Influência das propriedades de granulados de celulose nas características físicas dos comprimidos

The compaction behavior of powdered solids can be strongly influenced by the physicochemical properties of excipients because they are frequently present in the tablet in larger amounts than the drug itself. The aim of this study was to assess the influence of the granule size of the cellulose on the physical characteristics of tablets produced in punches of different diameters, since this relation has never been explored in the literature. Granules of several sizes were produced by wet granulation and compressed in punches of various diameters by applying different forces. Size distribution, apparent density and flow of granules were assessed, as well as physical characteristics of the tablets (weight, hardness, friability and disintegration time). Reducing the granule size resulted in tablets of adequate crushing strength and fast disintegration; moreover, it allowed tablets to be produced without the need to use forces near the upper limit of the press, thus avoiding premature wear on the tabletting machine. Thus, once a suitable size for a given tablet formulation has been chosen, the granule size selected has been shown to determine the crushing strength of the tablet.

Formulation and process engineering of freeze-dried orally disintegrating tablets

Orally disintegrating tablets (ODTs) which are also referred to as orodispersible and fast disintegrating tablets, are solid oral dosage forms which upon placing on the tongue, disperse/disintegrate rapidly before being swallowed as a suspension or solution. ODTs are therefore easier and more convenient to administer than conventional tablets and are particularly beneficial for paediatric and geriatric patients, who generally have difficulty swallowing their medication. The work presented in this thesis involved the formulation and process development of ODTs, prepared using freeze-drying. Gelatin is one of the principal excipients used in the formulation of freeze-dried ODTs. One of the studies presented in this thesis investigated the potential modification of the properties of this excipient, in order to improve the performance of the tablets. As gelatin is derived from animal sources, a number of ethical issues surround its use as an excipient in pharmaceutical preparations. This was one of the motivations, Methocel™ and Kollicoat® IR were evaluated as binders as alternative materials to gelatin. Polyox™ was also evaluated as a binder together with its potential uses as a viscosity increasing and mucoadhesive agent to increase the retention of tablets in the mouth to encourage pre-gastric absorption of active pharmaceutical ingredients (APIs). The in vitro oral retention of freeze-dried ODT formulations was one property which was assessed in a design of experiments – factorial design study, which was carried out to further understand the role that formulation excipients have on the properties of the tablets. Finally, the novel approach of incorporating polymeric nanoparticles in freeze-dried ODTs was investigated, to study if the release profile of APIs could be modified, which could improve their therapeutic effect. The results from these studies demonstrated that the properties of gelatin-based formulations can be modified by adjusting pH and ionic strength. Adjustment of formulation pH has shown to significantly reduce tablet disintegration time. Evaluating Methocel™, in particular low viscosity grades, and Kollicoat® IR as binders has shown that these polymers can form tablets of satisfactory hardness and disintegration time. Investigating Polyox™ as an excipient in freeze-dried ODT formulations revealed that low viscosity grades appear suitable as binders whilst higher viscosity grades could potentially be utilised as viscosity increasing and mucoadhesive agents. The design of experiments – factorial design study revealed the influence of individual excipients in a formulation mix on resultant tablet properties and in vitro oral retention of APIs. Novel methods have been developed, which allows the incorporation of polymeric nanoparticles in situ in freeze-dried ODT formulations, which allows the modification of the release profile of APIs.

The influence of formulation and manufacturing process parameters on the characteristics of lyophilized orally disintegrating tablets

Gelatin is a principal excipient used as a binder in the formulation of lyophilized orally disintegrating tablets. The current study focuses on exploiting the physicochemical properties of gelatin by varying formulation parameters to determine their influence on orally disintegrating tablet (ODT) characteristics. Process parameters, namely pH and ionic strength of the formulations, and ball milling were investigated to observe their effects on excipient characteristics and tablet formation. The properties and characteristics of the formulations and tablets which were investigated included: glass transition temperature, wettability, porosity, mechanical properties, disintegration time, morphology of the internal structure of the freeze-dried tablets, and drug dissolution. The results from the pH study revealed that adjusting the pH of the formulation away from the isoelectric point of gelatin, resulted in an improvement in tablet disintegration time possibly due to increase in gelatin swelling resulting in greater tablet porosity. The results from the ionic strength study revealed that the inclusion of sodium chloride influenced tablet porosity, tablet morphology and the glass transition temperature of the formulations. Data from the milling study showed that milling the excipients influenced formulation characteristics, namely wettability and powder porosity. The study concludes that alterations of simple parameters such as pH and salt concentration have a significant influence on formulation of ODT. © 2011 by the authors; licensee MDPI, Basel, Switzerland.

Investigation of the Performance of the Disintegration Test for Dietary Supplements

The aim of this study was to investigate how beaker size, basket assembly, use of disk, and immersion medium impact the disintegration time of dietary supplements. The disintegration times were determined for five tablet and two capsule products. A two-station disintegration tester was used with Apparatus A or Apparatus B as described in the United States Pharmacopeia (USP) chapters, < 701 > and < 2040 >. Two beakers complying with the harmonized specifications were used, one with a volume of 1,000 mL and one with a 1,500-mL volume. The disintegration data were analyzed using ANOVA for the following factors: beaker size, equipment (App A and B) and condition (with/without disk). Two tablet products were not sensitive to any changes in the test conditions or equipment configurations. One product was only partially sensitive to the test conditions. The other products showed impact on the disintegration time for all test conditions. The results revealed that these tablet products might pass or fail current USP disintegration requirements depending on the equipment configuration. Similar results were obtained for the two investigated capsule formulations. One product might fail current USP disintegration requirements if the large beaker was used, but might pass the disintegration requirements when the small beaker was used. Hydroxy propyl methyl cellulose capsules were mostly influenced if sodium instead of a potassium buffer was used as the immersion medium. The results demonstrate that the current harmonized ICH specifications for the disintegration test are insufficient to make the disintegration test into reliable test for dietary supplements.

Disintegration of magnetic tablets in human stomach evaluated by alternate current Biosusceptometry

Oral administration is the most convenient route for drug therapy. The knowledge of the gastrointestinal transit and specific site for drug delivery is a prerequisite for development of dosage forms. The aim of this work was to demonstrate that is possible to monitor the disintegration process of film-coated magnetic tablets by multi-sensor alternate current Biosusceptometry (ACB) in vivo and in vitro. This method is based on the recording of signals produced by the magnetic tablet using a seven sensors array and signal-processing techniques. The disintegration was confirmed by signals analysis in healthy human volunteers' measurements and in vitro experiments. Results showed that ACB is efficient to characterize the disintegration of dosage forms in the stomach, being a research tool for the development of new pharmaceutical dosage forms. (C) 2003 Elsevier B.V. All rights reserved.

Disintegration of magnetic tablets in human stomach evaluated by alternate current biosusceptometry

Oral administration is the most convenient route for drug therapy. The knowledge of the gastrointestinal transit and specific site for drug delivery is a prerequisite for development of dosage forms. The aim of this work was to demonstrate that is possible to monitor the disintegration process of film-coated magnetic tablets by multi-sensor alternate current Biosusceptometry (ACB) in vivo and in vitro. This method is based on the recording of signals produced by the magnetic tablet using a seven sensors array and signal-processing techniques. The disintegration was confirmed by signals analysis in healthy human volunteers' measurements and in vitro experiments. Results showed that ACB is efficient to characterize the disintegration of dosage forms in the stomach, being a research tool for the development of new pharmaceutical dosage forms.

Investigation of formulation and process of lyophilised orally disintegrating tablet (ODT) using novel amino acid combination

Lyophilised orally disintegrating tablets (ODTs) have achieved a great success in overcoming dysphagia associated with conventional solid dosage forms. However, the extensive use of saccharides within the formulation limits their use in treatment of chronic illnesses. The current study demonstrates the feasibility of using combination of proline and serine to formulate zero sacharide ODTs and investigates the effect of freezing protocol on sublimation rate and tablets characteristics. The results showed that inclusion of proline and serine improved ODT properties when compared to individual counterparts. Additionally, annealing the ODTs facilitated the sublimation process and shortened the disintegration time. © 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.

Comparison of the Rupture and Disintegration Tests for Soft-Shell Capsules

The USP General Chapter < 2040 > Disintegration and Dissolution of Dietary Supplements introduced a rupture test as a performance test of soft-shell capsules. Traditionally, the disintegration test was used for determining the disintegration time of all solid oral dosage forms. The aim of this investigation was to investigate differences between the rupture test and the disintegration test using soft-shell capsules. Five different soft-shell capsule products were chosen based on their filling contents and treated to simulate a production deficiency. The study design compared capsules as received with capsules that were treated by coating them with the liquid contents of another capsule. The capsules were incubated at room temperature and at 40 degrees C. The tests were repeated after two weeks, and at each time point, twelve capsules of each product were tested using the rupture and the disintegration tests. Six capsules were tested untreated, while the other six capsules were treated. Rupture and disintegration times were recorded as dependent variables in each experiment. Thedata were analyzed using ANOVA. According to the USP definition for disintegration, the rupture of a soft-shell capsule can be seen as fulfilling the disintegration criterion if the capsule contents is a semisolid or liquid. Statistical analysis showed no advantage of the rupture test over the disintegration test. On a product-by-product basis, both tests were sensitive to certain investigated parameters. A noticeable difference between both tests was that in most cases, the rupture test reached the defined endpoint faster than the disintegration test. Soft-shell capsules that are subject to a Quality by Design approach should be tested with both methods to determine which performance test is the most appropriate test for a specific product.

Influência da Motilidade Gastrintestinal no processo de desintegração de comprimidos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Efeito da concentração do amido de milho na liberação de paracetamol de comprimidos

Este trabalho avaliou a influência da concentração de amido de milho nas características físicas e na liberação in vitro de paracetamol a partir de comprimidos. Os granulados foram analisados quanto à granulometria e densidades aparentes bruta e compactada e os comprimidos quanto ao peso médio, espessura, dureza, friabilidade, tempo de desintegração. Os comprimidos foram preparados a partir de granulados obtidos por granulação a úmido, utilizando cozimento de amido a 10% como agente granulante, segundo três formulações. Embora os comprimidos obtidos tenham apresentado características dentro dos limites farmacopéicos, os resultados indicam que variações da concentração de amido provocam diferenças nos diversos parâmetros físicos estudados. Concentração mais alta de amido em pó dá origem, provavelmente, à interação entre os componentes da fórmula, interferindo na liberação in vitro do fármaco. Isto demonstra a importância de se otimizar a concentração dos adjuvantes numa formulação de comprimidos, pois, embora uma pequena variação nesta concentração não exerça efeito significativo no tempo de desintegração, a quantidade de fármaco liberado pode ser substancialmente alterada.

Gastrointestinal transit and disintegration of enteric coated magnetic tablets assessed by ac biosusceptometry

The oral administration is a common route in the drug therapy and the solid pharmaceutical forms are widely used. Although much about the performance of these formulations can be learned from in vitro studies using conventional methods, evaluation in vivo is essential in product development. The knowledge of the gastrointestinal transit and how the physiological variables can interfere with the disintegration and drug absorption is a prerequisite for development of dosage forms. The aim of this work was to employing the ac biosusceptometry (ACB) to monitoring magnetic tablets in the human gastrointestinal tract and to obtain the magnetic images of the disintegration process in the colonic region. The ac biosusceptometry showed accuracy in the quantification of the gastric residence time, the intestinal transit time and the disintegration time (DT) of the magnetic formulations in the human gastrointestinal tract. Moreover, ac biosusceptometry is a non-invasive technique, radiation-free and harmless to the volunteers, as well as an important research tool in the pharmaceutical, pharmacological and physiological investigations. (c) 2005 Elsevier B.V. All rights reserved.

Influence of compression forces on tablets disintegration by AC Biosusceptometry

Analysis of physical phenomena that occurs during tablet disintegration has been studied by several experimental approaches; however none of them satisfactorily describe this process. The aim of this study was to investigate the influence of compression force on the tablets by associating the AC Biosusceptometry with consolidated methods in order to validate the biomagnetic technique as a tool for quality control in pharmaceutical processes.Tablets obtained at five compression levels were submitted to mechanical properties tests. For uncoated tablets, water uptake and disintegration force measurements were performed in order to compare with magnetic data. For coated tablets, magnetic measurements were carried out to establish a relationship between physical parameters of the disintegration process. According to the results, differences between the compression levels were found for water uptake, force development and magnetic area variation measurements. ACB method was able to estimate the disintegration properties as well as the kinetics of disintegration process for uncoated and coated tablets. This study provided a new approach for in vitro investigation and validated this biomagnetic technique as a tool for quality control for pharmaceutical industry. Moreover, using ACB will also be possible to test these parameters in humans allowing to establish an in vitro/in vivo correlation (IVIVC). (C) 2007 Elsevier B.V. All rights reserved.

Influência das propriedades de granulados de lactose nas características físicas dos comprimidos

The compaction behavior of powdered solids used in tablets can be dominated by the physical-chemical properties of the excipients because, frequently, they are present in much larger amounts than the drug in tablet formulation. The aim of this study was to evaluate the influence of the size of lactose granules on the physical characteristics of tablets produced in punches of various diameters, since this relation has not been explored in the literature. Granules were produced in several sizes by wet granulation and compressed in punches of different diameters by applying different forces. Size distribution, apparent density and flow of granules were evaluated, as well as the physical characteristics of the tablets (weight, friability, hardness and disintegration time). The results indicate that in situations where excipient characteristics predominate due to low drug content, as in the 7 mm punch, the selection of granule size is important for the mechanical strength of tablet. On the other hand, with the 9, 11 and 13mm punches, it was possible to produce strong tablet from all sizes of granules.

Influência da Motilidade Gastrintestinal no processo de desintegração de comprimidos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Formulation and characterisation of lyophilised rapid disintegrating tablets using amino acids as matrix forming agents

Despite recent advances in the formulation of lyophilised rapid disintegrating tablets (RDTs), the inclusion of matrix supporting/disintegration enhancing agents has been limited to the use of saccharides and polyols. In this study, the feasibility of using amino acids as matrix forming agents in lyophilised RDTs was investigated. Twelve amino acids were chosen (alanine, arginine, threonine, glycine, cysteine, serine, histidine, lysine, valine, asparagine, glutamine and proline), and the suitability for freeze drying, mechanical properties and disintegration time after inclusion of the amino acids at varied concentration were studied. In addition, the porosity of the RDTs and wettability profile of the amino acids were investigated to understand the mechanisms of disintegration. The results suggest the suitability of these amino acids for the lyophilisation regime, as they displayed satisfactory safety margin between the glass transition and shelf temperature (-40 degrees C), except proline-based formulations. Moreover, the crystallisation behavior of alanine, glycine, cysteine and serine at high concentration increased the stability of the formulation. The characterisation of the RDTs suggests that high concentration of the amino acids is required to enhance the mechanical properties, whereas only optimum concentrations promote the disintegration. Moreover, wetting time of the amino acid and porosity of the tablet are the two factors that control the disintegration of RDTs.