The number of newly developed chemical entities exhibiting poor water solubility has increased dramatically in recent years. In many cases this intrinsic property results in poor or erratic dissolution in biological fluids. Improving aqueous solubility of these compounds, even temporarily, can have a significant impact on in vivo performance. Single phase amorphous solid dispersions of a drug and polymer have emerged as a technique to not only increase the level of drug supersaturation but also maintain these levels for extended periods of time. Hot-melt extrusion (HME) has become the preferred processing technique to prepare systems such as these but has a number of limitations that prevent the successful formulation of many drug substances. Within this dissertation, the use of concentration enhancing polymers was investigated in parallel with a thorough evaluation of a novel fusion-based processing technique, KinetiSol® Dispersing (KSD), to prepare single phase amorphous solid dispersions that could not be successfully prepared by HME. Studies showed that the KSD technique is suitable for rendering thermally labile and high melting point drug substances amorphous through a combination of frictional and shearing energy. Compounds such as these were shown to degrade during HME processing due to relatively long residence times and low shear forces. Similarly, the KSD process was shown to successfully process solid dispersion compositions containing a high viscosity polymer with significantly lower levels of polymer degradation than obtained by HME processing. In the final study, KSD processing was used to prepare solid dispersions containing the hydrophilic polymer Soluplus[superscript TM] and methods were evaluated to formulate a tablet with rapid tablet disintegration characteristics, a requirement for sufficient dissolution enhancement. Combined, the studies demonstrated the effectiveness of combining proper polymer selection and formulation approaches with a suitable processing technique to form solid dispersion systems that provide rapid and extended durations of supersaturation. / text

Process Analytical Technology (PAT) is framed with the objective of the design and development of processes to ensure predefined quality of the product at the end of manufacturing. PAT implementation includes better understanding of process, reduction in production time with use of in-line, at-line and on-line measurements, yield improvement and energy and cost reductions. Hot Melt Extrusion process (HME) used in the present work is proving increasingly popular in industry for its continuous and green processing which is beneficial over traditional batch processing. The present work was focused on applications of Raman spectroscopy as off - line and in - line monitoring techniques as a PAT for production of pharmaceutical solid dispersions and co-crystals. Solid dispersions (SDs) of the anti-convulsant Carbamazepine (CBZ) with two pharmaceutical grade polymers have been produced using HME at a range of drug loadings and their amorphous nature confirmed using a variety of analytical techniques. Off-line and in-line Raman spectroscopy has been shown to be suitable techniques for proving preparation of these SDs. Through calibration curves generated from chemometric analysis in-line Raman spectroscopy was shown to be more accurate than off-line measurements proving the quantification ability of Raman spectroscopy as well as a PAT tool. Pure co-crystals of Ibuprofen-Nicotinamide and Carbamazepine-Nicotinamide have been produced using solvent evaporation and microwave radiation techniques. Raman spectroscopy proved its superiority over off-line analytical techniques such as DSC, FTIR and XRD for co-crystal purity determination adding to its key advantage in its ability to be used as an in-line, non-destructive technique.

Fármacos pouco solúveis tendem a possuir baixa biodisponibilidade. Diversos métodos têm sido estudados para promover o aumento da solubilidade de fármacos pouco solúveis. As dispersões sólidas têm sido pesquisadas como uma estratégia de aumentar a solubilidade e, portanto a biodisponibilidade de fármacos pouco solúveis em água, entretanto, os mecanismos pelos quais ocorre o aumento da solubilidade desses fármacos ainda não foram completamente elucidados e parecem variar da combinação do fármaco e do polímero, bem como do método de obtenção empregado. No presente estudo, utilizaram-se técnicas de caracterização do estado sólido, baseadas na interação da energia térmica e eletromagnética radiante com a matéria. Foi detectado que as interações que ocorrem entre a hidroclorotiazida e a polivinilpirrolidona se devem a ligações de hidrogênio que mantêm o fármaco disperso na matriz amorfa do polímero provocando um aumento da solubilidade em água. / Poorly water-soluble drug frequently has low bioavailability. Solid dispersions have been used to improve the solubility and bioavailability of poorly watersoluble drugs. However, the mechanisms underlying this phenomenon have not been show yet. In this study solid dispersions with hydrochlorothiazide and polyvinylpyrrolidone was prepared by evaporation method and characterized by dissolution test, differential scanning calorimetry and powder X Ray diffraction, in order to elucidate the mechanisms underlying the water solubility improve of drug. Our results show the polymer increasing the drug solubility by hydrogen bonding forming glassy solutions.

Os fármacos pertencentes às classes II e IV do sistema de classificação biofarmacêutica são aqueles sujeitos a problemas relacionados com a sua biodisponibilidade. Um dos procedimentos utilizados para melhorar a solubilidade de fármacos pouco solúveis é a granulação com materiais lipídicos ou cerosos. Para aumentar a solubilidade da carbamazepina, fármaco de classe II, ou seja, que apresenta baixa solubilidade e alta permeabilidade, inicialmente esta foi associada com os excipientes Gelucire® 50/13 ou Polietilenoglicol 6000, através de uma mistura física ou dispersão sólida. Estas associações foram submetidas a procedimentos analíticos como DSC, Infravermelho, Difração de Raios-X e teste de solubilidade em água. Nas misturas físicas a carbamazepina permaneceu estável, porém nas dispersões sólidas houve o aparecimento de polimorfismo. No entanto estes polimorfos também apresentam atividade terapêutica. As misturas físicas e as dispersões sólidas foram submetidas ao teste de solubilidade e as amostras que continham Gelucire® 50/13 aumentaram em torno de 15 vezes a solubilidade da carbamazepina em água, enquanto que as amostras que continham Polietilenoglicol 6000 aumentaram em torno de 14 vezes. Optou-se pela utilização do PEG 6000 devido à melhor compatibilidade deste com o equipamento utilizado. A granulação por Hot Melt em leito fluidizado foi realizada após alguns ensaios de fluidodinâmica utilizando a lactose spray dried como substrato. Durante os experimentos as condições do processo permaneceram estáveis e a curva característica foi típica de leito fluidizado. Os granulados foram obtidos utilizando o planejamento fatorial Box Behnken cujos fatores estudados foram: vazão de dispersão sólida, quantidade de dispersão sólida e pressão de atomização e em seguida caracterizados e avaliados. A maioria das propriedades físicas e farmacotécnicas dos granulados foi dependente da quantidade de dispersão sólida. A utilização do método de granulação por fusão em leito fluidizado melhorou o perfil de dissolução das cápsulas contendo os granulados, sendo que com o maior nível da quantidade de dispersão sólida houve um aumento significante na quantidade de carbamazepina liberada. Os resultados mostram que esta técnica é relevante para preparar dispersões sólidas com fármacos que apresentam baixa biodisponibilidade devido a sua baixa solubilidade. / Drugs belonging to classes II and IV in the biopharmaceutical classification system are those having bioavailability problems. Granulation with waxy lipids is one of the procedures used to improve the solubility of poorly soluble drugs. To increase the solubility of carbamazepine a drug of class II that has low solubility but high permeability, its association with the excipients Gelucire® 50/13 or Polyethylene 6000, was done by physical mixtures or solid dispersions. The associations were subjected to analytical procedures such as Differential Scanning Calorimetry (DSC), infrared light, X-ray diffraction and tests of solubility in water. In physical mixtures carbamazepine remained stable, but showed different polymorphic forms in solid dispersions. However, the polymorphic forms were also therapeutically active.Solubility tests of physical mixtures and solid dispersions indicated that samples containing Gelucire ® 50 / 13 increased the solubility of carbamazepine in water about 15 times, while the ones containing Polyethylene glycol 6000 had an increase of about 14 times. PEG 6000 was the chosen carrier due to its better compatibility with the equipment used.Fluid dynamic tests using spray dried lactose as a substrate were preliminary to the granulation experiments in the fluidised bed. The process conditions remained stable during the experiments and the characteristic curve tracing was typical of fluidised beds. Granules were obtained in experiments that followed a Box Behnken factorial design, where the factors studied were: flow rate of the solid dispersion, amount of solid dispersion and atomization pressure .Most physical and technical granule properties were dependent on the quantity of solid dispersion. The method of granulation by hot melt in a fluidised bed improved the solubility profile of carbamazepine in granule containing capsules.Granules containing the highest amount of solid dispersion showed a significant increase in the amount of carbamazepine released. The results proved that this technique is relevant to the preparation of solid dispersions with low bioavailable drugs due to their poor solubility.

A granulação através do uso de dispersões sólidas é um recurso que pode ser utilizado para aumentar a solubilidade de fármacos pouco solúveis, como no processo de Hot Melt Granulation (HMG). Este processo pode ser realizado utilizando-se o aparelho de leito fluidizado, com a atomização de uma dispersão fundida de carreadores solúveis com fármacos pouco solúveis sobre um substrato efetuando sua granulação. Essa é uma alternativa em relação aos métodos de granulação tradicionais, sendo vantajoso por não utilizar solvente. O objetivo deste trabalho foi realizar a granulação de piroxicam por HMG em leito fluidizado com polietilenoglicol (PEG) na forma de dispersão fundida, usando lactose spray dried como substrato com o intuito de aumentar a solubilidade do fármaco que é pouco solúvel em água, classificado como classe 2 (baixa solubilidade e alta permeabilidade) no Sistema de Classificação Biofarmacêutica. Foi realizada também a avaliação de misturas físicas e dispersões sólidas dos excipientes e do fármaco para obter informações de pré-formulação. O processo de granulação em leito fluidizado foi realizado através de um planejamento fatorial do tipo Box-Behnken, no qual as variáveis de operação carga de substrato, vazão do ar do bico de atomização e altura do bico de atomização foram variadas para a caracterização do processo e o estudo do efeito das variáveis do processo sobre as propriedades dos grânulos também foi realizado. Os grânulos obtidos foram caracterizados pela avaliação das propriedades farmacotécnicas, doseamento, distribuição granulométrica e também pela determinação das propriedades físico-químicas através de análises de calorimetria exploratória diferencial (DSC), espectroscopia no infravermelho e difração de raios-X. O perfil de dissolução de cápsulas contendo os grânulos também foi determinado. De acordo com as análises realizadas, não ocorreram interações nas misturas físicas e dispersões sólidas, nem nos granulados obtidos. Em relação aos grânulos, o resultado da avaliação farmacotécnica demonstrou que a maioria apresentou valores de fluxo excelente e bom. Através da distribuição granulométrica e das imagens dos grânulos obtidas por microscopia eletrônica de varredura (M.E.V.), pode-se observar que ocorreu a aglomeração das partículas de lactose pela atomização da dispersão de piroxicam e PEG 4000. Na avaliação do perfil de dissolução, os grânulos mostraram-se com uma solubilidade superior ao piroxicam isolado, sendo a granulação por Hot Melt em leito fluidizado um processo vantajoso em relação aos métodos atuais de granulação. / Granulation through solid dispersions may be employed to increase drug solubility as in the Hot Melt Granulation (HMG). Fluidized beds are used in the procedure, which by atomizing a melted dispersion of soluble carriers and low solubility drugs on a substrate produces the desired granulation. This is an advantageous alternative to traditional granulation methods since solvents are not involved. The objective of this study was to granulate the low solubility drug, piroxicam, by HMG in a fluidized bed with polyethylene glycol (PEG) in the form of a melted dispersion and dried lactose spray as the substrate. The drug has low aqueous solubility and is classified as Class 2 (low solubility and high intestinal permeability) in the Biopharmaceutical Classification System (BCS). Physical mixtures and solid dispersions of excipients and drug were previously tested as to obtain pre-formulation data. A factorial planning of the Box-Behnken type was used for the granulation in a fluidized bed, with the operation variables as substrate load, air stream velocity through the atomizing outlet and its height being varied to characterize the process and to verify their effects on the granule properties. Characterization of the granules was by evaluation of pharmacotechnical properties, dosage of active principle, granule size distribution and also by physicochemical analyses. These were by differential scanning calorimetry (DSC), infrared spectroscopy and X-ray diffraction. Interactions in the physical mixtures, solid dispersions and granules were not detected. The dissolution profile of capsules containing the granules was determined. Evaluation results showed that most granules had excellent to good flux properties. Granulometric distribution and scanning electron microscopy (SEM) images indicated agglomeration of lactose particles by the atomization of the piroxicamPEG dispersion. Evaluating the granule dissolution profiles it was shown that they were more soluble than piroxicam only. These results suggest that granulation by Hot Melt in a fluidized bed is process with advantages when compared to methods currently used.

Fármacos pouco solúveis em água tendem a possuir baixa biodisponibilidade. Diversos métodos têm sido estudados para promover o aumento da solubilidade em água de fármacos pouco solúveis. As dispersões sólidas têm sido pesquisadas como uma estratégia de aumentar a solubilidade em água e melhorar o desempenho destes fármacos na biodisponibilidade, entretanto os mecanismos completamente elucidados parecem variar da combinação do fármaco e do polímero, bem como do método de obtenção empregado. No presente estudo, através da técnica de evaporação do solvente desenvolveu-se dispersões sólidas de loratadina em polivinilpirrolidona a fim de melhorar a solubilidade do fármaco. / Poorly water soluble drugs tend to have low bioavailability. Several methods have been studied to promote increased water solubility of poorly soluble drugs. Solid dispersions have been investigated as a strategy to increase the water solubility and improve performance on the bioavailability of these drugs, however elucidated the mechanisms seem to vary the combination of drug and polymer and production method employed. In this study, using the technique of solvent evaporation was developed from solid dispersions in polyvinylpyrrolidone loratadine to improve the solubility of the drug.

A doença de Chagas representa um grave problema de saúde pública, afetando principalmente a população de baixa renda, o que a torna negligenciada pela indústria farmacêutica. Atualmente, existe apenas um fármaco disponível para o tratamento, o benzonidazol, porém este apresenta eficácia limitada e está associado a diversos efeitos colaterais. O ácido ursólico, um triterpeno de origem natural, possui atividade tripanocida, porém, sua solubilidade aquosa baixa limita sua biodisponibilidade. Para o aumento da biodisponibilidade tem destaque o uso das dispersões sólidas, onde fármacos lipofílicos são dispersos molecularmente ou no estado amorfo em carreadores hidrofílicos, acarretando um aumento do perfil de dissolução. Neste trabalho, dispersões sólidas e misturas físicas contendo ácido ursólico foram preparadas com os carreadores polietilenoglicol 6000, Gelucire 50/13 e dióxido de silício coloidal, Poloxamer 407 e caprato de sódio, empregando as técnicas de fusão e evaporação do solvente. Os sistemas foram caracterizados através das técnicas de microscopia eletrônica de varredura, espectroscopia do infravermelho com transformada de Fourier, calorimetria exploratória diferencial, microscopia em hot stage e difratometria de raios-X. Em outra etapa, os produtos foram avaliados quanto à solubilidade aquosa, perfil de dissolução in vitro, citotoxicidade em linhagem celular LLC-MK2, e atividade tripanocida em modelo animal. Em conjunto, os resultados mostraram que o fármaco não teve suas propriedades afetadas pela manipulação em misturas físicas, mantendo sua estrutura cristalina. Por outro lado, os experimentos de difratometria de raios-X e as observações microscópicas em hot stage revelaram a alteração do ácido ursólico para o estado amorfo, principalmente para os sistemas preparados pelo método do solvente, enquanto que algumas formulações manipuladas pelo método da fusão exibiram alterações polimórficas. Além disso, evidenciaram-se interações intermoleculares do tipo ligações de hidrogênio para as dispersões sólidas preparadas pelo método do solvente. As alterações do fármaco observadas para as dispersões sólidas preparadas pelo método do solvente aumentaram sua solubilidade e melhoraram seu perfil de dissolução comparado às dispersões sólidas pelo método da fusão e misturas físicas, sendo este aumento maior para os sistemas compostos por Poloxamer 407 + caprato de sódio, seguido por Poloxamer 407, Gelucire 50/13 + dióxido de silício coloidal e PEG 6000, o que pode ser atribuído ao poder tensoativo dos três primeiros carreadores. As formulações mostram-se seguras até a concentração de 128 ?M do fármaco, através da avaliação da citotoxicidade. Por último, o ursólico teve um aumento significativo da atividade tripanocida para a formulação composta pelo tensoativo Poloxamer 407 junto com o promotor de absorção oral caprato de sódio, manipulada pelo método do solvente, sugerindo o aumento da biodisponibilidade do fármaco. / Chagas disease represents a severe problem in public health, affecting mainly the low-income population, making it neglected by the pharmaceutical industry. Currently, there is only one drug available for treatment, benznidazol, however, it presents limited efficacy and is associated with several side effects. Ursolic acid, a naturally occurring triterpene, presents trypanocidal activity, but its low water solubility limits the bioavailability. To increase the biovailability, solid dispersions, where lipophilic drugs are molecularly or in the amorphous state dispersed in hydrophilic carriers, can play an important role, resulting in enhanced dissolution profile of the drug. In this work, solid dispersions and physical mixtures containing ursolic acid were prepared with Polyethyleneglycol 6000, Gelucire 50/13 and silicon dioxide, Poloxamer 407 and sodium caprate as carriers, employing the fusion and solvent evaporation techniques. The products were characterized through scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, hot stage microscopy and X-ray diffractometry. In another step, the formulations were evaluated regarding the aqueous solubility, in vitro dissolution profile, citotoxicity using LLC-MK2 cell line, and trypanocidal activity in animal model. Together, results showed that the drug did not suffer any change in its properties when in physical mixture. On the other hand, X-ray diffractometry and hot stage microscopy revealed a transition from the crystalline to the amorphous state for ursolic acid, especially for the products prepared by the solvent method. In the fusion method, some formulations exhibited a polymorphic change. Moreover, we identified intermolecular interactions between drug and carrier by hydrogen bonding in the products prepared by the solvent method. These changes observed for solid dispersions prepared by the solvent method resulted in increased water solubility and dissolution profile and these effects were higher for the products prepared with Poloxamer 407 + sodium caprate, followed by Polomer 407 alone, Gelucire 50/13 + silicon dioxide and PEG 6000, which can be attributed to the surfactant property of the three first carriers. The formulations were safe up to 128 ?M of the drug, showed by the citotoxicity evaluation. Very importantly, we highlight that ursolic acid had a significant increase in the trypanocidal activity for the product prepared with the surfactant Poloxamer 407 and the penetration enhancer sodium caprate, prepared by the solvent method, suggesting that in this composition ursolic acid was more bioavailable.

<p>The symmetry requirements of both second harmonic generation (SHG) and triboluminescence (TL) provide outstanding selectivity to noncentrosymmetric crystals, leading to high signal to noise measurements of crystal growth and nucleation of active pharmaceutical ingredients (API) within amorphous solid dispersions (ASD) during accelerated stability testing. ASD formulations are becoming increasingly popular in the pharmaceutical industry due to their ability to address challenges associated with APIs that suffer from poor dissolution kinetics and low bioavailability as a result of low aqueous solubility. ASDs kinetically trap APIs into an amorphous state by dispersing the API molecules within a polymer matrix. The amorphous state of the API leads to an increase in apparent solubility, faster dissolution kinetics, and an increase in bioavailability. Both SHG and TL are used to quantitatively and qualitatively detect the crystal growth and nucleation within ASD formulations at the parts per million (ppm) regime. TL is the emission of light upon mechanical disruption of a piezoelectrically active crystal. Instrumentation was developed to rapidly determine the qualitative presence of crystals within nominally amorphous pharmaceutical materials in both powders and slurries. SHG was coupled with a controlled environment for <i>in situ</i> stability testing (CEiST) to enable <i>in situ</i> accelerated stability testing of ASDs. Single particle tracking enabled by the CEiST measurements provided insights into crystal growth rate distributions present due to local differences within the material. Accelerated stability testing monitored by <i>in situ</i> measurements increased the signal to noise in recovered nucleation and crystal growth rates by suppressing the Poisson noise normally present within conventional accelerated stability tests. The disparities between crystal growth and nucleation kinetics on the surface versus within bulk material were also investigated by single particle tracking and <i>in situ </i>measurements. Crystals were found to grow faster in the bulk compared to single crystals growing on the surface while total crystallinity was found to be higher on the surface due to radial growth habits of crystals on the surface compared to columnar growth within the bulk. To increase the throughput of the <i>in situ </i>measurements, a temperature and relative humidity array (TRHA) was developed. The TRHA utilizes a temperature gradient and many individual liquid wells to enable the use of a multitude of different conditions at the same time which can reduce time required to inform formulations design of stability information. </p>

CHARLES UNIVERSITY IN PRAGUE Faculty of Pharmacy in Hradec Králové Department of Pharmaceutical technology Name and surname: Marie Korpasová Title of diploma thesis: Adhesive and rheological properties of mixtures based on chitosan Supervisor: PharmDr. Eva Šnejdrová, Ph.D. Diploma thesis deals with evaluation of rheological and adhesive properties of compounds for matrix tablets formulation, based on Chitosan with addition of retardant compound. The retardant compound consists of Sodium Alginate and Hypromellose in concentrations of 30 %, 40 % and 50 %. Theoretical part describes Chitosan, Sodium Alginate and Hypromellose. As next is division of matrix tablets. Theoretically is also described evaluation of rotational, oscillational and adhesive testing which was used in practical part. From viscosity curves can be seen, that viscosity is decreasing with increasing stress. Viscosity increases with increasing concentration of Sodium Alginate and Hypromellose. Oscillational testing is better for gel characterization, because it provides lower stress on test samples. Samples of given compound were prepared by hydrating with phosphate buffer of pH 6,8. Coefficient of consistency K and index flow rate n characterize rheological behaviour of gels. Viscoelastic compounds behave like solids with plastic...

The success of an amorphous solid dispersion (ASD) formulation, consisting of a homogeneous molecular dispersion of drug and polymer, relies on its ability to create and maintain a supersaturated solution. However, supersaturated solutions are metastable and prone to crystallization. In solution, crystals are expected to serve as a template for crystal growth, depleting achieved supersaturation. Thus, in an ASD product, ideally no crystallinity should be present. However, technical challenges exist in both processing and characterization to routinely ensure this is achieved. The presented studies follow the process design, characterization, and dissolution performance of hot melt extruded amorphous solid dispersions, seeking insight into the significance of critical quality attributes of resulting extrudates, namely residual crystallinity and thermal degradation.<div>Selection of hot melt extrusion (HME) processing conditions to prepare ASDs is governed by thermodynamic and kinetic attributes of the drug and polymer system. Mapping the temperature-composition phase diagram to HME processing conditions provides a processing design strategy to prevent residual crystallinity while simultaneously avoiding thermal degradation. Through processing temperatures below the drug’s melting point (Tm) and above the formulation critical temperature (Tc), fully amorphous systems could be generated if sufficient kinetics were provided. The utility of thermogravimetric analysis was critically examined for prediction of the chemical stability processing window for HME formulations.<br></div><div>For characterization and product performance characterization, residual crystalline content in HME ASDs can be anticipated and tailored to various levels. Several HME ASDs were characterized by a range of analytical techniques, highlighting the sensitivity of available techniques to qualitatively or quantitatively detect crystalline content (depending on limitations which stem from properties of the instrument or sample). Transmission electron microscopy (TEM) was found to identify low levels of crystallinity not observed by other technique and provide insight into crystal dissolution mechanisms. A defect-site driven dissolution and fragmentation model was suggested, and supported by a Monte Carlo simulation, underscoring that crystal defect sites, either intrinsic to the crystals or formed during processing, expedite dissolution rates and generation of new surfaces for dissolution.<br></div><div>Non-sink dissolution was performed for indomethacin/PVPVA HME ASD samples with residual crystallinity ranging from 0-25% crystalline content. Due to effective crystal growth inhibition by the polymer, crystals had little impact on dissolution performance. Achieved supersaturation was reduced approximately by the level of crystallinity present, i.e. a lost solubility advantage. These studies have significance for HME processing design and risk assessment of crystallinity within ASD formulations.<br></div>