping and relate their composition and structure to the micro-scale arrangement of individual formulation components inside the tablet.

Preclinical evaluation of new formulation concepts for abiraterone acetate bioavailability enhancement based on the inhibition of pH-induced precipitation.

Abiraterone acetate is a potent drug used for the treatment of metastatic castration resistant prostate cancer. However, currently marketed product containing crystalline abiraterone acetate exhibits strong positive food effect which results in strict dosing regimen. In the present work, a rational approach towards design of novel abiraterone acetate formulations that would allow increased bioavailability on a fasting stomach and thus decreased food effect is presented. Precipitation experiments in biorelevant media were designed to assess pH induced precipitation of the drug and a pool of polymeric excipients was then screened for their potential to inhibit precipitation. The best performing polymeric excipients were subsequently used as carriers for the preparation of amorphous solid dispersions. Two main approaches were followed in order to formulate the drug. The first approach relies on the suppression of precipitation from a supersaturated solution whereas the second one is based on the hypothesis that when the release of the drug is tuned, optimal uptake of the drug can be reached. Optimized formulation prototypes were tested in a rat animal model in an incomplete block, randomized bioequivalence study to assess their relative bioavailability under fasting conditions. We show that both formulation approaches lead to increased bioavailability of abiraterone acetate on a fasting stomach with bioavailability in rats being enhanced up to 250% compared to the original drug product containing crystalline drug.

Effect of solvent selection on drug loading and amorphisation in mesoporous silica particles.

Increasing the dissolution rate of poorly water-soluble active pharmaceutical ingredients (APIs) is a key strategy used for improving their oral bioavailability. One of the formulation approaches is API loading to mesoporous carrier particles, which can increase the dissolution rate through the combination of improved powder wettability and dispersion, higher surface area, and API conversion from crystalline to the amorphous state. From the formulation process point of view, the maximum achievable drug loading is a crucial parameter, which depends on the loading method. Drug loading by sorption from a solution is a technologically attractive approach, since it involves familiar unit operations (mixing, filtration, drying). However, the success of the equilibrium sorption approach depends on the choice of the solvent. In this work we present an experimental study of loading efficiency to mesoporous silica particles, based on a set of 10 APIs combined with 6 different solvents at a range of concentrations. We show that due to the competitive nature of the adsorption process, the solvent with the highest API solubility is not necessarily the best candidate for maximising the API loading. Based on the investigated drug-solvent combinations, we show that the dielectric constant of the solvent is a good predictor of loading efficiency and can be used as a general guideline for solvent selection. On the other hand, we did not find any systematic correlation between commonly measured API properties such as logP and their loading efficiency.

Probing the early stages of tablet disintegration by stress relaxation measurement.

Rapid tablet disintegration is a requirement for the efficient dissolution of the active pharmaceutical ingredient (API) from immediate release tablets. From the mechanistic viewpoint, tablet disintegration begins by the wetting of the tablet surface and the ingress of dissolution medium into the tablet pore structure, followed by the loosening of inter-particle bonds. The present work introduces a new methodology for probing and quantifying the early stages of tablet disintegration by stress relaxation measurements using texture analysis (TA). The method is based on applying a pre-defined load on the tablet by means of a needle-shaped probe and measuring the tablet resistance in time after the addition of the dissolution medium. This measurement provides information about the extent and rate of stress relaxation within the tablet upon hydration. Using a tablet formulation containing ibuprofen as the API and lactose as excipient, the effect of the API content, compaction pressure, and pH of the dissolution medium on the stress relaxation rate was systematically investigated. It is shown that using a dissolution medium pre-saturated by the formulation components has only a minor effect on the tablet disintegration rate compared to a pure phosphate buffer, meaning that the surface dissolution of particles within the tablet is not the main pre-requisite of disintegration in this case. On the other hand, pH of the dissolution medium was found to have a very strong effect on the stress relaxation rate in the tablet after wetting, suggesting that van der Waals interactions rather than solid bridges are the predominant particle bonding mechanism in the investigated formulations.

Solid Forms of Tenofovir Disoproxil Fumarate, Their Mutual Conversion, and Stabilization of Form I in Formulation.

Tenofovir disoproxil fumarate (TDF, form I) is an orally delivered pharmaceutical salt used for the treatment of HIV and chronic hepatitis, which acts as an inhibitor of nucleotide reverse transcriptase. There are many solid forms of TDF described in the literature; 2 of them were identified in the drug products: form I and form A. It seems that during formulation, the active pharmaceutical ingredient undergoes partial to total conversion of TDF form I to TDF form A. The goals of this study were to investigate when and why did the conversion occur and whether the conversion could be avoided and how. The influence of pH and possible interaction with excipients were studied. The conditions enabling using wet granulation in technology while preventing the undesired conversion were found. The stabilization was achieved either by replacement of used disintegrants or by acid addition to the current composition of formulation.

Crystallization products of risedronate with carbohydrates and their substituted derivatives.

The gastrointestinal absorption of bisphosphonates is in general only about 1%. To address this problem mixtures of risedronate monosodium salt with twelve varied sugar alcohols, furanoses, pyranoses and eight gluco-, manno- and galactopyranoside derivatives as counterions were designed in an effort to prepare co-crystals/new entities with improved intestinal absorption. Crystalline forms were generated by means of kinetically and/or thermodynamically controlled crystallization processes. One hundred and fifty-two prepared samples were screened by means of FT-NIR and FT-Raman spectroscopy. No co-crystal was prepared, but noteworthy results were obtained. A new solid phase of risedronate monosodium salt generated in the presence of phenyl-ß-d-galactopyranoside under thermodynamically controlled crystallization conditions was found and also characterized using solid state NMR spectroscopy, X-ray powder diffraction and differential scanning calorimetry. This new polymorph was named as form P. Interactions between risedronate monosodium salt and both carbohydrates were confirmed by means of molecular dynamics simulation. In the present study the relationships between the chemical structures of the studied compounds required for crystalline form change are discussed.

Morphology and optical responses of SERS active pi-conjugated poly(N-ethyl-2-ethynylpyridinium iodide)/Ag nanocomposite systems.

The influence of the poly(N-ethyl-2-ethynylpyridinium iodide) (PEEP-I) concentration on the morphology and optical properties of nanocomposite systems prepared by mixing the polymer solution with a hydrosol of ca. 9 nm Ag nanoparticles (NPs) was investigated by a combination of surface plasmon extinction (SPE) measurements, transmission electron microscope (TEM) imaging and surface-enhanced Raman spectroscopy (SERS). The PEEP-I concentration was found to have a strong impact on the assembly of Ag NPs and, consequently, on the optical responses of the composite systems. At low polymer concentrations in the composite (corresponding to ca. 50-1800 monomer units/NP), the formation of fractal aggregates was observed. In particular, the average fractal dimension D = 1.9 +/- 0.1 was determined for aggregates in the system with 5 x 10(-6) M polymer concentration. By contrast, in systems with polymer concentrations higher than about 1 x 10(-5) M, relatively small aggregates of Ag NPs with large interparticle distances were formed. The differences in the morphology of the composite systems with various polymer concentrations manifested themselves clearly in their SPE spectra. Furthermore, upon optical excitation with appropriate wavelengths (488.0 and 514.5 nm), the fractal aggregates acted as carriers of "hot spots", i.e. strong, localized, nanoscale optical fields, from which intense and well resolved SERS spectra of the polymer were obtained.