New Aspects in the Formulation of Drugs Based on Three Case Studies.

The improvement of pharmaceutical dosage forms, such as tablets, towards drug delivery control and cost efficiency is of great importance in formulation technologies. Here, three examples: in situ coating, freeze casting and protein-based biocomposites are presented that address the above mentioned issues and contribute to further developments in formulation technologies. The in situ coating increases the economic efficiency by saving process steps in comparison to a conventional tableting process and provides a crystalline coating for a tailorable drug delivery rate. The freeze casting allows the control over the surface area of a drug delivery system (DDS) by providing different numbers and sizes of pores, which in conjunction with adequate additives offer an efficient instrument for drug delivery control, especially by accelerating the dissolution effect. Protein-based biocomposites are attractive materials for biomedical and pharmaceutical applications that can be applied as a polymeric DDS. They inherently combine degradability in vivo and in vitro, show a good biocompatibility, offer sites of adhesion for cells and may additionally be used to release embedded bioactive molecules. Here, a new approach regarding the incorporation of crystalline active pharmaceutical ingredients (API) into a protein matrix in one process step is presented. All three presented techniques mark decisive progress towards tailor-made drug delivery systems with respect to function, economic efficiency and the generation of additional values.

Novel mineralized heparin-gelatin nanoparticles for potential application in tissue engineering of bone.

Nanoparticles (NPs) were prepared from succinylated gelatin (s-GL) cross-linked with aldehyde heparin (a-HEP) and used subsequently as a nano-template for the mineralization of hydroxyapatite (HAP). Gelatin was functionalized with succinyl groups that made it soluble at room temperature. Heparin was oxidized to generate aldehyde groups and then used as a cross-linker that can react with s-GL to form NPs via Schiff's base linkage. The polymer concentrations, feed molar ratios and pH conditions were varied to fabricate NPs suspension. NPs were obtained with a spheroid shape of an average size of 196 nm at pH 2.5 and 202 nm at pH 7.4. These NPs had a positive zeta potential of 7.3 ± 3.0 mV and a narrow distribution with PDI 0.123 at pH 2.5, while they had a negative zeta potential of -2.6 ± 0.3 mV and formed aggregates (PDI 0.257) at pH 7.4. The NPs prepared at pH 2.5 with a mean particle size of 196 nm were further used for mineralization studies. The mineralization process was mediated by solution without calcination at 37 °C. The HAP formed on NPs was analyzed by Fourier transform infrared spectroscopy and X-ray diffraction. HAP coated s-GL/a-HEP NPs developed in this study may be used in future as osteoinductive fillers enhancing the mechanical properties of injectable hydrogel or use as potential multifunctional device for nanotherapeutic approaches.

From laboratory to pilot plant: the solid-state process development of a highly potent cathepsin S/K inhibitor.

The solid-state development for the low dose drug molecule SAR114137, a selective and reversible inhibitor of cysteine cathepsin S/K, is reported. Six polymorphic forms as well as various solvate phases were discovered by an extensive polymorphism screening. The solid phase characterizations revealed that phase 1, from which a single crystal structure could be obtained, is the thermodynamically most stable form and therefore it was chosen for pharmaceutical development. The successful scale-up from development laboratory into pilot plant for the crystallization and drying processes is presented. Testing of different drying techniques, like agitated drying in conical or filter dryers as well as spray drying, proved them to be very promising alternatives to the conventional tray drying process and might be used during the industrialization phase of the project. The use of online analytical tools (e.g., Raman spectroscopy) for a better process understanding and as tools for process optimization is shown. Furthermore, wet milling by ultrasound was performed on laboratory scale and discussed as potential option to reach the desired particle size distribution necessary for a good content uniformity of the API in an oral formulation.

Effect of additives on isothermal crystallization kinetics and physical characteristics of coconut oil.

The effect of lauric acid and low-HLB sucrose esters (L-195, S170) on the isothermal crystallization of coconut oil was investigated by differential scanning calorimetry. The fundamental crystallization parameters, such as induction time of nucleation and crystallization rate, were obtained by using the Gompertz equation. The Gibb's free energy of nucleation was calculated via the Fisher-Turnbull equation based on the equilibrium melting temperature. All additives, investigated in this work, proved to have an inhibition effect on nucleation and crystallization kinetics of coconut oil. Our results revealed that the inhibition effect is related to the dissimilarity of the molecular characteristics between coconut oil and the additives. The equilibrium melting temperature (T(m) degrees ) of the coconut oil-additive mixtures estimated by the Hoffman-Weeks method was decreased with the addition of lauric acid and increased by using sucrose esters as additives. Micrographs showing simultaneous crystallization of coconut oil and lauric acid indicated that strong molecular interaction led to the increase in lamellar thickness resulting in the T(m) degrees depression of coconut oil. The addition of L-195 modified the crystal morphology of coconut oil into large, dense, non-porous crystals without altering the polymorphic occurrence of coconut oil. The enhancement in lamellar thickness and crystal perfection supported the T(m) degrees elevation of coconut oil.

Microwave processing of natural biopolymers--studies on the properties of different starches.

In this study, the influence of microwave irradiation on some physico-chemical properties and several pharmaceutical technological parameters of potato and maize starches was investigated. Changes in their habits were observed and decrease in moisture contents caused by the electromagnetic irradiation was determined. The crystalline structures and the micromorphological parameters of the starches were affected by microwave irradiation in different ways depending on the botanical origin of the samples. The tensile strengths of the compacts containing starches were decreased, their wetting properties were enhanced by the thermal process applied. Furthermore, microwave irradiation reduced the surface free energy and the polarity of the compacts significantly. Samples treated by conventional heating were used to compare the effects of microwave irradiation on the examined properties and parameters of these starches.

Investigation of entrapped pore in the pastilles by a mercury porosimetery technique.

The pore in pastilles was investigated which are produced by a pastillation technology. Mercury intrusion porosimeter and scanning electron microscopy (SEM) techniques were used for the investigation. The formation of micro-pores and cracks were in dependence of the manufacturing conditions of the pastilles (final impacting velocity, degree of subcooling and surface roughness of cooled substrate). The total pore is decreased with decreasing degree of subcooling, final impacting velocity and surface roughness of the cooled substrate. In order to design a drug delivery system and to select an optimum manufacturing parameter the relationship between overall growth rate of the pastilles and total pore was experimentally investigated. The total pore increased with increasing the overall growth rate of pastilles.

Prediction of degree of deformation and crystallization time of molten droplets in pastillation process.

The direct solidification process of a melt into a particulate solid is studied to achieve the desired size and shape of the product and to predict the required crystallization time. For an example, a Bisacodyl melt is chosen. The role of the contact angle of the droplet is investigated as a function of Reynolds number, degree of subcooling and characteristic of used cooled surface (substrate). The static contact angle increases with increasing degree of surface roughness of the substrate. The contact angle, however, decreases with increasing Reynolds number and degree of subcooling. The phenomena of spreading and rebouncing of droplets are used in the discussion of the deformation process. By the model of Madejski the degree of deformation is found to be proportional to the Reynolds number to the power of 0.2. On the basis of a simple droplet solidification model and experimental data, a numerical study is presented. The equations allow to estimate the normalized deformation and crystallization times, which are proportional to the Reynolds number to the power of 1.23 and help the design of solidification processes.

Impurity distribution in a solid-liquid interface during static layer crystallization.

The impurity distribution inside crystalline layers in static layer crystallizations was explored theoretically and experimentally for a binary eutectic mixture of caprolactam and water. The impurity distribution in the layer is modeled by a mass balance equation coupled with an energy balance equation. The mass balance equation is established with a combination of the growth of the layer and the diffusional movement of impurity. The mathematical model was solved by a numerical method. The predictions are discussed with respect to the interfacial distribution coefficient, concentration, and temperature at the solid-liquid interface, crystalline layer thickness, and concentration of the layer. The impurity distribution obtained by the model was appropriately verified with the results obtained by the experiments.