Dissertations / Theses on the topic 'Pharmaceutical salts'

Thesis submitted in fulfilment of the requirements for the degree Magister Technologiae: Chemistry in the Faculty of Applied Sciences at the CAPE PENINSULA UNIVERSITY OF TECHNOLOGY 2014
The solid state modification of a given active pharmaceutical ingredient is a desired way to alter its physicochemical properties, such as solubility or bioavailability. The solubilitymelting point relationship of the ensuing co-crystal or salt is not fully understood. In this thesis, a series of model co-crystals and pharmaceutical co-crystals and salts of baclofen were investigated. The model co-crystals were prepared from 4,4’-bipyridine (BIPY) and 1,2-bis(4-pyridyl)ethane (ETBIPY) used as host compounds which were combined with a series of carboxylic acids as co-formers, such as p-toluic acid (PTA), rac-phenylbutyric acid (racPBA), racemic and S-phenylsuccinic acid (racPSA and S-PSA, respectively). In the second part, six new multicomponent crystals of baclofen (BAC, (RS) 4-amino-3-(4- chlorophenyl)-butanoic acid), were prepared with mono- and dicarboxylic acids: two pharmaceutical co-crystals obtained with benzoic acid (BAC•BA) and p-toluic acid (BAC•PTA) and four pharmaceutical salts with 1-hydroxy-2-naphthoic acid, (BAC+)(HNA-), oxalic acid, 2(BAC+)(OA2-), maleic acid, (BAC+)(MA-) and p-toluene sulfonic acid, (BAC+)(PTSA-)•IPA. The compounds prepared were analysed by single crystal and powder X-ray diffractometry, differential scanning calorimetry and their solubility was measured in water and ethanol. From the analysis of the model co-crystals it was concluded that their aqueous solubility is inversely related to the melting point values and this can be explained by packing features. Also, the introduction of a chiral building block, compared to its racemic counterpart, is a valuable way to limit the formation of the intermolecular interactions in the new multicomponent crystal and thus decrease the efficiency of the packing which eventually leads to lower melting points and better solubility. The analysis of the baclofen crystals suggests that a strong, robust and predictable hydrogen bonding network with a combination of molecular building blocks which show acceptable molecular flexibility is a good recipe for successful co-crystal design.

Thesis (MTech (Chemistry))--Cape Peninsula University of Technology, 2015.
Solvatomorphism of an active pharmaceutical ingredient (API) is one of the most studied areas in pharmaceutical science. Since APIs are exposed to solvents during many stages of their production, knowledge of the consequences from such exposure is essential. Salt formation has been known to improve some physicochemical properties of an API. Amongst these properties, API solubility is one of the most important characteristics as their use in the market is determined by this feature. Research presented here investigated the solvates and salts of mefenamic acid (MA) and tolfenamic acid (TFA); both representing fenamic acids belonging to a class of non-steroidal anti-inflammatory drugs (NSAIDs). Solvates were obtained by reactions of TFA and MA with the solvents 2-picoline, 3-picoline, 4-picoline, 3-bromopyridine and 3-chloropyridine. A solvate polymorph of MA and 2-picoline was isolated. The salts were obtained by using diethanolamine, ethylenediamine, 1-methylpiperazine, and triethylamine in combination with the fenamic acids. Morpholine formed a salt with TFA, but not with MA. Instead a zwitterionic form of MA was synthesised when the latter was mixed with morpholine. The resulting compounds were characterised and their crystal structures analysed. It was found that the conformation of the acids in the solvate and the salt compounds differed. Moreover, within the solvates, the conformation of the fenamate backbone varied depending on the acid and the solvent used for crystallisation. Although similar solvents were utilized, the structural packing arrangements of TFA solvates were very different from the arrangements associated with MA. The thermal analyses of the salts/solvates were determined by using both thermogravimetry and differential scanning calorimetry. The compounds were further investigated after manual grinding and the preparation of slurries. These preparation methods were successful for most compounds but not for MA•2PIC and (MA-)(EDM+). Instead, the recrystallization, grinding and slurry investigations of MA•2PIC yielded a polymorph of this particular solvate. In the case of (MA-)(EDM+), the PXRD results obtained from both the pulverised and slurry samples were completely different from one another and also from those determined for the starting materials. Generally, the desolvation studies of the MA salts and solvates produced the same crystal form as occurred in the starting material. The exception was (MA-)(TA+) wherein desolvation produced a mixture of two polymorphs of MA.

“Bath salts” and “plant food”, which were legally marketed synthetic cathinones, have a high potential for abuse. Several recent studies indicate that 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxymethcathinone (methylone), two common drugs of this type, have similar pharmacology to controlled psychostimulants such as cocaine, methamphetamine, and methylphenidate. MDPV acts as a norepinephrine (NE) and dopamine (DA) reuptake inhibitor via blockade of their transporters (DAT and NET), whereas methylone is a substrate for the NE, DA, and serotonin (5-HT) transporters, increasing the non-vesicular release of these monoamines. Both drugs cause significant increases in the levels of these neurotransmitters in the cleft. Increases in DA are associated with euphoric effects and thus promote drug abuse and addiction, hence the high addiction potential of MDPV and methylone. Indeed, MDPV is 50 times more potent at the DAT and 10 times more potent at the NET than cocaine. Here, we examined the pharmacokinetics of MDPV and methylone in the brain and plasma, following intraperitoneal injection in mice. These types of injections have similar pharmacokinetics to insufflation (snorting), which is the manner in which MDPV and methylone are commonly abused. Briefly, adolescent male Swiss-Webster mice were injected intraperitoneally with either 10 mg/kg MDPV or 10 mg/kg methylone, and brains and plasma were collected at the following time points: 1, 10, 15, 30, 60, and 120 minutes. Samples were then flash-frozen and stored at -70°C until analysis. Samples were spiked with deuterium-labeled MDPV or methylone (internal standards), and the drugs were extracted from tissue using a previously published solid phase extraction method. Chromatographic separation of the compounds was achieved using a HILIC column with a gradient elution of acetonitrile and 5 mM ammonium formate at a flow rate of 0.2 mL/min. Mass spectrometric detection utilized a Shimadzu IT-TOF system with the electrospray source running in positive mode. Data acquisition utilized a direct MS-MS method using a precursor ion of 276.3 m/z for MDPV and methylone. The calibration curve ranged from 100 ng/ml to 0.1 ng/ml. These conditions allowed for a lower limit of detection (LLOD) of less than or equal to 1 ng/mL and a lower limit of quantification (LLOQ) of less than or equal to 5 ng/mL for MDPV and methylone. MDPV and methylone peak concentrations in plasma were seen immediately at 1 min, while brain concentrations peaked at 15 min; however, MDPV reached higher concentrations in the brain the methylone. This is consistent with MDPV’s higher lipophilicity (logP value). In conclusion, the pharmacokinetic profile of these drugs reflects a quick uptake and distribution of the drugs to the brain, followed by the quick distribution out of the brain, which likely contributes to the binge use of these drugs.

Pharmaceutical industries aim for continuous improvement in the manufacturing process of producing medicines. Demands on the pharmaceutical industries are to produce quality products in a quick and cost effective way. Designing a robust crystallization process so as to produce quality crystals with the desired polymorphic form, morphology, size and size distribution, will contribute towards meeting these demands. The Food and Drug Administration regulating body encourages the development of quality by design (QbD) approaches, involving the use of process analytical technology (PAT) for the design of the crystallization process. This method enables the design of the crystallization process to be more flexible in terms of variation in operating conditions and process parameters so long as the quality of the product is maintained. The aim of this thesis work is to use QbD approaches involving the use of PAT tools and solid state analytical (SSA) techniques to increase process knowledge and understanding, which is required for the robust design of crystallization processes. Discovery of all possible polymorphic forms of an active pharmaceutical ingredient (API) is important for the design of a robust crystallization process in which product quality is consistent during scale up and to prevent late stage failures. This thesis work shows the importance of using PAT tools and SSA techniques for monitoring polymorphic transformations and for the discovery of new polymorphic forms that have not yet been reported in the literature. A range of PAT tools including the FBRM, turbidity probe and ATR-UV/Vis spectrometer detected polymorphic transformations during both cooling and antisolvent crystallization experiments using the model system sodium benzoate in water and a propan-2-ol (IPA)/water mixture. Information obtained from a range of SSA techniques provided supporting evidence for the discovery of a new channel hydrate, channel solvate and an anhydrous form of sodium benzoate. The problem of crusting (solid depositing on vessel walls) occurring within crystallization vessels has been investigated with the use of a combination of PAT tools and SSA techniques. The FBRM and turbidity probe detected a change occurring during the cooling crystallization process of para-amino benzoic acid (ABA) in ethyl acetate. Repeats of the experiments using the ATR-UV/Vis confirmed that the change was due to crusting forming on vessel walls and not a polymorphic transformation. PAT tools also detected changes occurring during a pH controlled polymorphic cooling crystallization experiment (Chapter 9), which was subsequently confirmed by SSA methods to be due to the formation of a mixture of products and not a polymorphic transformation. This research work shows the importance of using a combination of PAT tools and SSA techniques for gaining a deeper understanding of the crystallization process and to prevent misinterpretation of results, saving both time and money. Also this research work highlights the need for improvement within industrial scale vessel design, such as vessels with variable jacket height, to prevent the problems of crusting. Robust MSZW measurements are obtained at laboratory scale using the model crystallization systems para and meta-ABA in water. PAT tools used include the FBRM and turbidity probe. The robust MSZW takes into consideration variation in process parameters including ramp rate, vessel size (1 mL and 1 L), agitator speed and type. This robust MSZW can be used for the design of scale up experiments (pilot plant and industrial scale), increasing the likelihood of producing a quality product. Nucleation orders used within crystallization models were determined from the MSZW measurements. Results showed that the nucleation order varied within different crystallization set-ups (vessel size and mixing conditions) using the model system meta-ABA in water. Therefore model-based design and scale-up of crystallization processes must be used carefully and more detailed mechanistic models, which take into consideration the effect of mixing need to be designed to improve the generality and applicability of crystallization models. pH controlled polymorphic crystallization experiments were performed using the model systems meta and para-ABA in ethanol and water. A combination of 5 PAT tools were used in a single vessel to monitor the cooling crystallization process. PAT tools used include FBRM, ATR-UV/Vis, PVM, pH and a temperature probe. Various parameters including mixing conditions, solvent, pH of solution, strength and type of acid were varied to investigate the best conditions to produce salts. Results showed that careful selection of design parameters and salt selection is important for producing quality crystals of the desired morphology so as to prevent problems in downstream processing.

Ionic liquid forming compounds often display low melting points (a lack of crystallisation at ambient temperature and pressure) due to decreased lattice energies in the crystalline state. The degree of anion-cation contact with respect to the type, strength and number of interactions is a major factor determining the lattice energies, melting point and general behaviour of ionic liquid forming salts. Intermolecular interactions between the anion and cation and the conformational states of each component of the salt are of interest since distinctive properties ascribed to ionic liquids are determined to a significant extent by these interactions. The direct insight into the spatial relationship between cation and anion provided by the analysis of crystal structures provides a basis from which features of the ionic liquid can be generally understood, since the short range order and interactions of related, non-crystalline compounds may be similar to those of the crystalline form. However, it is difficult to predict whether a particular ionic pair will produce a liquid at room temperature, due to numerous possible combinations of cations and anions and the subtleties of their interactions. Crystal engineering is the ability to assemble molecular or ionic components into the desired crystalline architecture by engineering a target network of supramolecular interactions known as synthons. In this investigation the problem of ionic liquid design is addressed using the concepts of crystal engineering in an inverse sense, the so-called anti crystal-engineering approach. A topical area in which the anti crystal-engineering concept may be of some value is that of Ionic Liquid Phases of Pharmaceutically Active Ions (Active Ionic Liquids). Thus, by using the knowledge gained of the intermolecular interactions, packing and ionic conformation which occur within ‘traditional’ ionic liquids, combined with the knowledge of which functional group combinations yield supramolecular synthons resulting in crystalline subjects, and the subsequent prevention thereof (anti crystal-engineering), appropriate ions shall be selected which may result in ionic liquid formation. The intermolecular interactions of a series of: • crystallised bis(trifluoromethanesulfonyl)amide (NTf2) and bis(methanesulfonyl)amide (NMes2) ionic liquids, • low melting N-alkyl-2-methyl-3-benzylimidazolium iodide salts with a range of alkyl chain lengths, from n=1 to 6 and including both n-butyl and s-butyl chains, • 1-methyl-1-propylpyrrolidinium chloride and, • a number of low melting salts containing trihalide and monohalide ions, in combination with typical IL organic cations namely, 1-ethyl-3-methylimidazolium, 1-ethyl-1-methylpyrrolidinium and 1-propyl-1-methylpyrrolidinium, were qualitatively investigated and/or compared using a combination of crystallographic, Hirshfeld surface and thermal analysis techniques. The NMes2 salts are known to exhibit higher glass transitions and higher viscosities than those of the NTf2 salts. The origins of these differences were analysed in terms of the importance of factors such as the C-H•••O hydrogen bond, fluorination, presence of an aromatic moiety and length of alkyl chain, using the Hirshfeld surfaces and their associated fingerprint plots. Additionally, the existence of C-F•••π and C-H•••π interactions were elucidated and the significance of anion-anion interactions was recognised. Thermal analysis of the N-alkyl-2-methyl-3-benzylimidazolium iodide salts revealed that the methyl- and (s-)butyl substituted salts have a significantly higher melting point than the rest of the series. Analysis of these crystal structures allowed examination of the influence of the substitutions on the different cation-anion and cation-cation interactions and thus the physical properties of the salts. Thermal analysis of the monohalide and trihalide salts revealed that the tribromide salts are lower melting than their monohalide analogues. Analysis of these crystal structures revealed the influence of the anions and the crystal packing on the physical properties of the salts. A series of crystalline and liquid salts were prepared from cations and anions drawn from Active Pharmaceutical Ingredients (APIs) and Generally Recognized As Safe (GRAS) materials. The solid-state structures of the crystalline salts were used as a basis for the anti-crystal engineering approach in the preparation of several “Active Ionic Liquids” (AILs). However, a side product also resulted during the synthetic route namely, methyl 9H-xanthene-9-carboxylate, a side product resulting from the API, propantheline. The results and methodology of the anti-crystal engineering procedure and the subsequent successful preparation and characterization of pharmaceutical ionic compounds are reported herein.

Synthetic cathinones represent threatening and high abuse-potential designer drugs. These are analogs of cathinone (the b-keto analog of amphetamine (AMPH)) a naturally occurring stimulant found in the plant Catha Edulis. Methcathinone (MCAT) was the first synthetic analog of cathinone to be identified in 1987 by Glennon and co-workers and it exerted its action primarily through the dopamine transporter (DAT). Most central stimulants exert their action via monomaine transporters by causing either the release (e.g. cathinone analogs such as MCAT) or by preventing the reuptake (e.g. cocaine) of the neurotransmitter dopamine (DA) thus increasing the extracellular synaptosomal concentration of this neurotransmitter. In 2010, a new class of designer cathinone-like drugs called ‘bath salts’, initially a combination of methylenedioxypyrovalerone (MDPV), methylone (methylenedioxymethcathione, MDMC) and mephedrone (MEPH), soared to popularity. It caused extremely detrimental side effects; it was exceedingly popular for its recreational use and posed a threat to public health. At the time, their mechanisms of action were unknown. Our group identified that MDPV produced actions distinct from other cathinone analogs (i.e., it was identified as the first cathinone-like compound to act as a reuptake inhibitor at the dopamine transporter (DAT)). These findings suggested that not all cathinone-like compounds act uniformly and this insinuated that unique structural features on the cathinone scaffold might contribute to different effects at the transporter level. The overall goal of this project was to study the mechanisms of action of synthetic cathinones (including ‘bath salts’) at the monoamine transporters. We investigated the contribution of each of various structural features on the cathinone scaffold (i.e, the terminal amine, a and b positions, and the phenyl ring). We also constructed homology models of the human dopamine and serotonin transporters (hDAT and hSERT respectively) to help explain differences in selectivity between the neurochemical and behavioral aspects of DAT and SERT. Overall we found that structural features contributed to similar or distinctive mechanisms of action and also contributed to selectivity at monoamine transporters. Our studies provide information that can be useful to drug and health regulatory agencies to help prevent, treat, or curb the future abuse of such drugs.

The synthetic cathinones, 3,4- methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4- methylenedioxymethcathinone (methylone), gained worldwide notoriety as the psychoactive components of ‘bath salts;’ a marketing term used to circumvent federal drug laws and permit their legal sale. Previous studies have shown that these drugs share pharmacological characteristics with cocaine and the amphetamines, however, descriptions of their neurotoxic properties are limited. Moreover, while forensic analysis has revealed that the most frequently abused bath salts ‘brands’ contain binary and ternary mixtures of MDPV, mephedrone, and methylone, the majority of preclinical research has focused on explicating the individual effects of these drugs. Therefore, the present dissertation aimed to address this limitation and characterize the acute and chronic effects of combined synthetic cathinone exposure on dopaminergic tone in mesolimbic and nigrostriatal brain regions. To accomplish this, male Swiss-Webster mice were administered MDPV, mephedrone, and methylone, individually or concomitantly, 1 time or 7 times over the course of two weeks and the corresponding effects of each treatment on mesolimbic and nigrostriatal brain tissue levels of dopamine (DA) and DA metabolites were analyzed using a high performance liquid chromatography – electrochemical detection (HPLC-ECD) assay. Additionally, motor-stimulant activity was evaluated after both dosing regimens using locomotor activity assays, while immunoblot and immunostaining techniques were used to evaluate the chronic effects of co-synthetic cathinone exposure on tissue levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), monoamine oxidase B (MAO-B), catechol-O-methyltransferase (COMT), and glial fibrillary acidic protein (GFAP). Results from these studies provide evidence of a significant pharmacological interaction among major bath salt constituents, MDPV, mephedrone, and methylone. This was observed acutely as enhanced DA responses and chronically as functional toxicity at the DA synapse. Furthermore, such interactions may contribute to the deleterious effects reported by bath salt users. Together, these findings have shown that the composition of bath salts preparations can significantly influence their psychostimulant and toxic effects, substantiating the importance of modeling bath salts as drug mixtures.

The development of new solid forms of active pharmaceutical ingredients (API) is relevant both from fundamental as well as industrial perspectives. To this end, Crystal Engineering plays an ever-increasing important role in pharmaceutical sciences. Among the crystal engineering strategy, salt formation is the most important and implemented approach. The salt forms of API could be used to modulate and tuned the solubility and stability of API to provide optimal practical uses. Herein, we report pharmaceutical salts of two Selective Serotonin Reuptake Inhibitor antidepressants used in the treatment of depression and anxiety disorders, Paroxetine (PRX) and Fluoxetine (FLX). For this purpose, salt formers, supramolecular synthesis and crystallization protocols have been driven by the systematization of structural and supramolecular data of molecules and analogues from the Cambridge Structural Database. Paroxetine bromide hemihydrate ((PRXBr)0.5H2O), Paroxetine Nitrate hydrate (PRXNO3H2O) and two polymorphs of Fluoxetine Nitrate (FLXNO3) have obtained. All were characterized by a combination of techniques including Single Crystal X-ray Diffraction, Differential Scanning Calorimetry (DSC), Thermogravimetry analysis (TGA), Hot Stage Microscopy, Fourier transform infrared spectroscopy (IR) and solubility measurements. Since the hydration/dehydration process in APIs induces phase transitions that compromise its efficiency, the structural characterization of (PRXBr)0.5H2O help to understand its reversible dehydration process. Also, this study has implication in the understating of dehydration of isostructural PRX hydrochloride salt. Additionally, the (PRXNO3)H2O have shown the conformational flexibility and supramolecular diversity of PRX. On the other hand, the chirality of FLX is related to two nitrate salt polymorphs. A racemate and a non-centrosymmetric structure with independent enantiomers in the asymmetric unit were obtained for FLXNO3. Their packing have shown the existence of different racemic motifs, resulting in different enantiomer orientations The rare occurrence of racemic systems in non-centrosymmetric space groups becomes this event a noteworthy case. By their physicochemical properties, the polymorphs were monotropically related. The scientific contributions of this thesis show the diversity of the solid forms and define candidates to new antidepressants APIs solid formulations.
O desenvolvimento de novas formas sólidas de ingredientes farmacêuticos ativos (API) é relevante tanto numa perspectiva fundamental como industrial. Para tal, a Engenharia de cristais tem desempenhado um papel importante nas ciências farmacêuticas. Dentre as estratégias, a formação de sais é a abordagem mais importante e implementada. Os sais de APIs são capazes de modular e ajustar a solubilidade e a estabilidade, a fim de proporcionar uso prático. Nesta tese, são reportados sais de dois fármacos Inibidores Seletivos de Recaptação de Serotonina, consolidados no tratamento da depressão e distúrbios de ansiedade, a Paroxetina (PRX) e a Fluoxetina (FLX). Brometo de Paroxetina hemiidratado ((PRXBr)0.5H2O), Nitrato de Paroxetina hidratado (PRXNO3H2O) e polimorfos de Nitrato de Fluoxetina (FLXNO3), síntese e protocolos de cristalização foram cuidadosamente delineados, com base na sistematização de dados estruturais e supramoleculares das moléculas e seus análogos, depositados no Cambridge Structural Database. Todos os sais foram caracterizados por Difração de Raios-X por Monocristal, Calorimetria Explanatória Diferencial (DSC), Análise termogravimétrica (TGA), Termomicroscopia, Espectroscopia vibracional na região do infravermelho (IR) e solubilidade. Considerando que a hidratação/desidratação induz mudanças de fases que comprometem a eficiência do API, a caracterização do (PRXBr)0.5H2O auxiliou no entendimento do processo de desidratação reversível que ocorre para esse fármaco. Estas mudanças de fase resultam também em implicações sobre a compreensão do processo de desidratação do sal isoestrutural de cloreto de PRX hemiidratado. Além disso, por meio da elucidação estrutural do (PRXNO3)H2O, foi possível analisar a diversidade conformacional e supramolecular da PRX. Quanto à FLX, verificou-se que sua quiralidade está relacionada com seu polimorfismo. Um racemato e uma estrutura não centrossimétrica com dois enatiômeros independentes na unidade assimétrica foram obtidos para o FLXNO3. A comparação destas estruturas permitiu mostrar a existência de arranjos supramoleculares racêmicos, constituídos por diferentes orientações de enatiômeros. A rara ocorrência de sistemas racêmicos em grupos espaciais não-centrossimétricos tornou este evento um caso notável. A partir das propriedades físico-químicas, os polimorfos puderam ser monotropicamente relacionados. Os resultados desta tese trazem importantes contribuições científicas para diversidade de formas sólidas e também define novas formulações sólidas para utilização como antidepressivos.

Pharmaceutical companies and FDA (Federal Drug Administration) rules rely heavily on crystalline active pharmaceutical ingredients delivered as tablets and powders in the form of neutral compounds, salts and solvates of neutral compounds and salts. About half of all drugs sold in the market are in the form of salts which are held together by ionic bonds along with some other forces. Recently, Ionic liquids (ILs) an interesting class of chemical compounds have offered potential opportunity for exploration as novel drug ionic liquid salts, particularly in the field of transdermal/topical drug delivery. Due to the multifunctional nature of these salts they could allow generation of new pathway to manipulate the transport and deposition behaviour of the drug molecule. It is this modular approach of IL that forms the basis of the research presented here, in which pharmaceutically acceptable compounds are combined with selected drugs with known problems. IL salts were generated by combining at least one drug molecule with FDA approved compounds and were assessed for physicochemical properties, skin deposition and permeation studies. Skin deposition data suggested that these systems exhibit high skin retention, which was found to correlate with the molecular weight. On the other hand, permeation data displayed an inverse relationship between flux values and molecular weight of the permeant. Similar work was extended with ILs with mixed anions containing two drugs. The benzalkonium-sulfacetamide ILs were investigated for synergism and the biological studies data display no synergistic effect. It was also illustrated that in-situ IL based ibuprofen hydrogels systems could be manipulated via IL approach for topical application. These findings suggest the potential applicability of IL based formulations for topical delivery of drugs.

Asthma is a significant lung disease involving chronic inflammation and remodeling of the airways, resulting in reduced quality of life for those who suffer from the condition. Current therapeutic guidelines suggest the use of inhaled corticosteroids for long-term anti-inflammatory relief to manage moderate to severe chronic asthma; however, inhaled corticosteroids fail to provide prophylactic or reversal treatment of damaged airways incurred by chronic asthma as well as exhibiting adverse side effects (skeletal complications, diabetes, and weight gain).Therefore, there is a need for a new type of drug therapy to address these gaps in the treatment of chronic asthma. There is growing interest aimed towards the inhibition of the Janus Kinase and Signal Transducer and Activator of Transcription (JAK-STAT) pathway for the treatment of asthma. Despite the promising opportunity to investigate this new pathway towards this clinical application, no published work is available using an established and characterized JAK 1/3 inhibitor for the treatment of chronic asthma delivered via inhalation. This work investigated tofacitinib citrate, a selective JAK 3 inhibitor, and its potential to be delivered locally to the lungs for the treatment of chronic asthma. Several preformulation studies were conducted to determine the basic physical and chemical properties of the compound and its free base, tofacitinib, for proper inhalational formulation development. The drug was delivered to BALB/c mice challenged with house dust mite (HDM) allergen via nebulization utilizing a nose-only chamber. After a three week dosing schedule, mice treated with tofacitinib citrate exhibited an increase in monocyte cell numbers with a simultaneous decrease in eosinophil cell count, gathered from BAL fluid. Further, the experimental groups treated with tofacitinib citrate had a decrease in total protein concentrations in comparison to the experimental groups that were only challenged with HDM or were both exposed to HDM and vehicle. These findings demonstrated that the proper formulation was developed for nebulized delivery of tofacitinib citrate, and that the compound was capable of reducing total protein concentrations and eosinophil cell recruitment, both recognized as biomarkers for an asthmatic response. Although significant work is still needed to be done, these data hold promise for the potential of a locally delivered JAK 3 inhibitor as a treatment for chronic asthma. Further, the solubility of tofacitinib citrate and five other pharmaceutical salts were determined in HFA 134a, HFA 227, and DFP with varying cosolvent content (0-20% v/v ethanol). The experimental solubilities of the free acid and base compounds were larger than the solubilities of their respective salts in all three systems for tofacitinib, albuterol, and salicylic acid. Warfarin, phenytoin, and ciprofloxacin had similar solubilities with their respective salt forms. Solubilities also increased with increasing cosolvent concentration for all compounds investigated. The model propellant, DFP, provided a slightly stronger correlation of solubility values with HFA 134a in comparison to HFA 227. The observed solubility values were also compared to calculated values obtained from the ideal solubility model, where it was determined that the observed solubility was indeed also dependent on its surrounding solvent interactions and not solely on its ideal solubility (melting point). While some physical changes were observed for the pharmaceutical salts in HFA 134a and 227, more quantitative studies are needed for a larger database of compounds to better understand the factors that contribute to the solubility of pharmaceutical salts (and their correlation to DFP), in HFA-based systems. This information could potentially contribute to a predictive model, saving time and money during the process of pMDI formulation development.

Capillary electrophoresis (CE) is a modern analytical technique, which is electrokinetic separation generated by high voltage and taken place inside the small capillaries. In this dissertation, several advanced capillary electrophoresis methods are presented using different approaches of CE and UV and mass spectrometry are utilized as the detection methods. Capillary electrochromatography (CEC), as one of the CE modes, is a recent developed technique which is a hybrid of capillary electrophoresis and high performance liquid chromatography (HPLC). Capillary electrochromatography exhibits advantages of both techniques. In Chapter 2, monolithic capillary column are fabricated using in situ photoinitiation polymerization method. The column was then applied for the separation of six antidepressant compounds. Meanwhile, a simple chiral separation method is developed and presented in Chapter 3. Beta cycodextrin was utilized to achieve the goal of chiral separation. Not only twelve cathinone analytes were separated, but also isomers of several analytes were enantiomerically separated. To better understand the molecular information on the analytes, the TOF-MS system was coupled with the CE. A sheath liquid and a partial filling technique (PFT) were employed to reduce the contamination of MS ionization source. Accurate molecular information was obtained. It is necessary to propose, develop, and optimize new techniques that are suitable for trace-level analysis of samples in forensic, pharmaceutical, and environmental applications. Capillary electrophoresis (CE) was selected for this task, as it requires lower amounts of samples, it simplifies sample preparation, and it has the flexibility to perform separations of neutral and charged molecules as well as enantiomers. Overall, the study demonstrates the versatility of capillary electrophoresis methods in forensic, pharmaceutical, and environmental applications.

In recent years, the abuse of synthetic cathinones or ‘bath salts’ has become a major public health concern. Although these compounds were initially sold legally and labeled “not for human consumption”, the ‘bath salts’ are psychostimulants, with similar structures and pharmacologic mechanisms to cocaine, the amphetamines, and 3,4 methylendioxymethamphetamine (MDMA, Molly, or Ecstasy). The reported use of these substances by women of child-bearing age highlights the necessity of studies seeking to delineate risks of prenatal exposure. Three popular drugs of this type are methylone, mephedrone, and 3, 4-methylenedioxypyrovalerone (MDPV). Unfortunately, there is currently no information available on the teratogenicity of these compounds, or of the extent to which they cross the placenta. As such, the purpose of this study was to examine the pharmacokinetic profile of the ‘bath salts’ in a pregnancy model. Pregnant mice (E17.5 gestation) were injected intraperitoneally with a cocktail of 5mg/kg methylone, 10mg/kg mephedrone, and 3mg/kg (MDPV) dissolved in sterile saline. Maternal brain, maternal plasma, placenta, and fetal brain were collected at 30s, 1min, 5min, 10min, 15min, 30min, 1h, 2h, 4h, and 8h following injection. Methylone, mephedrone, and MDPV were extracted from tissue by solid phase extraction, and concentrations were determined using a previously validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Interestingly, all 3 cathinones reached measurable concentrations in the placenta, as well as the fetal brain; in fact, for MDPV, the maximal concentration (Cmax) was highest in fetal brain, while mephedrone's highest Cmax value was achieved in placenta. Additionally, the total drug exposure for all 3 compounds (as represented by area under the curve, AUC) was higher in fetal matrices (placenta and fetal brain) than in maternal matrices (maternal brain and plasma), and the half-lives for the drugs were longer. Given the extensive presence of methylone, mephedrone, and MDPV in the fetal brain following prenatal exposure, fetal risk is definitely a concern. As there are currently no prenatal studies available on the teratogenicity of these agents, pregnant patients should be informed about the potential risks that these substances may have.

Thesis (MSc)--Stellenbosch University, 2014.
ENGLISH ABSTRACT: A theoretical and experimental study was performed in order to identify factors that influence the propensity of compounds containing anionic functional groups that are commonly found on pharmaceutical drug compounds to form hydrates. A Cambridge Structural Database (CSD) survey was initially undertaken to determine the propensity of different pharmaceutically acceptable anions to form hydrates. The results showed that hydrate formation will take place more regularly when the polarity of the functional group increases. Furthermore, if the charge distribution is very concentrated over the polar groups, hydrate formation will occur more readily. This observation was further investigated by performing a series of potential energy surface (PES) scans for the hydrogen bond (H-bond) in the structure of N-(aminoiminomethyl)-N-methylglycine monohydrate (creatine monohydrate) with various Density Functional Theory (DFT) and Wave Functional Theory (WFT) methods. WFT is often also referred to as ab initio, which refers to the construction of the wave function from first principles when this theory is applied. The scans revealed that several strong and directional H-bonds with different geometrical parameters between the carboxylate group and the water molecule are possible, which suggests that the H-bond plays an important role in driving the formation of pharmaceutical hydrates. A total of 44 hydrate structures were identified that have pharmaceutically acceptable functional groups. Optimisations in the gas phase and in an implicit solvent polarisable continuum solvent model with a variety of solvents showed that there is a significant dependence of the H-bond interaction energy on the anionic group as well as the steric density of surrounding substituents. It was found that the M06-2X method utilising the 6-311++G(d,p) basis set outperformed the other methods that were tested when compared to optimisations performed with the benchmark MP2/aug-cc-pVTZ level of theory. Furthermore, the strength of the H-bond was measured in the 44 experimentally determined structures by using a total of five generalized gradient approximation (GGA) methods, of which two methods contained the DFT-D3 correction. The results of these DFT methods were subsequently compared to results obtained at the benchmark MP2/aug-cc-pVTZ level of theory. The M06-2X method was identified as the most economical method to calculate H-bond energies. It was also found that the H-bond interaction energy shows a substantial dependence on the electrostatic environment. This was observed by a significant decrease in H-bond strength as the relative permittivity of the solvent increases. The effect of steric density on the H-bond interaction energy was investigated by performing hydrogen bond propensity calculations. These values were then compared to the interaction energies of each structure and the results showed that the presence of large bulky substituents can lead to an increase in bond energy by forcing the anionic functional group closer to the water molecule. Contrastingly, the bulky group can also push the anionic group away from the water molecule and result in a decrease in bond energy. Approximate values for the amount of stabilisation offered to the H-bonding system by the surrounding crystalline environment were calculated by optimising the H-bond geometrical parameters of selected compounds with a combination of the M06-2X and MP2 methods utilising the 6-311++G(d,p) basis set. The H-bond interaction energies were then calculated at the M06-2X/6-311++G(d,p) level of theory and compared to the H-bond interaction energies in geometries that have been fully optimised. After these energies were compared and the crystal packing of each structure was investigated, it was found that the packing of some structures within the crystalline environment limits the number of H-bonds that can be formed between the water and the compound of interest. Full optimisation calculations result in structures with cooperative stabilisation, such that more than one H-bond is found between the two fragments. The effect of substituents on H-bond interaction energy was investigated by the addition of six electron-donating and electron-withdrawing groups on four aromatic compounds with different anionic functional groups, namely carboxylate, nitrogen dioxide, sulfonate and phosphonate. It should also be mentioned that the nitrogen dioxide is not an anionic functional group, but it was included as it is a neutral radical that often forms hydrogen bonds. A total of 80 structures were optimised with a combination of the M06-2X and MP2 methods utilising the 6-311++G(d,p) basis set. This was followed by counterpoise corrected single point calculations at the M06-2X/6-311++G(d,p) level of theory. The results showed that the H-bond interaction energy bears no relationship to the inductive strength or the inductive ability of the substituents, but rather the ability of these substituents to rotate the anionic functional group and allow cooperative stabilisation of the H-bond. Furthermore, AIM analysis was performed for the substituted H-bonded aromatic structure. The results showed that electron-donating groups that are placed at the para position yield stronger H-bonds, which is once again accompanied by cooperative stabilisation. Electron-withdrawing groups with sufficient inductive effects can result in a weaker H-bond when placed at the meta position. The effect of water activity (aw) on the hydrate crystal formation was investigated experimentally by performing a series of crystallisations in various solvent mixtures. These mixtures consisted of water mixed with acetone, ethanol and ethyl acetate. A total of three organic acids were used in crystal formation, namely pyridine-4-carboxylic acid (isonicotinic acid), N-amino-iminomethyl-N-methylglycine (creatine) and benzene-1,3,5-tricarboxylic acid. It was found that water activity affects the formation of the hydrate as well as the anhydrous product. Additionally, nucleation and super saturation plays a large role in crystal formation and can serve as an effective technique when the formation of crystals of an appropriate shape and size is required for further analysis.
AFRIKAANSE OPSOMMING: 'n Teoretiese en eksperimentele studie was uitgevoer om faktore te identifiseer wat die geneigdheid van verbindings met anioniese funksionele groepe wat algemeen gevind word op farmaseutiese dwelm verbindings om die hidraat produk te vorm, affekteer. 'n Opname van strukture in die Cambridge Strukturele Databasis (CSD) is onderneem om die geneigdheid van verskillende farmaseutiese aanvaarbare anione om hidrate te vorm te bepaal. Die resultate het getoon dat hidraatvorming meer gereeld plaasvind indien die polariteit van die funksionele groepe toeneem. Verder is daar ook opgemerk dat 'n gekonsentreerde ladingsverspreiding op die polêre groepe ook tot 'n toename in hidraat vorming sal lei. Hierdie waarneming is verder ondersoek deur 'n reeks potensiële energie oppervlak (PES) skanderings van die waterstof binding (H-binding) vir die struktuur van N-amino-iminometiel-N-metielglisien monohidraat (kreatien monohidraat) met verskeie Digtheids-Funksionele Teorie (DFT) en Golffunksie Teorie (WFT) metodes uit te voer. Die skanderings het getoon dat verskeie sterk, gerigte H-bindings met verskillende geometriese parameters tussen die karboksilaatgroep en die watermolekule kan vorm. Hierdie bevindinge lê klem op die belangrike rol wat H-bindings in die vorming van farmaseutiese koolhidrate speel. 'n Totaal van 44 hidraat strukture met farmaseutiese aanvaarbare funksionele groepe was geïdentifiseer. Optimaliserings is in die gas fase asook in 'n implisiete kontinuum polariseerbare oplosmiddel model met 'n verskeidenheid oplosmiddels uitgevoer. Die resultate het 'n beduidende afhanklikheid van die H-binding interaksie-energie op die anioniese groep asook die steriese afkskerming van omringende groepe getoon. Daar is bepaal dat die M06-2X metode wat saam met die 6-311++G(d,p) basisstel die mees akkuraatste resultate gelewer het in vergelyking met die ander DFT metodes asook die MP2/aug-cc-pVTZ maatstaf. Die H-binding se sterkte is vir hierdie strukture bereken deur vyf GGA metodes te gebruik, waarvan twee metodes van die DFT-D3 korreksie gebruik maak. Die resultate van die berekeninge met hierdie DFT metodes is daarna vergelyk met resultate verkry met die MP2/aug-cc-pVTZ maatstaf. Daar is gevolglik bepaal dat die M06-2X metode die mees ekonomiese metode is om H-binding energië te bereken. Die H-binding interaksie energie toon 'n aansienlike afhanklikheid op die diëlektriese konstante van die oplosmiddel aan. Hierdie waarneming is op grond van 'n beduidende afname in die H-binding interaksie-energie indien die relatiewe permittiwiteit van die oplosmiddel verhoog word gemaak. Die effek van steriese digtheid is ondersoek deur waterstofbindinggeneigdheid waardes te bereken. Hierdie waardes is met die interaksie-energië van elke struktuur vergelyk. Die resultate dui daarop dat steries digte groepe tot 'n toename in interaksie energie kan lei wanneer die anioniese funksionele groep nader aan die water molekule gestoot word. Verder is dit ook moontlik vir hierdie steries digte groepe om die anioniese groep weg van die water molekule te stoot en gevolglik 'n afname in interaksie energie te veroorsaak. Benaderde waardes vir die hoeveelheid stabilisering wat die omringende kristallyne omgewing aan die H-binding bied is bereken deur die H-binding geometriese parameters van geselekteerde verbindings met die M06-2X en MP2 metodes en die 6-311++G (d,p) basisstel te optimaliseer. Die H-binding interaksie-energië is gevolglik by die M06-2X/6-311++G(d,p) vlak van teorie bereken en met die H-binding energië in strukture wat volledige optimaliseer is vergelyk. Nadat hierdie waardes vergelyk is, is daar gevind dat die pakking van strukture in the kristallyne omgewing verhoed dat sekere H-bindings tussen die water molekule en die verbinding van belang kan vorm. Strukture wat volledig optimaliseer is, lei tot strukture wat in staat is om koöperatiewe stabilisering te ondergaan. Koöperatiewe stabilisering word gekenmerk deur die vorming van meer as een H-binding tussen twee fragmente. Die effek van substituente op die H-binding interaksie energie is ondersoek deur die bevoeging van ses elektrondonor- en elektronontrekkendegroepe op vier aromatiese verbindings, naamlike die karboksilaatgroep , stikstofdioksied , sulfonaat en fosfonaat. Dit moet ook genoem word dat stikstofdioksied nie 'n anioniese funksionele groep is nie, maar dit was wel ingesluit omdat dit ‘n neutrale radikaal groep is wat dikwels waterstofbindings vorm. 'n Totaal van 80 strukture optimiserings was uitgevoer met 'n kombinasie van die M06-2X en MP2 metodes wat gebruik maak van die 6-311++G(d,p) basisstel. Dit is gevolg deur interaksie-energie berekeninge op die M06-2X/6-311++G(d,p) vlak van teorie. Die resultate het getoon dat daar geen verband tussen die induktiewe vermoë van die substituente en die sterkte van die H-binding is nie, dit is eerder die vermoë van hierdie substituente om die anioniese funksionele groep te laat roteer wat toelaat dat koöperatiewe stabilisering van die H-binding kan geskied. Die AIM analise is op 'n gesubstitueerde H-binding struktuur toegepas. Die resultate het getoon dat elektrondonorgroepe wat by die para posisie geplaas word tot sterker H-bindings sal lei, wat weereens met koöperatiewe stabilisering vergesel word. Elektrononttrekkendegroepe met sterk induktiewe effekte kan tot 'n swakker H-binding lei indien hulle by die meta posisie geplaas word. Die effek van water aktiwiteit (𝑎w) op hidraatkristalvorming is deur die uitvoering van 'n reeks kristallisasies in verskeie oplosmiddelmengsels ondersoek. Hierdie oplosmiddel mengsels bestaan uit water met asetoon, etanol of etielasetaat gemeng. Kristallisasies is vir drie organiese sure, naamlik piridien-4-karboksielsuur, N-amino-iminometiel-N-metielglisien monohidraat en 1,3,5-benseen tri-karboksielsuur uitgevoer. Daar is gevind dat water aktiwiteit 'n invloed op die vorming van die hidraat en watervrye produkte kan hê. Daarbenewens, speel water aktiwiteit 'n belangrike rol in die nukleasie fase van kristalvorming en kan as 'n effektiewe tegniek dien om kristalle van 'n toepaslike vorm en grootte vir verdere analise te verkry.

The present dissertation investigates the influence of brand as well as substance-related marketing attributes on prescription pharmaceutical sales within a state-controlled market. For this purpose, a systematic literature review was conducted in the first instance, during which knowledge about the most relevant research within this field was gathered. Consequently, over 538 publications were reviewed and indicated as being potentially relevant, leading to an eventual count of 98 core publications. However, most of these studies had been conducted in the mainly unrestricted US market. These findings were then summarised and statistically evaluated. In a second step, based on the literature review, a qualitative study, containing focus and Delphi groups, was then performed. The participants in these studies were involved in pharmaceutical marketing within a state-controlled prescriptions pharmaceuticals market. Consequently, the findings were slightly different to those derived by the systematic literature review. Based on this second step, seven hypotheses were proposed. In the third step, these hypotheses were tested, using collected data and a secondary market dataset provided by a market research institute. A statistical analysis was then performed, applying descriptive as well as multiple regression analytical methods. The evaluation of the results resulted in a conceptual model of physician targeting, leading to several theoretical, methodological and managerial implications.

The process of milling drugs to obtain samples with a desirable particle size range has been widely used in the pharmaceutical industry, especially for the production of drugs for inhalation. However by subjecting materials to milling techniques surfaces may become thermodynamically activated which may in turn lead to formation of amorphous material. Polymorphic conversions have also been noted after milling of certain materials. Salt and cocrystal formation is a good way of enhancing the properties of an API but little or no work has been published which investigates the stability of these entities when subjected to milling. Different milling techniques (ball and jet) and temperatures (ambient and cryogenic) were used to investigate the milling behaviour of polymorphs, salts and cocrystals. All materials were analysed by XRPD and DSC to investigate any physical changes, i.e. changes in melting point and by inverse gas chromatography (IGC) to investigate whether any changes in the surface energetics occurred as a result of milling. Another aim of this thesis was to see if it was possible to predict the milling behaviour of polymorphs by calculating the attachment energies of the different crystal facets using Materials Studio 4.0. These results were compared to the IGC data to see if the predicted surface changes had occurred. The data collected in this study showed that different milling techniques can have a different effect on the same material. For example ball milling at ambient temperature and jet micronisation of the SFZ tosylate salt caused a notable increase in the melting point of the material whereas ball milling at cryogenic temperatures did not cause this to happen. The IGC data collected for this form also showed a contrast between cryomilling and the other two techniques. The study also showed that the formation of salts and cocrystals does not necessarily offer any increased stability in terms of physical properties or surface energetics. Changes in melting point were observed for the SFZ tosylate salt and the IMC:Benzamide cocrystal. Changes in the specific surface energies were also observed indicating that the nature of the surfaces was also changing. The materials which appeared to be affected the least were the two stable polymorphs, gamma IMC and SFZ III. The computational approach used has many limitations. The software does not allow for conversion to the amorphous form or polymorphic conversions. Such conversions were seen to occur, particularly for the metastable polymorphs used, meaning that this computational approach may only be suitable for stable polymorphs.

The principle behind outsourcing is that an organization outsources tasks it strategically elects not to do within the organization. It is estimated that outsourcing has become a $4 trillion a year business (Corbett, 2005). In today's competitive healthcare marketplace, many sponsors outsource functions that were once considered core to the organization. U.S. Census data show that 10% of all business-to-business sales originated from outsourced sales (Rogers, 2008). The objective of engaging in outsourcing of sales is to improve sales efficiency and gain an edge in today's challenging market. Competition within the pharmaceutical industry coupled with increased regulatory uncertainties and cost concerns have necessitated outsourcing of sales to maintain competitiveness and to apply internal resources more effectively. This research will contribute to the current available works specific to the outsourcing of pharmaceutical sales.

Salt formation is an important technique used in preclinical pharmaceutical development to modulate and optimise the physicochemical properties of a drug molecule containing an ionisable functional group. The current approach to salt selection relies on semi-empirical screening of the pharmaceutical molecule in combination with different counterions for the formation of a crystalline salt. This approach is necessitated by the limited understanding of the relationships between molecular and supramolecular structure and properties and the stoichiometry and ionisation state of the resultant crystalline solid. Presented in this work is a structural database containing 110 novel multi-component crystalline systems produced by the co-crystallisation of a library of pharmaceutically acceptable organic acid counterions with basic molecules that model the functional groups found on pharmaceutically active molecules. The structures were characterised by single crystal X-ray diffraction and their hydrogen bond interactions and molecular packing arrangements were examined using Mercury and XPac. This enabled the identification of robust hydrogen bonded synthons and supramolecular constructs for salts of secondary or tertiary amine bases in combination with different types of counterion. These observations were correlated to the molecular structures of the salt formers and a series of "salt selection rules" that can be potentially used to guide counterion selection for a novel pharmaceutical molecule were established. The applicability of these rules was assessed by the crystallisation of a validation set of 29 novel fluoroquinolone structures. Variable-temperature X-ray powder diffraction and structure determination from powder diffraction data were employed to generate four novel anhydrous salts from their corresponding hydrates. Comparison of the hydrogen bond interactions and molecular packing arrangements allowed the examination of the structural role of water in determining and stabilising the supramolecular structures of the hydrated systems.

O emprego de aditivos hidrossolúveis como açúcares, tensoativos, sais e polímeros é prática comum na tentativa de se estabilizar proteínas durante aquecimento. Diversos polímeros têm sido utilizados para estabilizar proteínas, sendo seu efeito dependente das características da proteína. Sais podem estabilizar, desestabilizar ou não ter efeito na estabilidade de proteínas; dependendo do tipo, concentração, natureza das interações iônicas e resíduos carregados da proteína. A termoestabilidade da proteína verde fluorescente (GFP) tem sido demonstrada ao calor úmido, à temperaturas elevadas (T ≥ 95°C), à valores de pH alcalinos e a alguns agentes químicos. Sua denaturação térmica é altamente reprodutível e a variação da intensidade de fluorescência pode ser facilmente determinada por espectrofluorimetria. O objetivo deste trabalho foi estudar o comportamento da GFP na presença de diferentes soluções aquosas de polímeros (polietileno glicol, DEAE-Dextrana e ácido poliacrílico) e sais (citrato e fosfato). A partir dos dados obtidos, pode-se concluir que o citrato favoreceu a preservação da estrutura nativa da GFP nas temperaturas estudadas (70 a 95ºC), em concentrações acima de 10% m/m. O ácido poliacrílico também auxiliou na manutenção da estrutura nativa da GFP, porém em menor intensidade, e com concentrações acima de 20% m/m.
The addition of hydrosoluble excipients, such as, sugars, surfactants, salts and polymers is a common practice in the intent of stabilization of proteins during heating. Several polymers have been used to proteins stabilization, being their effect dependent of protein characteristics, however in some cases, it could cause a reduction of stability. Salts can stabilize proteins, or have no influence in their stability, and these behaviors depend on the type, concentration, ionic interaction and charged protein residues. Thermal stability of green protein fluorescent (GFP) have been demonstrated to humid heat, elevated temperatures (T ≥ 95°C), alkaline pH and to some chemical agents. Its thermal denaturation is highly reproducible and the variation of fluorescence intensity can be easily determinate by spectrofluorometry. The objective of this work was study the behavior of GFP in the presence of different aqueous solutions of polymers (polyethylene glycol, DEAE-Dextran and acid polyacrylic) and salts (citrate and phosphate). From the results, it may be concluded that the citrate favored the preservation of native structure of GFP in the temperatures studied (70ºC to 95ºC), in concentrations above 10% m/m. The PAA polymer also favored the GFP thermal stability, but in a minor intensity and in concentrations above 20% m/m.

There are so many different communication styles utilized by pharmaceutical sales representatives. This thesis handles the quandary of whether those communication styles are not only effective among the interactions with medical providers, but whether those effective means of communicating are embedded with ethical communication as well. The theory of symbolic interactionism and the philosophical basis of persuasive speech expound on the methodology pharmaceutical sales representatives implement with the people he or she encounters. Medical providers also need to perceive that their encounters with pharmaceutical sales representatives are congruently effective and ethical interactions, which is revealed by qualitative research methods in the thesis. Lastly, the pharmaceutical sales representative's effective and ethical communication provides recommendations in how to maintain the proper perspective of keeping these medical interactions with the greatest credibility and reputation. Keywords: Pharmaceutical sales representative (PSR), symbolic interactionism, persuasive speech, nonverbal communication, ethical communication, creating reality

The improvement of the sales quotas development process in Spanish pharmaceutical organisations is challenging as the market environment becomes dramatically complex. Setting sales quotas has always been difficult, exemplified by the difficulties in quantifying future sales by sales territory. Extensive research has been conducted and several conceptual models created to facilitate the process of developing sales quotas. Effective management of this process has proved problematic mainly due to difficulties in estimating future sales by territory, the complexity of the systems utilised in the process, the granularity of the data required and the lack of attention to implementation issues. Therefore, determining organisational capabilities that facilitate developing an effective sales quotas process is paramount. This study uses goal setting theory to understand organisational capabilities for the sales quota development process. A sales quota development process for a mid-sized pharmaceutical organisation was examined in terms of activities, which satisfied stakeholders’ expectations. Based on empirical data organisational capabilities were identified and prioritised. Goal setting theory is advanced through the development of the SQD Model that includes a set of sixteen organisational capabilities that are critical for developing an effective sales quotas process for pharmaceutical organisations. This study created the SQP Maturity Framework, a diagnostic tool that allows organisations to assess their sales quota development process and understand which capabilities to acquire or further develop to improve the process. Differences by organisational contexts are highlighted. The focus of this research is the pharmaceutical sector in Spain. The organisational capabilities uncovered and assessed will be relevant to these and other sectors that rely on sales forces. Areas for future research include the replication of this study in different geographies and sectors focusing on identifying more organisational capabilities and routines that facilitate moving organisations towards an optimised level of maturity.

Thesis (MBA)--Stellenbosch University, 2002.
Some digitised pages may appear illegible due to the condition of the original hard copy.
ENGLISH ABSTRACT: A few years ago, pharmaceuticalcompanies were more inclined to look at business from the inside out. The principal focus was on the company's goals, and identifying and selling to customers were the method of achieving those goals. However,today the customer is king and therefore the focus is shifting to accommodatethis change. The road to success - or failure - is now an expressway, and companies must be ready to accelerate,tum, or stop quickly. Flexibilityand manoeuvrabilitymean a great deal in an increasinglycompetitivemarketplace(Gabe & Goldberg, 1999). What makes a sales team effective in today's competitive global market? What are the key drivers of success in pharmaceutical sales team effectiveness? The most prominent trend in the US market is customer focus, and the most prominent issue is the recruitment and retention of top performers. Today's focus on relationship building may have occurred in part because companies found that their relationships were less than ideal. Nearly 60% of US pharmaceutical companies use customersatisfaction results, among other measurements, to determine the effectiveness of their sales force. A sales force that can make the transition from selling the product to selling the solution - which is the essence of customer focus - has a better chance of earning customer confidence and "partnering" (Gabe & Goldberg, 1999). To isolate factors that make a pharmaceutical sales representative effective is not easy. The best pharmaceutical representatives have excellent selling skills and behaviours, exhibit consistent performance, build networks, contribute to their teams, focus on the most profitable accounts, open new accounts, and win customer loyalty. How does one identify top pharmaceutical salespeople? Look for the representatives with the ability to learn continuously from experience, to take full responsibility for professional development, to size up each situation, and to apply the most effective skills for that encounter. Most often, they will be the ones using consultative and adaptive selling dialogue techniques (Snader, 2002). According to the study, it was evident that the following effectiveness criteria or selling task characteristics have a definite impact on sales force effectiveness and in turn should be part of every salesperson's capabilities: territory management, objection handling, business planning, adaptive selling, customer focus, knowledge, service, selling skills and training.
AFRIKAANSE OPSOMMING: In die verlede was farmaseutiese maatskappye geneig om hul besigheid van binne na buite te ontleed. Die belangrikste fokuspunt was die maatskappy se doelwit en die identifisering van, en verkope aan hul kliënte die middel tot die doelom hierdie doelwitte te bereik. Vandag, daarenteen kraai die kliënt koning en die fokuspunt het verskuif om by hierdie verandering aan te pas. Die verskil tussen die sukses en mislukking van 'n maatskappy sal afhang van die buigsaamheid en stuurbaarheid van die maatskappy om gereed te wees vir enige aksie in hierdie toenemend mededingende mark (Gabe & Goldberg, 1999). Wat maak 'n verkoopspan doeltreffend in vandag se mededingende globale mark? Wat is die sleutel eienskappe wat sukses sal waarborg vir 'n farmaseutiese verkoopspan? Die belangrikste neiging in die Amerikaanse mark is kliënte-fokus en die mees prominente kwessie is die werwing en behoud van die top presteerders. Die fokusverskuiwing na die verhouding tussen die verkoopsverteenwoordiger en die kliënt het plaasgevind nadat maatskappye besef het hulle het nie ideale verhoudings met hulle kliënte nie. Nagenoeg 60% van alle Amerikaanse farmaseutiese maatskappye gebruik onder andere ook resultate van kliënte-tevredenheid vraelyste as 'n maatstaf om die doeltreffendheid van hulle verkoopspan te bepaal. 'n Verkoopspan wat in plaas van 'n produk verkoop eerder aan die kliënt 'n oplossing vir sy spesifieke probleem bied - wat die kern van 'n kliënt-gefokusde benadering is - skep vertroue by die kliënt en lei tot 'n suksesvolle vennootskap tussen die partye (Gabe & Goldberg, 1999). Dit is baie moeilik om eienskappe te identifiseer wat 'n farmaseutiese verteenwoordiger se doeltreffendheid verseker. Die beste farmaseutiese verkoopsverteenwoordigers gebruik uitstekende verkoopstegnieke, bou netwerke, is goeie spanlede, fokus op die mees winsgewendste kliënte, wen nuwe kliënte en die lojaliteit van hulle kliënte. Hoe word top farmaseutiese verkoopspersone dan geïdentifiseer? Kyk uit vir die verteenwoordiger wat die vermoeë het om te leer uit ondervinding, wat volle verantwoordelikheid neem vir sy persoonlike ontwikkeling, wat elke situasie ontleed en dan die toepaslike vaardighede gebruik vir die spesifieke situasie. Meestal sal dit die verteenwoordigers wees wat konsulterende en adaptiewe dialoogtegnieke gebruik (Snader, 2002). Volgens die studie was dit duidelik dat die volgende kriteria vir doeltreffende verkope of verkoopseienskappe 'n defnitiewe impak het op 'n verkoopsspan se doeltreffendheid en dus deel moet uitmaak van elke verkoopspersoon se vermoë: Areabestuur, die hantering van objeksies, besigheidsbeplanning, 'n adaptiewe verkoopstyl, 'n kliënt gefokusde benadering, kennis, diens en opleiding.

Ethics and compliance training of sales managers in the U.S. pharmaceutical industry showed little evidence that eLearning interventions developed to address employees' (a) awareness of unethical sales practices, (b) ability to judge a selling practice as unethical, and (c) intentions to speak up about unethical sales practices have had the desired effects. The purpose of this study was to compare the effectiveness of an entertainment-education video to an eLearning course, to improve ethical issue awareness, ethical judgment, and speaking-up behaviors in the pharmaceutical sales profession. Social cognitive theory and the extended elaboration likelihood model provided a theoretical framework for studying the effects of entertainment-education. The primary research question was, if entertainment-education programs can be used as an effective methodology to improve ethical decision-making and increase intentions to speak up, compared to a narrative-style eLearning course. In this quantitative study, 64 sales professionals from a U.S.-based pharmaceutical company were randomly assigned to either an entertainment-education video or an eLearning group to compare the effects of intervention format on ethical issue awareness, ethical judgment, and intentions to speak up, measured using two ethical scenarios and surveys. Although both treatments had a significant effect on behavioral intentions to speak up, there was only a moderate difference between the two groups t(62) = 2.20, p = .032 when participants observed a patient safety issue. Results from this study may impact social change by providing compliance managers with evidence to evaluate the use of entertainment-education strategies to increase sales representatives' intentions to speak-up when they observe behaviors that may put patient safety at risk.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007.
Includes bibliographical references (leaves 71-73).
The leading publicly traded pharmaceutical companies ("Big Pharma) in the US are facing a commercial crisis - their sales structure collectively consisting of more than 100,000 pharmaceutical sales representatives, originally setup to launch blockbusters, is suffering as a result of shrinking pipelines and low NME approvals. Although sales and marketing constitutes by far the largest corporate expense at 33% of revenues, sales productivity continues to decline. The goal of this study is to explore how pharmaceutical sales will change over the next 5 - 7 years and more specifically explore the role technology (including the internet) will play in the sales process. The study focuses on testing the perceptions of two key stakeholders -pharmaceutical executives and current medical students (future physicians) regarding the future of pharmaceutical sales process. Accordingly, 33 individuals were interviewed of which 18 were pharmaceutical executives and 15 were future physicians. The study tests three hypotheses: 1. Pharma executives believe that sales representative based detailing will continue to be the predominant method to engage and sell to physician customers while future physicians believe that technology will play a dominant role in the pharmaceutical detailing process. 2. Pharmaceutical executives agree that the most effective and ethical method to convey the benefits and challenges of an ethical pharmaceutical product are via a trained sales representative while future physicians believe that the sales representative does not effectively and ethically convey the merits of the relevant pharmaceutical therapy. 3. Person to person contact is not essential in conveying the merits of a particular ethical therapy - pharmaceutical executives disagree with this premise while future physicians agree.
(cont.) The data sets were compared using the following statistical tests: Yates' chi-square test, Armitage's chi-squared test and Two sample test of binomial proportions. In conclusion, the data showed that the perceptions of pharma executives and future physicians were in concurrence with each other.
by Rehan A. Khan.
S.M.

Mestrado em Marketing
A indústria Farmacêutica é um setor altamente regulamentado que nos últimos anos tem vindo a sofrer grandes alterações que se refletem na situação atual das empresas farmacêuticas. Neste sentido, na presente dissertação, as seguintes questões de investigação são formuladas: 1. Quais as características de Sales Force Management na Indústria Farmacêutica?; 2. Qual a importância das equipas de vendas na IF?; 3. Quais as tendências na organização das equipas de vendas na IF? e 4. Como são motivadas e compensadas as equipas de vendas na IF?. A investigação foi realizada adotando uma abordagem qualitativa, com uma estratégia de Case Study, a uma empresa multinacional do setor farmacêutico que representa um caso ilustrativo. A recolha de dados foi realizada, através da aplicação de um guião de entrevista com 28 perguntas, numa entrevista conjunta com os responsáveis de vendas e marketing da empresa farmacêutica. Após a análise dos dados conclui-se que: 1. As equipas de vendas são uma parte integrante e importante das empresas farmacêuticas porque são a principal forma de contacto entre empresas do setor e a classe médica; 2. A organização da força de vendas é definida, fundamentalmente, por estrutura geográfica. A adoção de Key Account Management (KAM) não está completamente implementado e 3. A motivação e compensação são implementadas através de sistemas de incentivo mistos, salário base e prémios de desempenho quando os objetivos de vendas são superados.
The highly regulated pharmaceutical Industry has been suffering great changes in these last years. These alterations have affected the present situation of the pharmaceutical businesses. Considering the aforementioned situation, in the present dissertation the following research questions are formulated: 1. Which are the Sales Force Management characteristics in the Pharmaceutical Industry? ; 2. What is the importance of the sales teams in the PI? ; 3. Which are the organisational tendencies in the sales teams in PI? ; 4. How are the sales teams motivated and rewarded in the PI? The multinational pharmaceutical company chosen for de research, represents an illustrative case. The research conducted adopted a qualitative approach, using the same strategy as in a Case Study. The collection of data was obtained by using a questionnaire, consisting of 28 questions, which was administered simultaneously in an interview setting, held with respective heads of both sales and marketing departments of a pharmaceutical company. Upon analysis of the data, it was concluded that: 1. The sales teams are an important and essential part of the pharmaceutical companies because they are the main source of contact among industry companies and the medical community; 2. The sales force is fundamentally organized according geographical structure. The implementation of the Key Account Management (KAM) is not fully complete; 3. A combination of incentives are used for motivational and compensation purposes. When sales objectives are met, the payment structures are applied through a base salary plus performance bonuses.

Cocrystals have generated a lot of interest due their ability to influence: physiochemical properties, optical properties etc. These properties are important in the pharmaceutical and food industry. In this thesis, the scale up of cocrystal synthesis is studied using a novel slurry cocrystallisation approach involving an anti-solvent and solvent mixture. The anti-solvent composition is typically > 97 %, with the solvent comprising the rest. This counter-intuitive approach resulted in > 95 % caffeine-oxalic acid cocrystal yield in less than 2 hrs. The mixed anti-solvent/solvent approach was applied successfully to four other cocrystal systems and a salt. The level of caffeine-oxalic acid cocrystal yield observed varied with the solvent used in the mixture. Using statistical analysis, it was shown that the hydrogen bonding Hansen solubility parameter (δH) of the solvent and oxalic acid solubility were the two most important factors for increasing cocrystal yield. The parameter Ra/(Oxalic acid) , however, showed even better correlation (94.2 %) with caffeine-oxalic acid cocrystal yield than both δH (78 %) and oxalic acid solubility (88 %). Ra is the Hansen solubility distance between the solvent and the coformer (oxalic acid) and includes all three Hansen solubility parameters (δD, δP, δH). Four new cocrystals (A-D) of 2-aminopyrimdine-glutaric acid were crystallised from three different solvents and their crystal structures reported. Two of them (A and B) are 1:1 polymorphs. The glutaric acid molecule in A has a linear conformation but it is twisted in B. Variable temperature PXRD analysis indicates that A and B are monotropic polymorphs, with A transforming to B at ≈73C, prior to the melting of B. D is a cocrystal-salt hybrid. D was crystallised from the same solvent as cocrystal B supporting the idea of a cocrystal-salt continuum when both the neutral and ionic forms are present in appreciable concentrations in solution.

Salt formation provides a means of altering the physicochemical and resultant biological characteristics of a drug entity without modifying its molecular structure. Many published reviews have indicated the importance of the selection of the most appropriate salt form. This work is an investigation into the salt formation of two heterocyclic drugs. This is done by the physicochemical and the crystallographic studies of 19 high resolution single crystal diffraction studies. The particular targets of the work are the selection of the most appropriate salt forms, investigations into the tautomerism and polymorphism (or pseudopolymorphism) and an understanding of the interactions most likely between these heterocyclic drugs and their specific receptor sites. Section 1 describes the effect of protonation on the absorption of drugs, the rationale for using various salt forms and the resultant effect this has on a number of physicochemical properties of the parent compound. Section 2 is a description of the experimental techniques used in the physicochemical investigations and in crystal structure determination. In Sections 3 and 7, the preparation and characterisation of the salts and modifications of the two heterocyclic drugs, GU and IM is described. In Sections 4 and 8, the physicochemical investigations into the hygroscopicity and solid-state stabilities of the salts of GU and IM is described. Van't Hoff solubility studies are used to determine the enthalpies of solution and where appropriate the relative thermodynamic stabilities of the various phases produced. The structures of 19 of the salts or modifications of GU and IM, together with their packing and hydrogen bonding interactions is described in Sections 5 and 9. Sections 6 and 10 describe the ionisation properties of these molecules. Both the guanidine and imidazole moieties of GU and IM, respectively, are tautomeric, the particular form(s) found in these investigations and the effect of protonation is discussed. The conformations of these structures are discussed and the effect of protonation, especially on the puckering of the piperazine ring, is described.

A significant amount of pharmaceutical marketing literature is available. Most of this marketing has doctors, physicians and specialists as main target audience due to the fact that, historically, these medical professionals were the main pharmaceutical purchase decision makers. Pharmaceutical marketing literature has, historically, also been biased towards the private health sector for obvious reasons as the private health sector constitutes the minority of the pharmaceutical market but with a significantly enormous purchasing power than the public healthcare market, constituting the biggest pharmaceutical market in numbers. It is not surprising therefore that majority of pharmaceutical marketing models have been tailor made for the private healthcare market as the growing number of pharmaceutical companies compete for a piece of the small but extremely profitable private healthcare market. South Africa is no exception as it reflects exactly the same pharmaceutical landscape as described above. For growth purposes, pharmaceutical companies have been showing a continued interest in the public healthcare market in Africa as the vast numbers of the African population present an opportunity for pharmaceutical sales. The inspiration of this research study emanated from the realisation that, in order for pharmaceutical companies to take advantage of the looming African opportunity, there is very little literature on pharmaceutical marketing in the public health sector of which majority of the African market constitutes. This study therefore investigates the impact of marketing communication mix elements on pharmaceutical purchasing decisions for pharmaceuticals in the public health sector in South Africa. Personal selling, public relations and promotions are the marketing communications mix elements being investigated in this study as they are the most commonly utilised in the pharmaceutical industry. Therefore, the study aims to develop an understanding on which of the chosen marketing communications mix elements has the most influence on the pharmaceutical purchasing decisions in the context of the public health sector in South Africa. The study also aims to explore the causal effects of such influences in the public health sector in South Africa. The findings will be valuable to pharmaceutical marketers that are trying to tap in the public health sector market as it is different from the private health sector. The study employs more qualitative approach. A small sample was utilised from the public health sector in the Eastern Cape Province in South Africa. Semi structured interviews were used to collect data which was analysed using grounded theory data analysis methodology. Empirical results revealed that personal selling influences pharmaceutical purchasing decision the most and promotions the least. Mitigating factors were uncovered to assist in optimising the marketing communication efforts for marketers in this sector.

The subject of this study is sales forecasting of pharmaceutical representative company. The aim of the project described in this document is to create the custom tailored sales forecasting software for pharmaceutical representative company. The document consists of three main parts. In the analytical part the document the literature analysis and overview of existing solutions is performed. Most widely used forecasting techniques, methods and their appliance possibilities are described and classified. Advantages and disadvantages of existing forecasting tools are exposed. In accordance with the performed analysis the type of the system and forecasting methods that should be implemented in the system were selected. Key features of the created software design are described in the design part of the document. The created software has been examined with the real data of a pharmaceutical representative company. Generated sales forecasts were compared with real sales indexes. Results of the performed research were summarized and conclusions for usage of the created system were drawn.

The studies on cocrystals and salts presented in the the chapters clearly bring out the influence of intermolecular interactions as the main evaluators of the cocrystal-salt regime. The observations made in Chapter 2 indicate that in case if the cocrystal formation is through hydrogen bonds the location of the proton decides the nature of the complex in the energy landscape. The observation that the coformer controls the topology of intermolecular space as demonstrated in Chapter 3 provides insights into the importance of directionality rather than strength of intermolecular interactions. Indeed halogen bonding in cocrystals gain importance in this context.

The studies on cocrystals and salts presented in the the chapters clearly bring out the influence of intermolecular interactions as the main evaluators of the cocrystal-salt regime. The observations made in Chapter 2 indicate that in case if the cocrystal formation is through hydrogen bonds the location of the proton decides the nature of the complex in the energy landscape. The observation that the coformer controls the topology of intermolecular space as demonstrated in Chapter 3 provides insights into the importance of directionality rather than strength of intermolecular interactions. Indeed halogen bonding in cocrystals gain importance in this context.

Five new metalloporphyrins, $\rm \lbrack Al\sp{III} (TPPCM)Cl\rbrack,$ $\rm \lbrack Al\sp{III} (TPPCN)Cl\rbrack,$ $\rm \lbrack Al\sp{III} (TPPC)Cl\rbrack,$ $\rm \lbrack Cr\sp{III} (TPPCM)Cl\rbrack,$ and $\rm \lbrack Cr\sp{III} (TPPCN)Cl\rbrack,$ have been synthesized and characterized as a first step toward the bulk synthesis of water-soluble C$\sb{60}\sp{.-}$ salts. According to a literature report, Cr$\rm \sp{II}$(TPP) and (Al$\rm \sp{III}$(TPP)$\sp{.-}\rbrack$ (TPP$\sp{2{-}}$ = tetraphenylporphyrinato) reduce C$\sb{60}$ to C$\sb{60}\sp{.-}$ under proper solvent conditions to form an insoluble $\rm \lbrack Cr\sp{III}(TPP)\rbrack\sp+(C\sb{60}\sp{.-})$ or (Al$\rm \sp{III}$(TPP)$\rbrack\sp+$(C$\sb{60}\sp{.-})$ salt. Here it is proposed to derivatize these Cr$\rm \sp{II}$ and Al$\rm \sp{III}$ tetraphenylporphyrins with substituents on the phenyl rings to produce water-soluble $\rm \lbrack Cr\sp{III} (TPPR)\rbrack\sp+(C\sb{60}\sp{.-})$ and $\rm \lbrack Al\sp{III} (TPPR)\rbrack\sp+(C\sb{60}\sp{.-})$ salts. Initial electrochemical data for precursor $\rm \lbrack Al\sp{III} (TPPCM)Cl\rbrack,$ $\rm \lbrack Al\sp{III} (TPPCN)Cl\rbrack,$ $\rm \lbrack Al\sp{III} (TPPC)Cl\rbrack,$ $\rm \lbrack Cr\sp{III} (TPPCM)Cl\rbrack,$ and $\rm \lbrack Cr\sp{III} (TPPCN)Cl\rbrack$ compounds suggest that adding water-solubilizing substituents does not interfere with the electron transfer between the reduced Al$\rm \sp{III}$ and C$\rm \sp{II}$ metalloporphyrins and C$\sb{60}.$ Hence, there is potential to produce bulk amounts of water-soluble C$\sb{60}\sp{.-}$ by this method. The radical anion has 150 A$\sp2$ of paramagnetic surface area (S = 1/2), and possible utility as a new magnetic resonance imaging contrast agent.

Ionic Liquids (ILs) are class of compounds, which have become popular since the mid-1990s. Despite the fact that ILs are defined by one physical property (melting point), many of the potential applications are now related to their biological properties. The use of a drug as a liquid can avoid some problems related to polymorphism which can influence a drug´s solubility and thus its dosages. Also, the arrangement of the anion or cation with a specific drug might be relevant in order to: a) change the correspondent biopharmaceutical drug classification system; b) for the drug formulation process and c) the change the Active Pharmaceutical Ingredients’ (APIs). The main goal of this Thesis is the synthesis and study of physicochemical and biological properties of ILs as APIs from beta-lactam antibiotics (ampicillin, penicillin G and amoxicillin) and from the anti-fungal Amphotericin B. All the APIs used here were neutralized in a buffer appropriate hydroxide cations. The cation hydroxide was obtained on Amberlite resin (in the OH form) in order to exchange halides. The biological studies of these new compounds were made using techniques like the micro dilution and colorimetric methods. Overall a total of 19 new ILs were synthesised (6 ILs based on ampicillin, 4 ILs, based on amoxicillin, 6 ILs based on penicillin G and 4 ILs based on amphotericin B) and characterized by spectroscopic and analytical methods in order to confirm their structure and purity. The study of the biological properties of the synthesised ILs showed that some have antimicrobial activity against bacteria and yeast cells, even in resistant bacteria. Also this work allowed to show that ILs based on ampicillin could be used as anti-tumour agents. This proves that with a careful selection of the organic cation, it is possible to provoke important physico-chemical and biological alteration in the properties of ILs-APIs with great impact, having in mind their applications.
Escola Superior de Tecnologia da Saúde do Instituto Politécnico do Porto. financial support (SFRH/PROTEC/49233/2008)

Tuberculosis (TB) is still today considered the major cause of death by infectious diseases in adults at the global scale. According to the WHO, 10.4 million cases of the disease were active in 2016, among which 1.6 million resulted in death. Over the last years, TB was mainly fought by resorting to the combination of several 1st and 2nd generation drugs, including rifampicin, ethambutol and isoniazid. However, such treatment regime is frequently ineffective to combat TB particularly for multi-resistant Mycobacterium tuberculosis cases. In this work, ethambutol (ETB) was selected as anti-TB drug and then to combine with suitable and biocompatible counter-ions in order to develop several ethambutol based organic salts and ionic liquids (OSILs). The employed sustainable methodologies allowed the quantitative preparation of mono- and di-cationic ETB-OSILs by direct protonation of the drug with one- and two equivalents of biocompatible sulfonic and carboxylic acids. All ETB-OSILs were characterized by NMR, FTIR and elemental analysis (C, H, N) in order to proof the desired compounds. Additionally, calorimetric studies by melting point determination or Differential Scanning Calorimetry (DSC) was performed for a better assessment of their thermal properties and polymorphic behaviour. Upon determination of the water and saline solubility studies (at 370C), three most promissory ETB-OSILs were selected for in vivo toxicity studies using zebrafish as biological model. In general, these ETB-OSILs showed similar toxicity profile to the original drug. Finally, a preliminary assessment of the in vitro activity studies against mycobacterium tuberculosis for the same dicationic and corresponding monocationic ETB-OSILs. These results showed a similar TB activity comparing to the original drug, but complementary biological studies should be required.
A tuberculose (TB) ainda hoje é considerada a principal causa de morte por doenças infeciosas em adultos à escala global. Segundo a OMS, 10,4 milhões de casos da doença estavam ativos em 2016, entre os quais 1,6 milhão resultaram em óbitos. Nos últimos anos, o combate à TB foi principalmente feito com o recurso à combinação de vários fármacos de 1ª e 2ª geração, incluindo rifampicina, etambutol e isoniazida. No entanto, esse regime de tratamento é frequentemente ineficaz para combater a TB, particularmente nos casos de Mycobacterium tuberculosis multirresistentes. Neste trabalho, o etambutol (ETB) foi selecionado como fármaco anti-TB e combinado com contra-iões adequados e biocompatíveis a fim de desenvolver vários sais orgânicos e líquidos iônicos à base de etambutol (ETB-OSILs). As metodologias sustentáveis foram otimizadas de modo a permitiram a preparação quantitativa de ETB-OSILs mono e di-catiónicos através da protonação direta do fármaco com um e dois equivalentes de ácidos sulfónicos e carboxílicos biocompatíveis. Todos os ETB-OSILs foram caracterizados por NMR, FTIR e análise elementar (C, H, N) para comprovar a estrutura dos compostos desejados. Adicionalmente, estudos calorimétricos baseados na determinação do ponto de fusão ou Calorimetria Exploratória Diferencial (DSC) foram realizados para uma melhor avaliação de suas propriedades térmicas e do seu comportamento polimórfico. Após a determinação dos estudos de solubilidade em água e solução salina (a 37oC), três ETB-OSILs mais promissores foram selecionados para estudos de toxicidade in vivo usando peixe-zebra como modelo biológico. Em geral, esses ETB-OSILs testados apresentaram um perfil de toxicidade semelhante ao do ETB original. Finalmente, uma avaliação preliminar dos estudos de atividade in vitro contra o Mycobacterium tuberculosis para os mesmos ETB-OSILs (dicationicos e correspondentes monocatiónicos). Esses resultados mostraram uma atividade de TB semelhante por comparação com ETB original, mas serão necessários estudos biológicos complementares.

Yes
The creation of salts is a frequently used approach for the modification of physicochemical properties of an active pharmaceutical ingredient. Despite the frequency of application, there has been little research into the structural-property relationships of the final material and the nature of the counterion present. This work reports on five new salts of sulfathiazole and compares the energetics of the intermolecular interactions with variation in the crystal packing motifs.

The thesis describes Bayer’s expansion strategy through virtual solutions in the Brazilian pharmaceutical market in 2013. The case study and analysis want to provide an international strategy teaching material with the aim to offer students a ground to apply and increase their knowledge based on real life examples. Bayer is a global enterprise in the fields of healthcare, agriculture and high-tech polymer materials with a history of more than 100 years in Brazil. The multinational recently approached a disruptive innovation in form of an online salesforce system since the healthcare segment suffered from high expenses for the sales force in the territorially demanding Brazilian market. Bayer could achieve prosperous results in a pioneering test of this virtual connection between sales representatives and doctors and the decision about a final implementation required further analysis. The management board was highly interested in conclusions regarding the market attractiveness, the strategic positioning in relation to competition and the strategic fit of the new approach. The overall analysis of these criteria resulted in a recommendation for the implementation of the virtual sales force unit in Brazil. The dissertation content is a case study reflecting the past events and a strategic analysis of the virtual representatives concept as expansion strategy. The latter comprises an assessment of macro- and microeconomic factors and the impact of the new concept on the competitive landscape. Furthermore, it includes a SWOT and VRIO analysis of the company and a review of the strategic fit and intent of the new virtual unit.

碩士
僑光科技大學
企業管理研究所
107
In recent years, the medical industry is booming. Although the number of clinics is increasing, the performance of pharmaceutical companies is not proportional to the competition among pharmaceutical companies is getting more and more intense. If you neglect the relationship between the customer and the product, will not be able to grasp the needs and trends of customers, therefore, pharmaceutical companies also need strategic planning and change to achieve the goal of locking customers and selling successfully. In this study, a total of 10,378 transaction data from January 2016 to December 2017 were analyzed by a pharmaceutical company. Through data collection, data preprocessing, data warehousing, data mining, pattern evaluation, and results display, the data mining process was constructed. First, establish a basic statistical query trend report through online analysis and processing. In order to further study the implicit knowledge between customers, commodities, seasons, institutional categories, and dosage fields, then, through the correlation rules in data mining technology, we can find out the correlation rules between the customer's and product's and each season's correlation rule pattern, organization type, and product and sales volume. And the relationship between the two doses of product A06 4mg, 5mg and the customer, season, sales, the analysis results will be provided to the decision makers of the pharmaceutical factory for reference.