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.

Enhanced dispersibility and deposition of spray-dried powders for pulmonary gene therapy

Spray-drying represents a viable alternative to freeze-drying for preparing dry powder dispersions for delivering macromolecules to the lung. The dispersibility of spray-dried powders is limited however, and needs to be enhanced to improve lung deposition and subsequent biological activity. In this study, we investigate the utility of leucine as a dry powder dispersibility enhancer when added prior to spray-drying a model non-viral gene therapy formulation (lipid:polycation:pDNA, LPD). Freeze-dried lactose-LPD, spray-dried lactose-LPD and spray-dried leucine-lactose-LPD powders were prepared. Scanning electron microscopy showed that leucine, increased the surface roughness of spray-dried lactose particles. Particle size analysis revealed that leucine-containing spray-dried powders were unimodally dispersed with a mean particle diameter of 3.12 μm. Both gel electrophoresis and in vitro cell (A549) transfection showed that leucine may compromise the integrity and biological functionality of the gene therapy vector. The deposition of the leucine containing powder was however significantly enhanced as evidenced by an increase in gene expression mediated by dry powder collected at lower stages of a multistage liquid impinger (MSLI). Further studies are required to determine the potential of leucine as a ubiquitous dispersibility enhancer for a variety of pulmonary formulations. © 2003 Taylor & Francis Ltd.

Pharmaceutical process optimisation of bulk lyophilisates:implications of powder handling

Lyophilisation or freeze drying is the preferred dehydrating method for pharmaceuticals liable to thermal degradation. Most biologics are unstable in aqueous solution and may use freeze drying to prolong their shelf life. Lyophilisation is however expensive and has seen lots of work aimed at reducing cost. This thesis is motivated by the potential cost savings foreseen with the adoption of a cost efficient bulk drying approach for large and small molecules. Initial studies identified ideal formulations that adapted well to bulk drying and further powder handling requirements downstream in production. Low cost techniques were used to disrupt large dried cakes into powder while the effects of carrier agent concentration were investigated for powder flowability using standard pharmacopoeia methods. This revealed superiority of crystalline mannitol over amorphous sucrose matrices and established that the cohesive and very poor flow nature of freeze dried powders were potential barriers to success. Studies from powder characterisation showed increased powder densification was mainly responsible for significant improvements in flow behaviour and an initial bulking agent concentration of 10-15 %w/v was recommended. Further optimisation studies evaluated the effects of freezing rates and thermal treatment on powder flow behaviour. Slow cooling (0.2 °C/min) with a -25°C annealing hold (2hrs) provided adequate mechanical strength and densification at 0.5-1 M mannitol concentrations. Stable bulk powders require powder transfer into either final vials or intermediate storage closures. The targeted dosing of powder formulations using volumetric and gravimetric powder dispensing systems where evaluated using Immunoglobulin G (IgG), Lactate Dehydrogenase (LDH) and Beta Galactosidase models. Final protein content uniformity in dosed vials was assessed using activity and protein recovery assays to draw conclusions from deviations and pharmacopeia acceptance values. A correlation between very poor flowability (p<0.05), solute concentration, dosing time and accuracy was revealed. LDH and IgG lyophilised in 0.5 M and 1 M mannitol passed Pharmacopeia acceptance values criteria with 0.1-4 while formulations with micro collapse showed the best dose accuracy (0.32-0.4% deviation). Bulk mannitol content above 0.5 M provided no additional benefits to dosing accuracy or content uniformity of dosed units. This study identified considerations which included the type of protein, annealing, cake disruption process, physical form of the phases present, humidity control and recommended gravimetric transfer as optimal for dispensing powder. Dosing lyophilised powders from bulk was demonstrated as practical, time efficient, economical and met regulatory requirements in cases. Finally the use of a new non-destructive technique, X-ray microcomputer tomography (MCT), was explored for cake and particle characterisation. Studies demonstrated good correlation with traditional gas porosimetry (R2 = 0.93) and morphology studies using microscopy. Flow characterisation from sample sizes of less than 1 mL was demonstrated using three dimensional X-ray quantitative image analyses. A platinum-mannitol dispersion model used revealed a relationship between freezing rate, ice nucleation sites and variations in homogeneity within the top to bottom segments of a formulation.

Physicochemical characterization of grewia polysaccharide gum:effect of drying method

Grewia polysaccharide gum, a potential pharmaceutical excipient was extracted from the inner stem bark of Grewia mollis, thereupon drying was achieved by three techniques: air-drying, freeze-drying and spray-drying. Analysis of the monosaccharide composition including 1H and 13C NMR spectroscopic analysis of the polysaccharide gum was carried out. The effect of the drying methods on the physicochemical properties of the gum was evaluated by Fourier transformed infra-red (FT-IR) spectroscopy, solid-state 13C nuclear magnetic resonance (NMR) spectroscopy, X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis, differential scanning calorimetry and gel permeation chromatography. Monosaccharide sugar analysis revealed that the gum is composed of glucose, rhamnose, galactose, arabinose and xylose as the main neutral sugars. These were supported by the results from 1H and 13C NMR spectroscopic analysis. FT-IR and solid-state NMR results indicated that drying technique has little effect on the structure of the polysaccharide gum but XPS showed that surface chemistry of the gum varied with drying methods. Thermogravimetric analyses showed that oxidation onset varied according to the drying method. The molecular weight was also dependent on the drying technique. For industrial extrapolation, air-drying may be preferable to spray-drying and freeze-drying when relative cost, product stability and powder flow are required, for example in tablet formulation. © 2010 Elsevier Ltd. All rights reserved.

Effect of pre-treatments and post-treatments on drying products

Freeze drying technology can give good quality attributes of vegetables and fruits in terms of color, nutrition, volume, rehydration kinetics, stability during storage, among others, when compared with solely air dried ones. However, published scientific works showed that treatments applied before and after air dehydration are effective in food attributes, improving its quality. Therefore, the hypothesis of the present thesis was focus in a vast research of scientific work that showed the possibility to apply a pre-treatment and a post-treatment to food products combined with conventional air drying aiming being close, or even better, to the quality that a freeze dried product can give. Such attributes are the enzymatic inactivation, stability during storage, drying and rehydration kinetics, color, nutrition, volume and texture/structure. With regard to pre-treatments, the ones studied along the present work were: water blanching, steam blanching, ultrasound, freezing, high pressure and osmotic dehydration. High electric pulsed field was also studied but the food attributes were not explained on detailed. Basically, water and steam blanching showed to be adequate to inactivate enzymes in order to prevent enzymatic browning and preserve the product quality during long storage periods. With regard to ultrasound pre-treatment the published results pointed that ultrasound is an effective pre-treatment to reduce further drying times, improve rehydration kinetics and color retention. On the other hand, studies showed that ultrasound allow sugars losses and, in some cases, can lead to cell disruption. For freezing pre-treatment an overall conclusion was difficult to draw for some food attributes, since, each fruit or vegetable is unique and freezing comprises a lot of variables. However, for the studied cases, freezing showed to be a pre-treatment able to enhance rehydration kinetics and color attributes. High pressure pre-treatment showed to inactivate enzymes improving storage stability of food and showed to have a positive performance in terms of rehydration. For other attributes, when high pressure technology was applied, the literature showed divergent results according with the crops used. Finally, osmotic dehydration has been widely used in food processing to incorporate a desired salt or sugar present in aqueous solution into the cellular structure of food matrix (improvement of nutrition attribute). Moreover, osmotic dehydration lead to shorter drying times and the impregnation of solutes during osmose allow cellular strengthens of food. In case of post-treatments, puffing and a new technology denominated as instant controlled pressure drop (DIC) were reported in the literature as treatments able to improve diverse Abstract Effect of Pre-treatments and Post-treatments on Drying Products x food attributes. Basically, both technologies are similar where the product is submitted to a high pressure step and the process can make use of different heating mediums such as CO2, steam, air and N2. However, there exist a significant difference related with the final stage of both which can comprise the quality of the final product. On the other hand, puffing and DIC are used to expand cellular tissues improving the volume of food samples, helping in rehydration kinetics as posterior procedure, among others. The effectiveness of such pre and/or post-treatments is dependent on the state of the vegetables and fruits used which are also dependent of its cellular structure, variety, origin, state (fresh, ripe, raw), harvesting conditions, etc. In conclusion, as it was seen in the open literature, the application of pre-treatments and post-treatments coupled with a conventional air dehydration aim to give dehydrated food products with similar quality of freeze dried ones. Along the present Master thesis the experimental data was removed due to confidential reasons of the company Unilever R&D Vlaardingen

The preparation of a certified reference material of polar pesticides in freeze-dried water (CRM 606)

The preparation of a certified reference material of polar pesticides in freeze-dried water is described. The pesticides selected were atrazine, simazine, carbaryl, propanil, linuron, fenamiphos and permethrin which were added to 6000 litres of tap water at 50–80 μg · L–1 (200–320 μg · L–1 for permethrin) level in presence of NaCl (2.5 g · L–1) prior lyophilization. After the freeze-drying process the residue was rehomogenized, filled into amber glass bottles and stored at –20 °C, +4 °C and +20 °C. All pesticides were determined by HPLC/diode array detector, except permethrin which was determined by GC/ECD. The results obtained for atrazine, simazine, carbaryl, propanil, linuron and fenamiphos showed no within- or between-bottle inhomogeneity, however the material was non-homogeneous for permethrin and therefore this was withdrawn from further studies. With respect to the stability for over one year, all pesticides were stable at –20 °C. At +4 °C all pesticides were stable for at least 9 months and at +20 °C the stability was demonstrated only during the first month of storage. The content (mass fractions) of atrazine, simazine, carbaryl, propanil and linuron in freeze-dried water (CRM 606) was certified by an interlaboratory testing and a certification campaign.

Aquivion-based spray freeze-dried composite catalysts for the cascade conversion of furfural to γ-valerolactone

Furfural is one of the most promising biomass derived platform molecules. It is to this day produced in volumes above 300 ktons per year from the hydrolysis and dehydration of hemicellulose, one of the main components of lignocellulosic biomass. While the majority of the yearly production is destined to selective reduction to furfuryl alcohol for the production of furan resins, these molecules hold great potential for the production of more valuable chemicals, fuels, fuel additives and solvents. Among these products are alkyl levulinates and γ-valerolactone. To convert furfural to these target products, a cascade process involving Lewis acidity-catalysed reduction steps and Brønsted acidity-catalysed steps. In order to develop catalysts capable of promoting the one-pot domino reaction from furfural to γ-valerolactone, the two kinds of acidity must both be present. To this end, in this work, the spray freeze-drying technique is employed to combine the high activity and strong Brønsted acidity of Aquivion with the structural properties and Lewis acidity of different supporting metal oxide, forming composite catalysts. The flexibility of the spray freeze-drying technique and the modulable composition of the catalysts allowed a thorough study of the complex network of equilibria underlying the cascade reaction, while achieving high selectivities towards the final product.

In Vitro and In Vivo Evaluation of Lyophilized Bioprosthetic Valve

Freeze-drying of biological tissues allows for dry storage and gamma ray sterilization, which may improve their use as a medical prosthesis. The objective of this study was to evaluate the rehydration characteristics and hydrodynamic performance of prosthetic valves before and after lyophilization. Two size 23 bovine pericardium aortic valve prostheses from different manufacturers were evaluated in a Shelhigh (Union, NJ, USA) pulse duplicator (80 ppm, 5 L/min) before and after lyophilization. Flow and transvalvular pressure gradient were registered in vitro and in vivo, and images of opening and closing of the prosthesis were obtained in the pulse duplicator in a digital camera. Rehydration was evaluated by comparison of dry valve weight with valve weight after 15 min, and 1, 24, 48, and 72 h in saline solution, inside the pulse duplicator. In vivo performance was assessed by surgical implantation in Santa Ines young male sheep in the pulmonary position after 30 min rehydration with 0.9% saline. Transvalvular pressure gradient and flow measurements were obtained immediately after implantation and 3 months after surgery when valves were explanted. Captured images showed a change in the profile opening and closing of valve prosthesis after lyophilization. The gradient measured (in vitro) in two valves was 17.08 +/- 0.57 and 18.76 +/- 0.70 mm Hg before lyophilization, and 34.24 +/- 0.59 and 30.40 +/- 0.97 mm Hg after lyophilization. Rehydration of both lyophilized valves was approximately 82%. Drying changed the profile of the opening and closing of valve prostheses, and increased on average by 83% the gradient in vitro tests. The result of the in vivo tests suggests maintaining pressure levels of the animal with the lyophilized prostheses within acceptable levels.

Binary and ternary inclusion complexes of finasteride in HP beta CD and polymers: Preparation and characterization

The aim of this study was to determine whether inclusion complexes between 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) and finasteride (FIN) are formed, and to characterize these. Equimolar FIN/HP beta CD solid systems in the presence or absence of 0.1% (w/v) of polyvinylpyrrolidone K30 (PVP K30) or 0.3% of chitosan were prepared by coevaporation and freeze-drying methods. The systems were characterized by phase solubility, NMR, DSC, and XRD analysis. The results suggest that true binary and ternary inclusion complexes were formed. (c) 2009 Elsevier Ltd. All rights reserved.

Obtention and Evaluation of Inclusion Complexes of Furosemide with beta-ciclodextrin and hidroxipropil-beta-ciclodextrin: Effects on Drug`s Dissolution Properties

Obtention and Evaluation of Inclusion Complexes of Furosemide with beta-ciclodextrin and hidroxipropil-beta-ciclodextrin: Effects on Drug`s Dissolution Properties. The purpose of this study was to prepare, characterize and evaluate the dissolution behavior of inclusion complexes of furosemide with beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Solid complexes of furosemide with P-CD and-HP-beta-CD were prepared by using a freeze-drying method. Physical mixtures were prepared for comparison. The inclusion complexes were characterized by differential scanning calorimetry (DSC), Infrared (IR) and dissolution test. ""In vitro"" dissolutions assays were performed at pH 1,2; pH 4,5 and pH 6,8 media for a 60 min period. Statistical analysis employing ANOVA and Tukey`s Test, for the dissolution efficiency values (ED%), showed that complexation of furosemide with both cyclodextrins improved significantly ED% of the drug in all tested media, suggesting a minor pH influence on dissolution properties of the drug.

Prospects in Lyophilization of Bovine Pericardium

Almost 30 years after the introduction of heart valve prostheses patients worldwide are benefiting from the implant of these devices. Among the various types of heart valves, the ones made of treated bovine pericardium have become a frequently used replacement of the heart`s native valve. Lyophilization, also known as freeze-drying, is an extremely useful technique for tissue storage for surgical applications. This article gives a brief overview on the current bovine pericardium lyophilization development, including the chemical modification to improve physical-chemical characteristics and the advanced technologies used to guarantee a high-quality product. It was shown that lyophilization process can be successfully applied as a method of bovine pericardium preservation and also as a technological tool to prepare new materials obtained by chemical modification of native tissues.

A new approach to the granulation of beta-cyclodextrin inclusion complexes

Cyclodextrins (CDs) are annular oligosaccharides containing 6-12 glucose unities joined together by alpha-1,4 bonds. They have a conical-truncated shape with a lipophilic cavity in which different molecules can be included resulting in a stable inclusion complex. The cyclodextrins have been widely applied in pharmaceutical technology with the objective of increasing the solubility, stability and bioavailability of drugs in different pharmaceutical dosage forms, such as tablets. In order to obtain beta-CD tablets, liquid dispersions of drug/beta-CD are usually submitted to different drying processes, like spray-drying, freeze-drying or slow evaporation, being this dry material added to a number of excipients. However, such drying processes can generate particulate materials showing problems of flow and compressibility, needing their conversion into granulates by means of wetting with granulation liquid followed by additional drying. In this work, the main objective was to evaluate the preparation of tablets without the need of this additional drying step. For this purpose an aqueous dispersion containing acetaminophen/beta-CD complex and cornstarch was dried using a spouted bed and the obtained granules were compressed in tablets. Acetaminophen was used as model drug due to its low water solubility and the inexpensive and widely available cornstarch was chosen as excipient. Acetaminophen powder was added into a beta-cyclodextrin solution prepared in distilled water at 70 degrees C. Stirring was kept until this dispersion cooled to room temperature. Then cornstarch was added and the resulting dispersion was dried in spouted bed equipment. This material was compressed into tablets using an Erweka Korsh EKO tablet machine. This innovative approach allowed the tablets preparation process to be carried out with fewer steps and represents a technological reliable strategy to produce beta-cyclodextrin inclusion complexes tablets. (C) 2010 Elsevier By. All rights reserved.

Estudo da cinética e influência dos métodos de secagem sobre as propriedades físico-químicas de soro de leite

O soro de leite é um subproduto da fabricação do queijo, seja por acidificação ou por processo enzimático. Em condições ideais, a caseína do leite se agrega formando um gel, que posteriormente cortado, induz a separação e liberação do soro. É utilizado de diversas formas em toda a indústria alimentícia, possui rica composição em lactose, sais minerais e proteínas. A desidratação é um dos principais processos utilizados para beneficiamento e transformação do soro. Diante disto, o objetivo deste trabalho foi avaliar a influência dos métodos de secagem: liofilização, leito de espuma (nas temperaturas de 40, 50, 60, 70 e 80ºC) e spray-dryer (nas temperaturas de 55, 60, 65, 70 e 75ºC), sobre as características de umidade, proteína, cor e solubilidade do soro, bem como estudar o seu processo de secagem. O soro foi obtido e desidratado após concentração por osmose reversa, testando 11 tratamentos, em 3 repetições, utilizando um delineamento inteiramente casualizado. Os resultados demonstraram que o modelo matemático que melhor se ajustou foi o modelo de Page, apresentado um coeficiente de determinação ajustado acima de 0,98 e erro padrão da regressão em todas as temperaturas abaixo de 0,04 para o método por leito de espuma. Para o método de liofilização os respectivos valores foram 0,9975 e 0,01612. A partir disso, pode-se elaborar um modelo matemático generalizado, apresentando um coeficiente de determinação igual a 0,9888. No caso do leito de espuma, observou-se que à medida que se aumenta a temperatura do ar de secagem, o tempo de secagem diminui e os valores do coeficiente de difusão efetiva aumentam. Porém, a redução no tempo de secagem entre os intervalos de temperatura, diminui com o aumento da mesma. A energia de ativação para a difusão no processo de secagem do soro foi de 26,650 kJ/mol e para todas as avaliações físico-químicas e tecnológicas, a análise de variância apresentou um valor de F significativo (p<0,05), indicando que há pelo menos um contraste entre as médias dos tratamentos que é significativo.

Development of Chitosan and Poly (Vinyl Alcohol) Blended scaffolds for cell culture using supercritical fluids technology

Dissertação apresentada na Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para obtenção do grau de Mestre em Mestrado Integrado em Engenharia Química e Bioquímica

Smart macroporous structures for the purification of viral particles

Dissertação para obtenção do Grau de Mestre em Engenharia Química e Bioquímica