RESUMO
Crystalline suspensions of monoclonal antibodies (mAbs) have great potential to improve drug substance isolation and purification on a large scale and to be used for drug delivery via high-concentration formulations. Crystalline mAb suspensions are expected to have enhanced chemical and physical properties relative to mAb solutions delivered intravenously, making them attractive candidates for subcutaneous delivery. In contrast to small molecules, the development of protein crystalline suspensions is not a widely used approach in the pharmaceutical industry. This is mainly due to the challenges in finding crystalline hits and the suboptimal physical properties of the resulting crystallites when hits are found. Modern advances in instrumentation and increased knowledge of mAb crystallization have, however, resulted in higher probabilities of discovering crystal forms and improving their particle properties and characterization. In this regard, physical, analytical characterization plays a central role in the initial steps of understanding and later optimizing the crystallization of mAbs and requires careful selection of the appropriate tools. This contribution describes a novel crystal structure of the antibody pembrolizumab and demonstrates the usefulness of small-angle X-ray scattering (SAXS) for characterizing its crystalline suspensions. It illustrates the advantages of SAXS when used to (i) confirm crystallinity and crystal phase of crystallites produced in batch mode; (ii) confirm crystallinity under various conditions and detect variations in crystal phases, enabling fine-tuning of the crystallizations for phase control across multiple batches; (iii) monitor the physical response and stability of the crystallites in suspension with regard to filtration and washing; and (iv) monitor the physical stability of the crystallites upon drying. Overall, this work highlights how SAXS is an essential tool for mAb crystallization characterization.
Assuntos
Anticorpos Monoclonais , Cristalização , Espalhamento a Baixo Ângulo , Difração de Raios X , Cristalização/métodos , Anticorpos Monoclonais/química , Difração de Raios X/métodosRESUMO
The success of obtaining solid dispersions for solubility improvement invariably depends on the miscibility of the drug and polymeric carriers. This study aimed to categorize and select polymeric carriers via the classical group contribution method using the multivariate analysis of the calculated solubility parameter of RX-HCl. The total, partial, and derivate parameters for RX-HCl were calculated. The data were compared with the results of excipients (N = 36), and a hierarchical clustering analysis was further performed. Solid dispersions of selected polymers in different drug loads were produced using solvent casting and characterized via X-ray diffraction, infrared spectroscopy and scanning electron microscopy. RX-HCl presented a Hansen solubility parameter (HSP) of 23.52 MPa1/2. The exploratory analysis of HSP and relative energy difference (RED) elicited a classification for miscible (n = 11), partially miscible (n = 15), and immiscible (n = 10) combinations. The experimental validation followed by a principal component regression exhibited a significant correlation between the crystallinity reduction and calculated parameters, whereas the spectroscopic evaluation highlighted the hydrogen-bonding contribution towards amorphization. The systematic approach presented a high discrimination ability, contributing to optimal excipient selection for the obtention of solid solutions of RX-HCl.
Assuntos
Química Farmacêutica , Excipientes , Polímeros , Cloridrato de Raloxifeno , Solubilidade , Difração de Raios X , Polímeros/química , Excipientes/química , Cloridrato de Raloxifeno/química , Análise Multivariada , Difração de Raios X/métodos , Química Farmacêutica/métodos , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Microscopia Eletrônica de Varredura/métodos , Ligação de Hidrogênio , Cristalização/métodosRESUMO
Environmental impacts of the industrial revolution necessitate adoption of sustainable practices in all areas of development. The pharmaceutical industry faces increasing pressure to minimize its ecological footprint due to its significant contribution to environmental pollution. Over the past two decades, pharmaceutical cocrystals have received immense popularity due to their ability to optimize the critical attributes of active pharmaceutical ingredients and presented an avenue to bring improved drug products to the market. This review explores the potential of pharmaceutical cocrystals as an ecofriendly alternative to traditional solid forms, offering a sustainable approach to drug development. From reducing the number of required doses to improving the stability of actives, from eliminating synthetic operations to using pharmaceutically approved chemicals, from the use of continuous and solvent-free manufacturing methods to leveraging published data on the safety and toxicology, the cocrystallization approach contributes to sustainability of drug development. The latest trends suggest a promising role of pharmaceutical cocrystals in bringing novel and improved medicines to the market, which has been further fuelled by the recent guidance from the major regulatory agencies.
Assuntos
Cristalização , Desenvolvimento de Medicamentos , Desenvolvimento de Medicamentos/métodos , Preparações Farmacêuticas/química , Indústria Farmacêutica/métodos , Humanos , Química Farmacêutica/métodosRESUMO
Phosphorus recovery from human waste will help assure global food security, reduce environmental impact, and ensure effective stewardship of this limited and valuable resource. This can be accomplished by the precipitation of struvite (MgNH4PO4·6H2O) in a two-zone reactor, continuously fed with nutrient-rich hydrolysed urine and a magnesium solution. The solid struvite crystals are periodically "harvested", removing accumulated crystal mass - and therefore recovered nutrients - from the process, and the operating campaign can, in principle, be continuously operated in a batch-continuous operating mode. A previously developed process model is augmented, incorporating two well-mixed volumes (upper zone and lower zone) that are coupled by intermixing forward and back flows. The intermixing back flow is parametrised and, therefore, adjusted for analysis. Crystal linear growth rate is modelled by a simple power-law kinetic, driven by the nutrient solution's saturation index (SI) of struvite. The instantaneous mass transfer rate of struvite constituents from liquid to solid phase is predicted, using the total interfacial area of the crystal population exposed to the well-mixed solution. This model describes a 12-L, laboratory reactor operated in the hybrid batch-continuous mode, although larger reactors could easily be accommodated, subject to their mixing behaviours. Experiments were performed at a 10-hour hydraulic residence time (HRT), which, importantly, is based on the volume of the well-mixed lower zone, since this is the volume of liquid that actively interacts with the suspended struvite crystals. The Mg/P feed molar ratio was varied (0.34, 0.64 and 1.29) to assess Mg feed rate-limiting behaviour. The concentration profiles of elemental P and Mg agree with experimentation, while P and Mg composition in the solid and X-ray diffraction support the production of struvite.
Assuntos
Fosfatos , Fósforo , Humanos , Estruvita/química , Fosfatos/química , Fósforo/química , Cristalização , Nutrientes , Eliminação de Resíduos LíquidosRESUMO
Pharmaceutical co-crystals represent a growing class of crystal forms in the context of pharmaceutical science. They are attractive to pharmaceutical scientists because they significantly expand the number of crystal forms that exist for an active pharmaceutical ingredient and can lead to improvements in physicochemical properties of clinical relevance. At the same time, machine learning is finding its way into all areas of drug discovery and delivers impressive results. In this review, we attempt to provide an overview of machine learning, deep learning and network-based recommendation approaches applied to pharmaceutical co-crystallization. We also present crystal structure prediction as an alternative to machine learning approaches.
Assuntos
Descoberta de Drogas , Aprendizado de Máquina , Descoberta de Drogas/métodos , Cristalização , Preparações FarmacêuticasRESUMO
Recent studies have demonstrated novel strategies for the organization of nanomaterials into three-dimensional (3D) ordered arrays with prescribed lattice symmetries using DNA-based self-assembly strategies. In one approach, the nanomaterial is sequestered into DNA origami frames or "material voxels" and then coordinated into ordered arrays based on the voxel geometry and the corresponding directional interactions based on its valency. While the lattice symmetry is defined by the valency of the bonds, a larger-scale morphological development is affected by assembly processes and differences in energies of anisotropic bonds. To facilely model this assembly process, we investigate the self-assembly behavior of hard particles with six interacting vertices via theory and Monte Carlo simulations and exploration of corresponding experimental systems. We demonstrate that assemblies with different 3D crystalline morphologies but the same lattice symmetry can be formed depending on the relative strength of vertex-to-vertex interactions in orthogonal directions. We observed three distinct assembly morphologies for such systems: cube-like, sheet-like, and cylinder-like. A simple analytical theory inspired by well-established ideas in the areas of protein crystallization, based on calculating the second virial coefficient of patchy hard spheres, captures the simulation results and thus represents a straightforward means of modeling this self-assembly process. To complement the theory and simulations, experimental studies were performed to investigate the assembly of octahedral DNA origami frames with varying binding energies at their vertices. X-ray scattering confirms the robustness of the formed nanoscale lattices for different binding energies, while both optical and electron microscopy imaging validated the theoretical predictions on the dependence of the distinct morphologies of assembled state on the interaction strengths in the three orthogonal directions.
Assuntos
DNA , Anisotropia , Simulação por Computador , Cristalização , Método de Monte CarloRESUMO
OBJECTIVE: This work introduces a material-sparing process that rapidly screens the solid form landscape for ophthalmic compound candidates. SIGNIFICANCE: Crystalline form of compound candidates generated by a Form Risk Assessment (FRA) can be used to reduce their downstream development risk. METHODS: This workflow evaluated nine model compounds with various molecular and polymorphic profiles by using less than 350 mg of drug substances. Kinetic solubility of the model compounds in a variety of solvents was screened to support the experimental design. The FRA workflow integrated several crystallization methods such as temperature-cycled slurrying (thermocycling), cooling, and evaporation. The FRA was also applied on ten ophthalmic compound candidates for verification. X-ray powder diffractometry (XRPD) was used for form identification. RESULTS: For the nine model compounds studied, multiple crystalline forms were generated. This demonstrates the potential of the FRA workflow to reveal polymorphic tendency. In addition, thermocycling process was found to be the most effective technique to capture the thermodynamically most stable form. Satisfactory results were observed with the discovery compounds intended for ophthalmic formulations. CONCLUSIONS: This work introduces a form risk assessment workflow by using sub-gram level of drug substances. The capability of this material-sparing workflow to discover polymorphs and capture the thermodynamically most stable forms within 2-3 weeks makes it suitable for discovery stage compounds, especially for ophthalmic candidates.
Assuntos
Fluxo de Trabalho , Cristalização/métodos , Composição de Medicamentos/métodos , Temperatura , Solubilidade , Medição de Risco , Varredura Diferencial de Calorimetria , Difração de Raios XRESUMO
Solubility of the drug is an important property of the drug as it affects the release, absorption, dissolution rate and ultimately bioavailability of the drug. Hence, the poorly aqueous soluble drug, need to be processed, to enhance its solubility and dissolution. The Biopharmaceutical System of Classification (BCS) II drugs are poorly soluble and have high permeability. Though their good ability to permeate through the membrane make them clinically useful but the problem associated with the solubility restrict their clinical use. Therefore, there is need to improve the solubility of such drug molecules to get effective pharmacological action. Itraconazole (ITZ) is an antifungal agent used in the treatment of fungal infections having poor aqueous solubility as belonging to BCS class II. The present study was aim to enhance the solubility of ITZ by solid dispersion and co-crystallization techniques. Investigation of simultaneous effect of media composition on drug dissolution was also the objective of this work. The ITZ-SD and ITZ-CCs were prepared from ITZ and other excipients like PEG 4000, oxalic acid, fumaric and malic acid by solvent evaporation, kneading technique, slurry conversion and solvent drop grinding methods. The prepared ITZ-SD, ITZ-OA-CCs, ITZ-FA-CCs and ITZ-MA-CCs were evaluated for FTIR, DSC, PXRD, % yield, micromeritic properties. The optimized ITZ-SD and ITZ-CCs were used to compress a tablet and subject to post-compression parameters. The results of FTIR and DSC showed the absence of interaction between the drug and excipients. The PXRD pattern demonstrated the formation of crystalline structures with 6 folds increased in solubility during saturation solubility analysis. In vitro dissolution was carried out in dissolution media with different pH which shows the maximum release from ITZ-SD and ITZ-CCs in pH 6.8. This also revealed the highly pH dependent solubility and dissolution behavior of the weakly basic BCS class II drug (ITZ) with pKa value of 3.7. The overall results in this study indicated the potential of solid dispersion and co-crystals for enhancement of solubility of the poorly water-soluble drugs.
Assuntos
Excipientes , Itraconazol , Solubilidade , Liberação Controlada de Fármacos , Cristalização , Itraconazol/química , SolventesRESUMO
Deposition of calcium oxalate (CaOx) crystals and oxidative stress-induced injury of renal tubular epithelial cell are the primary pathogenic factors of nephrolithiasis. In this study we investigated the beneficial effects of metformin hydrochloride (MH) against nephrolithiasis and explored the underlying molecular mechanism. Our results demonstrated that MH inhibited the formation of CaOx crystals and promoted the transformation of thermodynamically stable CaOx monohydrate (COM) to more unstable CaOx dihydrate (COD). MH treatment effectively ameliorated oxalate-induced oxidative injury and mitochondrial damage in renal tubular cells and reduced CaOx crystal deposition in rat kidneys. MH also attenuated oxidative stress by lowering MDA level and enhancing SOD activity in HK-2 and NRK-52E cells and in a rat model of nephrolithiasis. In both HK-2 and NRK-52E cells, COM exposure significantlylowered the expressions of HO-1 and Nrf2, which was rescued by MH treatment even in the presence of Nrf2 and HO-1 inhibitors. In rats with nephrolithiasis, MH treatment significantly rescued the down-regulation of the mRNA and protein expression of Nrf2 and HO-1 in the kidneys. These results demonstrate that MH can alleviate CaOx crystal deposition and kidney tissue injury in rats with nephrolithiasis by suppressing oxidative stress and activating the Nrf2/HO-1 signaling pathway, suggesting the potential value of MH in the treatment of nephrolithiasis.
Assuntos
Cálculos Renais , Metformina , Ratos , Animais , Oxalato de Cálcio/química , Oxalato de Cálcio/metabolismo , Oxalato de Cálcio/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Cristalização , Metformina/farmacologia , Metformina/uso terapêutico , Metformina/metabolismo , Rim/patologia , Cálculos Renais/tratamento farmacológico , Cálculos Renais/metabolismo , Cálculos Renais/patologia , Transdução de SinaisRESUMO
Crystal growth from nanoscale constituents is a ubiquitous phenomenon in biology, geology and materials science. Numerous studies have focused on understanding the onset of nucleation and on producing high-quality crystals by empirically sampling constituents with different attributes and varying the growth conditions. However, the kinetics of post-nucleation growth processes, an important determinant of crystal morphology and properties, have remained underexplored due to experimental challenges associated with real-space imaging at the nanoscale. Here we report the imaging of the crystal growth of nanoparticles of different shapes using liquid-phase transmission electron microscopy, resolving both lateral and perpendicular growth of crystal layers by tracking individual nanoparticles. We observe that these nanoscale systems exhibit layer-by-layer growth, typical of atomic crystallization, as well as rough growth prevalent in colloidal systems. Surprisingly, the lateral and perpendicular growth modes can be independently controlled, resulting in two mixed crystallization modes that, until now, have received only scant attention. Combining analytical considerations with molecular dynamics and kinetic Monte Carlo simulations, we develop a comprehensive framework for our observations, which are fundamentally determined by the size and shape of the building blocks. These insights unify the understanding of crystal growth across four orders of magnitude in particle size and suggest novel pathways to crystal engineering.
Assuntos
Simulação de Dinâmica Molecular , Nanopartículas , Cristalização , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Método de Monte CarloRESUMO
Active Pharmaceutical Ingredients (APIs) do not always exhibit processable physical properties, which makes their processing in an industrial setup very demanding. These issues often lead to poor robustness and higher cost of the drug product. The issue can be mitigated by co-processing the APIs using suitable solvent media-based techniques to streamline pharmaceutical manufacturing operations. Some of the co-processing methods are the amalgamation of API purification and granulation steps. These techniques also exhibit adequate robustness for successful adoption by the pharmaceutical industry to manufacture high quality drug products. Spherical crystallization and co-precipitation are solvent media-based co-processing approaches that enhances the micromeritic and dissolution characteristics of problematic APIs. These methods not only improve API characteristics but also enable direct compression into tablets. These methods are economical and time-saving as they have the potential for effectively circumventing the granulation step, which can be a major source of variability in the product. This review highlights the recent advancements pertaining to these techniques to aid researchers in adopting the right co-processing method. Similarly, the possibility of scaling up the production of co-processed APIs by these techniques is discussed. The continuous manufacturability by co-processing is outlined with a short note on Process Analytical Technology (PAT) applicability in monitoring and improving the process.
Assuntos
Indústria Farmacêutica , Tecnologia Farmacêutica , Cristalização/métodos , Tecnologia Farmacêutica/métodos , Indústria Farmacêutica/métodos , Comprimidos/química , Solventes/química , Preparações FarmacêuticasRESUMO
The addition of non-active components at the point of active pharmaceutical ingredient (API) isolation by means of co-processing is an attractive approach for improving the material properties of APIs. Simultaneously, there is increased interest in the pharmaceutical industry in continuous manufacturing processes. These often consist of liquid feeds which maintain materials in solution and mean that solids handling is avoided until the final step. Such techniques enable new forms of APIs to be used in final dosage forms which have been overlooked due to unfavourable material properties. API-based ionic liquids (API-ILs) are an example of a class of compounds that exhibit exceptional solubility and stability qualities at the cost of their physical characteristics. API-ILs could benefit from isolation-free manufacturing in combination with co-processing approaches to circumvent handling issues and make them viable routes to formulating poorly soluble APIs. However, API-ILs are most commonly synthesised via a batch reaction that produces an insoluble solid by-product. To avoid this, an ion exchange resin protocol was developed to enable the API-IL to be synthesised and purified in a single step, and also produce it in a liquid effluent that can be integrated with other unit operations. Confined agitated bed crystallisation and spray drying are examples of processes that have been adapted to produce or consume liquid feeds and were combined with the ion exchange process to incorporate the API-IL synthesis into isolation-free frameworks and continuous manufacturing streams. This combination of isolation-free and co-processing techniques paves the way towards end-to-end continuous manufacturing of API-IL drug products.
Assuntos
Química Farmacêutica , Líquidos Iônicos , Química Farmacêutica/métodos , Temperatura , Indústria Farmacêutica/métodos , Cristalização , Preparações Farmacêuticas , Composição de MedicamentosRESUMO
In this review, we aim to present new concepts for the revisited separation of enantiomers from racemic compounds and a protocol worth to be followed in designing the preparation of pure enantiomers. We have taken into account not only the influence of the properties (eutectic composition) and characteristics of the reactants (racemic compound, resolving agent), but also the behavior of the resulting diastereomers and the different conditions (e.g., crystallization time, solvents used, solvate-forming compounds, achiral additives, etc.). The examples discussed are resolutions developed by our research team, through which we will try to illustrate the impact of all these considerations, presenting the methodological investigations interpreting recent discoveries and observations. Some special solid-state analytical and structural investigations assisting us in the elucidation and invention design of the resolution processes of some active pharmaceutical ingredients, such as Tetramisole, tofisopam, and Amlodipine, are also shown.
Assuntos
Compostos Orgânicos , Cristalização , EstereoisomerismoRESUMO
A pilot-scale anaerobic-anoxic/nitrifying/induced crystallization (A2N-IC) process was established for phosphorus (P) recovery and nutrient removal from municipal wastewater with a treatment capacity of 80 m3d-1. Results show that the A2N-IC process can operate stably on a pilot scale; the recovery efficiency of influent P reached 62.2%, and the total P removal efficiency of the IC section was 65.4%. The IC section had little effect on the removal of chemical oxygen demand (COD) and nitrogen (N), and the P removal efficiency was improved. Soluble non-reactive P (sNRP) was the key factor affecting P recovery efficiency. Although P recovery increases the construction and maintenance costs, the process can be profitable if a market for P recovery products is established. To improve the P recovery efficiency, attention should be paid to the effects of sNRP and dissolved organic matter (DOM) on P recovery, and P-rich sludge should be considered.
Assuntos
Fósforo , Eliminação de Resíduos Líquidos , Humanos , Anaerobiose , Eliminação de Resíduos Líquidos/métodos , Cristalização , Reatores Biológicos , Esgotos/química , Hipóxia , Nitrogênio/análiseRESUMO
Thermoplastic elastomers such as polyether-b-polyamides (or -polyesters), polyurethanes (or with -urea) and olefin block copolymers are commonly processed through a stretching process for achieving high elasticity and high toughness in their products, while the size diversity of semicrystalline microdomains of hard blocks appears as the key factor. By means of dynamic Monte Carlo simulations of strain-induced crystallization of locally concentrated and diluted crystallizable blocks alternatingly connected with noncrystallizable blocks in diblock and tetrablock copolymers, we have studied the size diversity of semicrystalline microdomains presumably raised by local concentration fluctuations of crystallizable blocks and found the dilution effects to persist from diblock to tetrablock copolymers. In the present work, we continued to study the effects of asymmetric block rigidity between crystallizable and noncrystallizable blocks on strain-induced crystallization of concentrated and diluted crystallizable blocks in diblock copolymers. The results showed that when crystallizable blocks hold higher thermodynamic rigidity than noncrystallizable blocks, the large semicrystalline domains become larger and the small semicrystalline domains become more, enhancing their size diversity. However, asymmetric kinetic rigidity has little effect. Our observations imply that industrial stretching processing could enhance the toughness of semicrystalline thermoplastic elastomers when their crystallizable blocks hold a higher thermodynamic rigidity relative to noncrystallizable blocks. Our integrated approach paved the way for a better understanding of the structure-property relationship in thermoplastic elastomers.
Assuntos
Poliésteres , Polímeros , Cristalização , Método de Monte Carlo , Polímeros/química , Poliésteres/química , Elastômeros/químicaRESUMO
Nucleation of particles into crystalline structures can be observed in a wide range of systems from metallic and metal-organic compounds to colloidal and polymeric patch particles. Here, we perform kinetic Monte Carlo simulations to study the nucleation kinetics of particles with different ligancies z at constant supersaturation s. This approach allows one to determine several physico-chemical quantities as a function of s, including the growth probability P(n), the critical nucleus size n*, and the stationary nucleation rate Js. Our numerical results are rationalized in terms of a self-consistent nucleation theory where both n* and Js present a non-trivial dependence on s, but which can be determined from the values of effective z-dependent parameters.
Assuntos
Cristalização , Cinética , Método de Monte Carlo , ProbabilidadeRESUMO
Recovery of phosphorus from wastewater through struvite crystallization is one of the most attractive methods. However, the cost of chemical consumption makes this technology is unattractive to some extent. In this work, highly active serpentine was prepared by one-step mechanical activation and then used to recover phosphate as struvite from the black water containing 132.8 mg/L phosphorus and 3144 mg/L ammonia nitrogen. The results indicated that the prepared active serpentine can release magnesium ions and hydroxide ions simultaneously into an aqueous solution and is an ideal raw material for struvite crystallization. The factors for phosphorus recovery in this process mainly include mechanical activation intensity, serpentine dosage, and contact time. For the actual black water, a high recovery rate of phosphorus (>98%) is achieved by using active serpentine as the magnesium and alkali source for struvite precipitation. The recovery product was identified as struvite with a median particle size of 32.96 µm. It was confirmed that the mechanical activation damaged the crystal structure of the raw serpentine, improving the activity of Mg2+ and OH-. The undissolved Si-containing particles act as crystal seeds, accelerating the struvite crystallization process. Furthermore, a pilot-scale test was conducted with a rural public toilet in Xiong'an New District, Hebei Province. The results showed that an acceptable phosphorus recovery (98%) could be achieved using active serpentine. Additionally, it was demonstrated that the serpentine process to recover phosphate as struvite reduced the cost by 54.4% in compared with an ordinary chemical process. The active serpentine is a promising dual source of magnesium and alkali for the phosphorus recovery by the struvite method. It has a potential prospect for the large-scale application in phosphorus recovery and struvite fertilizer production.
Assuntos
Magnésio , Fósforo , Cristalização , Magnésio/química , Compostos de Magnésio/química , Fosfatos/química , Fósforo/química , Estruvita/química , Águas Residuárias/química , ÁguaRESUMO
The pharmaceutical industry has traditionally relied on mass manufacturing to make its products. This has created multiple problems in the drug supply network, including long production times, inflexible and sluggish manufacturing and lack of personalized dosing. The industry is gradually adapting to these challenges and is developing novel technologies to address them. Continuous manufacturing and 3D printing are two promising techniques that can revolutionize pharmaceutical manufacturing. However, most research studies into these methods tend to treat them separately. This study seeks to develop a new processing route to continuously integrate a 3D printing platform (Drop-on-Demand, DoD, printing) with crystallization that is generally the final step of the active ingredient manufacturing. Accomplishing this integration would enable harnessing the benefits of each method- personalized dosing of 3D printing and flexibility and speed of continuous manufacturing. A novel unit operation, three-phase settling (TPS), is developed to integrate DoD with the upstream crystallizer. To ensure on-spec production of each printed dosage, two process analytical technology tools are incorporated in the printer to monitor drug loading in manufactured drug products in real time. Experimental demonstration of this system is carried out via two case studies: the first study uses an active ingredient celecoxib to test the standalone operation of TPS; the second study demonstrates the operation of the integrated system (crystallizer - TPS - DoD) to continuously make drug products for the active ingredient- lomustine. A dissolution test is also performed on the manufactured and commercial lomustine drug products to compare their dissolution behavior.
Assuntos
Indústria Farmacêutica , Tecnologia Farmacêutica , Cristalização , Indústria Farmacêutica/métodos , Lomustina , Impressão Tridimensional , Tecnologia Farmacêutica/métodosRESUMO
Water resources are getting limited, which emphasises the need for the reuse of wastewater. The conventional waste(water) treatment methods such as reverse osmosis (RO) and multi-effect distillation (MED) are rendered limited due to certain limitations. Moreover, the imposition of stringent environmental regulations in terms of zero liquid discharge (ZLD) of wastewater containing very high dissolved solids has assisted in developing technologies for the recovery of water and useful solids. Membrane distillation crystallization (MDCr) is an emerging hybrid technology synergising membrane distillation (MD) and crystallization, thus achieving ZLD. MDCr technology can be applied to desalinate seawater, treat nano-filtration, and RO reject brine and industrial wastewater to increase water recovery and yield useful solids. This manuscript focuses on recent advances in MDCr, emphasizing models that account for application in (waste)water treatment. MDCr has dual benefits, first the environmental conservation due to non-disposal of wastewater and second, resources recovery proving the proverb that waste is a misplaced resource. Limitations of standalone MD and crystallization are discussed to underline the evolution of MDCr. In this review, MDCr's ability and feasibility in the treatment of industrial wastewater are highlighted. This manuscript also examines the operational issues, including crystal deposition (scaling) on the membrane surface, pore wetting phenomenon and economic consequences (energy use and operating costs). Finally, opportunities and future prospects of the MDCr technology are discussed. MDCr technology can amplify natural resources availability by recovering freshwater and useful minerals from the waste stream, thus compensating for the relatively high cost of the technology.
Assuntos
Destilação , Purificação da Água , Cristalização , Membranas Artificiais , Osmose , Tecnologia , Águas ResiduáriasRESUMO
We present Simu-D, a software suite for the simulation and successive identification of local structures of atomistic systems, based on polymers, under extreme conditions, in the bulk, on surfaces, and at interfaces. The protocol is built around various types of Monte Carlo algorithms, which include localized, chain-connectivity-altering, identity-exchange, and cluster-based moves. The approach focuses on alleviating one of the main disadvantages of Monte Carlo algorithms, which is the general applicability under a wide range of conditions. Present applications include polymer-based nanocomposites with nanofillers in the form of cylinders and spheres of varied concentration and size, extremely confined and maximally packed assemblies in two and three dimensions, and terminally grafted macromolecules. The main simulator is accompanied by a descriptor that identifies the similarity of computer-generated configurations with respect to reference crystals in two or three dimensions. The Simu-D simulator-descriptor can be an especially useful tool in the modeling studies of the entropy- and energy-driven phase transition, adsorption, and self-organization of polymer-based systems under a variety of conditions.