>Magister Scientiae - MSc / Efavirenz is a non-nucleoside reverse transcriptase inhibitor used as an anti-retroviral for the treatment of human immunodeficiency virus (HIV) type I. It is classified as a class IΙ drug under the Biopharmaceutical Classification System (BCS) and exhibits a low solubility (aqueous solubility of 9.0 μg/ml) and high permeability (variable oral bioavailability). This study aims to choose a pre-formulation protocol with the best efavirenz derivative in literature between co-crystals and CD inclusion complexes. Upon selection of the efavirenz derivative, the complications of both small scale and large scale laboratory pre-formulation production is highlighted for formulation of a tablet dosage form. Numerous variables were selected for the pre-formulation protocol. Physical, chemical, pharmacological, pharmaceutical and economical variables were investigated. Citric acid monohydrate (CTRC) was chosen as the best co-former for a co-crystal while hydroxypropyl-beta-cyclodextrin (HP-β-CD) was selected as a host for an inclusion complex. Pharmaceutically, the angle of repose, Carr’s index, Hausner’s ratio, moisture content, disintegration time, hardness/resistance to crush, manufacturing process problems and particle size of the CTRC and HP-β-CD were all evaluated. The CTRC was ultimately selected for formulation of a tablet. The preparation of small laboratory scale of EFA/CTRC co-crystal was successfully achieved after several attempts. The large laboratory scale of EFA/CTRC was prepared under various environmental seasons which were indicated as batches 1-6 for purposes of this study. Characterization of the large laboratory scale EFA/CTRC co-crystals was performed by scanning electron microscopy (SEM), hot-stage microscopy (HSM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and by physical inspection (i.e. season, texture, colour, shape and particle size) of the EFA/CTRC product. Batch 1 and 2 were prepared during the summer season. The SEM analysis showed that the particles were needle-like shaped. The thermal analysis values of batch 1 by HSM, DSC and TGA results were 123 °C, 119 °C and 1.68 % of mass loss, respectively. In batch 2, morphology results by SEM revealed spikes of irregular and agglomerated particles. Batch 2 melted at 123 °C and a small unmelted quantity was observed at 143 °C. The DSC and TGA (mass loss) analysis were 118 °C and 0.75 % respectively. The hardness test of EFA/CTRC tablet prepared in batch 2 was extremely hard hence failed the disintegration test. The EFA/CTRC prepared in batches 3, 4 and 5 was during the winter season which is associated with high humidity and wet weather conditions. The SEM, DSC, TGA results were significantly different from the previous batches. The SEM morphology was highly irregular particles for batch 3, clustered and randomly size particle for batch 4 and irregular, needle-like, spikes and spherical shaped particles for batch 5, respectively. The thermal results HSM, DSC and TGA confirmed the presence of moisture in the prepared EFA/CTRC products. The HSM melting point results of batches 3, 4 and 5 were 123 °C, 115 °C and 121 °C, respectively. The DSC results of 110 °C, 105 °C and 118 °C were observed for batches 3, 4 and 5 respectively. The mass loss i.e. TGA results for batches 3, 4 and 5 were 1.178%, 1.5 % and 2.235 % respectively. In batch 6, EFA/CTRC was prepared using a different commercial batch of EFA and CTRC. The SEM results indicated the formation of needle-like and clustered particles. The values obtained from HSM, DSC and TGA results were 124 °C, 114 °C and 0.54 % in mass loss. The physical appearance of EFA/CTRC prepared from batch 1 and 2 were white in colour while batch 3, 4, 5 and 6 of the prepared EFA/CTRC was pink in colour. The physical appearance of the individual batches differed but the identity of the sample remained intact implying the same pharmacological effects with differing pharmaceutical properties impacting the dosage form preparation.

New methods for the preparation of porous biomedical scaffolds have been explored for applications in tissue engineering and drug delivery. Scaffolds with controlled pore morphologies have been generated which incorporate cyclodextrin-drug inclusion complexes as the drug delivery component. Supercritical CO2 was explored as the main processing fluid in the complex formation and in the foaming of the polymer scaffold. The co-solvents, ethanol, ethyl acetate and acetone, were explored in each stage, as needed, to improve the solvent power of CO2. The first goal was to promote cyclodextrin-drug complex formation. Complex formation by traditional methods was compared with complex formation driven by processing in supercritical CO2. Complex formation was promoted by melting the drug in supercritical CO2 or in CO2 + co-solvent mixtures while in the presence of cyclodextrin. Some drugs, such as piroxicam, are prone to degradation near the drug's ambient melting temperature. However, this approach using CO2 was found to circumvent drug thermal degradation, since drug melting temperatures were depressed in the presence of CO2. The second goal was to produce porous polymeric matrices to serve as tissue engineering scaffolds. Poly(lactide-<i>co</i>-glycolide) and poly(ε-caprolactone) were investigated for foaming, since these biomedical polymers are already commonly used and FDA approved. Polymer foaming with CO2 is an alternative approach to conventional solvent-intensive methods for porosity generation. However, two major limitations of polymer foaming using CO2 as the only processing fluid have been reported, including the formation of a non-porous outer skin upon depressurization and limited pore interconnectivity. Approaches to circumvent these limitations include the use of a co-solvent and controlling depressurization rates. The effect of processing parameters, including foaming temperatures and depressurization rate, as well as co-solvent addition, were examined in polymer foaming using CO2. Drug release dynamics were compared for foams incorporated with either pure drug, cyclodextrin-drug physical mixture or cyclodextrin-drug complex. Pore morphology, polymer choice and drug release compound choice were found to alter drug release profiles. / Ph. D.

Le jus d'orange frais est largement apprécié par les consommateurs en raison de son goût agréable et sa haute valeur nutritionnelle. La qualité du jus d'orange frais est rapidement altérée, notamment par les microorganismes. L'addition des antimicrobiens d'origine végétale au jus d'orange pourrait augmenter la durée de vie de ce jus durant le stockage à 4 °C. Parmi ces antimicrobiens naturels, plusieurs sont sensibles aux facteurs environnementaux qui diminuent leur efficacité dans les produits alimentaires, ce qui nécessite leur incorporation dans des systèmes d'encapsulation. Bien que ce domaine soit promettant, l'évaluation de l'activité des molécules antimicrobiennes encapsulées dans des jus de fruits reste limitée. Nous avons recherché une molécule naturelle active contre Lactobacillus fermentum, une bactérie impliquée dans la détérioration du jus 'orange, dans le milieu de culture. Le nérolidol (Ner), un sesquiterpène alcool, a été sélectionné parmi 28 molécules naturelles (terpènes et phénols) criblées et a montré une puissante activité contre L. fermentum (concentration minimale inhibitrice (CMI) = 25 μM et concentration minimale bactéricide (CMB)= 50 μM) dans le milieu de culture à 37 °C. Dans la suite du travail, le Ner a été incorporé dans le complexe d'inclusion hydroxypropyl-β-cyclodextrin (HP-β-CD)/Ner, les liposomes conventionnels (LCs), les liposomes contenant le complexe d'inclusion (DCL) et les bicelles. Les analyses HPLC ont montré que les complexes d'inclusion, les LCs et le système DCL contenaient 40, 30 et 15 μg Ner/mg poudre, respectivement. En outre, les systèmes ont été caractérisés en termes de morphologie, de taille, d'homogénéité et de potentiel zêta. Le Ner a été incorporé dans les bicelles à un rapport molaire phospholipides:Ner de 100:1 sans altération de la structure du système (taille, homogénéité, potentiel zêta, morphologie). Cette formulation a montré une efficacité d'encapsulation du Ner et un taux d'incorporation des phospholipides élevés et un pourcentage de Ner dans les bicelles de 0,86%. A des concentrations plus élevées, le Ner a altéré les caractéristiques physiques (taille, homogénéité, morphologie) et thermodynamiques de la membrane des bicelles et a augmenté le désordre au niveau membranaire. Le complexe d'inclusion HP-β-CD/Ner (CMI = 100 μM et CMB= 200 μM) a montré une bonne efficacité contre L. fermentum dans le milieu de culture à 37 °C. L'efficacité du Ner libre et du complexe d'inclusion HP-β-CD/Ner a énormément diminué dans le jus d'orange réfrigéré, vu qu'un effet bactéricide total a été obtenu après 8 et 17 jours d'incubation, respectivement, à 2000 μM en Ner. Alors que les liposomes ont bloqué cette activité pour au moins 20 jours et ont altéré l'aspect du jus. A 4000 μM en Ner libre ou incorporé dans le complexe d'inclusion, une mort bactérienne totale a été observée après 5 et 6 jours, respectivement. En outre, la présence du complexe d'inclusion n'a pas modifié le pH et l'acidité titrable du jus, alors qu'une faible augmentation du degré de Brix a été observée. Des études ultérieures sur l'activité antibactérienne des bicelles incorporant le Ner peuvent être envisagées pour déterminer l'efficacité du système préparé. Ce système pourrait être aussi caractérisé en termes de cinétique de libération, de protection du Ner / Fresh orange juice is widely appreciated by consumers due to its pleasant taste and high nutritional value. Fresh orange juice is rapidly altered during storage, especially by microorganisms. The addition of plant-derived antimicrobials to orange juice may increase its shelf life during storage at 4 °C. Many of these natural antimicrobials are sensitive to environmental factors which reduce their effectiveness in food products. Therefore, their incorporation into encapsulation systems is required. Although this strategy is promising, the evaluation of the activity of encapsulated antimicrobials in fruit juices remains limited. In this study, we searched for a natural molecule active against Lactobacillus fermentum, a bacterium involved in the deterioration of orange juice, in the culture medium. Nerolidol (Ner), a sesquiterpene alcohol, was selected among 28 natural molecules (terpenes and phenols) and showed a potent activity against L. fermentum (minimum inhibitory concentration (MIC) = 25 μM and minimal bactericidal concentration (CMB) = 50 μM) in culture medium at 37 °C. Ner was incorporated into hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex, conventional liposomes (CLs), dug-in-cyclodextrin-in liposome (DCL) and bicelles. HPLC analysis showed a Ner content of 40, 30 and 15 μg per mg powder of HP-β-CD/Ner inclusion complex, LCs, and DCL system, respectively. In addition, the systems were characterized in terms of morphology, size, homogeneity, and zeta potential. Ner was incorporated in bicelles at a phospholipids to Ner molar ratio of 100:1 without altering the structural characteristics of the system (size, homogeneity, zeta potential, morphology). This formulation showed a high encapsulation efficiency of Ner, a high phospholipid incorporation rate, and a molar percentage of Ner in bicelles of 0.86%. At higher concentrations, Ner altered the physical (size, homogeneity, morphology) and the thermodynamic parameters of the bicelles membrane in addition to the increase in membrane fluidity. The HP-β-CD/Ner inclusion complex (MIC = 100 μM and CMB = 200 μM) showed good efficacy against L. fermentum in the culture medium at 37 C. The efficacy of free Ner and HP-β-CD/Ner inclusion complex was greatly reduced in refrigerated orange juice, as a total bactericidal activity was observed after 8 and 17 days of incubation, respectively, at a Ner concentration of 2000 μM. Whereas, liposomes blocked this activity for at least 20 days and altered the appearance of the juice. At 4000 μMof free Ner or Ner incorporated into the inclusion complex, a total bacterial death was observed after 5 and 6 days, respectively. In addition, the presence of the inclusion complex did not alter the pH and the titratable acidity of the juice, while a slight increase in the Brix degree value was observed. Subsequent studies on the antibacterial activity of bicelles incorporating Ner may be considered to determine the effectiveness of the prepared system. This system could also be characterized in terms of release rate and Ner stability

No description available.