Os métodos termo-analíticos são ferramentas úteis na avaliação da compatibilidade entre fármacos e adjuvantes, com destaque à calorimetria exploratória diferencial. Neste trabalho foram avaliados a compatibilidade e o comportamento térmico entre a isoniazida e adjuvantes tecnológicos primários usualmente empregados em formas farmacêuticas sólidas. A compatibilidade foi examinada por meio da preparação de misturas físicas binárias do tipo fármaco/adjuvante. Foi investigada também a influência da granulação por via úmida e do processo de compactação para as misturas de isoniazida e adjuvantes com função de material de enchimento e carga e deslizante. A isoniazida apresentou um comportamento térmico não encontrado na literatura. Os adjuvantes avaliados foram: ácido esteárico, amido, celulose microcristalina, crospovidona, croscarmelose sódica, dióxido de silício coloidal estearato de magnésio, glicolato de amido sódico, hipromelose, lactose, manitol, polidona e talco. Para as misturas físicas, a maioria dos adjuvantes mostrou-se compatível com o fármaco em questão. Foram verificadas interações com o ácido esteárico, o glicolato de amido sódico, a lactose, o manitol e a povidona. A isoniazida mostrou a formação de uma mistura eutética com o manitol e de interação química com a lactose. A agregação por via úmida e o processo de compactação não mostraram influências adicionais na compatibilidade das misturas avaliadas. Os resultados observados foram confirmados por métodos não-térmicos como difratometria de raios X, espectroscopia de infravermelho e ressonância nuclear magnética. / Thermo-analytical methods, and specially Differential Scanning Calorimetry, are useful support for the evaluation of compatibility between drug substances and pharmaceutical excipients. In this work were studied the compatibility and the thermal behavior of isoniazid and pharmaceutical excipients, commonly used for the formulation of solid dosage forms. Colloidal silicon dioxide, corn starch, crospovidone, hypromellose, lactose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, sodium starch glycolate, stearic acid and talc were the excipients employed in these experiments. The compatibility was analyzed testing binary physical drug/excipient admixtures. The effect of wet granulation and compression was also investigated, in this case especially between isoniazid, fillers and lubricant. For almost all excipients no incompatibilities with isoniazid were observed. Interactions were detected when the drug substance was added to stearic acid, sodium starch glycolate, lactose, mannitol and povidone. Isoniazid formed a euthetic mixture with mannitol, whereas a possible chemical reaction occurred between isoniazid and lactose. Wet granulation and compaction of the tested admixtures did not affect the results observed above. These observations were confirmed by non-thermal techniques, such as X-Ray diffractometry, infrared spectroscopy and nuclear magnetic resonance.

Nanoparticulate drug delivery systems (NDDS) such as nanocrystals, nanosuspensions, solid-lipid nanoparticles often formulated for the bioavailability enhancement of poorly soluble drug candidates are stabilized by a mixture of excipients including surfactants and polymers. Most literature studies have focused on the interaction of excipients with the NDDS surfaces while ignoring the interaction of excipients in solution and the extent to which the solution-state interactions influence the affinity and capacity of adsorption. Mechanisms by which excipients stabilize NDDS and how this information can be utilized by formulators a priori to make a rational selection of excipients is not known. The goals of this dissertation work were (a) to determine the energetics of interactions between HPMC and model surfactants and the extent to which these solution-state interactions modulate the adsorption of these excipients onto solid surfaces, (b) to determine and characterize the structures of various aggregate species formed by the interaction between hydroxypropyl methylcellulose (HPMC) and model surfactants (nonionic and ionic) in solution-state, and (c) to extend these quantitative relationships to interpret probable mechanisms of mixed adsorption of excipients onto the model NDDS surface. A unique approach utilizing fluorescence, solution calorimetry and adsorption isotherms was applied to tease apart the effect of solution state interactions of polymer and surfactant on the extent of simultaneous adsorption of the two excipients on a model surface. The onset of aggregation and changes in aggregate structures were quantified by a fluorescence probe approach with successive addition of surfactant. In the presence of HPMC, the structures of the aggregates formed were much smaller with an aggregation number (Nagg) of 34 as compared to micelles (Nagg ~ 68) formed in the absence of HPMC. The strength of polymer-surfactant interactions was determined to be a function of ionic strength and hydrophobicity of surfactant. The nature of these structures was characterized using their solubilization power for a hydrophobic probe molecule. This was determined to be approximately 35% higher in the polymer-surfactant aggregates as compared to micelles alone and was attributed to a significant increase in the number of aggregates formed and the increased hydrophobic microenvironment within these aggregates at a given concentration of surfactant. The energetics of the adsorption of SDS, HPMC, and SDS-HPMC aggregate onto nanosuspensions of silica, which is the model solid surface were quantified. A strong adsorption enthalpy of 1.25 kJ/mol was determined for SDS adsorption onto silica in the presence of HPMC as compared to the negligible adsorption enthalpy of 0.1 kJ/mol for SDS alone on the silica surface. The solution depletion and HPMC/ELSD methods showed a marked increase in the adsorption of SDS onto silica in the presence of HPMC. However, at high SDS concentrations, a significant decrease in the adsorbed amount of HPMC onto silica was determined. This was further corroborated by the adsorption enthalpy that showed that the silica-HPMC-SDS aggregation process became less endothermic upon addition of SDS. This suggested that the decrease in adsorption of HPMC onto silica at high SDS concentrations was due to competitive adsorption of SDS-HPMC aggregates wherein SDS is displaced/desorbed from silica in the presence of HPMC. At low SDS concentrations, an increase in adsorption of SDS was due to cooperative adsorption wherein SDS is preferentially adsorbed onto silica in the presence of HPMC. This adsorption behavior confirmed the hypothesis that the solution-state interactions between pharmaceutical excipients such as polymers and surfactants would significantly impact the affinity and capacity of adsorption of these excipients on NDDS surfaces.

<p>This thesis describes the application of multivariate methods in a novel approach to the formulation of tablets for direct compression. It begins with a brief historical review, followed by a basic introduction to key aspects of tablet formulation and multivariate data analysis. The bulk of the thesis is concerned with the novel approach, in which excipients were characterised in terms of multiple physical or (in most cases) spectral variables. By applying Principal Component Analysis (PCA) the descriptive variables are summarized into a few latent variables, usually termed scores or principal properties (PP’s). In this way the number of descriptive variables is dramatically reduced and the excipients are described by orthogonal continuous variables. This means that the PP’s can be used as ordinary variables in a statistical experimental design. The combination of latent variables and experimental design is termed multivariate design or experimental design in PP’s. Using multivariate design many excipients can be included in screening experiments with relatively few experiments.</p><p>The outcome of experiments designed to evaluate the effects of differences in excipient composition of formulations for direct compression is, of course, tablets with various properties. Once these properties, e.g. disintegration time and tensile strength, have been determined with standardised tests, quantitative relationships between descriptive variables and tablet properties can be established using Partial Least Squares Projections to Latent Structures (PLS) analysis. The obtained models can then be used for different purposes, depending on the objective of the research, such as evaluating the influence of the constituents of the formulation or optimisation of a certain tablet property.</p><p>Several examples of applications of the described methods are presented. Except in the first study, in which the feasibility of this approach was first tested, the disintegration time of the tablets has been studied more carefully than other responses. Additional experiments have been performed in order to obtain a specific disintegration time. Studies of mixtures of excipients with the same primary function have also been performed to obtain certain PP’s. Such mixture experiments also provide a straightforward approach to additional experiments where an interesting area of the PP space can be studied in more detail. The robustness of a formulation with respect to normal batch-to-batch variability has also been studied.</p><p>The presented approach to tablet formulation offers several interesting alternatives, for both planning and evaluating experiments.</p>

This thesis describes the application of multivariate methods in a novel approach to the formulation of tablets for direct compression. It begins with a brief historical review, followed by a basic introduction to key aspects of tablet formulation and multivariate data analysis. The bulk of the thesis is concerned with the novel approach, in which excipients were characterised in terms of multiple physical or (in most cases) spectral variables. By applying Principal Component Analysis (PCA) the descriptive variables are summarized into a few latent variables, usually termed scores or principal properties (PP’s). In this way the number of descriptive variables is dramatically reduced and the excipients are described by orthogonal continuous variables. This means that the PP’s can be used as ordinary variables in a statistical experimental design. The combination of latent variables and experimental design is termed multivariate design or experimental design in PP’s. Using multivariate design many excipients can be included in screening experiments with relatively few experiments. The outcome of experiments designed to evaluate the effects of differences in excipient composition of formulations for direct compression is, of course, tablets with various properties. Once these properties, e.g. disintegration time and tensile strength, have been determined with standardised tests, quantitative relationships between descriptive variables and tablet properties can be established using Partial Least Squares Projections to Latent Structures (PLS) analysis. The obtained models can then be used for different purposes, depending on the objective of the research, such as evaluating the influence of the constituents of the formulation or optimisation of a certain tablet property. Several examples of applications of the described methods are presented. Except in the first study, in which the feasibility of this approach was first tested, the disintegration time of the tablets has been studied more carefully than other responses. Additional experiments have been performed in order to obtain a specific disintegration time. Studies of mixtures of excipients with the same primary function have also been performed to obtain certain PP’s. Such mixture experiments also provide a straightforward approach to additional experiments where an interesting area of the PP space can be studied in more detail. The robustness of a formulation with respect to normal batch-to-batch variability has also been studied. The presented approach to tablet formulation offers several interesting alternatives, for both planning and evaluating experiments.

Direct compression has gained significant interest since its advent in the late 1950's due to its potential ease compared to wet granulation. The primary prerequisites for powders used in direct compression are (i) good flow properties (ii) good compressibility and (iii) an acceptable dilution potential to accommodate a relative high percentage of active ingredient. Several filler/binders have been manufactured especially for direct compression and co–processing is one of the recent methods used to produce good compressible excipients with acceptable flow properties. In this study, lactose–based filler/binders were used which included simple and modified lactose materials (Granulac, Lactopress, Flowlac and Tablettose) as well as co–processed excipients (Starlac, Cellactose and Microcelac). A comprehensive literature study on direct compression revealed the importance of the physical properties of filler/binders such as interparticle forces, particle shape, particle size and distribution, powder density, particle surface structure and particle packing geometry which influence the flow of powders. All the materials were subjected to the various tests available to evaluate powder flow, namely (i) angle of repose (AoR), (ii) critical orifice diameter (COD), (iii) flow rate and percentage compressibility (%C) in terms of the powders' bulk and tap densities. The results of these tests confirmed the expected flow properties of the various filler/binders, with only one material exhibiting extremely poor flow properties. The following rank order in terms of all flow tests conducted was established; Starlac >> Microcelac ~ Flowlac >> Cellactose > Tablettose > Lactopress >>> Granulac. The co–processed filler/binders presented with superior flow compared to the other lactose–based materials. During the next phase of the study, the compaction properties of the various fillers were evaluated, employing direct compression. Compacts of pure filler were tabletted on an eccentric tablet press at different compression pressures (manipulated by the upper punch setting of the tablet press). The modified lactose filler/binders (Lactopress, Flowlac and Tablettose) exhibited unexpectedly poor compression profiles, where the co–processed filler/binders (Starlac, Cellactose and Microcelac) produced compacts with acceptable appearance and compact properties. Two lubricants (Mg–St or Pruv), which were tested separately in formulations were added since no compacts could be produced from the pure filler/binders. None of the modified lactose filler/binders, in combination with a lubricant, were able to produce an acceptable compact, since lamination occurred during compression. The co–processed filler/binders produced satisfactory compacts with the addition of a lubricant, but lactose–cellulose fillers (Cellactose and Microcelac) also required the inclusion of a disintegrant (Ac–Di–Sol) to induce satisfactory compact disintegration. Poor compressible active ingredients (paracetamol), which exhibit very poor flow properties, are usually difficult to use during direct compression. Many excipients (tested in this study) are formulated to accommodate these drugs and produce acceptable functional tablets. After identifying the best filler/binders (co–processed fillers), according to their flow and compressible properties, paracetamol was added to the formulations. During a pilot study, the percentage paracetamol these fillers could accommodate in a 400 mg tablet was determined. Both Microcelac and Cellactose could accommodate 24.5% w/w paracetamol, whilst Starlac could only accommodated 19.5% w/w. Paracetamol is well known for its tendency to cause tablet capping and lamination. An acceptable upper punch setting range (20–22) was chosen for tabletting, followed by quality control tests done. All three formulations produced suitable tablets for testing and exhibited good tablet properties. All tablets disintegrated within two minutes, with hardness profiles between 120 N and 148 N and friability percentages less than 1%. Dissolution studies, however, are probably the ultimate test to distinguish between the capability of filler/binders to release the optimum percentage drug after disintegration. Dissolution studies were done on all three formulations using the AUC (area under the curve) and IDR (initial drug release) as parameters to evaluate drug release. All tablets exhibited high initial dissolution rates (between 0.018 - 0.023 mg/min/ml) and 100% drug release was observed. Starlac presented with a lower amount of drug released compared to the other two, but can be explained by the lower percentage (19.5%) paracetamol present in the formulation. It was once again confirmed that the physical and compressible properties of potential directly compressible filler/binders play a major role in direct compression. It was concluded that co–processed filler/binders (Starlac, Microcelac and Cellactose) definitely exhibited better tabletting properties during direct compression. They were able to accommodate a certain percentage of paracetamol, although it was expected that they would accommodate a higher amount (at least 50% of total tablet weight). / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Direct compression has gained significant interest since its advent in the late 1950's due to its potential ease compared to wet granulation. The primary prerequisites for powders used in direct compression are (i) good flow properties (ii) good compressibility and (iii) an acceptable dilution potential to accommodate a relative high percentage of active ingredient. Several filler/binders have been manufactured especially for direct compression and co–processing is one of the recent methods used to produce good compressible excipients with acceptable flow properties. In this study, lactose–based filler/binders were used which included simple and modified lactose materials (Granulac, Lactopress, Flowlac and Tablettose) as well as co–processed excipients (Starlac, Cellactose and Microcelac). A comprehensive literature study on direct compression revealed the importance of the physical properties of filler/binders such as interparticle forces, particle shape, particle size and distribution, powder density, particle surface structure and particle packing geometry which influence the flow of powders. All the materials were subjected to the various tests available to evaluate powder flow, namely (i) angle of repose (AoR), (ii) critical orifice diameter (COD), (iii) flow rate and percentage compressibility (%C) in terms of the powders' bulk and tap densities. The results of these tests confirmed the expected flow properties of the various filler/binders, with only one material exhibiting extremely poor flow properties. The following rank order in terms of all flow tests conducted was established; Starlac >> Microcelac ~ Flowlac >> Cellactose > Tablettose > Lactopress >>> Granulac. The co–processed filler/binders presented with superior flow compared to the other lactose–based materials. During the next phase of the study, the compaction properties of the various fillers were evaluated, employing direct compression. Compacts of pure filler were tabletted on an eccentric tablet press at different compression pressures (manipulated by the upper punch setting of the tablet press). The modified lactose filler/binders (Lactopress, Flowlac and Tablettose) exhibited unexpectedly poor compression profiles, where the co–processed filler/binders (Starlac, Cellactose and Microcelac) produced compacts with acceptable appearance and compact properties. Two lubricants (Mg–St or Pruv), which were tested separately in formulations were added since no compacts could be produced from the pure filler/binders. None of the modified lactose filler/binders, in combination with a lubricant, were able to produce an acceptable compact, since lamination occurred during compression. The co–processed filler/binders produced satisfactory compacts with the addition of a lubricant, but lactose–cellulose fillers (Cellactose and Microcelac) also required the inclusion of a disintegrant (Ac–Di–Sol) to induce satisfactory compact disintegration. Poor compressible active ingredients (paracetamol), which exhibit very poor flow properties, are usually difficult to use during direct compression. Many excipients (tested in this study) are formulated to accommodate these drugs and produce acceptable functional tablets. After identifying the best filler/binders (co–processed fillers), according to their flow and compressible properties, paracetamol was added to the formulations. During a pilot study, the percentage paracetamol these fillers could accommodate in a 400 mg tablet was determined. Both Microcelac and Cellactose could accommodate 24.5% w/w paracetamol, whilst Starlac could only accommodated 19.5% w/w. Paracetamol is well known for its tendency to cause tablet capping and lamination. An acceptable upper punch setting range (20–22) was chosen for tabletting, followed by quality control tests done. All three formulations produced suitable tablets for testing and exhibited good tablet properties. All tablets disintegrated within two minutes, with hardness profiles between 120 N and 148 N and friability percentages less than 1%. Dissolution studies, however, are probably the ultimate test to distinguish between the capability of filler/binders to release the optimum percentage drug after disintegration. Dissolution studies were done on all three formulations using the AUC (area under the curve) and IDR (initial drug release) as parameters to evaluate drug release. All tablets exhibited high initial dissolution rates (between 0.018 - 0.023 mg/min/ml) and 100% drug release was observed. Starlac presented with a lower amount of drug released compared to the other two, but can be explained by the lower percentage (19.5%) paracetamol present in the formulation. It was once again confirmed that the physical and compressible properties of potential directly compressible filler/binders play a major role in direct compression. It was concluded that co–processed filler/binders (Starlac, Microcelac and Cellactose) definitely exhibited better tabletting properties during direct compression. They were able to accommodate a certain percentage of paracetamol, although it was expected that they would accommodate a higher amount (at least 50% of total tablet weight). / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2011.

Com o objetivo de verificar a viabilidade de obtenção de comprimidos contendo alto teor de produto seco nebulizado (PSN) de Maytenus ilicifolia Martius ex Reiss., foi avaliada a influência de adjuvantes farmacêuticos através da realização de planejamento fatorial 2 3. Os fatores qualitativos estudados foram: tipo de desintegrante (croscarmelose sódica e glicolato de amido sódico), tipo de lubrificante (dióxido de silício coloidal e estearato de magnésio) e tipo de material de carga/aglutinante (celulose microcristalina e lactose). Os complexos farmacêuticos (CF) apresentaram características tecnológicas diferenciadas, dependentes da composição da formulação. Todos os CF demonstraram baixa densidade e más propriedades de fluxo. Os compactos foram obtidos em máquina de comprimir altenativa, por compressão direta e pesagem individual de cerca de 650 mg de cada formulação, contendo 375 mg de PSN de M. ilicifolia. As condições de compressão foram fixadas de modo que todos as compactos possuíssem a mesma dureza. Os parâmetros tecnológicos analisados foram friabilidade, tempo de desintegração e eficiência de dissolução. O material de carga/aglutinante (MCA) foi a classe de adjuvantes com maior influência sobre os parâmetros estudados. Todos os fatores estudados apresentaram efeito significativo sobre a friabilidade, sendo que os compactos contendo lactose apresentaram valores, cerca de vinte vezes superiores aos com celulose microcristalina. Os fatores significantes sobre o tempo de desintegração foram o tipo de desagregante e tipo de MCA. Todos os compactos produziram diferentes perfis de dissolução. A eficiência de dissolução mostrou-se superior a 50% e, neste parâmetro, os fatores mais significantes foram o tipo de lubrificante e o tipo de MCA. / The influence of pharmaceutical excipients on the technological characteristics of compacts containing high amounts of Maytenus ilicifolia Martius ex Reiss. spray dried extract was evaluated by a 2 3 factorial design. The qualitative factors studied were: type of disintegrant (croscarmellose sodium and sodium starch glycolate), lubricant (colloidal silicon dioxide and magnesium stearate) and filler/binder (microcrystalline cellulose and lactose). The compacts were prepared by direct compression using a single flat punch tablet machine by individual weighing of 650 mg each formulation, containing circa 60 % of spray dried extract. The compression parameters were chosen in order to produce compacts with similar hardness. The technological parameters analyzed were: friability, disintegration time, and dissolution efficiency (DE%). The results showed that the filler/binder was the excipient class with greatest influence on the compact characteristics. All factors influenced significantly the friability. Compacts containing lactose presented higher friability than the microcrystalline cellulose ones. The type of disintegrant and filler/binder were the most important factor affecting the disintegration time. All compacts showed DE% values higher than 50% but different dissolution profiles. The release was stronger influenced by the type of lubricant and filler/binder. The results demonstrated the technological feasibility of compacts containing high quantity of M. ilicifolia spray dried extract.

Os métodos termo-analíticos são ferramentas úteis na avaliação da compatibilidade entre fármacos e adjuvantes, com destaque à calorimetria exploratória diferencial. Neste trabalho foram avaliados a compatibilidade e o comportamento térmico entre a isoniazida e adjuvantes tecnológicos primários usualmente empregados em formas farmacêuticas sólidas. A compatibilidade foi examinada por meio da preparação de misturas físicas binárias do tipo fármaco/adjuvante. Foi investigada também a influência da granulação por via úmida e do processo de compactação para as misturas de isoniazida e adjuvantes com função de material de enchimento e carga e deslizante. A isoniazida apresentou um comportamento térmico não encontrado na literatura. Os adjuvantes avaliados foram: ácido esteárico, amido, celulose microcristalina, crospovidona, croscarmelose sódica, dióxido de silício coloidal estearato de magnésio, glicolato de amido sódico, hipromelose, lactose, manitol, polidona e talco. Para as misturas físicas, a maioria dos adjuvantes mostrou-se compatível com o fármaco em questão. Foram verificadas interações com o ácido esteárico, o glicolato de amido sódico, a lactose, o manitol e a povidona. A isoniazida mostrou a formação de uma mistura eutética com o manitol e de interação química com a lactose. A agregação por via úmida e o processo de compactação não mostraram influências adicionais na compatibilidade das misturas avaliadas. Os resultados observados foram confirmados por métodos não-térmicos como difratometria de raios X, espectroscopia de infravermelho e ressonância nuclear magnética. / Thermo-analytical methods, and specially Differential Scanning Calorimetry, are useful support for the evaluation of compatibility between drug substances and pharmaceutical excipients. In this work were studied the compatibility and the thermal behavior of isoniazid and pharmaceutical excipients, commonly used for the formulation of solid dosage forms. Colloidal silicon dioxide, corn starch, crospovidone, hypromellose, lactose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, sodium starch glycolate, stearic acid and talc were the excipients employed in these experiments. The compatibility was analyzed testing binary physical drug/excipient admixtures. The effect of wet granulation and compression was also investigated, in this case especially between isoniazid, fillers and lubricant. For almost all excipients no incompatibilities with isoniazid were observed. Interactions were detected when the drug substance was added to stearic acid, sodium starch glycolate, lactose, mannitol and povidone. Isoniazid formed a euthetic mixture with mannitol, whereas a possible chemical reaction occurred between isoniazid and lactose. Wet granulation and compaction of the tested admixtures did not affect the results observed above. These observations were confirmed by non-thermal techniques, such as X-Ray diffractometry, infrared spectroscopy and nuclear magnetic resonance.

Com o objetivo de verificar a viabilidade de obtenção de comprimidos contendo alto teor de produto seco nebulizado (PSN) de Maytenus ilicifolia Martius ex Reiss., foi avaliada a influência de adjuvantes farmacêuticos através da realização de planejamento fatorial 2 3. Os fatores qualitativos estudados foram: tipo de desintegrante (croscarmelose sódica e glicolato de amido sódico), tipo de lubrificante (dióxido de silício coloidal e estearato de magnésio) e tipo de material de carga/aglutinante (celulose microcristalina e lactose). Os complexos farmacêuticos (CF) apresentaram características tecnológicas diferenciadas, dependentes da composição da formulação. Todos os CF demonstraram baixa densidade e más propriedades de fluxo. Os compactos foram obtidos em máquina de comprimir altenativa, por compressão direta e pesagem individual de cerca de 650 mg de cada formulação, contendo 375 mg de PSN de M. ilicifolia. As condições de compressão foram fixadas de modo que todos as compactos possuíssem a mesma dureza. Os parâmetros tecnológicos analisados foram friabilidade, tempo de desintegração e eficiência de dissolução. O material de carga/aglutinante (MCA) foi a classe de adjuvantes com maior influência sobre os parâmetros estudados. Todos os fatores estudados apresentaram efeito significativo sobre a friabilidade, sendo que os compactos contendo lactose apresentaram valores, cerca de vinte vezes superiores aos com celulose microcristalina. Os fatores significantes sobre o tempo de desintegração foram o tipo de desagregante e tipo de MCA. Todos os compactos produziram diferentes perfis de dissolução. A eficiência de dissolução mostrou-se superior a 50% e, neste parâmetro, os fatores mais significantes foram o tipo de lubrificante e o tipo de MCA. / The influence of pharmaceutical excipients on the technological characteristics of compacts containing high amounts of Maytenus ilicifolia Martius ex Reiss. spray dried extract was evaluated by a 2 3 factorial design. The qualitative factors studied were: type of disintegrant (croscarmellose sodium and sodium starch glycolate), lubricant (colloidal silicon dioxide and magnesium stearate) and filler/binder (microcrystalline cellulose and lactose). The compacts were prepared by direct compression using a single flat punch tablet machine by individual weighing of 650 mg each formulation, containing circa 60 % of spray dried extract. The compression parameters were chosen in order to produce compacts with similar hardness. The technological parameters analyzed were: friability, disintegration time, and dissolution efficiency (DE%). The results showed that the filler/binder was the excipient class with greatest influence on the compact characteristics. All factors influenced significantly the friability. Compacts containing lactose presented higher friability than the microcrystalline cellulose ones. The type of disintegrant and filler/binder were the most important factor affecting the disintegration time. All compacts showed DE% values higher than 50% but different dissolution profiles. The release was stronger influenced by the type of lubricant and filler/binder. The results demonstrated the technological feasibility of compacts containing high quantity of M. ilicifolia spray dried extract.

Os métodos termo-analíticos são ferramentas úteis na avaliação da compatibilidade entre fármacos e adjuvantes, com destaque à calorimetria exploratória diferencial. Neste trabalho foram avaliados a compatibilidade e o comportamento térmico entre a isoniazida e adjuvantes tecnológicos primários usualmente empregados em formas farmacêuticas sólidas. A compatibilidade foi examinada por meio da preparação de misturas físicas binárias do tipo fármaco/adjuvante. Foi investigada também a influência da granulação por via úmida e do processo de compactação para as misturas de isoniazida e adjuvantes com função de material de enchimento e carga e deslizante. A isoniazida apresentou um comportamento térmico não encontrado na literatura. Os adjuvantes avaliados foram: ácido esteárico, amido, celulose microcristalina, crospovidona, croscarmelose sódica, dióxido de silício coloidal estearato de magnésio, glicolato de amido sódico, hipromelose, lactose, manitol, polidona e talco. Para as misturas físicas, a maioria dos adjuvantes mostrou-se compatível com o fármaco em questão. Foram verificadas interações com o ácido esteárico, o glicolato de amido sódico, a lactose, o manitol e a povidona. A isoniazida mostrou a formação de uma mistura eutética com o manitol e de interação química com a lactose. A agregação por via úmida e o processo de compactação não mostraram influências adicionais na compatibilidade das misturas avaliadas. Os resultados observados foram confirmados por métodos não-térmicos como difratometria de raios X, espectroscopia de infravermelho e ressonância nuclear magnética. / Thermo-analytical methods, and specially Differential Scanning Calorimetry, are useful support for the evaluation of compatibility between drug substances and pharmaceutical excipients. In this work were studied the compatibility and the thermal behavior of isoniazid and pharmaceutical excipients, commonly used for the formulation of solid dosage forms. Colloidal silicon dioxide, corn starch, crospovidone, hypromellose, lactose, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium croscarmellose, sodium starch glycolate, stearic acid and talc were the excipients employed in these experiments. The compatibility was analyzed testing binary physical drug/excipient admixtures. The effect of wet granulation and compression was also investigated, in this case especially between isoniazid, fillers and lubricant. For almost all excipients no incompatibilities with isoniazid were observed. Interactions were detected when the drug substance was added to stearic acid, sodium starch glycolate, lactose, mannitol and povidone. Isoniazid formed a euthetic mixture with mannitol, whereas a possible chemical reaction occurred between isoniazid and lactose. Wet granulation and compaction of the tested admixtures did not affect the results observed above. These observations were confirmed by non-thermal techniques, such as X-Ray diffractometry, infrared spectroscopy and nuclear magnetic resonance.