Dissertations / Theses on the topic 'Chemical-pharmaceutical technology'

A N-succinil-quitosana é um derivado quimicamente modificado do polímero quitosana. A inserção de radicais de anidrido succínico nas aminas protonadas presentes ao longo da cadeia do polímero quitosana, conferem diferentes características físico-químicas à molécula de quitosana. Esta modificação química possibilitou à quitosana, solubilidade em pHs que variam do ácido (2.0) até alcalino (14.0). Estas propriedades são atribuídas ao alongamento da cadeia alquílica, que afasta a ponte hidrofílica da cadeia fechada da D-glicosamina, facilitando o acesso da água, a qual irá estabelecer uma interação mais forte com a molécula de quitosana. Esta propriedade não está presente em amostras de quitosana pura, a qual sabe-se que solubiliza-se apenas em pHs abaixo de 5.5.
The N-succinil-chitosan is a chemically modified derivative of the biopolymer chitosan. The succinic anhydride attached to the free amino groups presented along the chitosan\'s polymer chain imparts to the molecule different physicochemical properties not exhibited before the modification. These chemical modifications enhance chitosan\'s solubility in slightly acid, neutral and alkaline media. These properties are related to the long alkyllic chains attached to hydrophilic parts. In this case the hydrophilic part of D-¬glucosamine promotes stronger interactions with the water molecules, and consequently, enhances the solubility of the chitosan polymer. It is worthy mentioning that non-modified free chitosan is soluble only in acidic medium (pH ≤5.5).

A emergência de cepas resistentes à isoniazida, principal fármaco utilizado no tratamento da tuberculose, tem causado renovado interesse nos tuberculostáticos denominados de \"segunda escolha\", dentre estes, o etambutol. O desenvolvimento de metodologias de obtenção de fármacos antimicobacterianos que sejam técnica e economicamente acessíveis e a otimização das técnicas existentes consistem em estratégias de grande importância em países em desenvolvimento onde os altos índices de incidência e prevalência estão diretamente relacionados à falta de recursos. Dentre os vários métodos de obtenção de (+)-2,2\'-(etilenodiimino)di-1-butanol, etambutol, a separação dos enantiômeros do (±)-2-amino-1-butanol com (+)-ácido tartárico seguida de condensação com dihaloetano apresenta-se como uma metodologia que atende aos requisitos anteriormente citados. Assim, efetuou-se neste trabalho, a otimização da resolução do 2-aminobutanol racêmico por formação de sais diastereoméricos neutros, (+)-bis-tartaratos de (+) e (-)-2-amino-1-butanol, seguida de separação por cristalização preferencial do sal contendo o isômero dextrógiro, precursor na síntese do etambutol. Pela formação de sais neutros elevou-se o rendimento da resolução em comparação aos resultados citados em literatura obtidos pela formação de sais ácidos em 63%, obtendo-se (+)-2-amino-1-butanol com elevada pureza química e enantiomérica.
The emergence of M. tuberculosis strains resistant to isoniazid, the main drug in tuberculosis treatment, has raised renewed interest in second choice drugs, like ethambutol. Researching into technical and economicaly accessible synthesis of antimycobacterial drugs and improving on existing ones is of great importance in developing countries where the rising of tuberculosis incidence and prevalence is related to the lack of resourses and inadequate control methods. Among various methods of preparation of (+)-2,2\'-(ethylenediimino)di-1-butanol -ethambutol-, resolution of (±)-2-amino-1-butanol with L-(+)-tartaric acid, followed by condensation to ethylene dichloride, consists in a procedure that is in accordance with these previous requirements. Resolution of racemic 2-aminobutanol was optimized, by diastereomeric neutral salts formation followed by preferential crystallization of the diastereomer containing the dextro isomer of 2-amino-1-butanol. This method resulted in yields 63% higher than resolutions performed by hemitartrates formation, and resulted in (+)-2-amino-1-butanol with high chemical and enantiomeric purity.

Roll compaction is commonly used as a dry granulation technique in the pharmaceutical industry to produce tablets for formulations sensitive to heat and moisture. This thesis reports systematic studies on the behavior of pharmaceutical excipients in associated unit operations (i.e. roll compaction, milling, tabletting), as well as their correlations. Roll compaction experiments were carried out using an instrumented roll compactor with a gravity feeding system. The influence of the process parameters, material properties and powder conditioning were investigated Ribbons produced in roll compaction were granulated using an oscillating mill to investigate the milling process. A first order kinetics equation was introduced to describe the mass throughput of the granules. Using positron emission particle tracking technique, which provided a measurement of instantaneous velocity and the location of the ribbons, two milling regions (i.e. impact and abrasion) involving distinct fracture mechanisms were identified. Tabletting of the granules was performed using a universal test machine. A reduction in the compressibility and compactibility of the granules compared to the feed powders, due to work hardening, was also observed. A method was introduced to determine the optimized process conditions for roll compaction and milling through a close examination of the correlation between the unit operations.

It is proposed that Ionic Liquids offer a new opportunity for exploration into a novel medium for processing Active Pharmaceutical Ingredients, particularly with respect to habit control and polymorphic form. A review of relevant literature relating to ionic liquids properties, commercial applications and current research has been summarised together with background into fundamental crystallisation theory. Crystallisations using thermal methods were employed at laboratory scale and the physical properties of the resultant powders were analysed and compared to commonly encountered crystal forms. For paracetamol it was found that the morphology of the crystals could be manipulated, producing in some cases, habits not reported for conventional organic solvent crystallisation. This was achieved through changing both the IL used and the saturation of the system whilst in all cases retaining the most stable polymorph. ILs ILs to be ‘designed’ for a given API but greater understanding of the interactions between IL and solute are required first. Properties such as increased solvation power, thermal stability, liquidus range and low vapour pressure bring a number of advantages when designing industrial crystallisations. However ILs also have a number of disadvantages including phase separation problems.

Roll compaction is a dry granulation method. In the pharmaceutical industry it assists in binding tablet ingredients together to form a larger mass. This is conducted to ease subsequent processing, decrease dust, improve flowability, improve material distribution, more suitable for moisture and heat sensitive materials than wet granulation methods, minimises operating space and suited for a continuous manufacturing set-up. In pharmaceutical roll compaction various types of powder material mixtures are compacted into ribbon that are subsequently milled and tableted. The aim of this research is to investigate the use of intelligent software (FormRules and INForm software) for predicting the effects of the roll compaction process and formulation characteristics on final ribbon quality. Firstly, the tablet formulations were characterised in terms of their particle size distribution, densities, compressibility, compactibility, effective angle of friction and angle of wall friction. These tablet formulations were then roll compacted. The tablet formulation characteristics and roll compaction results formed 64 datasets, which were then used in FormRules and INForm software training. FormRules software highlighted the key input variables (i.e. tablet formulations, characteristics and roll compaction process parameters). Next these key input variables were used as input variables in the model development training of INForm. The INForm software produced models which were successful in predicting experimental results. The predicted nip angle values of the INForm models were found to be within 5%, which was more accurate to those derived from Johanson’s model prediction. The Johanson’s model was not successful in predicting nip angle above the roll speed of 1 rpm due to air entrainment. It also over-predicted the experimental nip angle of DCPA and MCC by 200%, while the approximation using Johanson’s pressure profile under-predicted the experimental nip angle of DCPA by 5-20% and MCC by 20%.

Twin screw extruder (TSE) has been studied extensively as a granulator because it allows continuous processing. Initial work was carried out by comparing the TSE with conventional granulator shows that the mechanism of TSE granulation is different from conventional granulation with the absence of the consolidation stage. PEPT was also utilised and it reveals that the flow stream of the material is not only due to the conveying capacity but also the granulator fill, in particularly for the 90o mixing zone which is believed to be a dispersion type of mechanism driven by the granulator fill gradient. Residence time distribution was measured and simulated by fitting the experimental data using a continuous stirred tank reactors model. The model describes the experimental curves reasonably well when a plug flow fraction was considered. Generally the mean residence time (MRT) of the system is proportional to the mixing zone angle and is inversely proportional to the screw speeds and flowrate. A study using the variance reduction ratio demonstrates that the TSE granulator used in the present study is able to remove the feed instability given that the ratio of the frequency of the input stream fluctuation to the MRT is high.

The regulatory framework in which pharmaceutical companies have to work has changed significantly since the late 1990’s. The development and implementation of risk based approaches to processing pharmaceutical powders allows the pharmaceutical manufacturers the freedom to adopt real-time release for their products whist reducing the regulatory burden for both the statutory bodies and the manufacturers. This thesis has been a collaboration between Buck Systems and the University of Birmingham School of Chemical Engineering to evaluate and develop methods which would enhance the way in which Buck Systems can, in co-operation with their clients, enhance their understanding of how powder properties affect their products that are used in pharmaceutical manufacturing to better comply with the changes in the regulatory environment. To this end simple and quick screening methods for characterisation of customers’ powders with a view to identifying potential problems prior to blending tests have been developed to replace the current ad hoc approach. These include the use of tests that have been relied on historically as well as newer, more universal and robust techniques such as automated shear cells and powder rheometers. Detailed characterisation trials have shown where these techniques can be successfully applied and where their limitations lie. Further work has shown how powder systems can be better evaluated within the existing HAZOP framework. Specific evaluation of the hopper design methodology has resulted in the development of an expert system to enable the rapid sensitivity analysis of design options. In addition the limits of the hopper design method have been explored and some limitations identified where significant overdesign may occur. The evaluation of content uniformity in a laboratory scale blender using specialist Positron Imaging equipment available at the University of Birmingham has also been undertaken. The unique study of the blender contents using Positron Emission Tomography has provided a range of insights into the way binary and ternary powder systems interdisperse.

Multi-component crystallisation is investigated as a route to controlling crystalline forms of selected materials that possess pharmaceutical properties. This includes investigating the use of co-crystallisation methodology to selectively crystallise metastable polymorphs and solvated forms of these materials. This differs from the conventional use of co-crystallisation, as the aim of this aspect of the investigation is not to obtain a molecular complex of the two components, but instead for them to crystallise independently, while one component perturbs the solution environment to direct the crystallisation of the second component towards a different, often metastable, polymorph (or solvate). This co-crystallisation methodology is used as a route to crystallising new or elusive polymorphs (or solvates) of the active pharmaceutical ingredients paracetamol, piroxicam, gallic acid monohydrate and piracetam. It is also demonstrated that the use of this method can lead to crystal forms with otherwise unobtainable structural features. Co-crystallisation is also investigated as a route to controlling the ionisation state of piroxicam in the formation of molecular complexes. Molecular complexes were formed with a number of mono-substituted benzoic acids as well as with nitrogen-heterocycles and strong acids. In the molecular complexes formed, piroxicam was found to adopt the non-ionised, zwitterionic, anionic or cationic form, depending on the co-former used. Attempts are made to rationalise the occurrence of each ionisation state by consideration of the relative pKa values of piroxicam and the co-formers. The hydrogen bonded supramolecular synthons in these molecular complexes are also investigated. Co-crystallisation is also used as a route to obtaining molecular complexes of paracetamol and its derivative, 4-acetamidobenzoic acid, with nitrogen-heterocycles as co-formers. Molecular complexes of the two, with similar co-formers, are compared in terms of their hydrogen bonded supramolecular synthons. Despite having otherwise similar structural features, the phenolic hydroxyl group in paracetamol and carboxylic acid group in 4-acetamidobenzoic acid result in the formation of very different synthons and in some cases different component ratios. The susceptibility of 4-acetamidobenzoic acid to deprotonation is found to play a major role in the differences observed. Molecular complexes of paracetamol with co-formers containing multiple carboxylic acid groups are also investigated, with a view towards further crystal engineering approaches for molecular complexes of paracetamol. Piracetam complexes with carboxylic acids are investigated in a similar manner. The potential for transfer of a range of these multi-component crystallisations into a non-evaporative environment, with a view to implementing continuous crystallisation approaches, is also investigated. This transfer is found to be challenging for the systems investigated.

Notre travail a consisté en la synthèse et la caractérisation de nouveaux transporteurs de principes actifs formes par un molécule de cyclodextrine pour le piégeage du médicament, et par un motif galactose pour le ciblage de l'ensemble vers des cellules portant des lectines à galactoses sur leur surface. Deux familles de molécules ont été obtenues: - celles ayant une ou plusieurs unités thiogalactosyles liées sur un ou plusieurs hydroxyles primaires de la cyclodextrine ; - celles constituées par un polymère biocompatible portant sur des chaines pendantes, les cyclodextrines et les galactoses. La capacité de complexation des unités cyclodextrines a, dans les deux cas, été étudiée par la méthode rmn, et la reconnaissance des unités galactosyles a été testée à l'aide d'une lectine de levure galactose spécifique. Ces nouveaux types de transporteurs de médicaments ont donné des résultats positifs in vitro et peuvent présager des résultats intéressants in vivo

Thesis (PhD (Pathology. Medical Microbiology))--University of Stellenbosch, 2009.
ENGLISH ABSTRACT: Due to modern high-throughput technologies, large numbers of compounds are produced by parallel synthesis and combinatorial chemistry. The pharmaceutical industry therefore requires rapid and accurate methods to screen new drugs leads for membrane permeability potential in the early stages of drug discovery. Around 50 % of all investigational new drugs fail in pre-clinical and clinical phases of development due to inadequate absorption/permeation, distribution, metabolism, excretion and/or unacceptable toxicity. This may be decreased by applying in vitro screening methods early in the discovery process. Reliable in vitro models can be applied to determine permeation of the test compounds, which will help avoid the wasting of valuable resources for the development of drugs that are destined to fail in preclinical and clinical phases due to insufficient permeability properties. It is important to decide as early as possible on the most promising compound and physical formulation for the intended route of administration. With awareness of the increasing importance of in vitro models in the investigations of the permeability properties of drug compounds, this research project was specifically devoted to determine the suitability of our in vitro model to evaluate and predict drug permeability. A continuous flow-through diffusion system was employed to evaluate the permeability of nine different compounds/drugs with different chemical properties, across three biological membranes. The biological membranes chosen for the present study were human vaginal mucosa, human skin tissue and human small intestine mucosa. The continuous flow-through diffusion system was furthermore utilised to investigate the effects of de-epithelialisation of mucosal surfaces, chemical enhancers, temperature, permeant concentration and formulation on the permeability of the test compounds/drugs. The in vitro permeability information and data from the flow-through diffusion model were compared to in vitro and in vivo literature studies and drug profile. An in vitro model that is able to reliably predict in vivo data will shorten the drug development period, economise resources and may potentially lead to improved product quality. In this thesis research results are reported on the permeability of the mentioned biological membranes to the various chemical markers, including anti-HIV (human immunodeficiency virus) drugs. The permeability studies will be discussed in three sections: vaginal mucosa, skin tissue, small intestine mucosa. The results of the vaginal permeability studies showed that the three peptides (MEA- 5, MDY-19 and PCI) readily penetrated the vaginal mucosa. MDY-19 had a higher flux rate than MEA-5, commensurate with its smaller molecular size (weight). The surfactant enhanced the flux rate of MDY-19 approximately 1.3 times and decreased the lag time of the peptide. Removal of the vaginal epithelium increased the flux rates of the peptides across the mucosa and may have implications for a more rapid uptake of these and other microbicides in vivo. The permeability of 1 mM MDY-19 and PCI at 37 °C were significantly (p<0.05) higher than at 20 °C. At 37 °C the AUCs of the overall mean flux values of MDY-19 and PCI increased with concentration according to well-established diffusion theory. The experiments on the permeability of different terbinafine hydrochloride formulations through human skin demonstrated that the terbinafine hydrochloride formulations used in this study, readily diffused into the skin tissue. However, no flux values for any of the terbinafine hydrochloride formulations through the skin into the acceptor fluid were found. The mean terbinafine concentrations in the skin after 24 h exposure to the three commercial, terbinafine hydrochloride formulations were 3.589, 1.590 and 4.219 μg/ml respectively. The mean terbinafine concentration in the skin exposed to the 10 mg/ml PBS/Methanol solution was higher than those from the three commercial formulations. The results of the temperature study demonstrated that an increase of 5 ºC caused a significant increase in flux values of tritiated water across skin. The flux values for tritiated water across skin at 37 ºC were on average double those at a temperature of 32 ºC. The permeability of excised human small intestine mucosa to different oral dosage drugs was investigated over a 24 h period. The four drugs selected were zidovudine, propranolol hydrochloride, didanosine and enalapril maleate. They were selected as representative model compounds of drug classes 1 (high solubility, high permeability) and 3 (high solubility, low permeability) according to the Biopharmaceutics Classification System. The flux rates of the four chosen test drugs were influenced by the length of the experiment. Between the time periods 2-4 h and 4-6 h, zidovudine’s mean flux values across small intestine tissue were respectively 1.8 and 2.0 times higher than didanosine and 2.3 and 2.2 times higher than enalapril. Propranolol’s mean flux values were respectively 1.2 and 1.4 times higher than didanosine and 1.6 higher than enalapril during both the 2-4 and 4-6 h time periods. Between both the time periods 2-4 and 4-6 h AZT’s mean flux values were 1.4 times higher than propranolol and didanosine’s mean flux values were respectively 1.3 and 1.1 times higher than enalapril during the mentioned time periods. Class 1 drugs showed a significantly higher flux rate across the jejunal mucosa compared to the class 3 drugs and these results are in line with their Biopharmaceutics Classification System classification. The in vitro model has proved to be reliable to predict permeability of class 1 and 3 drugs and also showed correlation with human in vivo data. It seems that the in vitro flow-through diffusion model used in the present study have the potential to overcome some of the problems and limitations demonstrated by other in vitro techniques and may potentially serve as a future tool for pharmaceutical companies to predict the diffusion characteristics of new drugs and different formulations, across different biological membranes. Furthermore, it may serve as a prospective method for assessing the bioequivalence of alternative (generic) vehicles or formulations containing the same drug/compound.
AFRIKAANSE OPSOMMING: As gevolg van moderne hoë spoed tegnologie kan groot hoeveelhede middels vervaardig word deur ooreenkomende sintese en kombinasieleer chemie. Die farmaseutiese industrie benodig dus vinnige en akkurate metodes om nuwe geneesmiddels te evalueer t.o.v. membraan deurlaatbaarheid. Hierdie evaluasie moet verkieslik so vroeg moontlik in die geneesmiddel se ontwikkelingsproses geskied. Ongeveer 50 % van alle potensiële geneesmiddels misluk in pre-kliniese en kliniese fases van geneesmiddelontwikkeling. Die mislukte pogings kan toegskryf word aan onvoldoende absorbsie/deurlaatbaarheid, distribusie, metabolisme, ekskresie en/of onaanvaarbare middel toksisiteit. Dit is daarom belangrik om so vroeg moontlik in die geneesmiddelontwikkelingsproses te besluit op die mees belowende middel, asook die geskikte formulasie vir die spesifieke roete van toediening van die middel. Die farmaseutiese industrie benodig tans in vitro modelle met die potensiaal om die deurlaatbaarheid van geneesmiddels te bepaal en te voorspel. Betroubare in vitro modelle kan aangewend word om die deurlaatbaarheid van potensiële geneesmiddels te toets. Sodoende sal die onnodige uitgawes op die ontwikkkeling van geneesmiddels wat in elk geval later gaan faal in pre-kliniese en kliniese fases van geneesmiddelproewe a.g.v. deurlaatbaarheidseienskappe, vermy word. Hierdie navorsingsprojek was dus spesifiek onderneem om die waarde en toepaslikheid van ‘n in vitro deurlopende-vloei perfusie model te ondersoek. Die model se potensiaal om geneesmiddels se deurlaatbaarheid en absorpsie te voorspel was geëvalueer. Die deurlopende-vloei perfusie apparaat was gebruik om die deurlaatbaarheidsvloede van drie verskillende biologiese membrane t.o.v. nege chemiese stowwe (MEA-5, MDY-19, PCI, terbinafien hidrochloried, getritieerde water, zidovudien, propranolol, hidrochloried, didanosien, enalapril maleaat) te bepaal. Die drie biologiese membrane wat gebruik was, was vaginale weefsel, vel en klein intestinale weefsel. Al drie weefsel tipes was van menslike oorsprong. Die deurlopende-vloei perfusie apparaat was ook gebruik om die effek wat verwydering van die mukosa se epiteellaag op deurlaatbaarheidsvloede het, te ondersoek. Verder was navorsing gedoen op die effek van temperatuur en die konsentrasie en formulasie van die toetsmiddels op hulle diffusie vloedwaardes. Daar was ook gekyk na die invloed van ander chemiese stowwe op die toetsmiddels se diffusie vloedwaardes. Die in vitro deurlaatbaarheidsinformasie en -gegewens was vergelyk met ander in vitro en in vivo literatuurstudies en geneesmiddel databasisse. ‘n In vitro model wat in staat is om in vivo resultate betroubaar te voorspel, het die potensiaal om die tyd wat dit neem om geneesmiddels te ontwikkel, te verkort, finansiële uitgawes te besnoei en om geneesmiddelkwaliteit te verseker. In die tesis word dan die resultate gerapporteer van die deurlaatbaarheidsvloede van die verskillende tipes weefsel ten op sigte van verskeie chemiese stowwe, insluitende anti-MIV (menslike immuniteitsgebreksvirus) middels. Die deurlaatbaarheidstudies word bespreek in drie afdelings: vaginale mukosa, vel en klein intestinale mukosa. Die resultate van die deurlaatbaarheidstudies op die vaginale weefsel dui daarop dat die drie peptiede (MEA-5, MDY-19 and PCI) die vaginale mukosa goed penetreer. Soos verwag, het MDY-19 hoër diffusie vloedwaardes as MEA-5 gehad. Dit kan toegeskryf word aan MDY-19 se kleiner molekulere grootte (gewig). Surfaktant het die diffusie vloedwaardes van MDY-19 1.3 keer vergroot en het ook die tyd na vaste vlak verminder. Die verwydering van die vaginale epiteel het die diffusie vloedwaardes van die peptiede verhoog en mag dus dui op die vinniger opname van peptiede en moontlike ander mikrobisiede in vivo, wanneer die belyning van die epiteel onderbreek. Die deurlaatbaarheid van 1 mM MDY-19 en PCI by 37 °C was satisties beduidend (p<0.05) hoer as teem 20 °C. Die area onder die kurwe (AOK) van die gemiddelde vloedwaardes van MDY-19 en PCI by 37 °C, het toegeneem met ‘n toename in die konsentrasie van hierdie peptiede. Die toename vloedwaardes ondersteun dus die alombekende diffusie teorie. Die transdermale diffusie eksperimente van verskillende terbinafien formulasies het getoon dat terbinafien geredelik vrygestel word vanuit hierdie formulasies na die vel. Geen terbinafien vloedwaardes, van enige van die formulasies, was egter gevind in die ontvangselle van die deurlopende-vloei perfusie apparaat nie. Die gemiddelde terbinafien konsentrasies in die vel na 24 h se blootstelling aan drie kommersiële terbinafien hidrochloried formulasies was onderskeidelik 3.589, 1.590 en 4.219 μg/ml. Die gemiddelde terbinafien konsentrasie in die vel wat aan 10 mg/ml PBS/metanol blootgestel was, was hoër as die konsentrasies in die vel wat aan die drie kommersiële formulasies blootgestel was. Die resultate van die temperatuurstudie op vel het aangetoon dat ‘n temperatuur toename van 5 ºC ‘n statisties beduidende toename in vloedwaardes van getritieerde water oor vel veroorsaak. Die vloedwaardes van die getritieerde water oor vel teen ‘n temperatuur van 37 ºC was gemiddeld dubbeld so veel as teen 32 ºC. Die deurlaatbaarheidsvloede van klein intestinale mukosa ten opsigte van verskillende geneesmiddels (wat oraal toegedien word) was ondersoek gedurende ‘n 24 h eksperiment. Die vier geneesmiddels wat gebruik was, was zidovudine, propranolol hidrochloried, didanosien en enalapril maleaat. Hierdie geneesmiddels is verteenwoordigers van die Biofarmaseutiese Klassifikasie Sisteem se klas 1 (hoë oplosbaarheid, hoë deurlaatbaarheid) en klas 3 (hoë oplosbaarheid, lae deurlaatbaarheid) geneesmiddels. Die vloedwaardes van die vier geneesmiddels het gewissel na aanleiding van die tydsverloop in die eksperiment. Zidovudien se gemiddelde vloedwaardes tussen 2-4 en 4-6 h was onderskeidelik 1.8 en 2.0 keer hoër as didanosien se gemiddelde vloedwaardes vir hierdie tyd periodes en onderskeidelik 2.3 en 2.2 keer hoër as enalapril se gemiddelde vloedwaardes. Tydens hierdie selfde periodes was propranolol se gemiddelde vloedwaardes 1.2 en 1.4 keer hoër as didanosien en vir beide periods 1.6 keer hoër as enalapril se gemiddelde vloedwaardes. Gedurende beide genoemde tyd periodes was zidovudien se gemiddelde vloedwaardes 1.4 keer hoer as propranolol en didanosien se gemiddelde vloedwaardes was onderskeidelik 1.3 en 1.1 keer hoër as enalapril tydens 2-4 en 4-6 h. Die klas 1 geneesmiddels het statisties beduidende hoër vloedwaardes gehad as die klas 3 geneesmiddels. Hierdie resultate stem ooreen met die geneesmiddels se Biofarmaseutiese Klassifikasie Sisteem klassifikasie. Dit wil dus voorkom asof die in vitro model wat gebruik was in die studie, gebruik kan word om die deurlaatbaarheidsvloede van klas 1 en 3 te voorspel. Die resultate van hierdie studie stem ooreen met ander in vivo studies. Dit wil voorkom asof die in vitro deurlopende-vloei perfusie apparaat die potensiaal het om sommige van die probleme en tekortkominge van ander in vitro modelle te oorkom en dat dit moontlik die potensiaal het om die diffusie-eienskappe van nuwe geneesmiddels en verskillende formulasies oor verskillende biologiese membrane te voorspel. Die model kan verder moontlik dien as ‘n potensiële toestel om biogelykbaarheid van alternatiewe (generiese) formulasies, wat dieselfde geneesmiddel/chemiese stof bevat, te bepaal.

Cette thèse a pour objectif la diminution de la toxicité sanguine d'une polybase globulaire bifonctionnelle Q-P(TDAE)X, servant à vectoriser des principes actifs peu solubles dans l'eau. Pour cela, l'interaction de type polyanion-polycation avec des composés polyanioniques a été envisagée pour masquer tout ou une partie des charges électrostatiques ammonium quaternaire à la surface du globule. Une autre approche a consisté à modifier chimiquement les unités latérales amine tertiaire de l'homopolymère P(TDAE) en conservant l'hydrophilie du système. L'ensemble de ce travail est décrit en quatre chapitres. Dans le premier chapitre, l'héparine a été choisie, en raison de ses propriétés anticoagulantes, pour interagir avec la polybase globulaire. Le second chapitre présente l'influence de paramètres liés à des polyanions monofonctionnels sur la composition et la taille des particules de complexe. Dans le troisième chapitre, l'homopolymère P(TDAE) a été modifié chimiquement, soit par tentative de couplage d'oligomères de poly(éthylène glycol) sur les fonctions amine tertiaire de P(TDAE), soit par synthèse de polyzwitterions à partir de P(TDAE) et de 1,3-propane-sultone. Enfin, le dernier chapitre concerne l'étude du complexe formé entre la polybase globulaire et un copolymère poly(aspartate de sodium-b-éthylène glycol) et de sa toxicité par voie intra-veineuse.

Spherical agglomeration (SA) is a novel process intensification strategy for particulate manufacturing. In the context of pharmaceutical manufacturing, it has the potential to reduce the number of unit operations in downstream processing from seven to three, which significantly reduces the manufacturing cost. However, SA process development for a new API in the drug pipeline is still a challenging exercise, which has impeded its practical implementation. The major bottleneck lies in the lack of fundamental understanding of the mechanistic principles underlying agglomeration of primary crystals, which can enable rational process design. In addition, most SA processes reported in literature focus on only the API, which does not eliminate the blending and wet granulation unit operations. The major purposes of this thesis are to (i) develop a first principle mathematical framework which can identify the fundamental agglomeration mechanism (ii) develop a model based online optimization framework, which can control the process, even in the presence of model parametric uncertainties (iii) develop a rational framework for co-agglomerating APIs and excipients, guided by process analytical technology tools. It is believed that the novel technology developed in this thesis will lay the groundwork for fast and robust process development of co-agglomerating APIs and excipients in the future, thereby enabling one-step direct compression. The large-scale development and deployment of this technology will significantly reduce the time to market and the manufacturing costs for new APIs, thereby ensuring higher accessibility of life-saving drugs.