Browsing by discipline "Farmaceutisk teknologi"

The dissolution rate is one of the most important physicochemical properties of drug substances. Above all, it demonstrates the energetic interaction between solvent and solute molecules, and is therefore a valuable tool for understanding drug substance properties. Dissolution studies are a widely used method in many areas of the pharmaceutical development process, however, only lately has the value of dissolution testing in drug discovery and early development been assessed. The advantages of dissolution testing over other early screening methods, such as kinetic solubility and in silico screening, lies in the possibility of obtaining solid state dependent quantitative data, from small amounts of drug substances. While the general way of studying drug dissolution has been by the multiparticulate bulk approach, studying the constituent single particles of these systems, could give a deeper understanding of the core factors affecting the dissolution rate of drug substances. The aim of the present study was to develop a static and dynamic method, in which it would be possible to analyze the dissolution process of a single pure drug substance particle, by optical microscopy. Both methods produced practically identical dissolution profiles, for image analysis and UV-spectrophotometric data, from the same systems of a single dissolving particle. The dynamic method developed in the present study is the first flow-through technique, in which it is possible to assess the dissolution of a single freely moving drug particle, by continuous physical analysis. The possibility of using physical analysis instead of chemical analysis poses many advantages. These include reduced materials consumption, reduced experiment times, as well as a reduction in the possible sources of error. Most importantly, the advantage of physical analysis lies in the fact that no prior chemical knowledge about the studied substance is needed. This makes physical analysis an optimal technique for studying new chemical entities. The novel flow-through method succeeded in obtaining the dissolution characteristics and 3D particle morphological data, of a single pure drug substance particle, of sub-milligram initial weight. The theoretical detection limit of 1 pg, poses an intriguing opportunity for further development.

Flowability is an important powder character and, despite decades of research, there are still issues in finding a suitable measurement method. Common challenges are sample size and methodology’s suitability for cohesive powders due to their ability to form vault structures. Powder flowability properties depend strongly on particle features such as size and shape. As particles are in contact with other particles and materials, they receive electric charge and form bonds. In addition to these variables, the gravity and shear stress affect the powder. A combination of all these determine the powder properties such as flowability. Besides the particle properties, process and preservation conditions and especially humidity affects the powder properties significantly. Hence, the powder’s flow behavior varies in different conditions. There are several measurement devices available but none of them is able to yield intrinsic values. Reliability of the measurements presents another challenge as the measured values cannot be directly compared with published literature. Moreover, the flow measurement of cohesive powders is either impossible or extremely difficult with the devices currently available and the sample size needs to be sufficient. Hence, there is a need for new devices, which measure powder flow easily in small-scale. Small sample size is important especially when developing new, expensive drugs since their properties need to be explored in order to develop a new formulation. The aim of the empirical study was to develop a device, which measures particularly the flowability of cohesive powders in small-scale. A ground for the study was a device developed at University of Helsinki, which measures powder flowability by utilizing horizontal movement. In addition, the device breaks the problematic vault formation of cohesive powders by jolts. In the study a cuvette, which utilizes the horizontal movement and measures the powder flow, was developed. Flowability tests were run with five powders – Acetaminophen, Pharmatose 80M, Pharmatose 200M, Emcompress®, Avicel PH-101, Avicel PH-102, Avicel PH-200 and Maize Starch. The results were promising and the device was capable of classifying the powders by their flowabilities but more research is still needed.

Improvements in drug screening technology have resulted in a situation where more poorly soluble compounds enter the drug development pipeline. Poor aqueous solubility is a major issue especially in preclinical toxicity testing, where the generation of high drug loads is needed. For oral delivery, liquid formulations are often used and suspensions are potential options for poorly soluble drugs. While several different techniques to enhance solubility exist, most of them have method specific disadvantages or are not universal. Solid state modification, and especially the use of the high energy amorphous form, offers an efficient technique to enhance dissolution properties of a wide range of compounds. A problem of the amorphous form, however, is its physical instability. Amorphous drug in aqueous suspension can re-crystallize via solid-solid and/or solution-mediated pathways. To maintain the solubility advantage of amorphous forms for sufficient period of time, stabilization is needed. One way to stabilize the amorphous form is to prepare a solid dispersion, where the amorphous drug is dispersed in a stabilizing hydrophilic carrier matrix. Another way to add stabilizing agents is to dissolve them into the suspension medium prior to the amorphous solids. Solubilizing polymers may elevate the equilibrium solubility and reduce the driving force for solution mediated crystallization. The aims of this study were to stabilize amorphous indomethacin in aqueous suspensions and to understand the mechanisms behind stabilization. Indomethacin (IND) was used as a poorly soluble model drug (BCS class II). Four different polymers (PVP, HPMC, HPMC-AS and Soluplus®) were selected as stabilizing agents. Crystallization of solid amorphous IND and the concentration of dissolved IND in water were studied after adding: i) the pure amorphous IND, ii) solid dispersions (SDs) at 1:1 and 9:1 drug:polymer ratios (w/w), and iii) the pure amorphous IND into aqueous medium containing predissolved polymer at concentrations of 10 mg/ml or 1 mg/ml, total drug and polymer concentrations being equivalent to 1:1 and 9:1 drug:polymer ratios (w/w) in the SDs, respectively. For HPMC-AS only a 1 mg/ml polymer concentration was used due to its limited solubility. Both the solid and solution phases of the suspension were analysed at different time points for up to 24 h or until crystallization had occurred. Phase transformations in the solid phase were analysed using ATR-FT-IR spectroscopy combined with principal component analysis. The concentration of dissolved drug over the time was assessed by UV spectroscopy. In general, all the polymers, either in SDs or pre-dissolved in medium delayed the onset of crystallization of amorphous IND. Higher polymer concentrations inhibited the crystallization longer than lower ones. A general trend was that SDs were superior in stabilization of amorphous solids, but pre-dissolved polymer solutions generated and maintained higher IND concentrations in solution. Of the four polymers studied, Soluplus® showed the most promising results: SD of Soluplus® and IND at 1:1 ratio (w/w) stayed amorphous in aqueous medium for more than 28 days. On the other hand, crystallization was quite rapid (30 min) when the amount of polymer was inadequate (9:1 w/w). Soluplus® solution (10 mg/ml) generated a 20-fold higher IND concentration than the corresponding SD, possibly due to micellisation. Different polymers showed different abilities to inhibit crystallization and enhance the drug concentration in solution. The addition method and the drug-polymer ratio had an influence on the stabilization abilities of the polymer. Stabilization mechanisms may be both thermodynamic (type of polymer) and kinetic(method of addition).

3D-imaging is based on combining two or more pictures to form one three-dimensional picture. Most of the methods used provide only surface pictures, but tomography acquires also information about the inside-structure of investigated material. Young's modulus is a method, which has been used for long time to determine toughness hard materials, such as steal. In traditional method a beam-shaped piece is bent. When the size of piece, used force and amount of bending are known, Young's modulus of piece can be calculated. Although the method has traditionally been used to research very hard materials, it has been applied without changes with pharmaceutical materials. It is, however, open to the question whether or not the method is appropriate for those materials. There are also methods to determine Young's modulus based on compressing a tablet or using ultrasound. Determining tablet's toughness with ultimate strength test is complicated because it breaks tablet. For that reason it would be good to find compensatory methods to measure strength of tablet. The aim of the study was to validate Flash Sizer 3D appliance, which is used in 3D-imiging. Another goal was to investigate possible correlations between 3D-imiging, Young's modulus and traditional ultimate strength method. Lastly, the feasibility of Young's modulus as a substitute for traditional ultimate strength measurement in self life studies was investigated. Flash Sizer 3D was validated by measuring particle size distribution of pellets, which were made of microcrystalline cellulose (Cellets). Sizes of the investigated pellets were 100 µm, 200 µm and 500 µm. Also binary mixture of 100 µm and 200 µm was investigated. From microcrystalline cellulose was made tablets and 3D-pictures were taken. Ultimate strength test was made for half of the tablets. Young's modulus was measured from half of the tablets in tableting day, day after that and nine days after tableting. Results show that Flash Sizer 3D is suitable for investigating bigger Cellet. With smaller particles distinguishing of tablets wasn't probably good enough. Still it seems to be quite good method to determine surface roughness of tablet. Young's modulus seems to be very promising as compensating method for traditional ultimate strength measurement. In future in self life studies tablets hardness might be able to investigate by measuring Young's modulus and not measuring ultimate strength. If correlation between Young's modulus and solubility meets the case, Young's modulus might also replace also solubility measurements in self life studies.