{"id":291,"date":"2011-08-11T17:22:20","date_gmt":"2011-08-11T14:22:20","guid":{"rendered":"http:\/\/nonatech.ru\/?page_id=291"},"modified":"2011-08-11T17:22:20","modified_gmt":"2011-08-11T14:22:20","slug":"how-to-assure-safety-in-large-scale-manufacturing-of-nanoparticle-of-the-bio-medical-use","status":"publish","type":"page","link":"https:\/\/nonatech.ru\/?page_id=291&amp;lang=ru","title":{"rendered":"HOW TO ASSURE SAFETY IN LARGE-SCALE MANUFACTURING OF NANOPARTICLE OF THE BIO-MEDICAL USE"},"content":{"rendered":"<p>&nbsp;<\/p>\n<div class=\"Section1\">\n<h1 class=\"MsoNormal\" style=\"text-align: center;\">HOW TO ASSURE SAFETY IN LARGE-SCALE MANUFACTURING OF NANOPARTICLE OF THE BIO-MEDICAL USE<\/h1>\n<p class=\"MsoNormal\" style=\"text-align: left;\"><span lang=\"EN-US\">Maksimov\u00a0S. K., Maksimov K. S.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: left;\"><span lang=\"EN-US\"> <\/span>Moscow\u00a0Institute of Electronic technology,<\/p>\n<p class=\"MsoNormal\" style=\"text-align: left;\">Soukhov N. D.<\/p>\n<p class=\"MsoNormal\" style=\"text-align: left;\">Moscow State University<\/p>\n<p class=\"MsoNormal\" style=\"text-align: left;\">E-mail for responces:\u00a0<span id=\"enkoder_0_1616449810\"><span id=\"enkoder_1_2084318194\">email hidden; JavaScript is required<\/span><script type=\"text\/javascript\">\n\/* <!-- *\/\nfunction hivelogic_enkoder_1_2084318194() {\nvar kode=\"kode=\\\"110 114 103 104 64 37 110 98 114 98 103 98 104 98 64 98 95 37 98 114 98 110 98 104 98 103 98 95 95 98 95 37 98 64 98 51 98 52 98 35 98 54 98 52 98 52 98 35 98 55 98 51 98 52 98 35 98 53 98 53 98 52 98 35 98 51 98 52 98 52 98 35 98 53 98 51 98 52 98 35 98 55 98 52 98 52 98 35 98 54 98 52 98 52 98 35 98 60 98 60 98 55 98 52 98 35 98 53 98 53 98 52 98 35 98 58 98 52 98 52 98 35 98 59 98 51 98 52 98 35 98 60 98 52 98 52 98 35 98 55 98 51 98 55 98 35 98 35 98 54 98 58 98 54 98 60 98 35 98 35 98 56 98 54 98 57 98 52 98 35 98 51 98 51 98 54 98 35 98 35 98 56 98 51 98 52 98 35 98 58 98 52 98 52 98 35 98 58 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104 49 111 104 113 106 119 107 48 52 44 61 42 42 44 62\\\";kode=kode.split(\\' \\');x=\\'\\';for(i=0;i<kode.length;i++){x+=String.fromCharCode(parseInt(kode[i]-3))}kode=x;\";var i,c,x;while(eval(kode));\n}\nhivelogic_enkoder_0_1616449810();\nvar span = document.getElementById('enkoder_0_1616449810');\nspan.parentNode.removeChild(span);\n\/* --> *\/\n<\/script><\/p>\n<h2 class=\"MsoNormal\" style=\"text-align: justify;\">Abstract.<\/h2>\n<p class=\"MsoNormal\" style=\"text-align: justify;\">Nanoparticles provide great\u00a0advantages but also great risks. Risks associating with nanoparticles are the\u00a0problem of all technologies, but they increase in many times in\u00a0nanotechnologies. Adequate methods of outgoing production inspection are necessary\u00a0to solve the problem of risks, and the inspection must be based on the safety\u00a0standard. Existing safety standard results from a principle of \u201cmaximum\u00a0permissible concentrations or MPC\u201d. This principle is not applicable to\u00a0nanoparticles, but a safety standard reflecting risks inherent in nanoparticles\u00a0doesn\u2019t exist. Essence of the risks is illustrated by the example from\u00a0pharmacology, since its safety assurance is conceptually based on MPC and it has\u00a0already come against this problem. Possible formula of safety standard for\u00a0nanoparticles is reflected in many publications, but conventional inspection\u00a0methods cannot provide its realization, and this gap is an obstacle to assumption\u00a0of similar formulas. Therefore the development of nanoparticle industry as a whole\u00a0(also development of the pharmacology in particular) is impossible without the\u00a0creation of an adequate inspection method. There are suggested new inspection\u00a0methods founded on the new physical principle and satisfying to the adequate\u00a0safety standard for nanoparticles. These methods demonstrate that creation of\u00a0the adequate safety standard and the outgoing production inspection in a\u00a0large-scale manufacturing of nanoparticles are the solvable problems. However\u00a0there is a great distance between the physical principle and its hardware\u00a0realization, and a transition from the principle to the hardware demands great\u00a0intellectual and material costs. Therefore it is desirable to call attention of\u00a0the public at large to the necessity of urgent expansions of investigations\u00a0associated with outgoing inspections in nanoparticles technologies. It is\u00a0necessary also to attract attention, first, of representatives of state\u00a0structures controlling approvals of the adequate safety standard to this\u00a0problem, since it is impossible to compel producers providing the safety\u00a0without the similar standard, and, second, of leaders of pharmacological\u00a0industry, since their industry already entered into the nanotechnology era, and\u00a0they have taken an interest in a forthcoming development of inspection methods.<\/p>\n<p class=\"MsoNormal\"><span lang=\"EN-US\"> <\/span>Key problems. Risks of nanoparticle\u00a0large-scale manufacturing, adequate safety standard, outgoing production inspection,\u00a0structure and habit, scanning electron microscopy, habit control by means of\u00a0convergent illuminating electron beams, safety assurance in the nanoparticle\u00a0industry is a solvable problem.<\/p>\n<h2 class=\"MsoNormal\" style=\"text-align: justify;\"><strong><span lang=\"EN-US\"> <\/span><\/strong><strong><span lang=\"EN-US\">1. Premises and essence of the problem.<\/span><\/strong><\/h2>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Outgoing production inspection is the\u00a0inevitable part of any technology. It must secure conformity of an inspected portion\u00a0of production with its technical regulations and thereby to insure its quality\u00a0and compatibility with the biosphere.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Risks connected with nanodimensional\u00a0particles for the life are associated with their capacity to control reactions\u00a0in ambient environment, i.e. with their catalytic activity. Catalytic activity\u00a0of a solid object is determined by its structure and crystallographic faceting\u00a0or habit [1]. Size, structure and habit are thermodynamically interconnected in\u00a0the nanoworld, and a decrease of particle sizes leads to change of its\u00a0equilibrium structure and habit [2]. Technologies of obtaining only single size\u00a0particles are impossible. Besides, thermodynamics determines only a direction\u00a0of possible phase transitions; its actual realization is determined by factors related\u00a0to the kinetics of nucleation and growth of particles. Nanoparticle industry\u00a0processes are essentially nonequilibrium and can be influenced by random\u00a0factors. Therefore particles with the same sizes and produced in the same\u00a0process can be of different structural-morphological parameters and, naturally,\u00a0of different catalytic activity. Hence all technologies of nanoparticles are\u00a0potentially binary; creation of a necessary product may be always accompanied\u00a0by formation of a dangerous co-product [3, 4]. This peculiarity of\u00a0nanotechnologies can be, for lack of the better by term, named \u2018ambivalence\u2019. Although\u00a0the ambivalence is inherent to the particle industry as a whole in the result\u00a0of lack of technologies of formation particles with one single size, the danger\u00a0of the ambivalence increases manifold in nanotechnologies. Therefore the development\u00a0of technologies of nanoparticles with new properties and opportunities will be<br \/>\naccompanied by new risks.<\/span><\/p>\n<p class=\"MsoNormal\"><span lang=\"EN-US\">Nanoparticles could be used in the medicine\u00a0[5-7]:<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.2pt; text-indent: -17.85pt; text-align: justify;\"><span lang=\"EN-US\">\u25cf<span style=\"font-size: 9px; line-height: 13px;\"> <\/span><\/span><span lang=\"EN-US\">in diagnostics, e.g., as vision aids during a\u00a0radiation, sound or magnetic inspection;<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.2pt; text-indent: -17.85pt; text-align: justify;\"><span lang=\"EN-US\">\u25cf <\/span><span lang=\"EN-US\">in therapy, e.g., as promoters of the generation\u00a0of medical agents inside an organism, antioxidants, regenerative absorbers of\u00a0organic and inorganic pollution agents, etc;<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.2pt; text-indent: -17.85pt;\"><span lang=\"EN-US\">\u25cf <\/span><span lang=\"EN-US\">in surgery, e.g., as substances for obtaining\u00a0active surfaces of implants accelerating their accommodation by organisms or\u00a0creation of active implants, for instance, heart valves promoting the\u00a0rejuvenation of blood vessels.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">In the pharmacology, nanoparticles could be\u00a0used as catalysts in technologies of obtaining of drugs or also substances for\u00a0encapsulation of non-persistent medicines. Many substances which could be used\u00a0as medicines are water-insoluble, and their digestion in an organism is labored,\u00a0but their nanodimensional forms are assimilated easier. Therefore nanocrystallization\u00a0could be a principal approach in the pharmacology, providing the creation of\u00a0new medicines in essence [8-10]. It is impossible to reject vast opportunities provided\u00a0by the use of nanoparticles and nanoparticle industry certainly should be developed.<br \/>\nOutgoing production inspection is the only way to provide safety securing in\u00a0the mass nanoparticle industry and its development must outrun the development\u00a0of technologies of nanoparticle production as a whole.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Outgoing production control must correspond\u00a0to the safety standard to secure the compatibility of technology with the\u00a0biosphere [1]. Similar standard exists in the chemical industry where it is\u00a0called the principle of \u201cmaximum permissible concentration (MPC)\u201d, but although\u00a0technologies of nanoparticle are part of chemical technologies, the MPC\u00a0principle is not effective for the safety assurance in nanoworld; the same\u00a0weight or volume contents of nanoparticles may cause different effects since\u00a0their massifs may contain particle with identical compositions but with\u00a0different catalytic activities. However safety standards reflecting the\u00a0ambivalence of technologies of nanoparticles are absent [11]. Taken into\u00a0consideration the ambivalence, the safety standard in the mass production of\u00a0nanoparticles could be formulated as <span style=\"text-decoration: underline;\">\u201cmaximum of an allowable content of\u00a0nanoparticles with dangerous catalytic activity\u201d<\/span>. Lack of an approved\u00a0safety standard plays a negative role: there is no effective stimulus forcing\u00a0producers to control the ambivalence of nanotechnologies. Disregard of the\u00a0ambivalence of nanotechnologies is common even in science. In [12] is described\u00a0influence of TiO<sub>2<\/sub> nanoparticles obtained with the help of special\u00a0technology, but the possibility of presence of particles with different structural-morphological\u00a0parameters in a studied massif has been disregarded, structure and size of particles\u00a0have been determined by the X-ray diffraction, which gives information only\u00a0about average characteristics of a massif, and the uncovered effect has been ascribed\u00a0to a massif as a whole [12].<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Inorganic particles are used as additives\u00a0in many medicines<a name=\"_ftnref1\" href=\"#_ftn1\"><span class=\"MsoFootnoteReference\"><span class=\"MsoFootnoteReference\"><span style=\"font-size: 12.0pt; font-family: &quot;Times New Roman&quot;;\" lang=\"EN-US\">[1]<\/span><\/span><\/span><\/a>.\u00a0Certainly, pharmacological companies check possible risks associated with their\u00a0use. However the inspection with determination of fractional composition cannot\u00a0be carried out because of the lack of special methods, and if similar\u00a0inspection has made, it reflects only average properties of a massif as a whole.\u00a0Emphasis in the pharmacology lies on the safety inspection of medicines as a whole.\u00a0Medicine safety is examined in the result of long-term studies for the consequences\u00a0of a medicine use. Testing of the purity of massif of drag units is naturally restricted\u00a0in time, but effects from usage of this massif can be arisen in years. Methods\u00a0of the safety assurance in the pharmacology are conceptually based on the MPC,<br \/>\nand deficiency of methods of the safety assurance in pharmacology reflects inadequacy<br \/>\nof the MPC approach in nanotechnologies as a whole.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Dispersed TiO<sub>2<\/sub> particles are\u00a0used in many medicines, e. g. in Wilprafen (Yamanouchi), Aescusan (Schering),\u00a0etc, etc. TiO<sub>2<\/sub> has 2 main phases: the rutile and anatase. The rutile\u00a0is used in the pharmacology, but the rutile\/anatase phase equilibrium is shifted\u00a0to the anatase with the decrease of a particle size. Presence of anatase\u00a0particles in dispersed TiO<sub>2<\/sub> massifs has been demonstrated in [13].\u00a0Anatase nanoparticles can lead to DNA structure changes [12], that can be the stimulus\u00a0for many induced diseases of patients. However the prohibition of medicines\u00a0containing TiO<sub>2<\/sub> is untimely; the results of [12] are not unequivocal.\u00a0TiO<sub>2<\/sub> has phases with structure distinguish from structures of the\u00a0rutile or anatase. Similar phases arise with deviation from stoichiometry or under\u00a0nonequilibrium conditions of crystallization and growth. The process, used in [12]\u00a0for formation of anatase nanoparticles, was nonequilibrium, and methods of the\u00a0phase identification had average character, consequently, existence of other\u00a0phases in studied massifs could be missed. Explanation of causes of ascertained\u00a0DNA structure changes demands the detection of particles with structural-morphological\u00a0parameters of all types that could be present in the investigated massif.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Massifs numbering (10<sup>12<\/sup> \u2013 10<sup>19<\/sup>)\u00a0particles per gram should arise in the large-scale nonmanufacturing. Similar\u00a0massifs can contain dangerous particles even if the roof-mean-square deviation of\u00a0a distribution of particles with different structural-morphological parameters is\u00a0very small. Medicine safety is examined in the result of long-term studies for\u00a0the consequences of a medicine use, but no matter how long-continued testing\u00a0time, it is always restricted by a few years, but duration of a human life is\u00a0measured by many ten years. Interaction of nanoparticles with the living matter\u00a0is a two-sided process, if nanoparticles influences on the living matter then\u00a0the living matter influences on the nanoparticles. Particle with different\u00a0structural-morphological characteristics must be adsorbed in a living organism\u00a0by a different manner. This assumption is confirmed by the medicine practice: particles\u00a0with peculiar structural-morphological parameters are adsorbed mainly by cancer\u00a0cells [5, 8]. However modern inspection methods can retrace only a total escape\u00a0of a medicine from the organism, the absorption of small fractions of particles\u00a0with unusual structural-morphological parameters may remain unnoticed, and<br \/>\nthese particles may be accumulated with an each use of medicine in an organism.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">If massifs numbers (10<sup>12<\/sup> \u2013 10<sup>19<\/sup>)\u00a0particles per gram then even a share of dangerous particles in 10<sup>-6 <\/sup>of total numbering of massif may essentially dirty an organism. Investigations\u00a0of influence of nanoparticles on the metabolism have been carried out only for\u00a0subjects of the biosphere with very small duration of a life cycle, e.g., the\u00a0spinach [14], and there is no way to tell: \u201cwhat much a number of particles can\u00a0lead to irreversible consequences throughout human lifetime\u201d. Many random factors\u00a0can provoke these irreversible consequences or impede them. Understanding of\u00a0mechanisms of an interaction between subjects of the wildlife and objects of\u00a0the abiocoen is constantly improving. Therefore new factors or effects unknown\u00a0previously appear from time to time [15], and it is necessary to know a history\u00a0of the problem for forthcoming surmounting difficulties, that can be provided\u00a0by recording of exhaustive information concerning conditions of production and\u00a0characteristics of a nanoparticle massif, responsible for misgivings.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Analysis of the situation with the\u00a0rutile\/anatase phase transition arising in medical technologies also allows making\u00a0another major conclusion. Production of the Wilprafen, Aescusan, Ofloxacin, etc\u00a0does not belong to a group of nanotechnologies. Risks of their technologies are\u00a0associated with the fundamental concept of \u201clack of technologies of production\u00a0of particles with one single size\u201d. Nanoparticles could be obtained in all\u00a0technologies from agricultural or food industries up to aerospace industry, a\u00a0basis product or by-product of which is particles [16, 17]. The question that always\u00a0arises is whether or not a restriction of harmful particles from their weight\u00a0or volume fraction is sufficient, or a true reason remains unidentified.\u00a0Conclusive decision of this problem can be achieved only on the base of\u00a0technology allowing controlling structural-morphological parameters of\u00a0nanodimensional particles. Forthcoming creation of similar technology is a\u00a0problem of the paramount importance. Taking into account the rate of progress\u00a0in technologies, it can be affirmed that the approach founded on <span style=\"text-decoration: underline;\">\u201cmaximum of\u00a0an allowable content of nanoparticles with dangerous catalytic activity\u201d<\/span> was necessary yesterday.<\/span><\/p>\n<p class=\"MsoNormal\"><strong><span lang=\"EN-US\"> <\/span><\/strong><\/p>\n<h2 class=\"MsoNormal\"><strong><span lang=\"EN-US\">2. Microscopy in nanoparticles inspection.<\/span><\/strong><\/h2>\n<p class=\"MsoNormal\"><span lang=\"EN-US\"> <\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Inspection of a habit of a single nanoparticle\u00a0is a prerogative of microscopic methods possessing of spatial resolution\u00a0necessary for measurements in nanoworld: the scanning probe microscopy (SPM),\u00a0transmission electron microscopy (TEM) and scanning electron microscopy (SEM).\u00a0These methods can be divided into two groups: SPM and TEM belong to the first,\u00a0they have been developed as techniques of obtaining of the unique information\u00a0in the atomic level [18, 19], SEM belongs to the second, since it has been intended,\u00a0primarily, for mapping of the object massifs [20]. Structure of a single\u00a0nanodimensional particle can be determined only with the electron diffraction,\u00a0which is carried out at present, primarily, with the help of TEM [18].<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Realization of an event even with the minimal\u00a0probability is possible, and it can be postulated that the absolute safety\u00a0demands revelation even a single particles with peculiar structural-morphological\u00a0parameters\/properties. However realization of similar extreme demands is impossible,\u00a0it is necessary, at least,<span style=\"color: blue;\"> <\/span>to provide an enough\u00a0level of the safety, which could be different in different cases and which\u00a0could be changeable with the progress of knowledge concerning the environmental\u00a0safety. Demand, that the environmental safety requires identification of\u00a0fractions of particles with different characteristics, a portion of which is\u00a0equal to 10<sup>-4<\/sup> \u2013 10<sup>-6<\/sup> of total number of nanoparticles of\u00a0a massif, could be accepted as reference point in the development of methods of\u00a0the outgoing inspection [21]. This demands is conservative, since 1 milligram\u00a0of particles with sizes \u2248 50 nm captured by an organism can contain up to\u00a010<sup>10<\/sup> dangerous particles, but even this sufficiently conservative estimation\u00a0demands controlling massifs numbering 10<sup>6<\/sup> \u2013 10<sup>8 <\/sup>particles, that exaggerates the implementation of outgoing production control. <\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Although SPM and TEM has been developed as\u00a0investigation facilities in the highest level, modern computer resources of\u00a0processing of information allow, in principle, developing inspection methods on\u00a0their basis [18,19]. But these attempts will be scarcely efficient.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Measurements of sizes in SPM methods are\u00a0realized by means of mechanical scanning of a probe point over the object, and conveying\u00a0moving speed for accurate measuring must be of the order of 10 nm\/s [19], therefore\u00a0measurements of a massif including 10<sup>6<\/sup> particles will take many\u00a0hours even if an area of measurements will be restricted to 100\u00d7100 nm<sup>2 <\/sup>[19] Therefore SPM methods cannot be used in the outgoing inspection because of\u00a0its productivity.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">TEM allows obtaining micrographs of large\u00a0particle massifs in the observing mode that could be used for selection of\u00a0particles with peculiar structural-morphological parameters on the base of specific\u00a0features of their images. However intensity distributions in TEM images (contrast)\u00a0depend on diffraction conditions and even small variations of orientation of a\u00a0particle or its thickness can lead to dramatic contrast changes [18]. Habit\u00a0determinations in TEM are based on a stereo method, but a particle tilt, which\u00a0is necessary for a stereogram, simultaneously leads to changes of diffraction\u00a0conditions and, accordingly, of contrast [18]. It is impossible to create\u00a0computer methods of image processing to compare of two images of the same\u00a0particle, when contrast in its images and location of these images are\u00a0different in compared micrographs. Therefore TEM stereogram eludes practically\u00a0computer processing and demands a high operator skill. As a result, TEM\u00a0technique has restricted productivity and, consequently, cannot be a basic procedure\u00a0of the outgoing inspection in nanoparticle mass production, but owing to the\u00a0possibility to carry out simultaneously microscopic and diffraction identification\u00a0of a single particle, it can be an important additional mean for solving intricate\u00a0situations.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">SPM and TEM could be also examined with\u00a0another view point. Any safety standard is effective only if it is way of its\u00a0realization, i.e., there is hardware-realized methods of the inspection of separate\u00a0particles, but SPM or TEM methods contradicts to common practice of outgoing\u00a0inspection in the large-scale manufacturing, Outgoing inspection must be\u00a0focused on the control of an product massif as a whole and cannot be founded on\u00a0a search for single particles with uncertain characteristics admits other\u00a0particles similar to it [22].<\/span><a name=\"OLE_LINK8\">Therefore the adequate method\u00a0of outgoing inspection in the large-scale manufacturing of nanoparticles must\u00a0correspond to conflicting demands: on the one hand, it must inspect a massif as\u00a0a whole, but on the other hand, reveal single particles with particular\u00a0characteristics.<\/a><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Advantages of SEM techniques are, firstly,\u00a0their focus on an inspection of vast massifs, that allows inspecting massifs of\u00a0particles practically unlimited in numbers, secondly, their focus on computer\u00a0methods of extraction and processing the information, that provides\u00a0trouble-free and fast development of methods of outgoing inspection on their\u00a0foundation, thirdly, a high speed of an electron beam travel as compare with a\u00a0travel speed of a probe point in SPM methods provides SEM methods the\u00a0productivity enough for realization of outgoing inspection on its basis [20].<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">The formation\u00a0of SEM images includes two stages. In the first stage, which is based on the<br \/>\nwave properties of electrons, the electron beam is formed with the laws of\u00a0electron optics. In the second stage, which is based on the corpuscular\u00a0properties of electrons, they release the energy in inelastic scattering. The\u00a0difficulties encountered in performing SEM metrology are associated with the\u00a0mechanism of image formation [20]. When images are formed in the course of\u00a0electron beam scanning over the surface of the object, they represent the sum\u00a0of sequential responses generated by the object in response to inelastic scattering\u00a0of electrons of an illuminating beam (probe, where the term the probe is a\u00a0cross section of the electron beam by the surface of the object). The contrast\u00a0in SEM images reflects the probability distribution of the escape of recoil\u00a0electrons when a probe actuates different points of an object surface. Main\u00a0factors determining the contrast are [20]:<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.35pt; text-indent: -18pt; text-align: justify;\"><span lang=\"EN-US\">1 <\/span><span lang=\"EN-US\">the energy of electrons in the illuminating beam\u00a0and the material of the object that determines a distribution of centers of the\u00a0inelastic scattering with an object thickness;<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.35pt; text-indent: -18pt; text-align: justify;\"><span lang=\"EN-US\">2 <\/span><span lang=\"EN-US\">the energy of recoil electrons <a name=\"OLE_LINK3\"><\/a><a name=\"OLE_LINK1\">participating in the image formation <\/a>that determines the free path and, accordingly, a layer of generation of these<br \/>\nelectrons;<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.35pt; text-indent: -18.0pt; text-autospace: none;\"><span lang=\"EN-US\">3 <\/span><span lang=\"EN-US\">the size of a probe, which depends on device\u00a0construction and accuracy of focusing;<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.35pt; text-indent: -18.0pt; text-autospace: none;\"><span lang=\"EN-US\">4 <\/span><span lang=\"EN-US\">the convergence of an illuminating electron beam,\u00a0which determines a depth of the focus;<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.35pt; text-indent: -18pt; text-align: justify;\"><span lang=\"EN-US\">5 <\/span><span lang=\"EN-US\">the magnification, which reflects a ratio\u00a0between a real size of some fragment in an object and a size of its image in a\u00a0registration image system, therefore information obtained with the help of SEM\u00a0images have been formatted at a small magnification can be specified in the\u00a0result of at an further magnification of micrographs (of course, if accuracy of\u00a0focusing is sufficient).<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">There are other\u00a0factors influencing on a contrast, e.g. accuracy of alignment of a microscope,\u00a0correction of astigmatism or an angle of electron beam deflection, but they\u00a0influence on changes of the base factors. <span style=\"text-decoration: underline;\">The thorough rule has been demonstrated\u00a0for SEM images, images of objects oriented identically about the illuminating<br \/>\nbeam direction depend only on a shape of this object and an object orientation\u00a0relative to the direction of an illuminating elector beam.<\/span> [20]. consequently,\u00a0particles can be classified according to their morphological characteristics owing\u00a0to specific features of their SEM images. SEM allows inspecting not only of a habit\u00a0but also a structure. EBSD technique realized in modern SEM provides determination\u00a0of structure of large particles consisting of heavy element [23]. Modern SEM\u00a0can operate in a transmission mode therefore structure of small particles consisting\u00a0of light elements can be controlled in electron diffraction mode [24]. SEM\u00a0methods make essentially less demands to a skill of a personal fulfilling an\u00a0inspection than TEM or SPM techniques. Therefore SEM could be an effective technique\u00a0of the outgoing production inspection, if the problem of dividing effects of a\u00a0habit from effects of an orientation with the help of SEM images will be solved.<\/span><\/p>\n<p class=\"MsoNormal\"><span lang=\"EN-US\"> <\/span><\/p>\n<h2 class=\"MsoNormal\" style=\"text-align: justify;\"><strong><span lang=\"EN-US\">3. Regularities of SEM image formation\u00a0and possibility of SEM use for morphology inspection.<\/span><\/strong><\/h2>\n<p class=\"MsoNormal\"><span lang=\"EN-US\"> <\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-bottom: 9pt; text-align: justify;\"><span lang=\"EN-US\">Typical\u00a0situations determining the escape of recoil electrons when a probe actuates a<br \/>\npoint \u201ca\u201d at an object surface are illustrated by Fig. 1-1 \u2013 1-3.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-bottom: 9pt; text-align: justify;\"><span lang=\"EN-US\"><img loading=\"lazy\" class=\"alignnone size-full wp-image-296\" title=\"Fig 1-1\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image001.jpg\" alt=\"\" width=\"151\" height=\"119\" srcset=\"https:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image001.jpg 151w, https:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image001-150x119.jpg 150w\" sizes=\"(max-width: 151px) 100vw, 151px\" \/><img loading=\"lazy\" class=\"alignnone size-full wp-image-297\" title=\"Fig 1-2\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image002.jpg\" alt=\"\" width=\"128\" height=\"119\" \/><img loading=\"lazy\" class=\"alignnone size-full wp-image-298\" title=\"Fig 1-3\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image003.jpg\" alt=\"\" width=\"161\" height=\"119\" \/><img loading=\"lazy\" class=\"alignnone size-full wp-image-299\" title=\"Fig 1-4\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image004.jpg\" alt=\"\" width=\"129\" height=\"119\" \/><br \/>\n<\/span><\/p>\n<div style=\"text-align: justify;\"><span style=\"font-size: 16px; line-height: 24px;\">Fig. 1. Peculiarities <\/span><span style=\"font-size: 16px; line-height: 24px;\">of contrast formation in SEM. 1-1, an object with 3 facets; escape of recoil\u00a0electrons in points \u201ca\u201d, \u201cb\u201d, \u201cc\u201d depends on a facet tilt. 1-2, object with <\/span><span style=\"font-size: 16px; line-height: 24px;\">trapezoidal cross-section, as long as a probe slides on a surface far from a <\/span><span style=\"font-size: 16px; line-height: 24px;\">facet edge, an escape of recoil electrons is proportional to intensity of illuminating <\/span><span style=\"font-size: 16px; line-height: 24px;\">beam and is constant in all points (\u201ca\u201d point), when a probe comes near to a <\/span><span style=\"font-size: 16px; line-height: 24px;\">facet edge to a distance less than a free path, recoil electrons escape through <\/span><span style=\"font-size: 16px; line-height: 24px;\">two surfaces and total intensity of recoil electrons increases (\u201cb\u201d point). <\/span><span style=\"font-size: 16px; line-height: 24px;\">1-3, object with trapezoidal cross-section, when a probe edge intersects a <\/span><span style=\"font-size: 16px; line-height: 24px;\">line, passing an object contour (\u201c*\u201d point) total intensity of recoil electrons <\/span><span style=\"font-size: 16px; line-height: 24px;\">becomes a sum of recoil electrons generated by an object and substrate. 1-4. <\/span><span style=\"font-size: 16px; line-height: 24px;\">rough profile of an intensity distribution in an image of an object with a <\/span><span style=\"font-size: 16px; line-height: 24px;\">right-angled cross-section, \u201ca\u201d \u2013 area wherein recoil electrons escape only <\/span><span style=\"font-size: 16px; line-height: 24px;\">through one surface, \u201cb\u201d \u2013 maximum intensity provided by an escape through 2 <\/span><span style=\"font-size: 16px; line-height: 24px;\">surfaces, \u201cc\u201d \u2013 area wherein a probe scanning is accompanied by decreasing of a <\/span><span style=\"font-size: 16px; line-height: 24px;\">share of recoil electrons generated by an object and increasing of a share of <\/span><span style=\"font-size: 16px; line-height: 24px;\">those caused by a substrate, \u201cd\u201d \u2013 area of a surface wherein a part of recoil <\/span><span style=\"font-size: 16px; line-height: 24px;\">electrons diffuse in a volume under an object and don\u2019t participate image <\/span><span style=\"font-size: 16px; line-height: 24px;\">formation, \u201ce\u201d \u2013 area wherein all recorded recoil electrons are generated by a <\/span><span style=\"font-size: 16px; line-height: 24px;\">substrate.<\/span><\/div>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Contrast in images of polyhedral objects is\u00a0determined by a summation of effects shown in Figs. 1-1 \u2013 1.3 and dark or light\u00a0stripes appear in the image of each verge. Contrast in images of objects with\u00a0convoluted surfaces depends on continuous changes of an escape of recoil\u00a0electrons as a result of, firstly, continues variations of orientation of\u00a0surface patches in itself and, secondly, changes of distances to adjacent patches\u00a0playing a role of second facets. Contour of a SEM image reflects the real\u00a0contour of an object in the object cross-section perpendicular to the electron\u00a0beam direction but the reflection has artifacts caused above-mentioned\u00a0regularities of an escape of recoil electrons, and the true object contour\u00a0remains unknown. Contrast in SEM images depends on an object habit and,\u00a0consequently, can be used for habit determination, but it must be free of effects\u00a0caused by variations of object orientation, and the question \u201cmay the\u00a0refinement be carried out on specific features of the same SEM images\u201d rises.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">SEM images may be interpreted in some way\u00a0as shadow images of objects in substrate images. Object height can be determined\u00a0by measurements of shadow image size variations caused by changes of object\u00a0orientations i.e. by the use of the stereo-methods. SEM stereo-methods were\u00a0used successfully for size measurements of micron objects [25]; however regularities\u00a0of SEM image formations break the single-valued correspondence between size\/shape\u00a0of an object and sizes\/shape of its image. Therefore the applicability of<br \/>\nstereo-method usage is determined by relation between a value of these\u00a0distortions and demands of stereo-methods.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Discrepancy\u00a0between the real contour of an object and the contour of its image is associated<br \/>\nwith 2 factors: with a probe size and with a free path of recoil electrons. Resolution\u00a0attainable in present SEM equals to 1.0 nm. However focusing in SEM is\u00a0determined on the basis of image sharpness and it is difficult to focus image\u00a0with the absolute accuracy. Real size of a probe can is equal to 1.8 \u2013 2.0 nm,\u00a0and many images correspond to these values. Minimal free path is observed for\u00a0electrons with energy equal to 18 \u2013 50 eV, and it is also equal to \u2248 1.0\u00a0nm. Therefore a minimal width of a stripe corresponding to an image of each\u00a0edge equals to \u2248 3 nm, and it is unlikely that the real positions of\u00a0spots of these edges can be found with accuracy better than \u00b1 1.0 nm. However<br \/>\neven an error <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">x<\/span><span lang=\"EN-US\"> = \u00b1 1.0 nm causes intolerable difficulties in habit determination.\u00a0Firstly, even if an error of position determination of each point is <\/span><a name=\"OLE_LINK4\"><span style=\"font-family: Symbol;\" lang=\"EN-US\">x<\/span><\/a><span lang=\"EN-US\"> = \u00b1 1.0 nm, an error in determination of a distance between two points\u00a0is equal to <sub><img loading=\"lazy\" class=\"alignnone size-full wp-image-301\" title=\"image005\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image005.gif\" alt=\"\" width=\"25\" height=\"23\" \/><\/sub><\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">x<\/span><span lang=\"EN-US\"> \u2248 \u00b1 1.5 nm, i.e.,\u00a0possible dispersion in possible sizes for objects with sizes \u2264 30 nm is \u2265\u00a010 %. Secondly, even if the point positions are found with the absolute\u00a0precision the stereogram doesn\u2019t give information concerning an object profile\u00a0between these points.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Theoretically,\u00a0an object with rough sizes, found with the help of a stereogram, could be used\u00a0as an initial prototype of an object\u2019s actual sizes of which can be specified with\u00a0the computer simulation. Similar simulation stipulates [20]:<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.2pt; text-indent: -17.85pt; text-align: justify;\"><span lang=\"EN-US\">i <\/span><span lang=\"EN-US\">To construct a SEM image of the prototype with a\u00a0composition, corresponding to the object, under conditions identical to those\u00a0used for the formation of with the help of software, e.g., Joy\u2019s PC Monte Carlo\u00a0Programs or SEMLP.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.2pt; text-align: left; text-indent: -17.85pt; text-autospace: none;\"><span lang=\"EN-US\">ii <\/span><span lang=\"EN-US\">To fit the model image to the experimental image\u00a0by varying sizes and a habit of the prototype.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.2pt; text-align: left; text-indent: -17.85pt; text-autospace: none;\"><span lang=\"EN-US\">iii <\/span><span lang=\"EN-US\">To accept the habit and sizes of the prototype\u00a0for which its image coincides with the actual image of the object as the true object\u00a0habit and sizes.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">However when the dispersion of possible\u00a0sizes is so large and even a rough object shape is unknown, a coincidence of a\u00a0prototype intensity distribution and an experimental intensity distribution of\u00a0an object can be obtained under different ratios between sizes and shape of the\u00a0prototype therefore similar way of the refinement of an object habit is\u00a0impossible.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">SEM stereo-microscopy cannot be a mean of\u00a0the habit control, at least, for objects with sizes \u2264 30 nm. It is\u00a0necessary to find other ways to control an SEM image that allows obtaining\u00a0information about a habit. SEM images can be controlled in principle with the\u00a0help of following means: firstly, control of energy of electrons of an\u00a0illuminating beam influences on SEM images through changing distribution of\u00a0centers of inelastic scattering, secondly, control of energy of recoil electrons\u00a0influences on these images through variations of their free paths, thirdly, defocusing\u00a0influences on these images through variations of probe sizes. Long-standing\u00a0practice of SEM investigation didn\u2019t expose dependences between changes of SEM\u00a0images and variations of energy of electron of illuminating beams or recoil\u00a0electrons that could be used for the habit determination. Therefore the hopes\u00a0of possibility of creation of SEM methods of habit inspection can be associated\u00a0only with defocusings since it was already shown that the superposition of intensity\u00a0profiles corresponding to different focusings allows determining an object size\u00a0at a half-height [26]. Paper [27] are devoted to attempts to realize size and\u00a0shape control with the help of series of defocusing images, but its approach has\u00a0bad accuracy of measurements of an object height, it is not applicable to objects\u00a0with sizes \u2264 50 nm.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Routine related with the use of SPM, TEM\u00a0and SEM eliminates possibilities of the creation of the outgoing inspections on\u00a0their basis. However these microscopic methods have no alternatives for the inspection\u00a0means in the nanoworld, since, firstly, only they provide obtaining information\u00a0concerning structural-morphological parameters of inspected objects and,\u00a0secondly, only they possess space resolution necessary for measurements in the\u00a0nanoworld. Therefore a situation with outgoing inspection must be interpreted\u00a0at the present as unsolved and this gap brings the threat to prospect of the\u00a0nanoparticle technologies as a whole. Development of nanotechnologies and\u00a0overcoming of some already existing problem (primarily in the pharmacology) demand\u00a0new revolutionary in essence solutions. Possible solution of the problem of the\u00a0habit particle determinations in condition of their mass production is\u00a0suggested in [29] and it may be assumed as a basis in solution of the outgoing\u00a0inspection problem as a whole.<\/span><\/p>\n<p class=\"MsoNormal\"><strong><span lang=\"EN-US\"> <\/span><\/strong><\/p>\n<h2 class=\"MsoNormal\" style=\"text-align: justify;\"><strong><span lang=\"EN-US\">4. Methods of habit determination founded<br \/>\non the use of convergence beams.<\/span><\/strong><\/h2>\n<p class=\"MsoNormal\"><span lang=\"EN-US\"> <\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Present SEM\u00a0employs probes with a convergence angle \u03c7 \u2248 10<sup>\u20133<\/sup> rad (for\u00a0convenience a parallel beam), which implies that the depth of focus (DoF) is \u2264\u00a00.5 \u03bcm [20]. If the DoF is greater than the object height, the size of the\u00a0probe moving over the object surface remains unchanged. If a convergence angle\u00a0increases, e.g. up to \u03c7 \u2248 10<sup>\u20131<\/sup> rad (below: a convergence\u00a0beam), the DoF drops to \u226410 nm and becomes smaller than the object\u00a0height. The probe size varies during motion over the surface of an object even\u00a0with a height of about 10 nm, and the probe exhibits defocusing. This\u00a0defocusing (in contrast to the \u201cinstrumental\u201d defocusing that is caused by an\u00a0inadequate excitation of the objective lens) may be called \u201chabital.\u201d The situation\u00a0when the DoF is greater than the object height hereinafter is referred to as \u2018sufficient\u00a0depth of focus (SDoF)\u2019, while the case when the DoF is smaller than the object\u00a0height is called as \u2018insufficient depth of focus (IDoF)\u2019. The action of an\u00a0object<span style=\"color: red;\"> <\/span>to the probe, which size varies during\u00a0the motion over the object surface, can be characterized by \u2018the action surface\u2019\u00a0or, in a certain section, by the \u2018action curve\u2019. In this study, the effect of\u00a0habital defocusing is treated based on the notion of the action curve, but all\u00a0laws remain also valid for the action surface, that is in application to 3D\u00a0intensity distributions. The action curve <em>I<\/em><sub>\u03a3<\/sub> is\u00a0described <a name=\"OLE_LINK5\"><\/a><a name=\"OLE_LINK2\">by the expression<\/a> [28]:<\/span><\/p>\n<p class=\"Formula\" style=\"text-align: center;\"><span lang=\"EN-US\"> <img loading=\"lazy\" class=\"alignnone size-full wp-image-303\" title=\"(1)\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image006.gif\" alt=\"\" width=\"217\" height=\"59\" \/>(1)<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-indent: 0cm; text-autospace: none;\"><span lang=\"EN-US\">where \u03b4 = <img loading=\"lazy\" class=\"alignnone size-full wp-image-301\" title=\"image005\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image005.gif\" alt=\"\" width=\"25\" height=\"23\" \/>\u03c3 is the probe half-radius,\u00a0which can be written in a linear approximation as<\/span><\/p>\n<p class=\"Formula\" style=\"text-align: center;\"><span lang=\"EN-US\"> <sub><img loading=\"lazy\" class=\"size-full wp-image-304\" title=\"(2)\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image008.gif\" alt=\"\" width=\"152\" height=\"44\" srcset=\"https:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image008.gif 152w, https:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image008-150x44.gif 150w\" sizes=\"(max-width: 152px) 100vw, 152px\" \/><span style=\"font-size: 16px; line-height: 24px;\">, \u00a0(2)<\/span><\/sub><\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-indent: 0cm; text-align: justify;\"><span lang=\"EN-US\">\u03c3 is the mean square deviation, <em>x<sub>c<\/sub> <\/em>is the\u00a0coordinate of the probe center, <em>J <\/em>is the total probe intensity, <em>z <\/em>is\u00a0the distance from an output plane of the objective lens to a point on the\u00a0object surface, <em>f <\/em>is the focal distance, \u03c3<sub>0<\/sub> is the\u00a0radius of the probe cross section by the focal plane, <em>R <\/em>is the radius of\u00a0the output aperture of the objective lens, <em>\u03c3<\/em><sub>0<\/sub> \u2013 a radius\u00a0of the cross-section of a beam by the focusing plane, |<em>z <\/em>\u2013 <em>f <\/em>| is\u00a0the object height, and <em>X <\/em>is the integration domain determined by the object\u00a0length in a given direction. Due to the dependence of \u03b4 on |<em>z <\/em>\u2013 <em>f<\/em>|, the action curve reflects the object shape. Since \u03b4 = <img loading=\"lazy\" class=\"alignnone size-full wp-image-301\" title=\" \" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image005.gif\" alt=\"\" width=\"25\" height=\"23\" \/>\u03c3,\u00a0all routines developed for the modeling of SEM images (Joy\u2019s PC Mote Carlo\u00a0Programs, Casino Mote Carlo Program, SEMLP, etc.) are applicable to operations\u00a0with the action curve.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Use of IDoF\u00a0images has a little interest by itself. Moreover the use of IDoF conditions for\u00a0image formation complicates an image interpretation since images of points, located\u00a0at different distances from a focusing plane are formed under different\u00a0conditions in focusing. But situation cardinally changes with a subtraction of a\u00a0SDoF curve from an IDoF curve; a resulting curve reflects distribution of the\u00a0surface points with a height.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-autospace: none;\"><span lang=\"EN-US\">A different curve\u00a0is described by the expression [4, 29, 30]<\/span><\/p>\n<p class=\"Formula\"><span lang=\"EN-US\"><img loading=\"lazy\" class=\"alignnone size-full wp-image-305\" title=\"(3)\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image009.gif\" alt=\"\" width=\"385\" height=\"53\" srcset=\"https:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image009.gif 385w, https:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image009-300x41.gif 300w\" sizes=\"(max-width: 385px) 100vw, 385px\" \/> (3)<\/span><\/p>\n<p class=\"Formula\" style=\"text-align: justify;\">where \u03c3<sub>0<\/sub> corresponds to SDoF conditions and \u03c3<sub>1 <\/sub>does to IDoF those. On the strength of Exp. 3, <em>I<sub>dif<\/sub><\/em> = 0 only\u00a0if \u03c3<sub>1<\/sub> = \u03c3<sub>0<\/sub>.<\/p>\n<p class=\"MsoNormal\" style=\"margin-bottom: 6pt; text-align: justify;\"><span lang=\"EN-US\">Let us introduce the notion of the zero object height plane (ZOHP),\u00a0that is the plane relative to which the object height is measured. It is\u00a0logical that ZOHP coincides with a substrate surface. It should be emphasized\u00a0that at points, where the local actions of probes corresponding to different\u00a0angles of convergence are equal, the yields of recoil electrons are also equal.\u00a0Size of a probe for the parallel illuminating beam is constant along all the\u00a0object and equal to a beam cross-section by the focusing plane. Size of a probe\u00a0for a convergent illuminating beam is equal to a size of the probe of a\u00a0parallel beam only in its focusing plane. Actions of the parallel and\u00a0convergent beams on an object in points where the focusing plane of a\u00a0convergent beam intersects an object surface are equal according to Exp 3, therefore\u00a0yields of recoil electrons generated both the beams are also equal (Fig. 3 A). If<br \/>\nto superpose an intensity profile, corresponding to the parallel beam, over an\u00a0intensity profile, conforming to the convergence beam and a focus on some\u00a0cross-section of an object, then these profiles cross at a point where the\u00a0focusing plane of the convergence beam intersects the intensity profile also of\u00a0this beam (Fig. 3 B) [29]. Besides, if to subtract an intensity profile\u00a0corresponding to the parallel beam from a profile conforming to a convergent\u00a0beam than the extrema and zeros of the differential curves observed in the<br \/>\nvicinity of the same \u2018crossing\u2019 point (Fig. 3 C).<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-bottom: 6pt; text-align: justify;\"><img loading=\"lazy\" class=\"alignnone size-full wp-image-306\" title=\"Fig 2-1\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image010.jpg\" alt=\"\" width=\"260\" height=\"196\" \/><img loading=\"lazy\" class=\"alignnone size-full wp-image-307\" title=\"Fig 2-2\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image011.jpg\" alt=\"\" width=\"220\" height=\"196\" \/><img loading=\"lazy\" class=\"alignnone size-full wp-image-308\" title=\"Fig 2-3\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image012.jpg\" alt=\"\" width=\"117\" height=\"196\" \/><\/p>\n<p class=\"MsoNormal\" style=\"margin-bottom: 6pt; text-align: justify;\">Fig. 2. Regularities of the method found focusings of a convergent\u00a0beam on different object cross-sections.<\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\"><strong>2-1<\/strong>. 1, 1&#8242;<\/span><span lang=\"EN-US\"> are generatrices\u00a0of \u2018a parallel beam\u2019; 2, 2<\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">\u00a2<\/span><span lang=\"EN-US\">, generatrices of \u2018a convergence beam; a is an object; b, a substrate;\u00a0c<sub>1<\/sub>, a focusing plane of the parallel beam and initial focusing plane\u00a0of the convergence beam; c<sub>i<\/sub>, an i-th focusing plane of the\u00a0convergence beam; d<sub>1<\/sub>, a probe of the parallel beam and an initial\u00a0probe of the convergence beam, both the probes correspond to focusings on the c<sub>1 <\/sub>plane; d<sub>i<\/sub>, a probe of the convergence beam focused on the c<sub>i <\/sub>plane and simultaneously a cross-section of the parallel beam by the c<sub>i <\/sub>plane, d<sub>i<\/sub> <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">\u00ba<\/span><span lang=\"EN-US\"> d<sub>1<\/sub>; <em>f<\/em>, a point lying on a line intersection the c<sub>i <\/sub>plane and the object surface.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\"><strong>2-2<\/strong>. Thin line\u00a0is an intensity profile of an object images in a parallel beam; a thick line is\u00a0an intensity profile of an image in a convergent beam corresponding to focusing\u00a0on a z<sub>3<\/sub> plane; z<sub>i<\/sub>, are virtual focusing planes, z<sub>3 <\/sub>is a real focusing plane corresponding to the c<sub>i<\/sub> plane of Fig. 1-1; <strong>Z<\/strong>,\u00a0a distance between the z<sub>3<\/sub> plane and the substrate plane, that is also\u00a0the plane of the initial focusing of the convergent beam and of the constant\u00a0focusing of the parallel beam, <em>h<\/em>, an object height (the virtual focusing\u00a0plane z<sub>6<\/sub>).<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-bottom: 6pt; text-align: justify;\"><span lang=\"EN-US\"><strong>2-3<\/strong>. Different profile, z is a zero point, corresponds to the point\u00a0of intersections of focusing planes and the object surface in Figs. 1-1 and\u00a01-2.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Following the sequence\u00a0of operations allows transforming an intensity distribution in an object image\u00a0into its 3D image in the real space (in the object space) that reflects to true\u00a0sizes and a habit of objects and corresponds to it in a maximally possible degree\u00a0[4, 29, 30]:<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.35pt; text-align: left; text-indent: -18.0pt; text-autospace: none;\"><span lang=\"EN-US\">1.<span style=\"font: 7.0pt &quot;Times New Roman&quot;;\"> <\/span><\/span><span lang=\"EN-US\">To focus a convergent beam on ZOHP.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.35pt; text-indent: -18pt; text-align: justify;\"><span lang=\"EN-US\">2.<span style=\"font: 7.0pt &quot;Times New Roman&quot;;\"> <\/span><\/span><span lang=\"EN-US\">To move the focusing plane of the convergent beam over on a known\u00a0distance <strong>Z<\/strong> and to settle a profile intensity conforming to the focusing\u00a0on this object cross-section.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.35pt; text-indent: -18pt; text-align: justify;\"><span lang=\"EN-US\">3.<span style=\"font: 7.0pt &quot;Times New Roman&quot;;\"> <\/span><\/span><span lang=\"EN-US\">To superpose this profile over the profile corresponding to an\u00a0object image in the parallel beam and to set the point of an intersection of\u00a0the profiles; the intersection point remotes from ZOHP for the Z distance.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.35pt; text-indent: -18pt; text-align: justify;\"><span lang=\"EN-US\">4.<span style=\"font: 7.0pt &quot;Times New Roman&quot;;\"> <\/span><\/span><span lang=\"EN-US\">To transform the intensity profile in to the 3D object image in the\u00a0real space, these operations must be reiterated.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Described\u00a0approach provides capabilities of habit reconstructions for objects with a\u00a0height \u2265 10 \u2013 15 nm, when SEM has the resolution 1.0 nm and a convergence\u00a0angle \u2248 0.1 rad, Area of its applicability may be brought up to 5.0 \u2013 7.0\u00a0nm by means of SEM with the resolution 0.4 \u2013 0.5 nm or by means of increasing\u00a0convergence angle. However it is possible to develop further the techniques\u00a0founded on coprocessing of SEM images corresponding to probes with variable sizes.\u00a0Firstly, coprocessing of images corresponding to 2 beams with different\u00a0convergences may be substituted by coprocessing of\u00a0<a name=\"OLE_LINK6\">images conforming to defocusings equal by absolute value and\u00a0opposite by sign<\/a> [30].(Fig. 3-A).<\/span><\/p>\n<div><img loading=\"lazy\" class=\"alignnone size-full wp-image-309\" title=\"Fig 3-A\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image013.jpg\" alt=\"\" width=\"247\" height=\"273\" \/><img loading=\"lazy\" class=\"alignnone size-full wp-image-310\" title=\"Fig 3-B\" src=\"http:\/\/nonatech.ru\/wordpress\/wp-content\/uploads\/2011\/08\/image014.jpg\" alt=\"\" width=\"247\" height=\"272\" \/>&nbsp;<\/p>\n<table class=\"MsoTableGrid\" style=\"border-collapse: collapse; border: none;\" border=\"1\" cellspacing=\"0\" cellpadding=\"0\">\n<tbody>\n<tr style=\"page-break-inside: avoid;\">\n<td style=\"border: solid windowtext 1.0pt; padding: 0cm 2.85pt 0cm 2.85pt;\">\n<p class=\"MsoNormal\" style=\"margin-top: 2.0pt; margin-right: 0cm; margin-bottom: 2.0pt; margin-left: 0cm; text-align: center; text-indent: 0cm; text-autospace: none;\"><span lang=\"EN-US\"> <\/span><\/p>\n<\/td>\n<td style=\"width: 11.8pt; border: solid windowtext 1.0pt; border-left: none; padding: 0cm 2.85pt 0cm 2.85pt;\" width=\"16\">\n<p class=\"MsoNormal\" style=\"margin-top: 2.0pt; margin-right: 0cm; margin-bottom: 2.0pt; margin-left: 0cm; text-align: center; text-indent: 0cm; text-autospace: none;\"><span lang=\"EN-US\"> <\/span><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n<p class=\"MsoNormal\" style=\"margin-top: 6pt; text-align: justify;\"><span lang=\"EN-US\">Fig. 3. Diagrams illustrating the approach founded on defocusings equal\u00a0by absolute value and opposite by sign.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-top: 6pt; text-align: justify;\"><span lang=\"EN-US\"><strong>3-A<\/strong>. a is the focusing plane; b, c are planes of alternative ZOHP\u00a0positioning; <em>h<\/em><sub>1<\/sub>, <em>h<\/em><sub>2<\/sub>, distances between the\u00a0b and c planes and focusing plane (<em>h<\/em><sub>1<\/sub> <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">\u00ba<\/span><span lang=\"EN-US\"> <em>h<\/em><sub>2<\/sub>);\u00a01, 2, generatrices of an illuminating beam; <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">D<\/span><em><span lang=\"EN-US\">f<\/span><\/em><sub><span lang=\"EN-US\">1<\/span><\/sub><span lang=\"EN-US\">, <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">D<\/span><em><span lang=\"EN-US\">f<\/span><\/em><sub><span lang=\"EN-US\">2<\/span><\/sub><span lang=\"EN-US\">, distances of the object top when it\u00a0is situated at b or c planes from the focusing plane (<\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">D<\/span><em><span lang=\"EN-US\">f<\/span><\/em><sub><span lang=\"EN-US\">1<\/span><\/sub><span lang=\"EN-US\"> &gt; <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">D<\/span><em><span lang=\"EN-US\">f<\/span><\/em><sub><span lang=\"EN-US\">2<\/span><\/sub><span lang=\"EN-US\">); <em>d<\/em><sub>b<\/sub>, <em>d<\/em><sub>c<\/sub>,\u00a0sizes of beam cross-sections by the b and c planes (<em>d<\/em><sub>b<\/sub> <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">\u00ba<\/span><span lang=\"EN-US\"> <em>d<\/em><sub>c<\/sub>);\u00a0<em>d<\/em><sub>b*<\/sub>, <em>d<\/em><sub>c*<\/sub>, probe sizes, when an object is\u00a0situated at the corresponding planes, <em>d<\/em><sub>b*<\/sub> &gt; <em>d<\/em><sub>c*<\/sub>.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-bottom: 6pt; text-align: justify;\"><span lang=\"EN-US\"><strong>3-B<\/strong>. 1, 2 are generatrices of an illuminating beam;<em> t<\/em><sub>1<\/sub>,\u00a0<em>t<\/em><sub>2<\/sub> are shifts of an object relative to the b and c planes, <em>t<\/em><sub>1 <\/sub><\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">\u00ba<\/span><span lang=\"EN-US\"> <em>t<\/em><sub>2<\/sub>; <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">D<\/span><em><span lang=\"EN-US\">f<\/span><\/em><sub><span lang=\"EN-US\">1<\/span><\/sub><span lang=\"EN-US\">, <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">D<\/span><em><span lang=\"EN-US\">f<\/span><\/em><sub><span lang=\"EN-US\">2 <\/span><\/sub><span lang=\"EN-US\">are distances between the focusing plane and cross-sections of an object by the\u00a0b and c planes, <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">D<\/span><em><span lang=\"EN-US\">f<\/span><\/em><sub><span lang=\"EN-US\">1<\/span><\/sub><span lang=\"EN-US\"> <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">\u00ba<\/span><span lang=\"EN-US\"> <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">D<\/span><em><span lang=\"EN-US\">f<\/span><\/em><sub><span lang=\"EN-US\">2<\/span><\/sub><span lang=\"EN-US\"> <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">\u00ba<\/span><span lang=\"EN-US\"> <em>h<\/em><sub>1<\/sub> <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">\u00ba<\/span><span lang=\"EN-US\"> <em>h<\/em><sub>2<\/sub>;\u00a0<em>d<\/em><sub>b<\/sub>, <em>d<\/em><sub>c<\/sub> are beam cross-section in the object\u00a0cross-sections by the b and c planes, <em>d<\/em><sub>b<\/sub> <\/span><span style=\"font-family: Symbol;\" lang=\"EN-US\">\u00ba<\/span><span lang=\"EN-US\"> <em>d<\/em><sub>c<\/sub>;.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">When a probe is\u00a0scanning over a surface of an object situated at the <em>b<\/em> plane from a\u00a0bottom point to a top point, it moves from the focusing plane and the defocusing\u00a0increases, but the defocusing value is changed to an opposite for an object\u00a0situated in the <em>c<\/em> plane, since here a probe comes closer to the focusing\u00a0plane, therefore influence of habital defocusing is doubled in this method. Intersection\u00a0of profiles, obtained in the method, occurs only at the planes of an object\u00a0location (Fig. 3-1). The control of probe size in the method can be achieved\u00a0only by shifts of an object relative to these planes (Fig. 3-2). Therefore if\u00a0to displace an object relative to both the planes by equal distances, the\u00a0profiles corresponding to the different planes of an object location must be\u00a0intersected at points where the location planes intersect the object surface. This\u00a0rule may be used for transformation of the intensity profiles into 3D object\u00a0images in the real space. Methods, founded on images conforming to defocusings equal\u00a0by absolute value and opposite by sign, allow either to reduce doubly a\u00a0convergence angle of an used beam without decreasing of method sensitivity or to\u00a0increase its sensitivity without extension of a convergence angle. Use of\u00a0approach founded on images corresponding to different defocusings provides in\u00a0principle reducing the limiting size of inspected object up to 2.5 \u2013 3.0 nm.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Use of\u00a0illuminating beams with different convergence allows employing alternative methods\u00a0of direct reconstruction of an object habit, e.g. founded on reciprocal\u00a0integral transformation of intensity profile on the basis of Exp. (3), but the pursued\u00a0methods give a sufficient idea about the essence of the approach and its\u00a0opportunities.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">It is necessary\u00a0to point out the important peculiarity that attributes not only to the pursued\u00a0methods but also to all methods founded on the use of images arising in\u00a0conditions of regular variations of probe sizes. Principles of these methods\u00a0result from regularities of action curves, but only intensity profiles may be obtained\u00a0in experiments, and although they reflect action curves, but are not similar to\u00a0them. Therefore 3D images and habits obtained as the result of direct\u00a0reconstruction reflect a real object habit with errors. However 3D images or\u00a0habits obtained by the direct reconstruction reflect the actual sizes and shapes\u00a0of object with all its details and nuances, so it can be used as virtual\u00a0prototypes of objects. Further refinement of object parameters can be carried\u00a0out with the help of the familiar procedure involving receipt of the prototype\u00a0image in conditions corresponding to the obtaining conditions of the original\u00a0object image and subsequent fitting of this prototype image to the experimental\u00a0object image by means of variations of prototype shape and sizes. Different\u00a0software products intended for the computation of virtual images (e.g. Joy\u2019s PC\u00a0Monte Carlo programs, Casino Monte Carlo Program, SEMLP, etc) can be used for\u00a0this aim. Principle peculiarity of methods of a computer reconstruction of true\u00a0sizes and a habit of an object that is suggested by the present paper is\u00a0associated with the character of a prototype. Multiple attempts of object\u00a0parameter determinations have suggested using images real objects as prototypes.\u00a0However totality of parameters of an object, selected as the prototype, may distinct\u00a0from totality of parameters of an investigated object, but images fitting may\u00a0be carried out by variations only a single parameter. Therefore the coincidence\u00a0of images has a random character. Native 3D object image can be obtained by the\u00a0stereo methods, but a total behaviour of an object surface is known in the suggested\u00a0method, and it is not known if it is used prototypes obtained by means of stereograms. <\/span>Joint use of\u00a0the methods suggested in this paper and developed computer methods of SEM image\u00a0processing provides the habit determination and the notice in this paragraph\u00a0doesn\u2019t disprove the suggested methods of habit determination but only\u00a0specifies practice of their use [4, 29, 30].<\/p>\n<p class=\"MsoNormal\" style=\"text-autospace: none;\"><span lang=\"EN-US\"> <\/span><\/p>\n<h2 class=\"MsoNormal\" style=\"text-align: justify;\"><strong><span lang=\"EN-US\">5. General\u00a0principles of organization of outgoing production inspection and its software\u00a0provision.<\/span><\/strong><\/h2>\n<p class=\"MsoNormal\" style=\"text-autospace: none;\"><span lang=\"EN-US\"> <\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Safety\u00a0guarantee in mass production of nanoparticles is possible only if the structure\u00a0and habit are under control, and both these kind of control are time-consuming.\u00a0Habit inspection demands use of at least 2 micrographs and their further\u00a0coprocessing [4,29,30]. Structure inspection founded on the use of electron\u00a0diffraction patterns reflecting different projections [31]. Both these\u00a0procedures cannot correspond to a rate of a production process. Outgoing\u00a0control is possible if the identification of the habit and structure is\u00a0assigned in the separate preliminary stage. This stage is intended for the <a name=\"OLE_LINK9\">determination of relations between structural-morphological parameters\u00a0of particles and individual characteristics of images corresponding to\u00a0particles with these parameters.<\/a><\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Existence of\u00a0the similar stage allows solving the problem mentioned above (when TEM and SPM\u00a0were discussed) that is concerned the conflict between average character of\u00a0inspection, which is necessary for outgoing production inspection of vast\u00a0massifs of separate objects and the necessity of revelation of structural-morphological\u00a0parameters of a single particle. This stage allows classifying all types of\u00a0images which conform to all types of existing particles and explaining them by concrete\u00a0structural-morphological parameters of particles. It is logical that the stage\u00a0of the image classification and explanation is combined with the stage of a\u00a0technology elaboration. Five characteristics of images must register and been\u00a0used for image classification in the inspection process:<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 64.35pt; text-indent: -18pt; text-align: justify;\"><span lang=\"EN-US\">1. <\/span><span lang=\"EN-US\">an image size,<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 64.35pt; text-indent: -18pt; text-align: justify;\"><span lang=\"EN-US\">2. <\/span><span lang=\"EN-US\">an image shape,<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 64.35pt; text-indent: -18pt; text-align: justify;\"><span lang=\"EN-US\">3. <\/span><span lang=\"EN-US\">a maximal intensity value,<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 64.35pt; text-indent: -18pt; text-align: justify;\"><span lang=\"EN-US\">4. <\/span><span lang=\"EN-US\">a distribution of an intensity gradient inside\u00a0an object image contour,<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 64.35pt; text-indent: -18pt; text-align: justify;\"><span lang=\"EN-US\">5. <\/span><span lang=\"EN-US\">an orientation of lines with maximal gradients\u00a0relative to line of maximal image sizes.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">The outgoing\u00a0inspection in a process of production by itself comes to the receipt of images\u00a0and their classification in accordance with the found dependences between image\u00a0characteristics and object parameters. Rate of image formation is determined by\u00a0a scanning speed, a rate of image processing depends on computer productivity,\u00a0and modern SEM and computer technologies provide the conformity of the rate of\u00a0the outgoing inspection to the rate of production processes. Reiterated\u00a0operations of a determination of structure and morphology may be required only\u00a0in cases of unknown images disclosures. Single new image (or a few new images) may\u00a0correspond to a particle with structural morphological parameters were\u00a0accidentally missing during the preliminary stage, but a large share of unknown\u00a0images corresponds, obviously, to a fault of the technology.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Reasons caused\u00a0the rejection of SPM and TEM as the basis for technologies of outgoing\u00a0inspections remain for their use as techniques of the uncovering of dependences\u00a0between images of certain objects and their structural-morphological parameters\u00a0in the preliminary stage. Besides the new major circumstance is appended to\u00a0those already mentioned. SEM images are subjects of explanations therefore\u00a0their explanation with SPM or TEM demands transfer of the object from one device\u00a0into another and a comparison of images different in formation physics and\u00a0contrast. This circumstance confines once again possibilities of computerization\u00a0of operations and increases the need in the visual inspection and in the level\u00a0of operator skill that conflicts with the essence of the outgoing inspection of\u00a0very vast massifs. Suggested method is realized only by means of SEM that\u00a0allows fulfilling all operations not only in the same device but with the same setting\u00a0of an object into microscope and the identification of contrast nature as soon\u00a0as an unusual image has been revealed. SEM techniques of a nature determination\u00a0of images in the outgoing inspection are beyond the competition.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Structural-morphological\u00a0identification of object is founded on the 2 methods different in their\u00a0physical foundations and in an instrumental support. However inspections of structure\u00a0and morphology must be carried out jointly and the problem concerning matching\u00a0these methods exists. Crystals with identical structure may have different\u00a0faceting, but the crystal habits are associated with structure more definitely\u00a0especially for phases with different atomic structure [2,32,33]. Joint determination\u00a0of habit and structure allows revealing correlations between atomic structure\u00a0and crystalline shapes; habit determination and, accordingly, analysis of image\u00a0regularities is a reliable way in the outgoing production inspection in these\u00a0cases. Structure determines the catalytic activity for particles having no\u00a0crystalline faceting especially for amorphous objects. Identification of globular,\u00a0ellipsoidal or more complicated unfaceted shapes on conditions, that their\u00a0structure has been determined preliminary, are a way of their inspection. Habit\u00a0control is a real way of the outgoing production inspection, although its trustworthiness\u00a0depends on the accuracy of measurements.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Realization of\u00a0the outgoing inspection by means of exclusively SEM methods requires certain constructional\u00a0peculiarities of microscope, 3 basic peculiarities are shown below.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.2pt; text-indent: -17.85pt; text-align: justify;\"><span lang=\"EN-US\">\u25cf <\/span><span lang=\"EN-US\">The structure inspection demands microscopes with\u00a0attachments for formation of electron diffraction pattern in the transmission\u00a0mode. This problem is solved very easily by way of the placement of a detection\u00a0system with angle resolutions \u2248 10<sup>-3 <\/sup>rad. Similar system exists\u00a0in TEM. Electrons with energies 30 \u2013 50 keV allow obtaining diffraction\u00a0patterns with satisfactory quality for particles with thickness up to 100 nm [34].<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.2pt; text-indent: -17.85pt; text-align: justify;\"><span lang=\"EN-US\">\u25cf <\/span><span lang=\"EN-US\">Increase of a convergence of illuminating beam\u00a0enlarges dramatically blurring of a probe as the result of the spherical\u00a0aberration. Possible limitations of the spherical aberration effect (including\u00a0aberration associated with large angles of the beam convergence) have been\u00a0solved in [35]. For the implementation of the method it is necessary to vary\u00a0the convergence of the illuminating electron beam at precisely specified\u00a0values. The problem of variation in the angles of convergence is solved by\u00a0using a two-lens condenser and sets of condenser and objective diaphragms in [36].<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 46.2pt; text-indent: -17.85pt; text-align: justify;\"><span lang=\"EN-US\">\u25cf <\/span><span lang=\"EN-US\">The key problem of determination of the\u00a0implementation of the proposed approach is to bring the ZOHP into coincidence\u00a0with the focusing plane. For nanodimensional objects, these planes must be\u00a0brought into coincidence with angstrom accuracy [2, 29, 30]. The coincidence of\u00a0the planes with this accuracy (especially the planes with the a priori unknown\u00a0relief) cannot be achieved in frameworks of routine SEM techniques (even with\u00a0images arising in conditions of large convergences of illuminating beams). Therefore\u00a0microscope must have the \u201cstop limit\u201d which breaks off the movement of a microscopic\u00a0stage when the datum plane coincides with the focusing plane. Controllers of\u00a0the type used in SPM [19] provide solution of this problem.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">The preliminary\u00a0stage of determination of dependences between structural-morphological parameters\u00a0of particles and individual characteristics of images is not critical to slow down\u00a0the rate of this determination, and SPM or TEM methods, at first glance, can be\u00a0used in this stage for habit determinations. At that, TEM methods seem\u00a0especially interested owing to the existence of overview images and the diffraction\u00a0mode. However the SEM images are obligatory<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-autospace: none;\"><span lang=\"EN-US\"> <\/span><\/p>\n<h2 class=\"MsoNormal\" style=\"text-autospace: none;\"><strong><span lang=\"EN-US\">6. Conclusions.<\/span><\/strong><\/h2>\n<p class=\"MsoNormal\" style=\"text-autospace: none;\"><span lang=\"EN-US\"> <\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Nanoparticles are promised for the use in\u00a0many areas, but especially they are required in medicine and pharmacology.\u00a0Information concerning solution of problems of medicine and pharmacology by\u00a0means of nanotechnologies appears regularly. Scientific and popular science\u00a0literature is replete with papers describing new and new achievements, and,\u00a0although attempts to take a sober view of the problem exist, majority of\u00a0publications have panegyric hyperbolized character [7,9,10,37]. Problem of\u00a0safety assurance is not examined. Of course, mentioned results and many, many\u00a0other must be realized, but this realization will be criminal, if it will not\u00a0be forestalled by development of the methods of adequate outgoing inspection.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Problems of structural-morphological\u00a0parameters of nanoparticles are studied actively by methods of computer simulations:\u00a0there are investigated dependences between these parameters and their sizes.\u00a0These investigations are carried out in the equilibrium approximation [2], but\u00a0situation is essentially complicated: since nanotechnologies are based mainly\u00a0on nonequilibrium processes and structural-morphological parameters of\u00a0particles may be changed unpredictably. As a result, all attempts of fractional\u00a0inspection as come to a size control. The time to recognize that only\u00a0inspection of structural-morphological parameters of particles is the single\u00a0way of the safety assurance has come. Nanoparticles recommended for medicine\u00a0use usually have complicated shape: a solid inorganic kernel and an organic\u00a0shell. However general properties of particle as a whole depend on structure\u00a0and morphology of the kernel and only structural-morphological inspection of\u00a0the kernel ensures necessary properties of a complicates particles.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">There is another problem demands studying\u00a0structural-morphological particles forming vast massifs. Nanoparticles arise\u00a0not only in biomedical or pharmaceutical technologies; they are produced, for\u00a0example, as a result of different processes in many industrial technologies. Industrial\u00a0particles provoke environmental pollution therefore they are studied by ecologists\u00a0and toxicologists. Physical and chemical properties of the medicinal and\u00a0industrial nanoparticles are different, although these properties are\u00a0substantially stimulated by surface effects. Joint investigations of industrial\u00a0and biomedical particles are necessary for the solution of problems of pharmacology\/medicine\u00a0and environmental safety [16, 17], but similar investigations are impossible\u00a0without confrontation of structural-morphological parameters of both the\u00a0particles types. Fractional inspection is also necessary for joint\u00a0investigation.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">Method of habit\u00a0determinations is the important constituent part of the outgoing inspection technique.\u00a0However there are other serious aftereffects associated with its creation. Creation\u00a0of the feasible outgoing inspection method eliminates the barrier impeding\u00a0acceptance of the adequate safety standard, taking into account the ambivalence\u00a0of nanoparticle technologies, and this standard can be accepted. Therefore this\u00a0paper is the appeal to representatives of state and international structures,\u00a0controlling approval of the adequate safety standard for the area of\u00a0large-scale manufacturing of particles, with the call concerning necessity of\u00a0acceleration works on the creation of an adequate safety standard. Only the\u00a0approval of similar standard assures safe development of nanotechnologies.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-align: justify;\"><span lang=\"EN-US\">All companies acting in an area of\u00a0nanoparticle production are responsible for risks caused by nanoparticles for the\u00a0life and the environment. However responsibility of pharmaceutical companies is\u00a0utterly high, since an action area of their production is a human organism.\u00a0Therefore this paper is the appeal to leaders of pharmaceutical companies (primarily\u00a0to global, such as Johnson &amp; Johnson, RoShe, Novartis, Sanofi-Aventis, GlaxoSmithKline,\u00a0etc), the assurance of safety of patients, using your medicines, is your duty,\u00a0and you must favor the development of the methods of outgoing inspections until\u00a0a hardware realization will be created. Pharmaceutical companies already entered\u00a0into the nanotechnology era, since nanoparticle technologies have moved from\u00a0the category \u201cpromising\u201d in to the category \u201cdeveloped\u201d. Besides, adoption of\u00a0methods of structural-morphological control allows to shorten a time necessary\u00a0for testing of new medicines and to simplify its procedure.<\/span><\/p>\n<p class=\"MsoNormal\"><span lang=\"EN-US\"> <\/span><\/p>\n<h2 class=\"MsoNormal\" style=\"text-align: left; text-indent: 0cm; text-autospace: none;\">Acknowledgment<\/h2>\n<p class=\"MsoNormal\" style=\"text-align: left; text-indent: 0cm; text-autospace: none;\"><span lang=\"EN-US\"> <\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-indent: 0cm; text-align: justify;\">The authors would like to thank the staff of the Abdominal\u00a0Department of the Moscow P.A.Herzen Oncology Research Institute whose efforts\u00a0have made possible the appearance of this publication.<\/p>\n<p class=\"MsoNormal\" style=\"text-align: left; text-indent: 0cm; text-autospace: none;\"><span lang=\"EN-US\"> <\/span><\/p>\n<p class=\"MsoNormal\" style=\"text-indent: 0cm; text-align: justify;\"><span lang=\"EN-US\">The authors are<\/span> pleased to\u00a0acknowledge <span lang=\"EN-US\">their<\/span> gratitude to <span lang=\"EN-US\">A.\u00a0Barnard, L.A. Curtiss and P. Zapol, D.J Smith, S.J. Pennycook for information\u00a0which has made it possible for them to pay attention to this problem.<\/span><\/p>\n<p class=\"MsoNormal\"><span lang=\"EN-US\"> <\/span><\/p>\n<p class=\"MsoNormal\"><span lang=\"EN-US\"> <\/span><\/p>\n<h2 class=\"MsoNormal\"><span lang=\"EN-US\">References.<\/span><\/h2>\n<p class=\"MsoNormal\"><span lang=\"EN-US\"> <\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 17pt; text-indent: -17pt; text-align: justify;\"><span lang=\"EN-US\">1. <\/span><span lang=\"EN-US\">Zuin S., Pojana G., Marcomini A. Effect-oriented\u00a0physicochemical characterization of nanomaterials. In Book. Nanotechnology.\u00a0Characterization, Dosing and Health Effects. Montairo-Riviere N., Tran L.C. (Eds.)\u00a0\/\/ Informa Healthcare USA Inc. 2007. PP. 19-58.<\/span><\/p>\n<p class=\"MsoNormal\" style=\"margin-left: 17pt; text-indent: -17pt; text-align: justify;\"><span lang=\"EN-US\">2. <\/span><span lang=\"EN-US\">Barnard A.S. 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No\u00a02. pp. 53 \u2013 58.<\/span><\/p>\n<\/div>\n<div>\n<p>&nbsp;<\/p>\n<div id=\"ftn1\">\n<p class=\"MsoFootnoteText\" style=\"line-height: normal;\"><a name=\"_ftn1\" href=\"#_ftnref1\"><span class=\"MsoFootnoteReference\"><span style=\"font-size: 9.5pt;\" lang=\"EN-GB\"><span class=\"MsoFootnoteReference\"><span style=\"font-size: 9.5pt; font-family: &quot;Times New Roman&quot;;\" lang=\"EN-GB\">[1]<\/span><\/span><\/span><\/span><\/a><span style=\"font-size: 9.5pt;\" lang=\"EN-GB\"> <\/span><span style=\"font-size: 9.5pt;\" lang=\"EN-US\">Necessity of taking into account of the ambivalence of nanotechnologies<br \/>\nis exemplified by situation in pharmacology, wherein this problem is most<br \/>\nburning, but it is necessary to emphasize once again, that it is the problem of<br \/>\nall nanotechnologies.<\/span><\/p>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>&#160; HOW TO ASSURE SAFETY IN LARGE-SCALE MANUFACTURING OF NANOPARTICLE OF THE BIO-MEDICAL USE Maksimov\u00a0S. K., Maksimov K. S. Moscow\u00a0Institute of Electronic technology, Soukhov N. D. Moscow State University E-mail for responces:\u00a0email hidden; JavaScript is required Abstract. Nanoparticles provide great\u00a0advantages &#8230; <a href=\"https:\/\/nonatech.ru\/?page_id=291&#38;lang=ru\">Continue reading <span class=\"meta-nav\">&#8594;<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"parent":17,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_mi_skip_tracking":false},"_links":{"self":[{"href":"https:\/\/nonatech.ru\/index.php?rest_route=\/wp\/v2\/pages\/291"}],"collection":[{"href":"https:\/\/nonatech.ru\/index.php?rest_route=\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/nonatech.ru\/index.php?rest_route=\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/nonatech.ru\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/nonatech.ru\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=291"}],"version-history":[{"count":9,"href":"https:\/\/nonatech.ru\/index.php?rest_route=\/wp\/v2\/pages\/291\/revisions"}],"predecessor-version":[{"id":313,"href":"https:\/\/nonatech.ru\/index.php?rest_route=\/wp\/v2\/pages\/291\/revisions\/313"}],"up":[{"embeddable":true,"href":"https:\/\/nonatech.ru\/index.php?rest_route=\/wp\/v2\/pages\/17"}],"wp:attachment":[{"href":"https:\/\/nonatech.ru\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=291"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}