About consistency of Solid's solubility data in supercritical CO2 and some thermodynamic properties estimation

In chemical industry, usual solvents are being replaced by supercritical fluids. Last few years, extraction by these environmentally benign solvents has had much attention and now is considered as the newest separation technology. However, developing new applications and improving existing ones is based on a set of thermodynamic and physical properties of pure solutes related to phase equilibrium for which experimental values cannot be found and consequently, there is an increase need for accurate estimates of these properties. This paper is interested firstly to a thermodynamic property which is the Krichevskii parameter and secondly to a thermophysical one which is the sublimation pressure. First parameter is considered as a governor of thermodynamic properties in binary dilute mixtures near the solvent's critical point and can be calculated from some rigorous relationships and in this paper a review and a new way for its estimation are presented based on consistency of solid's solubility data in supercritical fluids and dilute solution theory. Second parameter is considered as the predominant influencer on solubility in supercritical fluids and unavailability of its experimental values presents an obstacle to thermodynamic modeling of solubility data. For this reason and as a second step, in this paper we present a new manner for its estimation. Obtained results are relevant, very promising for each considered property and the methodology can be applied for other solutes with more complex structures as Pharmaceuticals (antibiotics, drugs, anti-inflammatories …), polycyclic aromatic hydrocarbons (PAHC) and dyestuffs.     

Analysis of mono-, di- and triglycerides in pharmaceutical excipients by capillary supercritical fluid chromatography.

Mono-, di- and triglycerides are important components of oils, fats and other natural products. Since in general fatty acids are mixtures and glycerol can be differently substituted, finger-prints of the composition are suitable for better characterization. Since capillary supercritical fluid chromatography (SFC) employing carbon dioxide as mobile phase is compatible with flame ionization detection, it is possible to analyse many solutes at trace levels. Supercritical carbon dioxide offers higher solute diffusivity compared with the inert carrier gas conventionally used in gas chromatography and has a lower viscosity than the liquid solvents used in HPLC. Thus, glycerides of fatty acids can be separated and eluted at a lower temperature and with shorter analysis time in SFC. In this study the analysis of mono-, di- and triglyceride mixtures in several pharmaceutical excipients is reported using capillary SFC. Quantitative analysis is possible on the basis of a response factor established for each analyte. The accuracy of the method and its advantages are demonstrated.     

Impact of heat treatment on the physical properties of noncrystalline multisolute systems concentrated in frozen aqueous solutions

The purpose of this study was to elucidate the effect of heat treatment on the miscibility of multiple concentrated solutes that mimic biopharmaceutical formulations in frozen solutions. The first heating thermal analysis of frozen solutions containing either a low-molecular-weight saccharide (e.g., sucrose, trehalose, and glucose) or a polymer (e.g., polyvinylpyrrolidone and dextran) and their mixtures from -70°C showed a single transition at glass transition temperature of maximally freeze-concentrated solution (T(g) ') that indicated mixing of the freeze-concentrated multiple solutes. The heat treatment of single-solute and various polymer-rich mixture frozen solutions at temperatures far above their T(g) ' induced additional ice crystallization that shifted the transitions upward in the following scan. Contrarily, the heat treatment of frozen disaccharide-rich solutions induced two-step heat flow changes (T(g) ' splitting) that suggested separation of the solutes into multiple concentrated noncrystalline phases, different in the solute compositions. The extent of the T(g) ' splitting depended on the heat treatment temperature and time. Two-step glass transition was observed in some sucrose and dextran mixture solids, lyophilized after the heat treatment. Increasing mobility of solute molecules during the heat treatment should allow spatial reordering of some concentrated solute mixtures into thermodynamically favorable multiple phases.     

Supercritical carbon dioxide processing of active pharmaceutical ingredients for polymorphic control and for complex formation

Supercritical fluid technique have been exploited in extraction, separation and crystallization processes. In the field of pharmaceutics, supercritical carbon dioxide (scCO(2)) has been used for the purpose of micronization, polymorphic control, and preparation of solid dispersion and complexes. Particle design of active pharmaceutical ingredients is important to make the solid dosage forms with suitable physicochemical properties. Control of the characteristic properties of particles, such as size, shape, crystal structure and morphology is required to optimize the formulation. For solubility enhancement of poorly water-soluble drugs, preparation of the solid dispersion or the complexation with proper drugs or excipients should be a promising approach. This review focuses on aspects of polymorphic control and complexation behavior of active pharmaceutical ingredients by scCO(2) processing.     

Pharmaceutical applications of supercritical carbon dioxide.

The appearance of a supercritical state was already observed at the beginning of the 19th century. Nevertheless, the industrial extraction of plant and other natural materials started about twenty years ago with the decaffeination of coffee. Today carbon dioxide is the most common gas for supercritical fluid extraction in food and pharmaceutical industry. Since pure supercritical carbon dioxide is a lipophilic solvent, mixtures with organic solvents, especially alcohols, are used to increase the polarity of the extraction fluid; more polar compounds can be extracted in this way. The main fields of interest are the extraction of vegetable oils from plant material in analytical and preparative scale, the preparation of essential oils for food and cosmetic industry and the isolation of substances of pharmaceutical relevance. Progress in research was made by the precise measurement of phase equilibria data by means of different methods. Apart from extraction, supercritical fluid chromatography was introduced in the field of analytics, as well as micro- and nanoparticle formation using supercritical fluids as solvent or antisolvent. This review presents pharmaceutical relevant literature of the last twenty years with special emphasis on extraction of natural materials.     

Micronization by means of supercritical fluids: possibility of application to pharmaceutical field.

The state of the art in drug micronization is briefly reviewed. The Authors propose and discuss the adoption of a new micronization technique based on supercritical fluids properties: high solvent power and selectivity, fast solute precipitation. A supercritical spray apparatus that has been designed to maximize micronization of pharmaceutical interest products is described. A preliminary scanning of supercritical solvents and cosolvents suitable to dissolve poorly soluble products is also proposed.     

Pharmaceutical applications of supercritical carbon dioxide

The supercritical state of a fluid is intermediate between that of gases and liquids. Supercritical fluids exhibit some solvent power which is tunable in function of pressure and temperature. In the pharmaceutical field, supercritical carbon dioxide is by far the most commonly used fluid; of course, the first applications of supercritical fluids were the replacement of organic solvents in extraction processes; other applications appeared during the last twenty years: supercritical fluids are also used as eluents in chromatography, as solvents in organic synthesis or for the processing of solid dosage forms by drug micronization, by the production of nanospheres, of solid dispersions, of porous polymeric matrices containing different active substances. Supercritical carbon dioxide has been proposed for encapsulating both hydrophilic and hydrophobic drug substances into liposomes as well as for including different active substances into cyclodextrins. There are also future prospects for the use of pressurized carbon dioxide as a sterilizing agent.     

An Examination of Water Vapor Sorption by Multicomponent Crystalline and Amorphous Solids and Its Effects on Their Solid-State Properties

This commentary critically evaluated the unique effects of water vapor sorption by multicomponent solid forms of active pharmaceutical ingredients (APIs), and its effects on their physical and chemical properties. Such multicomponent forms include the following: (1) crystalline salts and cocrystals, and (2) amorphous salts, coamorphous mixtures, and amorphous solid dispersions (ASDs). These solid forms are commonly used to increase the solubility, dissolution, and bioavailability of poorly soluble APIs. To achieve this increase, selected counterions or coformers exhibit much greater polarity, and have a tendency to enhance water vapor sorption, leading to possible instabilities. Such instabilities include salt disproportionation, cocrystal dissociation, and phase separation and crystallization from amorphous forms. Regarding crystalline multicomponent systems, significant instabilities arise on account of deliquescence or crystal hydrate formation. Such behavior often follows water-induced salt disproportionation or cocrystal dissociation. Regarding amorphous salts, coamorphous mixtures, and ASDs, we see the importance of absorbed water as a disrupter of API-coformer interactions and as a plasticizer in bringing about subsequent phase separation and crystallization. In preparing multicomponent solid forms, it is important to measure the water vapor sorption isotherm of the counterion or coformer to better understand the mode by which water is sorbed, and to anticipate and correct possible instabilities.     

What determines drug solubility in lipid vehicles: is it predictable?

Lipid-based drug delivery systems are of increasing interest to the pharmaceutical scientist because of their potential to solubilize drug molecules that may be otherwise difficult to develop. The ability to predict lipid solubility is an important step in being able to identify the right excipients to solubilize and formulate drugs in lipid formulations. However, predicting lipid solubility is complicated by the fact that interfacial effects may play a dominant role in these mixtures and the solubility may be affected by the microstructure (microemulsions, emulsions, oily solutions, etc.), as well as by the physicochemical properties of the oil, surfactant, co-solvent, and the drug. This review illustrates the fundamental factors that govern solubility in lipid mixtures and discusses models built at varying levels of sophistication to estimate the solubility. Examples from the literature are presented that demonstrate the application of these models, how their choice is related to the drug/lipid employed, and the challenges involved in solubility prediction. New data on the role water plays in altering lipid solubility, not only through its interaction with the solute, but also by changing the structure of lipids by promoting lipid organization are highlighted. The available data demonstrate that a rational understanding of solubilization in lipids is a worthwhile pursuit and models to predict at least the relative solubility from chemical structure have potential. Prediction of absolute solubility is more difficult as it requires knowledge of the drug's escaping tendency from the crystalline state. In recent years, it has become amply clear that for polar solutes, specific interactions are a critical factor governing solubility. Methods that can better take into account the specific as well as non-specific interactions between the solute and solvent, and the lipid microstructure, hold considerable promise for the future.     

中空纤维膜组件在生物分子反应萃取中的应用

纯化从发酵培养液和其它天然来源的生物分子,分离步骤较多,会造成一定的损失。通过待分离的“靶”分子与载体分子反应,形成复合物,可选择性地纯化“靶”分子。反应形成的复合物由于在有机相中的溶解性提高,从而使“靶”分子从复杂的培养液混合物中分离出来的方法称为“反应萃取”。该方法克服了常规分离技术的许多缺点．在降低分离过程中产品的损失方面很有潜力本文报道了该方法在一些药物．包括氨基酸和二肽分离中的应用。实验系统是一套允许两种溶液分别流过管层和壳层的,具有列管式结构的中空纤维膜组件,料液和有机溶剂分别流过管层和壳层。靶溶质分子扩散到水-有机相界面与载体形成复合物：载体溶质复合物被转运到壳层而被重新回收得到。该项研究的目的有以下三方：1．应用商品化的膜组件．研究在不同条件(如料液的pH和有机相浓度)下．溶质的萃取百分率;2.直接应用实验数据推导出模式方程以确定总传质系数;3．尝试从“工业的”样品中分离掉杂质(如多肽)。     

An atomic and molecular view of the depth dependence of the free energies of solute transfer from water into lipid bilayers

Molecular interactions and orientations responsible for differences in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer partitioning of three structurally related drug-like molecules (4-ethylphenol, phenethylamine, and tyramine) were investigated. This work is based on previously reported molecular dynamics (MD) simulations that determined their transverse free energy profiles across the bilayer. Previously, the location where the transfer free energy of the three solutes is highest, which defines the barrier domain for permeability, was found to be the bilayer center, while the interfacial region was found to be the preferred binding region. Contributions of the amino (NH2) and hydroxyl (OH) functional groups to the transfer free energies from water to the interfacial region were found to be very small both experimentally and by MD simulation, suggesting that the interfacial binding of these solutes is hydrophobically driven and occurs with minimal loss of hydrogen-bonding interactions of the polar functional groups which can occur with either water or phospholipid head groups. Therefore, interfacial binding is relatively insensitive to the number or type of polar functional groups on the solute. In contrast, the relative solute free energy in the barrier domain is highly sensitive to the number of polar functional groups on the molecule. The number and types of hydrogen bonds formed between the three solutes and polar phospholipid atoms or with water molecules were determined as a function of solute position in the bilayer. Minima were observed in the number of hydrogen bonds formed by each solute at the center of the bilayer, coinciding with a decrease in the number of water molecules in DOPC as a function of distance away from the interfacial region. In all regions, hydrogen bonds with water molecules account for the majority of hydrogen-bonding interactions observed for each solute. Significant orientational preferences for the solutes are evident in certain regions of the bilayer (e.g., within the ordered chain region and near the interfacial region 20-25 ? from the bilayer center). The preferred orientations are those that preserve favorable molecular interactions for each solute, which vary with the solute structure.     

Miscibility as a Factor for Component Crystallization in Multisolute Frozen Solutions

The relationship between the miscibility of formulation ingredients and their crystallization during the freezing segment of the lyophilization process was studied. The thermal properties of frozen solutions containing myo-inositol and cosolutes were obtained by performing heating scans from −70°C before and after heat treatment at −20°C to −5°C. Addition of dextran 40,000 reduced and prevented crystallization of myo-inositol. In the first scan, some frozen solutions containing an inositol-rich mixture with dextran showed single broad transitions (T_g′s: transition temperatures of maximally freeze-concentrated solutes) that indicated incomplete mixing of the concentrated amorphous solutes. Heat treatment of these frozen solutions induced separation of the solutes into inositol-dominant and solute mixture phases (T_g′ splitting) following crystallization of myo-inositol (T_g′ shifting). The crystal growth involved myo-inositol molecules in the solute mixture phase. The amorphous–amorphous phase separation and resulting loss of the heteromolecular interaction in the freeze-concentrated inositol-dominant phase should allow ordered assembly of the solute molecules required for nucleation. Some dextran-rich and intermediate concentration ratio frozen solutions retained single T_g′s of the amorphous solute mixture, both before and after heat treatments. The relevance of solute miscibility on the crystallization of myo-inositol was also indicated in the systems containing glucose or recombinant human albumin.     

Supercritical fluid technologies: an innovative approach for manipulating the solid-state of pharmaceuticals

Solid-state, crystallographic purity and careful monitoring of the polymorphism of drugs and excipients are currently an integral part of the development of modern drug delivery systems. The reproducible preparation of organic crystals in a specific form and size is a major issue that must be addressed. A recent approach for obtaining pharmaceutical materials in pure physical form is represented by the technologies based on supercritical fluids. The present work aims to provide a critical review of the recent advances in the use of supercritical fluids for the preparation and control of the specific physical form of pharmaceutical substances with particular attention to those fluids used for drug delivery systems. These innovative technologies are highly promising for future application in particle design and engineering.     

The Relationship Between the Glass Transition Temperature and the Water Content of Amorphous Pharmaceutical Solids

The glass transition temperature of an amorphous pharmaceutical solid is a critical physical property which can dramatically influence its chemical stability, physical stability, and viscoelastic properties. Water frequently acts as a potent plasticizer for such materials, and since many amorphous solids spontaneously absorb water from their surroundings the relationship between the glass transition temperature and the water content of these materials is important. For a wide range of amorphous and partially amorphous pharmaceutical solids, it was found that there is a rapid initial reduction in the glass transition temperature from the dry state as water is absorbed, followed by a gradual leveling off of the response at higher water contents. This plasticization effect could generally be described using a simplified form of the Gordon–Taylor/ Kelley–Bueche relationships derived from polymer free volume theory. Most of the systems considered showed a nearly ideal volume additivity and negligible tendency to interact. This is consistent with the hypothesis that such mixtures behave as concentrated polymer solutions and indicates that water acts as a plasticizer in a way similar to that of other small molecules and not through any specific or stoichiometric interaction process(es).     

Mathematical representation of solute solubility in binary mixture of supercritical fluids by the Jouyban-Acree model

Applicability of a solution model for calculating the solute solubility in binary mixtures of supercritical fluids at different SCF compositions and pressures was shown using phenanthrene solubility data in supercritical carbon dioxide and supercritical ethane at 313 K and a pressure range of 100-350 bar. The correlation ability of the proposed model was evaluated by fitting all data points and computing error term employing back-calculated solubilities. The prediction capability of the model was assessed by dividing each data set to two subsets, namely training and test subsets. The predicted solubilities using trained models were used to calculate the prediction error term. The results show that both correlative and predictive error terms were less than the experimentally obtained RSD values.     

Recent advances in trace analysis of pharmaceutical genotoxic impurities

Genotoxic impurities (GTIs) in pharmaceuticals at trace levels are of increasing concerns to both pharmaceutical industries and regulatory agencies due to their potentials for human carcinogenesis. Determination of these impurities at ppm levels requires highly sensitive analytical methodologies, which poses tremendous challenges on analytical communities in pharmaceutical R&D. Practical guidance with respect to the analytical determination of diverse classes of GTIs is currently lacking in the literature. This article provides an industrial perspective with regard to the analysis of various structural classes of GTIs that are commonly encountered during chemical development. The recent literatures will be reviewed, and several practical approaches for enhancing analyte detectability developed in recent years will be highlighted. As such, this article is organized into the following main sections: (1) trace analysis toolbox including sample introduction, separation, and detection techniques, as well as several ‘general’ approaches for enhancing detectability; (2) method development: chemical structure and property-based approaches; (3) method validation considerations; and (4) testing and control strategies in process chemistry. The general approaches for enhancing detection sensitivity to be discussed include chemical derivatization, ‘matrix deactivation’, and ‘coordination ion spray-mass spectrometry’. Leveraging the use of these general approaches in method development greatly facilitates the analysis of poorly detectable or unstable/reactive GTIs. It is the authors’ intent to provide a contemporary perspective on method development and validation that can guide analytical scientists in the pharmaceutical industries.     

Accelerated aging: prediction of chemical stability of pharmaceuticals

Methods of rapidly and accurately assessing the chemical stability of pharmaceutical dosage forms are reviewed with respect to the major degradation mechanisms generally observed in pharmaceutical development. Methods are discussed, with the appropriate caveats, for accelerated aging of liquid and solid dosage forms, including small and large molecule active pharmaceutical ingredients. In particular, this review covers general thermal methods, as well as accelerated aging methods appropriate to oxidation, hydrolysis, reaction with reactive excipient impurities, photolysis and protein denaturation.     

Control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients (APIs)

This paper continues the review of the relevant scientific literature associated with the control and analysis of potential genotoxic impurities (PGIs) in active pharmaceutical ingredients (APIs). The initial review [D.P. Elder, A. Teasdale, A.M. Lipczynski, J. Pharm. Biomed. Anal. 46 (2008) 1-8.] focused on the specific class of sulfonate esters but in this instance reference is made to the analysis of alkyl and benzyl halides and other related reactive organohalide alkylating agents. Such reactive materials are commonly employed in pharmaceutical research and development as raw materials, reagents and intermediates in the chemical synthesis of new drug substances. Consequently a great deal of attention and effort is extended by the innovative and ethical pharmaceutical industry to ensure that appropriate and practicable control strategies are established during drug development to ensure residues of such agents, as potential impurities in new drug substances, are either eliminated or minimized to such an extent so as to not present a significant safety risk to volunteers and patients in clinical trials and beyond. The reliable trace analysis of such reactive organohalides is central to such control strategies and invariably involves a state-of-the-art combination of high-resolution separation science techniques coupled to sensitive and selective modes of detection. This article reports on the most recent developments in the regulatory environment, overall strategies for the control of alkylating agents and the latest developments in analysis culminating in a literature review of analytical approaches. The literature is sub-categorized by separation technique (gas chromatography (GC), high-performance liquid chromatography (HPLC), thin layer chromatography (TLC) and capillary zone electrophoresis (CZE)) and further tabulated by API type and impurity with brief method details and references. As part of this exercise, a selection of relevant pharmacopoeial monographs was also reviewed. The continued reliance on relatively non-specific and insensitive TLC methodologies in several monographs was noteworthy.     

Effect of Small Levels of Impurities on the Water Vapor Sorption Behavior of Ranitidine HCl

Purpose Deliquescence is the process by which a solid undergoes dissolution by sorbing moisture from its surroundings when a characteristic relative humidity, RH₀, is reached. For mixtures of two or more deliquescent solids, RH₀ will generally be lowered. The goal of this research was to investigate the effect of small amounts of impurities or degradants on RH₀ for a model deliquescent pharmaceutical salt.Materials and Methods The model salt chosen for this work was ranitidine HCl, which has two polymorphic forms. Moisture sorption profiles for each polymorph and samples of different purities were obtained using a gravimetric water vapor sorption balance.Results Polymorphs of a similar purity yielded virtually identical moisture sorption profiles. In contrast, samples containing higher levels of impurities had both enhanced moisture sorption below RH₀ and a lowered value of RH₀.Conclusions It was concluded that small levels of degradants and/or impurities can drastically affect the moisture sorption profile of a deliquescent material, both through affecting the deliquescence relative humidity and by altering the overall interaction of the substance with moisture. Such changes in behavior may have significant effects on both active pharmaceutical ingredient and drug product stability during both processing and storage.     

Design and process aspects of laboratory scale SCF particle formation systems

Consistent production of solid drug materials of desired particle and crystallographic morphologies under cGMP conditions is a frequent challenge to pharmaceutical researchers. Supercritical fluid (SCF) technology gained significant attention in pharmaceutical research by not only showing a promise in this regard but also accommodating the principles of green chemistry. Given that this technology attained commercialization in coffee decaffeination and in the extraction of hops and other essential oils, a majority of the off-the-shelf SCF instrumentation is designed for extraction purposes. Only a selective few vendors appear to be in the early stages of manufacturing equipment designed for particle formation. The scarcity of information on the design and process engineering of laboratory scale equipment is recognized as a significant shortcoming to the technological progress. The purpose of this article is therefore to provide the information and resources necessary for startup research involving particle formation using supercritical fluids. The various stages of particle formation by supercritical fluid processing can be broadly classified into delivery, reaction, pre-expansion, expansion and collection. The importance of each of these processes in tailoring the particle morphology is discussed in this article along with presenting various alternatives to perform these operations.