Novel biopharmaceutical development investigations towards drug and formulation performance optimization

For a drug to excerpt pharmacological action after oral intake, it first needs to be released from the formulation, get into solution (dissolve), be absorbed, and reach the systemic circulation. Since only solubilized drugs can be absorbed, and thus have therapeutic effect, the understanding of the dissolution and drug release processes of a drug product is of primary importance. Such understanding allows a robust formulation development with an ideal in vivo performance. In order to meet set standards, the performance assessment of oral drug products, such as dissolution testing, often applies conditions that are not reflective of the in vivo environment. The use of non-physiologically relevant dissolution method during the drug product development phase can be misleading and give poor mechanistic understanding of the in vivo dissolution process. Hence, we hypothesized that applying physiologically relevant conditions to the dissolution test would result in more accurate in vivo predictability for a robust and precise development process. Since the buffering system in the intestinal lumen operates at low molarity values, phosphate buffer at low buffer capacity was used as a first approach to an in vivo relevant parameter. Furthermore, a biphasic system was used, that is, the low buffer capacity medium was paired with an organic layer (n-octanol) to mimic the concurrent drug absorption that happens with the in vivo dissolution. Both poorly and highly soluble drugs in immediate release formulations (ibuprofen and metronidazole, respectively) were tested in this set-up to assess the dissolution in the aqueous medium and the partitioning to the organic phase. Additionally, enteric coated formulations were tested in bicarbonate buffer at the in vivo reported molarities values to assess the impact of buffer species on drug dissolution. The evaluated parameters were the buffer system (bicarbonate buffer vs. phosphate buffer), buffer capacity and medium pH. In all approaches, dissolution was also carried out in compendial buffer for comparison purposes. Our results demonstrate that the USP-recommended dissolution method greatly lacked discriminatory power, whereas low buffer capacity media discriminated between manufacturing methods. The use of an absorptive phase in the biphasic dissolution test assisted in controlling the medium pH due to the drug removal from the aqueous medium. Hence, the applied noncompendial methods were more discriminative to drug formulation differences and manufacturing methods than conventional dissolution conditions. In this study, it was demonstrated how biphasic dissolution and a low buffer capacity can be used to assess drug product performance differences. This can be a valuable approach during the early stages of drug product development for investigating drug release with improved physiological relevance. Similarly, all the enteric coated formulations displayed a fast release in phosphate buffer and complied with the compendial performance specifications. On the other hand, they all had a much slower drug release in bicarbonate buffer and failed the USP acceptance criteria. Also, the nature of the drug (acid vs base) impacted the dissolution behavior in bicarbonate buffer. This study indicates that compendial dissolution test for enteric coated tablets lacks physiological relevance and it needs to be reevaluated. Thus, an in vivo relevant performance method for EC products is needed. Overall, the findings of this thesis comprehensively demonstrates that meaningful differences in performance and accordance to clinical reports were only obtained when physiological relevant conditions were applied. Hence, our results indicate that the central hypothesis was answered positively

Para que um medicamento exerça a ação farmacológica após a ingestão oral, ele primeiro precisa ser liberado da formulação, dissolver, ser absorvido e atingir a circulação sistêmica. Uma vez que apenas medicamentos solubilizados podem ser absorvidos e, assim, ter efeito terapêutico, a compreensão dos processos de dissolução e liberação de um medicamento é de extrema importância. Tal compreensão permite o desenvolvimento de uma formulação robusta com o desempenho in vivo ideal. Para atender aos padrões regulatórios previamente estabelecidos, a avaliação da performance de formulações orais, como por exemplo, o teste de dissolução, frequentemente aplica condições que não refletem o ambiente fisiológico. O uso de métodos de dissolução não fisiologicamente relevante durante a fase de desenvolvimento do medicamento pode gerar resultados equivocados sem uma compreensão mecanistica do processo de dissolução in vivo. Portanto, a hipótese desse trabalho é que a aplicação de condições fisiologicamente relevantes no teste de dissolução resultaria em uma predição mais precisa da dissolução in vivo para um processo de desenvolvimento robusto e preciso. Uma vez que o sistema tampão no lúmen intestinal possui baixa molaridade, o tampão fosfato com baixa capacidade tamponante foi usado como uma primeira abordagem como um meio de dissolução fisiologicamente relevante. Além disso, foi utilizado um sistema bifásico, ou seja, o meio de baixa capacidade tamponante combinado a uma fase orgânica (n-octanol) para imitar a absorção in vivo. Formulações de liberação imediata contendo fármacos de baixa e de alta solubilidade (ibuprofeno e metronidazol, respectivamente) foram testadas no sistema bifásico para avaliar a dissolução no meio aquoso e a partição para a fase orgânica. Ademais, formulações com revestimento entérico foram testadas em tampão bicarbonato nos valores de molaridades fisiológicos para avaliar o impacto da espécie tamponante na dissolução do fármaco. Os parâmetros avaliados foram o sistema tampão (tampão bicarbonato vs. tampão fosfato), capacidade tamponante e pH médio. Em todas as abordagens, a dissolução também foi realizada em tampão farmacopeico para fins de comparação. Nossos resultados demonstraram que o método de dissolução farmacopeico não foi discriminativo, enquanto o meio com menor capacidade tamponante diferenciou entre as formulações obtidas via granulação úmida ou compressão direta. Ademais, a utilização da fase orgânica no teste de dissolução bifásica auxiliou no controle do pH do meio aquoso. Portanto, os métodos não compendiais aplicados foram mais discriminativos do que as condições de dissolução convencionais. Neste estudo, foi demonstrado como a dissolução bifásica e uma baixa capacidade tamponante podem ser usadas para avaliar as diferenças na performance de formulações. Esta pode ser uma abordagem valiosa durante os estágios iniciais do desenvolvimento de medicamentos para investigar a liberação destes sob condições fisiologicamente relevantes. Da mesma forma, todas as formulações com revestimento entérico exibiram uma liberação rápida em tampão de fosfato e atenderam às especificações farmacopeicas. Entretanto, a liberação do fármaco foi muito mais lenta em tampão de bicarbonato e consequentemente não cumpriram com as especificações farmacopeicas. Além disso, a natureza do fármaco (ácido vs. base) impactou o comportamento de dissolução no tampão de bicarbonato. Este estudo indica que o teste de dissolução convencional para comprimidos de liberação retardada não possui relevância fisiológica e precisa ser reavaliado. Portanto, os resultados desta tese demonstram de forma abrangente que diferenças significativas na performance condizentes com relatórios clínicos foram obtidas apenas quando as condições fisiológicas relevantes foram aplicadas. Esses resultados indicam que a hipótese central foi respondida positivamente

Emerging Trends in Flow Chemistry and Applications to the Pharmaceutical Industry.

The field of flow chemistry has garnered considerable attention over the past 2 decades. This Perspective highlights many recent advances in the field of flow chemistry and discusses applications to the pharmaceutical industry, from discovery to manufacturing. From a synthetic perspective, a number of new enabling technologies are providing more rationale to run reactions in flow over batch techniques. Additionally, highly automated flow synthesis platforms have been developed with broad applicability across the pharmaceutical industry, ranging from advancing medicinal chemistry programs to self-optimizing synthetic routes. A combination of simplified and automated systems is discussed, demonstrating how flow chemistry solutions can be tailored to fit the specific needs of a project.

Real-time potentiometric sensor; an innovative tool for monitoring hydrolysis of chemo/bio-degradable drugs in pharmaceutical sciences.

In recent years, the whole field of ion-selective electrodes(ISEs) in pharmaceutical sciences has expanded far beyond its original roots. The diverse range of opportunities offered by ISEs was broadly used in a number of pharmaceutical applications, with topics presented ranging from bioanalysis of drugs and metabolites, to protein binding studies, green analytical chemistry, impurity profiling, and drug dissolution in biorelevant media. Inspired from these advances and with the aim of extending the functional capabilities of ISEs, the primary focus of the present paper is the utilization of ISE as a tool in personalized medicine. Given the opportunity to explore biological events in real-time (such as drug metabolism) could be central to personalized medicine. (ATR) is a chemo-degradable and bio-degradable pharmaceutically active drug. Laudanosine (LDS) is the major degradation product and metabolite of ATR and is potentially toxic and reported to possess epileptogenic activity which increases the risk of convulsive effects. In this work, ATR have been subjected to both chemical and biological hydrolysis, and the course of the reactions is monitored by means of a ISE. In this study, we have designed an efficient real-time tracking strategy which substantially resolve the challenges of the ATR chemical and biological degradation kinetics. By utilizing a potentiometric sensor, tracking of ATR chemical and biological degradation kinetics can be performed in a very short time with excellent accuracy. The LOD was calculated to be 0.23 µmol L-1, the potential drift was investigated over a period of 60 min and the value was 0.25 mV h-1. Real serum samples for measurement the rate of in vitro metabolism of ATR was performed. Furthermore, a full description of the fabricated screen-printed sensor was presented.

A systematic reactor design approach for the synthesis of active pharmaceutical ingredients.

Today's highly competitive pharmaceutical industry is in dire need of an accelerated transition from the drug development phase to the drug production phase. At the heart of this transition are chemical reactors that facilitate the synthesis of active pharmaceutical ingredients (APIs) and whose design can affect subsequent processing steps. Inspired by this challenge, we present a model-based approach for systematic reactor design. The proposed concept is based on the elementary process functions (EPF) methodology to select an optimal reactor configuration from existing state-of-the-art reactor types or can possibly lead to the design of novel reactors. As a conceptual study, this work summarizes the essential steps in adapting the EPF approach to optimal reactor design problems in the field of API syntheses. Practically, the nucleophilic aromatic substitution of 2,4-difluoronitrobenzene was analyzed as a case study of pharmaceutical relevance. Here, a small-scale tubular coil reactor with controlled heating was identified as the optimal set-up reducing the residence time by 33% in comparison to literature values.

Development of a stability- indicating HPLC method for simultaneous determination of ten related substances in vonoprazan fumarate drug substance.

Vonoprazan fumarate is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. In the present study, a simple, fast, and economic reversed-phase liquid chromatography (LC) method was developed for the analysis of ten related substances (raw materials, by-products and degradants) in vonoprazan fumarate. The optimized separation was performed on a Phenomenex Kinetex EVO C18 (250mm×4.6mm, 5.0µm) column. The mobile phase consisted of (A) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - methanol - acetonitrile (72:25:3, v/v/v) and (B) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - acetonitrile (30:70, v/v). Detection of the analytes was conducted at 230nm using a UV detector. The stability-indicating ability of this method was demonstrated by carrying out forced degradation studies. Vonoprazan underwent significant degradation when subjected to alkaline and oxidative stress conditions, while the drug proved to be stable to acidic, thermal and photolytic degradation. The degradants did not interfere with the detection of vonoprazan fumarate and its impurities. The performance of this method was validated in accordance to the regulatory guidelines recommended by the International Conference on Harmonisation (ICH) and this validation included specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and robustness. The method proposed in this paper could be applied for process development as well as quality assurance of vonoprazan in bulk drug, since no monograph is available in official compendia.

Simultaneous determination of rutin and ascorbic acid in a sequential injection lab-at-valve system.

A green, simple, accurate and highly sensitive sequential injection lab-at-valve procedure has been developed for the simultaneous determination of ascorbic acid (Asc) and rutin using 18-molybdo-2-phosphate Wells-Dawson heteropoly anion (18-MPA). The method is based on the dependence of the reaction rate between 18-MPA and reducing agents on the solution pH. Only Asc is capable of interacting with 18-MPA at pH 4.7, while at pH 7.4 the reaction with both Asc and rutin proceeds simultaneously. In order to improve the precision and sensitivity of the analysis, to minimize reagent consumption and to remove the Schlieren effect, the manifold for the sequential injection analysis was supplemented with external reaction chamber, and the reaction mixture was segmented. By the reduction of 18-MPA with reducing agents one- and two-electron heteropoly blues are formed. The fraction of one-electron heteropoly blue increases at low concentrations of the reducer. Measurement of the absorbance at a wavelength corresponding to the isobestic point allows strictly linear calibration graphs to be obtained. The calibration curves were linear in the concentration ranges of 0.3-24mgL-1 and 0.2-14mgL-1 with detection limits of 0.13mgL-1 and 0.09mgL-1 for rutin and Asc, respectively. The determination of rutin was possible in the presence of up to a 20-fold molar excess of Asc. The method was applied to the determination of Asc and rutin in ascorutin tablets with acceptable accuracy and precision (1-2%).

Trends in the Assessment of Drug Supersaturation and Precipitation In Vitro Using Lipid-Based Delivery Systems.

The generation of drug supersaturation close to the absorptive site is an important mechanism of how several formulation technologies enhance oral absorption and bioavailability. Lipid-based formulations belong to the supersaturating drug delivery systems although this is not the only mechanism of how drug absorption is promoted in vivo. Different methods to determine drug supersaturation and precipitation from lipid-based formulations are described in the literature. Experimental in vitro setups vary according to their complexity and proximity to the in vivo conditions and, therefore, some tests are used for early formulation screening, while others better qualify for a later stage of development. The present commentary discusses this rapidly evolving field of in vitro testing with a special focus on the advancements in analytical techniques and new approaches of mechanistic modeling. The importance of considering a drug absorption sink is particularly emphasized. This commentary should help formulators in the pharmaceutical industry as well as in academia to make informed decisions on how to conduct in vitro tests for lipid-based delivery systems and to decide on the implications of experimental results.

Investigation of an 11mm diameter twin screw granulator: Screw element performance and in-line monitoring via image analysis.

As twin screw granulation (TSG) provides one with many screw element options, characterization of each screw element is crucial in optimizing the screw configuration in order to obtain desired granule attributes. In this study, the performance of two different screw elements - distributive feed screws and kneading elements - was studied in an 11 mm TSG at different liquid-to-solid (L/S) ratios. The kneading element configuration was found to break large granules more efficiently, leading to narrower granule size distributions. While pharmaceutical industry shifts toward continuous manufacturing, inline monitoring and process control are gaining importance. Granules from an 11 mm TSG were analysed using the Eyecon™, a real-time high speed direct imaging system, which has been used to capture accurate particle size distribution and particle count. The size parameters and particle count were then assessed in terms of their ability to be a suitable control measure using the Shewhart control charts. d10 and particle count were found to be good indicators of the change in L/S ratio. However, d50 and d90 did not reflect the change, due to their inherent variability even when the process is at steady state.

Mixing monoclonal antibody formulations using bottom-mounted mixers: impact of mechanism and design on drug product quality.

UNLABELLED: Using bottom-mounted mixers, particularly those that are magnetically driven, is becoming increasingly common during the mixing process in pharmaceutical and biotechnology manufacturing because of their associated low risk of contamination, ease of use, and ability to accommodate low minimum mixing volumes. Despite these benefits, the impact of bottom-mounted mixers on biologic drug product is not yet fully understood and is scarcely reported. This study evaluated four bottom-mounted mixers to assess their impact on monoclonal antibody formulations. Changes in product quality (size variants, particles, and turbidity) and impact on process performance (sterile filtration) were evaluated after mixing. The results suggested that mixers that are designed to function with no contact between the impeller and the drive unit are the most favorable and gentle to monoclonal antibody molecules. Designs with contact or a narrow clearance tended to shear and grind the protein and resulted in high particle count in the liquid, which would subsequently foul a filter membrane during sterile filtration using a 0.22 µm pore size filter. Despite particle formation, increases in turbidity of the protein solution and protein aggregation/fragmentation were not detected. Further particle analysis indicated particles in the range of 0.2-2 µm are responsible for filter fouling. A small-scale screening model was developed using two types of magnetic stir bars mimicking the presence or absence of contact between the impeller and drive unit in the bottom-mounted mixers. The model is capable of differentiating the sensitivity of monoclonal antibody formulations to bottom-mounted mixers with a small sample size. This study fills an important gap in understanding a critical bioprocess unit operation. LAY ABSTRACT: Mixing is an important unit operation in drug product manufacturing for compounding (dilution, pooling, homogenization, etc.). The current trend in adopting disposable bottom-mounted mixers has raised concerns about their impact on drug product quality and process performance. However, investigations into the effects of their use for biopharmaceutical products, particularly monoclonal antibody formulations, are rarely published. The purpose of this study is three-fold: (1) to understand the impact of bottom-mounted disposable mixer design on drug product quality and process performance, (2) to identify the mixing mechanism that is most gentle to protein particle formation, (3) to apply the learning to practical mixing operations using bottom-mounted mixers. The outcomes of this study will benefit scientists and engineers who develop biologic product manufacturing process by providing a better understanding of mixing principles and challenges.

Pharmaceutical process chemistry: evolution of a contemporary data-rich laboratory environment.

Over the past 20 years, the industrial laboratory environment has gone through a major transformation in the industrial process chemistry setting. In order to discover and develop robust and efficient syntheses and processes for a pharmaceutical portfolio with growing synthetic complexity and increased regulatory expectations, the round-bottom flask and other conventional equipment familiar to a traditional organic chemistry laboratory are being replaced. The new process chemistry laboratory fosters multidisciplinary collaborations by providing a suite of tools capable of delivering deeper process understanding through mechanistic insights and detailed kinetics translating to greater predictability at scale. This transformation is essential to the field of organic synthesis in order to promote excellence in quality, safety, speed, and cost efficiency in synthesis.

Uneven batch data alignment with application to the control of batch end-product quality.

Batch processes are commonly characterized by uneven trajectories due to the existence of batch-to-batch variations. The batch end-product quality is usually measured at the end of these uneven trajectories. It is necessary to align the time differences for both the measured trajectories and the batch end-product quality in order to implement statistical process monitoring and control schemes. Apart from synchronizing trajectories with variable lengths using an indicator variable or dynamic time warping, this paper proposes a novel approach to align uneven batch data by identifying short-window PCA&PLS models at first and then applying these identified models to extend shorter trajectories and predict future batch end-product quality. Furthermore, uneven batch data can also be aligned to be a specified batch length using moving window estimation. The proposed approach and its application to the control of batch end-product quality are demonstrated with a simulated example of fed-batch fermentation for penicillin production.

Characterization of a laboratory-scale container for freezing protein solutions with detailed evaluation of a freezing process simulation.

A 300-mL stainless steel freeze container was constructed to enable QbD (Quality by Design)-compliant investigations and the optimization of freezing and thawing (F/T) processes of protein pharmaceuticals at moderate volumes. A characterization of the freezing performance was conducted with respect to freezing kinetics, temperature profiling, cryoconcentration, and stability of the frozen protein. Computational fluid dynamic (CFD) simulations of temperature and phase transition were established to facilitate process scaling and process analytics as well as customization of future freeze containers. Protein cryoconcentration was determined from ice-core samples using bovine serum albumin. Activity, aggregation, and structural perturbation were studied in frozen rabbit muscle l-lactic dehydrogenase (LDH) solution. CFD simulations provided good qualitative and quantitative agreement with highly resolved experimental measurements of temperature and phase transition, allowing also the estimation of spatial cryoconcentration patterns. LDH exhibited stability against freezing in the laboratory-scale system, suggesting a protective effect of cryoconcentration at certain conditions. The combination of the laboratory-scale freeze container with accurate CFD modeling will allow deeper investigations of F/T processes at advanced scale and thus represents an important step towards a better process understanding.

Extruder scale-up assessment in the process of extrusion-spheronization: comparison of radial and axial systems by a design of experiments approach.

Scaling-up the extrusion-spheronization process involves the separate scale-up of each of the five process steps: dry mixing, granulation, extrusion, spheronization, and drying. The aim of the study was to compare two screw extrusion systems regarding their suitability for scaling-up. Two drug substances of high- and low-solubility in water were retained at different concentrations as formulation variables. Different spheronization times were tested. The productivity of the process was followed up using the extrusion rate and yield. Pellets were characterized by their size and shape, and by their structural and mechanical properties. A response surface design of experiments was built to evaluate the influence of the different variables and their interactions on each response, and to select the type of extrusion which provides the best results in terms of product quality, the one which shows less influence on the product after scale-up ("scalability") and when the formula used changes ("robustness"), and the one which allows the possibility to adjust pellet properties with spheronization variables ("flexibility"). Axial system showed the best characteristics in terms of product quality at lab and industrial scales, the best robustness at industrial scale, and the best scalability, by comparison with radial system. Axial system thus appeared as the easiest scaled-up system. Compared to lab scale, the conclusions observed at industrial scale were the same in terms of product quality, but different for robustness and flexibility, which confirmed the importance to test the systems at industrial scale before acquiring the equipment.

Comparison of two in vitro methods to evaluate the water resistance of sunscreens.

For a long time, the water resistance of sunscreens has been determined in vivo, according to Colipa's (Comité de Liaison des Industries de la Parfumerie) procedure. This method is not so ethical as healthy volunteers are irradiated, and can be replaced by an in vitro method which is easy and quick to perform. The objective of this work was to correlate the experimental device proposed by Choquenet et al. and the dissolutest (Sotax AT6). This equipment is used in the pharmaceutical industry to control the tablets. The experimental conditions have been fixed to correlate the results obtained with both methods. The stirring speed for the dissolutest was fixed at 75 rpm, which is the speed value recommended by the European Pharmacopeia to study the dissolution over time of tablets.

Multiple-test assessment of devices to protect healthcare workers when administering cytotoxic drugs to patients.

PURPOSE: Evaluation of containment safety devices designed and introduced to protect preparers and administrators of hazardous drugs, through a multiple-test assessment. METHODS: Six devices were compared: (1) Kis1 gravity-fed infusion set (Doran International, France), (2) Tevadaptor Spike Port Adapter (Teva Pharma AG, France), (3) Phaseal Infusion Adapter C100 (Carmel Pharma AB, France), (4) Codan Connect Z (Codan, France), (5) Pchimx with or without a cap (Doran International, France), and (6) Clave extension set 011-H1225 with or without Spiros (Hospira, France). Assessment of exposure to hazardous drugs was performed using quinine as fluorescent marker. Mechanical tests included tightness, tension tests, and estimation of the force required to connect the infusion device to the bag. Ergonomic tests were performed by six pharmaceutical technicians. Microbiological contamination was tested with media-fill, on connected bag. RESULTS: No cytotoxic contamination was detected when using Phaseal, Tevadaptor or the Clave extension set with Spiros, Pchimx with a cap or Connect Z devices. For mechanical tests, all devices complied with the norm. Microbiological growth was observed neither in bags nor in tubings. The ergonomic study revealed differences between the devices for potential cytotoxic contamination risk only, but not for handling. CONCLUSIONS: The use of containment safety devices offers improved handling conditions of hazardous compounds. As this study takes various selection criteria into account, its results offer assistance in choosing the most suitable device.

Hazard analysis and risk assessment in the development of biomedical drug formulation equipment.

Hazard analysis and risk assessment techniques are utilized within many private sector industries and government agencies, including the medical device and pharmaceutical industry, within a structured process to control human injuries and environmental and property damage. In the U.S. the Federal Drug Administration (FDA) requires a hazard analysis be performed on all medical devices. While there are biomedical engineering applications reported which deal with human hazards in clinical, patient care environment, no previous studies extend these traditional techniques to a university-based, research environment. This study applies a tiered approach to hazard analysis and risk assessment to a biomedical, university-based, research environment in the design of a high throughput platform that screens chemical excipients (additives) for their ability to increase protein solubility. Each design stage (conceptual, preliminary, system, and detailed) requires a unique hazard analysis technique based on available information. The analysis techniques applied here are evaluated for their use in a biomedical research environment where experiment accuracy is a primary concern.

Microreactors for continuous processing ­ How close to commercial utility?

Microreactor technology holds great promise for simplifying process chemistry. The design of microreactors inherently simplifies heat transfer and flow. Continuous processing on a commercial scale is also achievable using these reactors, providing significant improvements in efficiency compared with batch processing. Two-phase reactions with liquid-gas and liquid-solid phases present difficulties for microreactor-based processing; however, advances in reactor design are providing some solutions to such challenges. The potential efficiencies provided by microreactors suggest that this technology will be adopted increasingly for widespread commercial applications, particularly following greater investment by companies and further improvements in engineering.

Recent patents and trends in orally disintegrating tablets.

Orally disintegrating tablets (ODTs) offer many advantages over the conventional oral dosage forms in terms of convenience and ease of use. Over the last decade, substantial advances in the formulation of ODTs have been achieved in academia and industry that resulted in the emerging of a large number of patents. The aim of this review is to summarise the most recent patents in ODT formulations and highlight their motivations, inventive steps and significances in the development of ODT formulations. Five major techniques have been applied in manufacturing of ODTs, namely conventional tablet press, moulding, freeze drying, tablet loading and pulverization, with majority of the patents dedicated to the use of conventional tablet pressing. The patents have addressed various issues concerning the manufacturing of robust and practical ODT formulations by disclosing new manufacturing techniques, advantageous materials, and innovative formulation steps. However, future developments are required to reduce the cost and widening the application of the new manufacturing techniques, while simplifying and shortening the formulation steps will be crucial in the well established ones.

Assessment of segregation potential of powder blends.

Pharmaceutical blends consist of several components each with its own unique characteristics, with different size, shape, density, and particle-particle interactions. With so many degrees of complexity, prediction of segregation behavior becomes intractable. The objective of this study was to develop a segregation test method or a segregation tool that would assess the segregation potential of blends. Literature reports generally seek to predict the segregation behavior based on only one mechanism by which the segregation occurs, primarily sifting or fluidization. This study makes an attempt to combine both of these mechanisms by which segregation occurs. A test is developed and used to assess the segregation behavior of blends at large scale and compare the content uniformity results of tablets with the results of the segregation test. The segregation testing model was successful in predicting the segregation tendency of the formulation and also in rank ordering large scale formulation blends based on their segregation potential. A segregation risk classification system is proposed to assess the potential of segregation at large scale.