Charles University in Prague, Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical Technology Student: Vlachová Hana Consultant: Doc. RNDr. Milan Řehula, CSc. Determination of optimal compression forces and speed of compression for the production of aciclovir tablets. This thesis deals with the characterisation of impact compression process on hardness of the tablets. The theoretical part of the thesis describes the effective substance - aciclovir. It also describes compression equations which explain process of compression and factors influencing terminal weight and hardness of tablets. The aim of the experimental part of the work is to measure physical properties of the tablets and find compression forces and speed of compression which are suitable for compression tablets. Tablets were pressed using Kilian Synthesis 700 machine at six compression forces in the range from 4 kN to 14 kN. The height, weight and hardness of each tablet were measured immediately after dressing and note to help for later calculation. The result of the study was to determine the impact of compression forces and compression speed on tablet hardness and weight. Tablet weight decreses with increasing comppession forces. Hardness increases with increasing compression forces. The range of radial hardness...

<p> Since first being proposed as a biological oxidant in 1990 by Beckman¹, the understanding of peroxynitrite&rsquo;s role in oxidative and nitroxidative stress has rapidly expanded. Peroxynitrite has been shown to react wide a wide variety of biomolecules through both nitration and oxidation events, causing extensive cellular damage. Physiological and biochemical studies have implicated peroxynitrite in a wide range of disease states including cardiac disease, ischaemia/reperfusion injury, cancer, diabetes, and both inflammatory and neuropathic pain. Clearly, compounds that are capable of scavenging peroxynitrite are highly desirable.</p><p> Compounds known to reduce peroxynitrite, primarily Mn(III) and Fe(III) Porphyrin, Corrole and Salen complexes, have been widely described in the literature. Typically these are polycationic complexes which render them highly water soluble and excellent for <i>in vitro</i> laboratory measurements, yet poor candidates for <i>in vivo</i> pharmacology due to poor solubility through the hydrophobic spaces within membranes. In order to develop more ideal drug candidates, with the ultimate goal of oral bioavailability, our group initially synthesized charge shielded, cyclohexyl fused, Mn(III) porphyrin complexes that have demonstrated remarkable results in the animal models of antinociceptive, neuropathic and inflammatory pain, conditions known to be driven by the over production of peroxynitrite. Further investigations by our group have also proven Mn(III) complexes derived from the B,O chelated boron dipyrromethene dyes first reported by Burgess are also highly effective in animal pain models.</p><p> The work herein describes the development of Mn(III) complexes of both porphyrins and bis-hydroxyphenyl dipyrromethenes for the use as pharmacological tools in understanding of the role of peroxynitrite in pain and other diseases. A history of porphyrin chemistry and the development of the charge shielded porphyrin scaffold as a synthetic peroxynitrite reductase is given. Design and synthesis of the newly designed Mn(III) bishydroxyphenyl dipyrromethene based complexes is discussed including their advantages over Mn(III) porphyrins. New synthetic work in creating non-cyclohexyl fused analogues of our prototype compounds through a set of orthogonal, Palladium(0) mediated cross-coupling reaction conditions is presented. As the library of catalyst compounds grew a rapid method for the assay of catalytic activity was sought. The development of a novel <i>in vitro</i> chemical assay is demonstrated and its utility in ranking compounds with regards to their peroxynitrite reductase activity, as well as estimating the 2^nd order rate constants is also illustrated.</p>

M.Com. (Business Economics) / Please refer to full text to view abstract

BACKGROUND: Stereochemistry is often used in the development of drugs. Enantiomers of a chiral drug are two non-superimposable mirror images of the molecule and a racemic mixture consists of equal quantities of both enantiomers. This study looks at the phenomenon of “chiral switching” where a molecule previously developed and marketed by an innovator company as a racemate medicine is later developed and launched as a single enantiomer. Drug utilization and market share data of three molecules that underwent chiral switching were investigated retrospectively to determine the clinical and economic impact of these occurrences in the private South African pharmaceutical market. METHOD: Unit sales and rand sales data of the racemate (and its generics) and the single enantiomer of three drug substance pairs, namely omeprazole-esomeprazole, citalopram-escitalopram and cetirizine-levocetirizine were gathered a year preceding the launch of the single enantiomer to three years subsequent to the launch of the single enantiomer onto the private market. DATA ANALYSIS: Descriptive statistical analysis included plotting trend lines of the annual unit and rand sales of both the racemate (and its generics) and the single enantiomer products during the study period, pie charts illustrating the year on year differences in market share (in both unit sales and rand value of sales) as well as box and whisker plots of the racemate and its generics plotted for the year before the single enantiomer was launched, the year after its launch, two years after launch and three years after launch. The probability of the enantiomer being prescribed/ sold instead of the racemate at different time points was also calculated to determine whether the drug utilization of the single enantiomer increased or decreased from introduction until three years subsequent to its launch. CONCLUSION: Results were consistent with global literature indicating that “chiral switching’ is a successful strategy employed by innovator companies to extend their market share. Drug utilization of the single enantiomer generally showed an upward trend following its launch indicating that there is a perceived belief of enhanced clinical outcomes for the patient. There are, however, many other influencing factors such as pricing strategies, prescription status, marketing efforts to physicians and/or consumers and patent challenges specific to each market that make it difficult to draw a general conclusion from the case studies.

.A Thesis presented for the degree of Doctor of Medicine at the University of the Witwatersrand SEPTEMBER 1962. / Plasmoquine (piasmochin, paiuaquin) was the first synthetic antimalarial drug, and it aroused a great deal of interest when it became available in 1926. Dixon (1933) estimated that at least 415 papers relating to plasmoquine hid appeared in the first 4 years following iti introduction, thereafter the volume of communications decreased somewhat,until fresh interest was stimulated by the Second world <.ar and the horean »,ar with fighting in maiariou. areas / IT2018

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Master of Science 6 February 2017, Johannesburg. / Polymorphism is not only limited to single component systems. Co-crystals have exhibited polymorphism and various polymorphic co-crystals have been reported. Polymorphism in co-crystals presents an expansion of the optimization space around a pharmaceutical compound and also offers the opportunity to develop novel patentable material. Polymorphism of pharmaceutical co-crystals was investigated by means of an exhaustive data mining survey and the formation of polymorphic co-crystals. The search was performed using the Cambridge Structural Database (CSD). The search aimed to find and tally neutral pharmaceutical co-crystals which are polymorphic. The survey of the CSD showed that 14% of the pharmaceutical co-crystals were polymorphic. The co-crystal of theophylline and 3,4-dihydroxybenzoic acid was found to be polymorphic and the novel polymorph was synthesized and characterized. The co-crystals were characterized by x-ray crystallographic techniques and Differential Scanning Calorimetry. The single crystals of carbamazepine and cinnamic acid was grown and characterized by SCXRD for the first time. The single crystal data was able to show that the hydrogen bonding packing that was modelled in the literature is incorrect. / MT2017

Further studies on the amine directed hydrocarboxylation are presented. Hydrocarboxylation of (N-(2-butyl-3,3-dideutero)-4-pentenyl-n-butylamine) carbonyl rhodium chloride gave rise to 1-butyl-3-methyl-4,4-dideutero-5-butyl-2-piperidinone exclusively in 71% yield with no evidence of deuterium scrambling. This result strongly suggests that the hydrocarboxylation does not proceed through a $\pi$-allyl rhodium complex. The diastereoselectivity of the formation of Rh(I) complexes was influenced by alkene geometry, amine substituents and a chiral group on nitrogen. Steric interactions in the Rh(I) complexes account for the diastereofacial selectivity of the coordination of the alkene to the rhodium. / Investigations were performed on approaches to the stereoselective synthesis of corynantheidol. Studies towards the preparation of cis 3,4-disubstituted piperidinone key intermediates indicated that reaction of cis bishomoallylic amines with (Rh(CO)$\sb2$Cl) $\sb2$ or (Rh(CO)(ethylene)Cl) $\sb2$ did not give rise to Rh(I) complexes and oxygen functionalities in the olefin amines hindered the hydrocarboxylation of Rh(I) complexes. Cis-3-ethyl-4-(3-methyl-2-butenyl)-2-piperidinone which was a suitable key intermediate for synthesis of corynantheidol was obtained with high diastereoselectivity, but in modest yield. Attempts to hydrocarboxylate of Rh(I) complexes with a number of ligands on nitrogen are also described. / Source: Dissertation Abstracts International, Volume: 55-04, Section: B, page: 1445. / Major Professor: Marie E. Krafft. / Thesis (Ph.D.)--The Florida State University, 1994.

The binding of bis(1,10-phenanthroline)Cu(I)$\sp{+}$, Phen$\sb2$Cu$\sp{+}$, to DNA was investigated. Biochemical and physical techniques were employed to determine (1) the sequence preferences for binding, (2) the properties of the DNA macromolecule responsible for the binding preferences, and (3) the equilibrium binding constant and the mode of binding. / Binding specificity was primarily at the level of triplets and quartets. The trimer TAT was consistently the most preferred sequence with strong cleavage occurring at the central adenosine. The trimer, TGT, and the tetramer sequences, TAGT, CAGT, and TAAT, were moderately to strongly preferred. Preferential cleavage was also observed for the pentamer CAAGC. / An oligonucleotide duplex containing TAT was strongly cleaved at the central adenosine. Duplexes containing C(:G)AT, TGT, TAC(:G), and TAC(:I) all showed significantly reduced cleavage. Duplexes containing C(:I)AT and TIT were cleaved at level nearly equivalent to that for the TAT duplex. These results support a favored intercalation site at TA steps as the primary determinant of Phen$\sb2$Cu$\sp{+}$ preferential binding with inhibition arising due to guanine amino groups in the minor groove. / The mono-complex, PhenCu$\sp{+}$, preferentially cleaved at CG sequences and not at TA sequences, indicating a crucial role in specificity determination for the non-intercalated phenanthroline. Inhibition of cleavage by guanine 2-amino groups can then be attributed to unfavorable contacts with the protons at the 2 and 9 positions of the non-intercalated phenanthroline. / An induced, conservative circular dichroism spectrum and increases in the viscosity of DNA solutions upon addition of Phen$\sb2$Cu$\sp{+}$ confirmed intercalation as the mode of binding. From visible spectroscopy studies an equilibrium binding constant on the order of 10$\sp4$ at 0.2 M ionic strength was determined. Binding was observed to be positively cooperative and dependent upon the concentration of uncomplexed phenanthroline in solution. Cooperative binding can be attributed to the need to distort the complex from its preferred geometry upon intercalation with subsequent favorable structural rearrangement of the DNA helix after binding. / Source: Dissertation Abstracts International, Volume: 51-01, Section: B, page: 0195. / Major Professor: Randolph L. Rill. / Thesis (Ph.D.)--The Florida State University, 1989.

University of Macau / Institute of Chinese Medical Sciences

University of Macau / Institute of Chinese Medical Sciences