Enhancing the physicochemical properties of solid-state materials through crystal engineering enables optimization of these materials without covalent modification. Cocrystals have become a reliable means to generate novel crystalline forms with multiple components and they exhibit different physicochemical properties compared to the individual components. This dissertation exemplifies methodologies to generate cocrystals of active pharmaceutical ingredients (API's) based upon knowledge of supramolecular interactions (supramolecular synthons), while focusing on enhanced delivery through in vitro and in vivo processes with both salts and cocrystals respectively. The utility of mechanochemistry involving small amounts of an appropriate solvent, or solvent drop grinding (SDG), has been shown to reliably reproduce cocrystals with the anti-convulsant carbamazepine that were originally obtained by solution crystallization. This technique has been confirmed as a reliable screening method using solvents in which both components exhibit some solubility. The benefits of this technique lie in the time and cost efficiency associated with it as well as its inherently small environmental impact making it a "Green" method. SDG was also used as an efficient way to discover cocrystals of the anti-inflammatory meloxicam with carboxylic acids after analysis of existing reports and the analysis of structural data from the Cambridge Structural Database (CSD) to guide the choice of coformer. It has been shown that SDG can be used to screen for cocrystalline forms that are also obtainable by solution crystallization which is important in later stage development and manufacturing including but not limited to large scale up processes. Single crystals suitable for single crystal X-ray diffraction were obtained with meloxicam and two of the coformers, fumaric and succinic acid. Some of the meloxicam cocrystals exhibited enhanced pharmacokinetic (PK) profiles in rats exemplifying significantly higher serum concentrations after only fifteen minutes and consistently higher exposure over the time studied while others maintained lower exposure. This reveals that cocrystals can fine tune the PK profile of meloxicam in order to reduce or enhance exposure. Two different sulfonate salts, 4-hydroxybenzenesulfonate (p-phenolsulfonate) and 4-chlorobenzenesulfonate, of the anti-spastic agent (R,S) baclofen were developed by strategically interrupting the intramolecularly stabilized zwitterionic structure of baclofen. This zwitterionic structure results in low solubility associated with physiological pH required for intrathecal administration. Structural data for both salts in the form of single crystal X-ray diffraction data was successfully obtained. Solubility based on baclofen was assessed and shown to increase in pure water and at pH's 1 and 7. Only the 4-chlorobenzenesulonate salt maintained an increased solubility over two days at pH 7 making it a viable candidate for further study in terms of intrathecal administration. During crystallization experiments with (R,S) baclofen two polymorphic forms of the baclofen lactam were generated, Forms II and III. Both forms are conformational polymorphs confirmed by single crystal X-ray diffraction and Form II has a Z' of 4 with an unusual arrangement of enantiomers.

The knowledge of physicochemical properties of organic compounds becomes increasingly important. In this study, we developed UPPER (Unified Physical Property Estimation Relationships), a comprehensive model for the estimation of 20 physicochemical properties of organic compounds. UPPER is a system of thermodynamically sound relationships that relate the various phase-transition properties to one another, which includes transition heats, transition entropies, transition temperatures, molar volume, vapor pressure, solubilities and partition coefficients in different solvents and etc. UPPER integrates group contributions with the molecular geometric factors that affect transition entropies. All of the predictions are directly based on molecular structure. As a result, the proposed model provides a simple and accurate prediction of the properties studied. UPPER is designed to predict industrially, environmentally and pharmaceutically relevant physicochemical properties of organic compounds. It also can be an aid for the efficient design and synthesis of compounds with optimal physicochemical properties.

The influence of pH (3.0, 5.0 and 7.0) and ionic strength (0, 50 and 100 mM NaCl) on the physicochemical and emulsifying properties of cruciferin-rich (CPI) and napin-rich (NPI) protein isolates were examined. Specifically, the surface characteristics (charge and hydrophobicity), solubility, interfacial tension and emulsifying activity (EAI) and stability (ESI) indices were measured. In the case of the cruciferin-rich protein isolate, surface charge was found to be negatively and positively charged at pHs above and below its isoelectric point (~4.6-4.8), respectively, ranging in potential from -33 mV at pH 8.0 to +33 mV at pH 3.0. In the presence of NaCl, the overall magnitude of charge became reduced at all pHs. In contrast, hydrophobicity, solubility and the ability for CPI to reduce interfacial tension all were found to be dependent upon both pH and NaCl concentration. Solubility was found to be lowest at pH 5.0 (~11%) and 7.0 (16%) for CPI without salt, but was significantly improved with the addition of NaCl (>80%). Interfacial tension was found to be lowest (10-11 mN/m) for pH 5.0 – 0 mM NaCl and pH 7.0 – 50/100 mM NaCl. Overall, the presence of salt reduced EAI with increasing levels of NaCl at pH 5.0 and 7.0, but not at pH 3.0. In contrast, ESI became reduced with the addition of NaCl (regardless of the concentration) from ~15.7 min at 0 mM NaCl to ~12 min with 50/100 mM NaCl, from ~14.7 min at 0 mM NaCl to ~11.5 min with 50/100 mM NaCl and from 15.1 min at 0 mM NaCl to ~11.7 min with 50/100 mM NaCl for pH 3.0, 5.0 and 7.0, respectively. ESI also was found to be unaffected by pH. In the case of a napin-rich protein isolate, surface charge for the NPI in the absence of NaCl ranged between ~ +10 mV to ~ -5 mV depending on the pH, becoming electrically neutral at pH 6.6. The addition of NaCl acted to reduce the surface charge on the NPI and caused a shift in its isoelectric point to pH 3.5 and 3.9 for the 50 and 100 mM NaCl levels, respectively. Overall, surface hydrophobicity for the NPI was reduced as the pH increased, whereas as NaCl levels were raised the hydrophobicity declined. In contrast, NPI solubility was found to be high (~93-100%) regardless of the solvent conditions. The ability of NPI to reduce interfacial tension was enhanced at higher pHs, however the effect of NaCl was pH dependent. Overall, EAI values were similar in magnitude at pH 3.0 and 5.0, and lower at pH 7.0. The effect of NaCl on EAI was similar at pH 3.0 and 7.0, where EAI at the 0 mM and 100 mM NaCl levels were similar in magnitude, but increased significantly at 50 mM NaCl. However, the EAI values at pH 5.0 were reduced as the level of NaCl increased. Overall, the stability of NPI-stabilized emulsions degraded rapidly and the addition of salt induced faster emulsion instability. In summary, CPI and NPI were very different in terms of their physicochemical properties. However, the emulsifying properties were similar in magnitude indicating that they had similar emulsifying potential under the solvent conditions examined.

Percutaneous delivery of drugs promises many advantages over oral or intravenous administration, such as a better control of blood levels, a reduced incidence of systemic toxicity, an absence of hepatic first-pass metabolism, better patient compliance, etc. However, the dermal drug transport is limited by the unsuitable physicochemical properties of most drugs and the efficient barrier function of the skin. Thus, numerous attempts have been reported to improve topical absorption of drugs, concentrating mainly on the barrier function of the stratum corneum by use of penetration enhancers and/or skin warming. An alternative and interesting possibility for improved dermal permeability is the synthesis of derivatives or analogues with the aim of changing the physicochemical properties in favour of skin permeation, efficacy and therapeutic value. Cyclizine (I) is an anti-emetic drug primarily indicated for the prophylaxis and treatment of nausea and vomiting associated with motion sickness, post operation and Meniere's disease. It acts both on the emetic trigger zone and by damping the labyrinthine sensitivity. Pharmacologically it has anti-histaminic, antiserotonergic, local anaesthetic and vagolytic actions. It is widely used and also suitable for children from six year of age. Percutaneous absorption of (I) can, among others, avoid the "first-pass" effect and the discomfort of injection. The main objective of this study was to explore the feasibility of percutaneous absorption of (I) and its alkyl analogues via physicochemical characterization and assessment of their permeation parameters. The intent was also to establish a correlation between the physicochemical properties of these compounds and their percutaneous rate of absorption. To achieve these objectives, the study was undertaken by synthesizing the alkyl analogues and determining the physicochemical parameters relevant to skin transport. Identification and level of purity for the prepared analogues were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry and infrared (IR) spectrometry. Experimental aqueous solubility (25 °c & 32 °C) and partition coefficient for each compound were determined. In vitro permeation studies were performed at pH 7.4, using Franz diffusion cells with human epidermal membranes. Diffusion experiments were conducted over a period of 24 hours maintaining a constant temperature (37 DC) by means of water bath. All samples were analysed by high pressure liquid chromatography (HPLC). Cyclizine (I) has a methyl group at N-4. Increasing the alkyl chain length on N-4 of the piperazine ring resulted' in compounds with lower melting points and higher water solubility than (I). (II) exhibited 3-fold increase in water solubility, followed by (IV) with about 2.5 fold increase. The water solubility of (III) was almost the same as that of (I). Log partition coefficients increased linearly with increasing alkyl chain length. The analogues therefore, possessed more favourable physicochemical properties to be delivered percutaneously. Indeed, the in vitro skin permeation data proved that these analogues could be delivered more easily than (I) itself. The flux of (I) was 0.132 ug/cm2/h in a saturated aqueous solution. Compound (II) resulted in a 53-fold (6.952 ug/cm2/h) increase in permeation compared to (I). (III) and (IV) resulted in a 2- and 5fold enhancement of permeation respectively. Based on the results of the study, it seems that increased aqueous solubility and low level of crystallinity play a vital role in optimizing percutaneous absorption of (I) and its alkyl analogues. But the importance of the effect of increased lipophilicity cannot be ignored. The low percutaneous• absorption of (I) might be attributed to its low aqueous solubility and increased crystallinity, as is evident from the higher melting point than the analogues. From all the permeability data using aqueous solutions, it is clear that compound (II) is the best permeant of this series and in addition it is known that this compound antagonizes the effects of histamine. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.

Dermatologijoje emulsinio tipo produktai dažnai sutinkami dėl savo elegantiškos išvaizdos, vartojimo priimtinumo bei universalumo. Stabili pusiau kieta emulsinė sistema iš natūralių medžiagų farmacijoje yra aktuali savo pritaikymu kosmetinių ir gydomųjų kremų gamyboje. Tyrimo objektas – pusiau kieta emulsinė sistema iš natūralių medžiagų. Tyrimo tikslas – sumodeliuoti pusiau kietos emulsinės sistemos (vanduo aliejuje) iš natūralių medžiagų sudėtį, ištirti ir įvertinti fizikocheminius rodiklius bei juslines savybes. Tyrimo uždaviniai: parinkti emulsinės sistemos (v/a) iš natūralių medžiagų optimalią sudėtį pagal fizikocheminius rodiklius ir fizikines savybes; parinkti technologines sąlygas emulsiklio įterpimui į optimalios sudėties pusiau kietą emulsinę sistemą; palyginti chitozano tirpalo ir išgryninto vandens, skirtingų matricos užpildytojų įtaką optimalios sudėties emulsinės sistemos savybėms; -20°C ir natūralių sąlygų temperatūros įtaką; ištirti optimalios sudėties pusiau kietos emulsinės sistemos juslines savybes. Atlikus tyrimus ir gavus rezultatus, nustatyta, kad tinkamas emulsiklis yra cholesterolis. Pritaikius matematinį modeliavimą, buvo sudaryta ir ištirta 16 emulsinės sistemos sudėčių, ir pagal pH reikšmės, klampos, mikrostruktūros ir fizikinių savybių kriterijus parinkta optimali emulsinės sistemos sudėtis: avokadų aliejus 40 dalių, chitozano 0,5% tirpalas 40 dalių, kiaulių taukai 15 dalių, bičių vaškas 5 dalys, cholesterolis 5 dalys, tokoferolis 0,05 dalys... [toliau žr. visą tekstą] / Emulsion-type products are frequent in dermatology because of their sleek appearance, universality and consumer acceptability. Stable emulsified semi-solid system from natural materials is relevant because it can be used in pharmacy for cosmetic and medicinal cream production. Object of the study – a semisolid emulsified system from natural materials. Purpose of the survey was to model a composition of the semisolid emulsion system (w/o) from natural materials and to test and evaluate the physicochemical characteristics and sensory properties. The objectives: to choose the optimal composition of the emulsion system (w/o) from natural ingredients according to physicochemical characteristics and physical properties; to choose the technological conditions for inserting emulsifier into semi-solid emulsion system; to compare the properties of optimal composition emulsion system with different aqueous phase and different matrix fillers; to evaluate the influence of natural conditions and -20°C temperatures to the system; to test organoleptic properties of the optimal composition semi-solid emulsion system. According to the results of the study it was found that cholesterol is a suitable emulsifier. In application of mathematical models there were formed and tested 16 emulsion system configurations. According to the criteria of pH value, viscosity, microstructure and physical properties it was selected an optimal emulsion system consisting of: 40 parts of avocado oil, 40 parts... [to full text]

This study showed that hydrodynamic particle breakage had potential as a method to help improve the disinfection of wastewater effluents. The physicochemical properties of flocs from four distinct effluents sources (combined sewer overflow, settled combined sewer overflow, primary effluent, and final effluent) were compared before and after hydrodynamic treatment. The use of hydrodynamic force to cause floc breakage was shown to be effective, though variable, across all source types. This variation in floc breakage did not have a significant impact on the UV disinfection achieved, as the UV dose kinetics were similar across samples from the same source type. The results of this study demonstrate how the physicochemical properties of floc are affected when exposed to shear force. These observations further the understanding of floc composition and behaviour when shear forces are applied while also providing evidence to indicate this process improves the performance of UV disinfection technology.

No description available.

Percutaneous delivery of drugs promises many advantages over oral or intravenous administration, such as a better control of blood levels, a reduced incidence of systemic toxicity, an absence of hepatic first-pass metabolism, better patient compliance, etc. However, the dermal drug transport is limited by the unsuitable physicochemical properties of most drugs and the efficient barrier function of the skin. Thus, numerous attempts have been reported to improve topical absorption of drugs, concentrating mainly on the barrier function of the stratum corneum by use of penetration enhancers and/or skin warming. An alternative and interesting possibility for improved dermal permeability is the synthesis of derivatives or analogues with the aim of changing the physicochemical properties in favour of skin permeation, efficacy and therapeutic value. Cyclizine (I) is an anti-emetic drug primarily indicated for the prophylaxis and treatment of nausea and vomiting associated with motion sickness, post operation and Meniere's disease. It acts both on the emetic trigger zone and by damping the labyrinthine sensitivity. Pharmacologically it has anti-histaminic, antiserotonergic, local anaesthetic and vagolytic actions. It is widely used and also suitable for children from six year of age. Percutaneous absorption of (I) can, among others, avoid the "first-pass" effect and the discomfort of injection. The main objective of this study was to explore the feasibility of percutaneous absorption of (I) and its alkyl analogues via physicochemical characterization and assessment of their permeation parameters. The intent was also to establish a correlation between the physicochemical properties of these compounds and their percutaneous rate of absorption. To achieve these objectives, the study was undertaken by synthesizing the alkyl analogues and determining the physicochemical parameters relevant to skin transport. Identification and level of purity for the prepared analogues were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry and infrared (IR) spectrometry. Experimental aqueous solubility (25 °c & 32 °C) and partition coefficient for each compound were determined. In vitro permeation studies were performed at pH 7.4, using Franz diffusion cells with human epidermal membranes. Diffusion experiments were conducted over a period of 24 hours maintaining a constant temperature (37 DC) by means of water bath. All samples were analysed by high pressure liquid chromatography (HPLC). Cyclizine (I) has a methyl group at N-4. Increasing the alkyl chain length on N-4 of the piperazine ring resulted' in compounds with lower melting points and higher water solubility than (I). (II) exhibited 3-fold increase in water solubility, followed by (IV) with about 2.5 fold increase. The water solubility of (III) was almost the same as that of (I). Log partition coefficients increased linearly with increasing alkyl chain length. The analogues therefore, possessed more favourable physicochemical properties to be delivered percutaneously. Indeed, the in vitro skin permeation data proved that these analogues could be delivered more easily than (I) itself. The flux of (I) was 0.132 ug/cm2/h in a saturated aqueous solution. Compound (II) resulted in a 53-fold (6.952 ug/cm2/h) increase in permeation compared to (I). (III) and (IV) resulted in a 2- and 5fold enhancement of permeation respectively. Based on the results of the study, it seems that increased aqueous solubility and low level of crystallinity play a vital role in optimizing percutaneous absorption of (I) and its alkyl analogues. But the importance of the effect of increased lipophilicity cannot be ignored. The low percutaneous• absorption of (I) might be attributed to its low aqueous solubility and increased crystallinity, as is evident from the higher melting point than the analogues. From all the permeability data using aqueous solutions, it is clear that compound (II) is the best permeant of this series and in addition it is known that this compound antagonizes the effects of histamine. / Thesis (M.Sc. (Pharm.))--North-West University, Potchefstroom Campus, 2004.

Made available in DSpace on 2014-06-11T19:23:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2003-06-30Bitstream added on 2014-06-13T20:10:52Z : No. of bitstreams: 1 peroni_fhg_me_sjrp.pdf: 520841 bytes, checksum: 9b519101966877f66941bfb83c70d8e0 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Características estruturais e físico-químicas de amidos estão relacionadas a sua fonte botânica. Países tropicais como o Brasil, possuem uma grande variedade de espécies amiláceas que poderiam substituir amidos modificados em alimentos processados. Neste trabalho, amidos isolados de nove espécies diferentes (mandioca, batata-doce, araruta, mandioquinha-salsa, biri, inhame, taro, açafrão, gengibre) foram analisados. Distribuições de peso molecular dos amidos e comprimentos de cadeias ramificadas da amilopectina foram analisadas por cromatografia de permeação em gel (GPC) usando Sepharose CL-2B e Bio gel P-6, respectivamente. Teores de fósforo e de amilose foram determinados por método colorimétrico e medida da afinidade com iodo, respectivamente. As propriedades de pasta e térmicas dos amidos foram determinadas usando-se um Rápido Visco Analisador (RVA) e um Calorímetro Diferencial de Varredura (DSC), respectivamente. O poder de inchamento e solubilidade dos amidos foram determinados a temperaturas entre 60-90ºC, com exceção do amido de gengibre que foi também determinado a 95ºC. Os resultados mostraram diferentes padrões de distribuições de comprimentos de cadeias ramificadas da amilopectina para os diferentes amidos. Através de Bio gel P-6, os cromatogramas mostraram cadeias ramificadas longas da amilopectina com DP (grau de polimerização) variando de 21 a 38, e cadeias ramificadas curtas com DP variando de 7 a 19. Os amidos de biri e açafrão mostraram altas proporções de cadeias muito longas da amilopectina enquanto que o amido de taro mostrou altas proporções de cadeias curtas com alto grau de ramificações. Em Sepharose CL-2B, foi observado que os amidos de batata-doce, araruta e taro, apresentaram moléculas de amilose de alto peso molecular, enquanto que o amido de açafrão mostrou o mais baixo. Os amidos de açafrão, inhame e biri apresentaram... / Structural and physicochemical characteristics of starches are related to their botanical sources. Tropical countries have a great variety of starchy species that could replace modified starches in processed foods. In this work, starch samples isolated from nine different species (cassava, sweet potato, arrowroot, Perurian carrot, canna, yam, taro, curcuma, ginger) were analyzed. Molecular weight distributions of the starches and branch chains lengths of debranched amylopectins were analyzed by gel permeation chromatography (GPC) by using Sepharose CL-2B and Bio gel P-6, respectively. Phosphorous and amylose contents were determined by a colorimetric method and measuring iodine affinity, respectively. Pasting and thermal properties of the starches were determined using Rapid Visco Analyzer (RVA) and Differential Scanning Calorimetry (DSC), respectively. Swelling power and solubility of the starches were determined at temperatures between 60-90ºC, with exception of the ginger starch swelling power that was also determined at 95ºC. The results showed different patterns of amylopectin branch chains length distributions for different starches. From Bio gel P-6 GPC, chromatograms displayed long branch chains of amylopectin with DP (polimerization degree) varying from 21 to 38, and short branch chains with DP varying from 7 to 19. The canna and curcuma starches displayed higher proportions of very long chains of amylopectin whereas the taro starch showed higher proportions of short chains with a higher degree of branching. From Sepharose CL-2B, it was observed that the sweet potato, arrowroot and taro starches displayed amylose molecules with higher molecular weight, whereas the curcuma starch showed the lowest. The curcuma, yam, and canna starches displayed higher amylose contents (45.1, 35.0, and 33.7%, respectively) whereas the taro starch showed the lowest (10.2%)...(Complete abstract click electronic access below)

O objetivo deste trabalho foi avaliar as propriedades físico-químicas de diferentes matérias-primas de talidomida visando à identificação de parâmetros críticos a serem observados para garantir a aquisição de insumo com qualidade farmacêutica. Sete amostras foram caracterizadas a partir de estudos tecnológicos, espectroscópicos, morfológicos, térmicos e cristalográficos, sendo avaliadas frente a processos de dissolução e compactação. Os resultados obtidos demonstraram a inexistência de homogeneidade entre as matérias-primas analisadas, apresentando diferenças em relação à constituição cristalina e morfológica, comportamento térmico, velocidade de dissolução intrínseca e comportamento frente à compactação. Foi observada e quantificada a presença de fases polimórficas a e b e materiais semicristalinos. A amostra T5 demonstrou desfavoráveis propriedades tecnológicas, gerando indicativos de problemas relativos à processabilidade do fármaco em medicamento, ao contrário de T1. A análise térmica forneceu indícios de transição sólido-sólido entre fases polimórficas de fármaco, provavelmente relacionada a propriedades químico-mecânicas das amostras associadas à inserção de calor. Amostras semicristalinas apresentaram maior velocidade de dissolução intrínseca, principalmente associada ao polimorfo b, representando, possivelmente, um desvio de qualidade em processos sintéticos. Estudos preliminares indicaram que a amostra T1 exibiu melhor compactabilidade que T5. Devido a sua pureza cristalográfica e propriedades tecnológicas, a amostra T1 se mostrou a mais indicada ao desenvolvimento de comprimidos de talidomida. / The objective of this work was to evaluate physicochemical properties of different thalidomide raw material in order to identify critical parameters to assure the acquisition of a product with pharmaceutical quality. Seven samples were characterized by technological, spectroscopic, morphological, thermal and crystallographic approaches. Dissolution tests and degree of compaction were used to evaluate the samples. The results demonstrated raw materials with lack of homogeneity and differences related to crystal and morphological constitution, thermal behavior, intrinsic dissolution rate and compaction behavior. Polymorphic forms a and b and semicrystalline materials were observed and quantified. In contrast to T1, the sample T5 presented unfavorable technological properties generating indicatives of relative problems impairing the tablets manufacturing process. Thermal analysis indicated solid-solid transition between polymorphic phases probably related to chemical-mechanical properties of the samples associated with heating. Semicrystalline materials presented higher intrinsic dissolution rate than other samples, mainly related to the polymorph b, possibly representing quality deviation associated with synthetic process. Early studies indicated better compactability of sample T1 than T5. Due its crystallographic purity and technological properties, it is suggested that T1 is the sample choice to be used during the development of a pharmaceutical solid oral dosage form containing thalidomide.