Study on Optimization of Wet Milling Process for the Development of Albendazole Containing Nanosuspension with Improved Dissolution

The main objective of this work was to show the potential of the optimization of top-down wet planetary bead milling process parameters (milling speed, process time and size of the milling medium) by Design Of Experiments (DOE) approach for the development of albendazole (ABZ) containing nanosuspension with improved dissolution. In addition, the influence of process parameters (capacity of milling container, applied volume of milling beads, size of the milling medium, milling speed, milling time) on ABZ polymorphic transition has also been investigated. The optimized, milled formula yielded ~ 145.39 times reduction in mean particle size (182.200 ± 1.3130 nm) compared to unmilled dispersion, which demonstrated 13.50 times gain in mean dissolution rate value compared to the unmilled dispersion in medium at pH = 1.2. No lag time values were observed in the dissolution kinetics of the nanosuspension in comparison with the unmilled samples. Moreover, maximal mean solubility value was also improved by 1.45 times compared to the unmilled suspension, in medium at pH = 6.8, supporting the significance of the Ostwald-Freundlich equation. Diffraction pattern comparisons have indicated a polymorphic transition of albendazole to Form II, which was more pronounced in smaller container at high milling speed values and prolonged operation

Comparative study of different methods for the prediction of drug-polymer solubility

YesIn this study, a comparison of different methods to predict drug−polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug−polymer solubility at 25 °C was predicted using the Flory−Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine−PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug−polymer solubility.The Irish Research Council and Eli Lilly S.A. through an Irish Research Council Enterprise Partnership Scholarship for C.M.B., in part by The Royal Society in the form of Industrial Fellowship awarded to G.A., and in part by a research grant from Science Foundation Ireland (SFI) under Grant Number SFI/12/RC/2275 (for A.M.H., L.T., K.P., and A.K.)

Continuous twin-screw melt granulation of poorly compressible and thermal labile drug

Continuous twin-screw melt granulation (TSMG) has been widely used for the last 50 years in various industrial processes. For pharmaceutical manufacturing, TSMG offers many advantages over continuous twin-screw wet granulation and roller compaction. However, TSMG is still limited since there is still a lack of understanding and familiarity by pharmaceutical scientists for the continuous manufacturing of tablets. Therefore, this dissertation aims to facilitate the broader adoption of TSMG by mechanistic understanding of the granulation behavior and the challenges that need to be concerned during the process. In Chapter 1, the processes, challenges, and the future of twin-screw granulation (wet and melt granulation) for manufacturing oral tablets and capsules are reviewed. Four aspects of twin-screw granulation, including (1) granule formation mechanisms, (2) benefit over conventional batch process, (3) process control and monitoring, and (4) history, recent progress, and the future will be highlighted in this chapter. In Chapter 2, the recent progress of twin-screw melt granulation (TSMG) will be reviewed. As TSMG is a solvent-free process, it is a preferable granulation method for a moisture-sensitive drug as compared to twin-screw wet granulation (TSWG). Therefore, this chapter focuses on the understanding of how the formulation and process impact the granule properties as well as the challenges of TSMG that is needed to be considered. In Chapter 3, the effect of thermal binders (PEG, HPC, and Compritol), molecular weight, and binder particle size on the physicochemical properties of gabapentin (GABA), a thermally labile drug, in granules prepared using TSMG was investigated. It was found that higher degradation and crystal size reduction of GABA were observed in HPC-based formulation. Smaller particle size and lower molecular weight of HPC led to faster granule growth. The tabletability of granules was insensitive to the variations in particle size and molecular weight of HPC. In Chapter 4, the effect of screw profile and processing conditions on the process-induced transformation and chemical degradation of gabapentin was studied. It was found that both the granules size and gabapentin degradant level correlated positively with the specific rate, the ratio between feed rate and screw speed. At the higher specific rate, the barrel was filled to a greater extent, enhancing the compressive forces. This resulted in more interaction between the powder particles, facilitating the granule growth as well as generating the crystal size reduction which led to more degradation. In Chapter 5, the difference of granulation behavior in two sizes of twin-screw extruder (Nano-16 and Micro-18) was investigated. It was observed that due to the difference in extruder geometries between the two extruders, correlations between granule properties and processing parameters are different. For Nano-16, DF was a critical parameter, where higher DF led to higher degradant levels and more compressible granules. For granules prepared using the Micro-18, SME was a critical parameter, where a higher SME led to higher degradant level and more compressible granules.Pharmaceutical Science

Challenges for pulmonary delivery of high powder doses

In recent years there is an increasing interest in the pulmonary delivery of large cohesive powder doses, i.e. drugs with a low potency such as antibiotics or drugs with a high potency that need a substantial fraction of excipient(s) such as vaccines stabilized in sugar glasses. The pulmonary delivery of high powder doses comes with unique challenges. For low potency drugs, the use of excipients should be minimized to limit the powder mass to be inhaled as much as possible. To achieve this objective the inhaler design should be adapted to the properties of the API in order to achieve a compatible combination of the drug formulation and inhaler device. The inhaler should have an appropriate powder dosing principle for which prefilled compartments seem most appropriate. The drug formulation should not only allow for accurate filling of these compartments but also enable efficient compartment emptying during inhalation. The dispersion principle must have the capacity to disperse considerable amounts of powder in a short time frame that allows the powder to reach the deep lung. Last, but not least, the inhaler should be simple and intuitive in use, be cost-effective and exhibit accurate and consistent, preferably patient independent, pulmonary delivery performance

Single Vial Monitoring of Pharmaceutical Freeze Drying Processes using Through Vial Impedance Spectroscopy

Currently, there is no single process analytical technology (PAT) in the market that can provide non-invasively, product and process related information which is representative of the entire batch at key stages of the freeze drying process: (i) the ice nucleation onset and the ice solidification endpoint, and the resulting ice crystal structure at the end of the freezing stage; and (ii) the true batch endpoint of ice sublimation to ensure all the ice is removed before switching to the secondary drying stage. Through Vial Impedance Spectroscopy (TVIS) employs a pair of electrodes that measure the electrical impedance of the glass vial and its contents. TVIS has been used as a PAT tool for the non-invasive monitoring of the critical events during the freeze drying process. While it has already been established previously that the TVIS parameters, (sensitive to product temperature) and ′(0.2) (largely sensitive to phase change) can be employed together to determine the ice nucleation onset and the ice solidification endpoint respectively, and ″ can be used for drying rate determination (largely sensitive to ice cylinder height), the present work involves the use of and ′(0.2) to demonstrate a direct dependency of ice nucleation temperature (or the freezing method) on the ice growth time, and subsequently the stability of the ice crystal microstructure determined using ″. Further, the present study establishes a high sensitivity of another TVIS parameter, ′(100 ), towards the changes in the shape of the ice sublimation interface and subsequently the removal of the last vestiges of ice from a single vial during primary drying. This feature has been exploited for the prediction of the primary drying endpoint at any vial location by employing a mathematical methodology, which has been extended to a simple sugar solution, wherein visual imaging cannot be used to detect ice disappearance. Finally, TVIS was multiplexed with batch measurement sensors (comparative pressure measurement and pressure rise test) for a comparison between the batch endpoint and the TVIS endpoints predicted at the shelf edge and the core. It has been demonstrated none of the PAT tools can determine the true endpoint of the batch (though the TVIS method is a significant improvement over one that relies on the thermocouple response). In conclusion, the study highlights a significant potential of TVIS for delivering additional product and process related information when it is multiplexed with batch measurement tools non-invasively, such as the thermal history of the sample before primary drying and the primary drying endpoints at various locations on the shelf

Novel development tools for processing of recombinant virus-like particles

The focus of this thesis is laid on the implementation of integrated bioprocesses and the development of novel methods for recombinant protein-based virus-like particles (VLPs). Due to their pathogen-associated molecular patterns and the lack of viral nucleic acids, VLPs represent promising bionanoparticles for vaccine applications. This thesis aims to generate straightforward production, purification and analytical procedures for VLPs by advancing rational design tools for large biomolecules

The study of protohistoric Maori material culture

An interdisciplinary approach to the study of change and retention in Maori material culture during the protohistoric is recommended. The principal disciplines involved are history, ethnology, ethnography and archaeology. Each exploits a different research resource and together in synthesis they can offer a more comprehensive understanding of culture change. This study concentrates on the material culture subsystem of Maori culture; yet it can only be effectively studied if the relationship between this subsystem and others is unravelled. Hence the need for an interdisciplinary methodology. 'Classic' Maori material culture is briefly outlined in Chapter One. Historical aspects of the protohistoric period are discussed in Chapter Two. Chapter Three outlines the various potential sources of interdisciplinary. input in a study of contact period Maori material culture change and assesses contributions made to this study by other researchers. Chapter Four summarizes the major themes of retention and adaptation in relation to particular aspects of post-contact Maori material culture. Hypotheses towards a model for Maori material culture change in the protohistoric period are outlined in Chapter Five. This study has taken a generalized approach to a problem which has a number of different regional manifestations. A framework is provided within which detailed regional assessments can be made. Such studies will be the most effective way of testing whether the hypotheses derived from this research are adequate to explain the changes, retentions and adaptations in Maori material culture during the protohistoric period

Stability Study of Engineered Ferritin Nano-vaccines by Combined Molecular simulation and Experiments

Ferritins are a type of protein that is present in almost all living things. They have a symmetric spherical shape with strong physical and chemical stabilities. Human heavy-chain ferritins (HFns) have an inner cavity of 12 nm and 24 identical subunits. Ferritins are known to be assembled and stabilised by hydrogen bonds, salt bridges, and hydrophobic interactions at 2-3-4 symmetry. Previous research has indicated that it is possible to create vaccines using human heavy-chain ferritin with a portion of EBNA1 inserted at the C-terminus. Four mutant ferritins with short C-terminal amino acid mutations and the letters C1 through C4 are used in this project. C1 was neutrally charged (Gln 167 and 171), C2 was positively charged (Arg 167 and 171), and C3 and C4 were hydrophobic (Val 165 and 169, Ile 166,168, and 170) and hydrophilic (Gln 165 and 169, Asn 166,168, and 170). The changes were done in order to comprehend the relationship between the general stability of the structures and E-helices mutations. The majority of past research has focused on the mutations and stability changes of ferritin. To study the effects of the mutations, this project, however, analysed the ferritin carrier, linker, and antigen as a unified system. As a result, this study is more useful for demonstrating the safety of the developed vaccine. In this project, experiments and MD simulations on Gromacs were used to examine the hydrophobic, thermal, and pH stability of four genetically altered human heavy-chain ferritins (C1, C2, C3, and C4). By working on this project, we can determine how the mutation will impact the HFns' stability performance. Additionally, to employ simulation in the project to examine the viability of using simulation for vaccine development research. E. coli was used to express the four mutant HFns. On the basis of recently released data, the purification process for the 4 mutants was examined and improved. C1 was satisfactorily purified by heat-acid precipitation, followed by HIC utilising a prepacked butyl FF column to remove the nucleic acids. C2, C3, and C4 each contained an extra IEC stage with a Sartobind Q column to remove the remaining HCPs. The final SEC flow through samples of C1 and C2 had purity levels of over 90% and were suitable for characterisation tests. Unexpectedly, C3 and C4 were unable to be purified to an extremely high purity throughout this process. Following purification, the self-assembly of these proteins was verified using SEC-MALS, and the purity and recovery rate were measured using the Bradford assay and SDS-PAGE. A prepacked Butyl FF column was utilised to compare the hydrophobicity of the proteins, and fluorescence was employed to evaluate the changes in tertiary structure over a volume of temperature and pH. Additionally, Gromacs was used to conduct MD simulations at varied pH and temperature levels. For analysis, it was necessary to calculate the solvent accessible surface area (SASA), root mean square deviation (RMSD), radius of gyration (Rg), root mean square of fluctuation (RMSF), and the distance between subunits. While C1 and C2 were correctly assembled into a symmetric spherical shape, according to SEC-MALS and MD simulation, they had differing hydrodynamic diameters. C1 is extremely close to the unmutated HFn (F1L3E1), while C2 is larger. The results demonstrate that these helices E mutations would not prevent ferritin from self-assembling. However, the positively charged amino acids of C2 strengthen the electrostatic interaction at the C-terminus, which may result in the larger structure of C2. Based on experiments, C2 had a higher hydrophobicity, while C1 was similar to F1L3E1. And the computed SASA confirmed these findings, since C2 had a larger SASA than C1 and F1L3E1, and a larger SASA theoretically implied a higher hydrophobicity. The repelling power of the altered amino acids may contribute to additional hydrophobic interactions as the E-helices create the hydrophobic fourfold symmetries. The SASA of C3 and C4 was used to compare their hydrophobicity. The SASA in C3 was the smallest, while C4 had the largest. Therefore, the hydrophobic interactions at the C-terminus contribute a greater contribution to the final structure and consequently influence the hydrophobicity. The fluorescence results demonstrated that the modification of C1 increased its pH stability while having little effect on its thermal resistance. And C1 had demonstrated a more stable structure than others in all of the simulation results. The C2, C3, and C4 thermal and pH experiments were carried out using MD simulations. The most unstable compounds were C3, C4, and C2. Due to the mutation of C2 into positively charged amino acids, the initial electrostatic bond has been destroyed, increasing interactions in acidic environments, resulting in lower thermal and pH stability. As a result of changing the hydrophobic channels, C3 and C4 displayed greater fluctuation and instability in simulations, potentially leading to significant changes in their structural stability. However, the simulation failed to indicate the denature of all proteins at the experimentally determined temperature and pH. This study showed that the C-terminal E-helices can significantly affect stability through mutations. Overall, C-terminus mutation research is essential for the security and effectiveness of this ferritin-based vaccine. And MD simulation is a useful method for developing studies, but more research is required to advance this method.Thesis (MPhil) -- University of Adelaide, School of Chemical Engineering, 202

Historia kryształów rezorcynolu i nowe sposoby stabilizowania wysokociśnieniowych polimorfów w warunkach normalnych

Wydział ChemiiMy thesis tells The story of resorcinol crystals and a new perspective for stabilizing high-pressure polymorphs at ambient conditions. Resorcinol is an important natural product and chemical compound of many applications, including technological ones. Resorcinol is also important from the point of view of the history of science, as it was the first organic compound for which the structures of two polymorphs were determined by X-ray diffraction in the 1930s. Actually, those historic determinations were puzzling, and they continued to be puzzling in the most recent times, because both polymorphs have the same space-group symmetry type and the high-temperature polymorph β is denser than the low-temperature one (α); in 2016 a still denser polymorph ε was discovered, which was even more puzzling. I have shown that polymorph β is not stable under pressure, as it was suggested, and that polymorph ε is the high-pressure form of resorcinol between 0.2 and 0.7 GPa, above which still another new polymorph ζ is stable. This was a surprising outcome because polymorph ε was discovered under ambient pressure (0.1 MPa), but only in the mixture with tartaric acid and with polymorph β. I have obtained polymorph ε in its pure form (without additions), as a single crystal, and I have shown that it is unstable below 0.2 GPa. I have also shown that resorcinol is prone to form solvates under pressure: I have obtained two new hydrates (mono- and duotritohydrate) and the methanol solvate. These solvates are quite intriguing by themselves, as the monohydrate and mono-methanol solvates are isostructural, but the monohydrate is metastable with respect to duotritohydrate, while the duotritomethanol solvate was not found. Also, the duotritohydrate forms a passivation layer on the surface of monohydrate crystals, protecting the metastable phase from dissolution. I established that it is characteristic to all resorcinol phases that they transform between phases with a wide hysteresis, which hampers the investigations of resorcinol forms. Therefore, I had to use the methods of high-pressure in situ isothermal and isochoric recrystallizations in the diamond anvil cell for outlining the pressure/temperature phase diagram and also the preference diagram for the solvates. I consider the discovery of the new polymorph ζ of resorcinol and of the solvates and their stability relations to be a significant achievement. Particularly, polymorph ζ is the first layered structure of pure resorcinol and the first centrosymmetric structure. As for the general achievements, the phase diagram of pure resorcinol indicated that polymorph ε cannot exist under ambient pressure and therefore it was somehow stabilized – I found the method of stabilizing high-pressure phases and tested it not only for resorcinol, but also for other compounds. Thus, this new method to recover and stabilize high-pressure polymorphs is quite general method for other organic compounds. In fact, my research shows that high-pressure polymorphs can be used for practical applications, which can solve one of the big challenges of high-pressure research, i.e. overcoming the instability of the obtained high-pressure polymorphs at ambient conditions. Some of the puzzles connected to the polymorphism of resorcinol still remain unsolved, but certainly many new information about the polymorphs and crystalline forms of resorcinol have been provided in my thesis. Besides the thesis, these results have been summarized in three articles on resorcinol published in Crystal Growth & Design and in Journal of Physical Chemistry C. In the first article (R1), I show that the polymorphs α and β can be compressed up to 5.6 GPa and that their α-to-β phase transition does not occur at 0.5 GPa. However, the hydrogen bonds network in polymorphs α show some destabilizing effects close to 0.5 GPa, which is due to the molecular reorientations in the compressed crystal environment. This structural feature of hydrogen bonds OH∙∙∙O can be the reason for observations by the NMR and IR techniques of the α-to-β phase transition reported in the literature. Solvates of resorcinol with water and methanol have been discussed in article R2. The monohydrate and duotritohydrate revealed a formation of the passivation layer protecting the metastable form from dissolution. Surprisingly, the duotritohydrate, the more stable and higher-pressure form is disordered, while the monohydrate contains geometrically unfavourable hydrogen bond (by over 0.3 Å longer than expected for OH∙∙∙O bonds) in its structure. In article R3, two new high-pressure polymorphs ε and ζ of resorcinol have been revealed. Moreover, in this paper, we stabilized the high-pressure polymorph ε at ambient conditions by doping the resorcinol sample with tartaric acid. We have explained the mechanism leading to this stabilization by the effect of internal pressure. The range of this internal pressure induced by doping can be calculated according to the formula based on our model. These results of high-pressure polymorph stabilization for resorcinol have been consistent also for other well-known compounds (imidazole and benzimidazole derivatives), for which high-pressure polymorphs were obtained previously.Moja praca dyplomowa opowiada Historię kryształów rezorcynolu i nowych sposobów stabilizowania wysokociśnieniowych polimorfów w warunkach normalnych. Rezorcynol jest ważnym produktem naturalnym i związkiem chemicznym o wielu zastosowaniach, w tym technologicznych. Rezorcynol jest również ważny z punktu widzenia historii nauki, ponieważ był pierwszym związkiem organicznym dla którego w latach 30-tych XX wieku określono struktury dwóch odmian polimorficznych metodą dyfrakcji rentgenowskiej. Jednakże, uzyskane wtedy wyniki nawet do niedawna stanowiły zagadkę, ponieważ obie formy mają symetrię tej samej grupy przestrzennej, a wysokotemperaturowa odmiana β ma wyższą gęstość niż niskotemperaturowa odmiana polimorficzna (α); w 2016 roku odkryto formę ε o jeszcze wyższej gęstości, co było jeszcze bardziej zagadkowe. Wykazałam, że wbrew wcześniejszym przypuszczeniom to nie odmiana polimorficzna β jest stabilna pod ciśnieniem, lecz faza ε jest wysokociśnieniową formą rezorcynolu w ciśnieniu w zakresie między 0,2 a 0,7 GPa, a powyżej tego ciśnienia stabilna jest jeszcze inna forma rezorcynolu, nowy polimorf ζ. Był to zaskakujący wynik, ponieważ odmiana polimorficzna ε odkryta została pod ciśnieniem atmosferycznym (0,1 MPa), jednak otrzymana została jedynie, gdy w próbce znajdowała się domieszka kwasu winowego i polimorfu β. W wyniku moich badań uzyskałam formę ε w czystej postaci (bez dodatków) jako monokryształ i wykazałam, że jest ona niestabilna poniżej 0,2 GPa. Wykazałam również, że rezorcynol ma skłonność do tworzenia solwatów pod ciśnieniem: uzyskałam dwa nowe hydraty (mono- i duotritohydrat) oraz solwat z metanolem. Odkryte solwaty są same w sobie dość intrygujące, ponieważ monohydrat i solwat z metanolem (w stosunku 1:1) są izostrukturalne, ale monohydrat jest metastabilny w stosunku do duotritohydratu, podczas gdy solwat duotritometanolu nie został znaleziony. Ponadto, duotritohydrat tworzy warstwę pasywacyjną na powierzchni kryształów monohydratu, dzięki czemu są one chronione przed rozpuszczeniem pomimo ich metastabilności. Stwierdziłam, że dla wszystkich faz rezorcynolu charakterystyczne jest występowanie dużej histerezy dla przejść między fazami, co utrudnia ich badania. Dlatego w celu określenia ciśnieniowo-temperaturowego wykresu fazowego oraz wykresu warunków tworzenia solwatów, konieczne było zastosowanie metod izotermicznej i izochorycznej rekrystalizacji wysokociśnieniowej z zastosowaniem komory z kowadełkami diamentowymi. Uważam, że odkrycie nowej odmiany polimorficznej ζ i solwatów rezorcynolu, oraz wyznaczenie zakresów ich stabilności są znaczącym osiągnięciem. W szczególności odkrycie formy ζ, która jest pierwszą warstwową strukturą czystego rezorcynolu i pierwszą strukturą centrosymetryczną. W kontekście ogólnych osiągnięć, wykazałam na podstawie diagramu fazowego czystego rezorcynolu, że odmiana ε nie może istnieć pod ciśnieniem atmosferycznym w związku z czym musi ona być w jakiś sposób ustabilizowana. Doprowadziło mnie to do znalezienia metody stabilizacji faz wysokociśnieniowych, która przetestowana została nie tylko dla rezorcynolu, ale także dla innych związków. Zatem, ta nowa metoda uzyskiwania i stabilizacji wysokociśnieniowych odmian polimorficznych stosowana być może dla innych związków organicznych. Moje badania pokazują więc, że wysokociśnieniowe odmiany polimorficzne mogą być wykorzystane w praktyce, dzięki rozwiązaniu jednego z wielkich wyzwań badań wysokociśnieniowych, tj. przezwyciężenia niestabilności otrzymanych wysokociśnieniowych odmian polimorficznych w warunkach atmosferycznych. Niektóre zagadki związane z polimorfizmem rezorcynolu wciąż pozostają nierozwiązane, niemniej moja praca z pewnością dostarcza wiele nowych informacji na temat odmian polimorficznych i form krystalicznych tego związku. Wyniki stanowiące podstawę tej dysertacji, zostały podsumowane w trzech artykułach naukowych na temat rezorcynolu opublikowanych w czasopismach Crystal Growth & Design oraz w Journal of Physical Chemistry C. W pierwszym artykule (R1) pokazuję, że odmiany polimorficzne α i β mogą zostać ściśnięte do ciśnienia równego 5,6 GPa bez zajścia przejścia fazowego z formy α do β w ciśnieniu 0,5 GPa. Niemniej sieć wiązań wodorowych w odmianie polimorficznej α wykazuje pewne efekty destabilizujące w ciśnieniu bliskim 0,5 GPa, co spowodowane jest zmianą położenia cząsteczek w ściśniętym krysztale. To z kolei może być powodem zaobserwowania przejścia fazowego z formy α do β, opisanego w literaturze na podstawie wyników badań NMR i IR. Solwaty rezorcynolu z wodą i metanolem zostały omówione w artykule R2. Monohydrat i duotritohydrat ujawniły tworzenie się warstwy pasywacyjnej chroniącej formę metastabilną przed rozpuszczeniem. Co zaskakujące, duotritohydrat, bardziej stabilna forma powstająca w wyższym ciśnieniu jest nieuporządkowana, a w strukturze monohydratu występuje geometrycznie niekorzystne wiązanie wodorowe (o ponad 0,3 Å dłuższe niż by oczekiwano dla wiązań OH∙∙∙O). W artykule R3 przedstawiłam dwie nowe wysokociśnieniowe odmiany polimorficzne ε i ζ rezorcynolu. Ponadto w tej publikacji pokazałam, że wysokociśnieniową odmianę polimorficzną ε można ustabilizować w warunkach atmosferycznych poprzez domieszkowanie próbki rezorcynolu kwasem winowym. Mechanizm prowadzący do tej stabilizacji wyjaśniliśmy efektem ciśnienia wewnętrznego. Zakres tego wewnętrznego ciśnienia wywołanego domieszkowaniem można obliczyć według wzoru opartego na naszym modelu. Wyniki stabilizacji wysokociśnieniowej odmiany polimorficznej rezorcynolu są zgodne z wynikami uzyskanymi dla innych dobrze znanych związków (pochodnych imidazolu i benzimidazolu), których wysokociśnieniowe odmiany polimorficzne zostały otrzymane w przeszłości