Browsing by Subject "säilyvyys"
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(2010)The purpose of this study was to develop articaine gargling water for local anesthesia in mouth and throat. Articaine is an amide type local anesthetic. Articaine has quick onset and it is short-acting. Articaine is safe and effective and it has rarely any adverse events. Allergic reactions are also uncommon. It has been planned to be done clinical trials with this gargling water. Xylitol and apple flavour were chosen as sweeteners to the gargling water and sodium carboxymethylcellulose was chosen as a viscosity enhancer. The purpose was also to increase preformulation knowledge of articaine in solution and in solid state. Articaine hydrochloride powder was investigated for shelf-life and for properties which are important in tableting in case it will be developed to a tablet formulation later. Compatibility of articaine hydrochloride and excipients of gargling water as powders was investigated by storing powders in temperature of 25 °C and relative humidity of 60 % up to three months. The shelf-life of articaine gargling water was investigated by storing the formulation in temperature of 25 °C and relative humidity of 60 % up to three months. Articaine concentration of solutions was determined by UV/VIS-spectrophotometry and high performance liquid chromatography (HPLC). Powders were investigated by HPLC and differential scanning calorimetry. Solid state of articaine hydrochloride powder was also investigated by X-ray powder diffractometry. In addition tablets were compressed from articaine hydrochloride. Compatibility of articaine with preservatives was also investigated in case it is necessary to add preservative to gargling water later. Methylparaben, propylparaben and potassium sorbate were chosen to this study. This study was done in solutions by storing solutions in temperature of 40 °C up to one and half months and determining articaine concentrations with HPLC. Articaine gargling water which is stabile for at least three months in room temperature was successfully developed. There were not any incompatibilities with articaine and excipients except with potassium sorbate. Articaine gargling water can be taken to the clinical trials. In compression study it was found that it is possible to make tablets from articaine hydrochloride. Breaking strengths of these tablets of pure articaine hydrochloride were not high but with suitable excipients it will be possible to create tablets hard enough.
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(2013)Some problems in dry powder inhaler formulation include low dose efficiency and changes in dispersibility during storage. For lung deposition particles should have aerodynamic size of 1 - 5µm. Poor dispersion of drug particles from carriers' surface is thought to be the main reason for low dose efficacy. A tertiary component of small particles has been generally added to formulation to improve fine particle dose. Small particles are usually manufactured by micronization. This may induce crystal defects and amorphous sites on the surface of crystals. Amorphous sites are metastable and they may crystallize during storing. Changes in particles crystallinity may have an action on efficiency and stability of dry powder inhalers. Conditioning is designated as stabilisation of particles surface by mixture of solvent vapour and inert gas. Vapour may also dissolve surface roughness. This is called deliquescence. Ostwald ripening is phenomenon whereby small particles dissolves and recrystallizes onto larger crystals. This can be extended for surface asperities. Amorphous materials have also better solubility than crystalline materials so amorphous sites may also dissolve and recrystallize onto crystalline surface. Amorphous sites may crystallize spontaneously by absorbing plasticizing agents from vapour phase or by influence of temperature. The purpose of this work was to study process variables in conditioning and their effect on modification of surface roughness and stabilization of micronized α-lactose monohydrate and test drug substance. The purpose was also to study how surface modification and stabilization effects on powders flowability and stability of dry powder inhaler. The dry powder inhaler contained two different vicinity of lactose and two different drug substances. Conditioning was based on evaporation of liquid from open surface. Studied process variables were temperature of powder, temperature of bath of liquid phase and flow rate of nitrogen gas. The aim of this study was to form a process design for conditioning of new substances, to improve powders flowability and to remove changes in fine particle dose during storage. Surface roughness was studied by laser diffraction analysis and specific surface area measurements and also by electron microscopy. Specific surface area was measured by nitrogen adsorption method. Stabilization of amorphous sites ware studied by dynamic vapour sorption. Flowability was measured by angle of repose and with FlowPro device. Fine particle dose was measured with next generator impactor device. The study showed that increasing the amount of solvent in vapour increases surface smoothness and stabilization. Also increase of temperature of sample increased stabilization. Influence of temperature on surface smoothness was not as clear. Changes in temperature may have altered adsorption and kinetic of crystallization of dissolved molecules. Flowability of lactose was significantly improved. Condition did not improve dry powder inhalers fine particle dose, but there was significant difference between different process conditions. This was concluded to be caused of surface modification. It was also shown that different process conditions affected on formulations stability.
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(2011)Nowadays growing number of new active pharmaceutical ingredients (API) have large molecular weight and are hydrophobic. The energy of their crystal lattice is bigger and polarity has decreased. This leads to weakened solubility and dissolution rate of the drug. These properties can be enhanced for example by amorphization. Amorphous form has the best dissolution rate in the solid state. In the amorphous form drug molecules are randomly arranged, so the energy required to dissolve molecules is lower compared to the crystalline counterpart. The disadvantage of amorphous form is that it is unstable. Amorphous form tends to crystallize. Stability of amorphous form can be enhanced by adding an adjuvant to drug product. Adjuvant is usually a polymer. Polymers prevent crystallization both by forming bonds with API molecules and by steric hindrance. The key thing in stabilizing amorphous form is good miscibility between API and polymer. They have to be mixed in a molecular level so that the polymer is able to prevent crystallization. The aim of this work was to study miscibility of drug and polymer and stability of their dispersion with different analytical methods. Amorphous dispersions were made by rotary evaporator and freeze dryer. Amorphicity was confirmed with X-ray powder diffraction (XRPD) right after preparation. Itraconazole and theophylline were the chosen molecules to be stabilized. Itraconazole was expected to be easier and theophylline more difficult to stabilize. Itraconazole was stabilized with HPMC and theophylline was stabilized with PVP. Miscibility was studied with XRPD and differential scanning calorimetry (DSC). In addition it was studied with polarized light microscope if miscibility was possible to see visually. Dispersions were kept in stressed conditions and the crystallization was analyzed with XRPD. Stability was also examined with isothermal microcalorimetry (IMC). The dispersion of itraconazole and theophylline 40/60 (w/w) was completely miscible. It was proved by linear combination of XRPD results and single glass transition temperature in DSC. Homogenic well mixed film was observed with light microscope. Phase separation was observed with other compositions. Dispersions of theophylline and PVP mixed only partly. Stability of itraconazole dispersions were better than theophylline dispersions which were mixed poorer. So miscibility was important thing considering stability. The results from isothermal microcalorimetry were similar to results from conventional stability studies. Complementary analytical methods should be used when studying miscibility so that the results are more reliable. Light microscope is one method in addition to mostly used XRPD and DSC. Analyzing light microscope photos is quite subjective but it gives an idea of miscibility. Isothermal microcalorimetry can be one option for conventional stability studies. If right conditions can be made where the crystallization is not too fast, it may be possible to predict stability with isothermal microcalorimetry.
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(2016)Suspension is nowadays the most commonly used dosage form in preclinical animal studies. However, suspension can be physically unstable and changes in particle size or crystal form of an active pharmaceutical ingredient (API) can occur during storage. Conventionally suspensions are also prepared in a mortar, and hence the quality of suspensions is operator-dependent. One of the aims in this study was to prepare suspensions using a mortar and pestle and an Ultra-turrax homogenizer to find out how the preparation method affects the particle size of suspension. A solution containing methylcellulose and Tween 80 was used as a vehicle, and five active APIs with different physico-chemical properties as model drugs. Moreover, an aim of the study was to evaluate the stability of the suspensions stored at room temperature and in the refrigerator and freezer by physical (laser diffraction, optical microscopy, X-ray powder diffraction) and chemical (high-performance liquid chromatography) methods of analysis. The aim of the study was also to assess and compare the suitability of laser diffraction and optical microscopy for the determination of partice size during preclinical studies. The suspensions prepared using a mortar and pestle and Ultra-turrax had a similar particle size in almost all cases. The particle size of API that was difficult to grind decreased significantly, also when using Ultra-turrax although the capacity used was minimum. Both prepation methods had the best repeatability of particle size when the API was easy to grind. However, Ultra-turrax could provide better homogeneity of quality than a mortar and pestle if the settings were optimized. The effect of different operators was not studied in this study. The stability of suspensions in different storage conditions was dependent on the properties of API. The particle size of all frozen suspensions decreased after two days based on laser diffraction results. Although the reason was not found from literature or supplementary tests (particle size analysis of the vehicle and pH-measurements), freezing of suspensions should be treated with caution based on this study. The crystal structures of APIs remained stabile with the exception of typical disproportionation of the API salt. Suspensions were mainly chemically stabile in all conditions, but water-solubility of API seemed to decrease stability. The micellar solubilization of drugs was also observed. The best way to determine the particle size of preclinical suspensions proved to be the combination of laser diffraction and optical microscopy images. The microscopy images confirmed the validity of the size distributions measured by laser diffraction and provided information about e.g. particle aggregation. On the other hand, optical microscopy image analysis was not suitable method for particle sizing.
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(2010)Automated dose dispensing is an increasing field in which medicines are packaged mechanically into small one-dose pouches in portions of two weeks. Suitability of tablets for automated dose dispensing has not been researched systematically earlier. The study was made in collaboration with the dose dispensing unit of Espoonlahti pharmacy. The aim of the study was to define optimal characteristics for an automatically dispensed tablet from a viewpoint of the dose dispensing process to reduce breakings and transitions. Breaking means that tablet crumbles, splits up or breaks up otherwise during mechanical dose dispensing process. Transition means that tablet is dispensed in a wrong dose pouch. Percentually breakings and transitions occur very little, but quantitatively plenty and increasingly when automated dose dispensing is becoming more common. Breakings and transitions cause plenty extra work because of correcting pouches, so their amount should be aimed to reduce. In addition, the aim is to find out matters to enquire from the manufacturers of medicines that would help concluding whether a product is suitable for automated dose dispensing based on written information. Results of the study indicate that to reduce breakings and transitions, an optimal tablet product for dose dispensing is rather small or middle sized, coated, strong and without a breakline and the optimal relative humidity of air in the product room of dose dispensing unit would be around 30 - 40 %. Matters to enquire from the manufacturers of medicines besides size, coating, breaking strength and breakline are stability of the product outside of its original package and light, heat and moisture sensitiveness of the product. Besides breakings and transitions, also stability of a moisture sensitive acetylsalicylic acid product (Disperin 100 mg) was investigated in 25 °C/60 % RH because air humidity in the product room is not adjustable. Duration of the test was four weeks. It is enough since it is the maximum time that tablets are outside their original packages during drug dispensing process before use. Tablets were kept in opened original container (bottle), in closed original container, in cassette of dispensing machine and in two different dose pouches (new material and the one in use). According to the results, cassettes are protecting tablets from moisture as poorly as an opened bottle. Instead, new pouch material protects tablets better than the material in use. Results of Raman spectroscopy measurements indicate no change in acetylsalicylic acid to salicylic acid during four weeks test. Moisture affects to tablets by decreasing breaking strength, which may cause more breakings. Air humidity should be adjusted in product rooms or tablets should be unpacked into cassettes as near operating the machine as possible to prevent breakings. Especially when air humidity is high. Among others, a heat sensitive drug product was researched because of the seaming unit of dose dispensing machine which is radiating heat of about 75 °C to pouches if machine is pulled over in the middle of work. Study was performed with variable temperature XRPD. Results of the study of heat sensitiveness indicate that 75 °C for 60 minutes doesn't induce changes in carbamazepine tablet (Neurotol 200 mg). However, results of the study reveal that researched product did not contain the most heat sensitive form of carbamazepine, so other heat sensitive drug products should be examined to get more information about effects of heat.
Now showing items 1-5 of 5